CA1120923A - Cephalosporanic acid derivatives and processes for the preparation thereof - Google Patents

Cephalosporanic acid derivatives and processes for the preparation thereof

Info

Publication number
CA1120923A
CA1120923A CA000316120A CA316120A CA1120923A CA 1120923 A CA1120923 A CA 1120923A CA 000316120 A CA000316120 A CA 000316120A CA 316120 A CA316120 A CA 316120A CA 1120923 A CA1120923 A CA 1120923A
Authority
CA
Canada
Prior art keywords
methyl
hydrogen
formula
acceptable salt
ylthiomethyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired
Application number
CA000316120A
Other languages
French (fr)
Inventor
Takashi Kamiya
Kazuo Sakane
Yoshiharu Nakai
Tsutomu Teraji
Jiro Goto
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Fujisawa Pharmaceutical Co Ltd
Original Assignee
Fujisawa Pharmaceutical Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Fujisawa Pharmaceutical Co Ltd filed Critical Fujisawa Pharmaceutical Co Ltd
Application granted granted Critical
Publication of CA1120923A publication Critical patent/CA1120923A/en
Expired legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/73—Unsubstituted amino or imino radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
    • C07D213/80—Acids; Esters in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/10—Compounds having one or more C—Si linkages containing nitrogen having a Si-N linkage

Abstract

ABSTRACT OF THE DISCLOSURE

Novel cephalosporanic acid derivatives and pharma-ceutically acceptable salts thereof which have anti-bacterial activities and processes for the preparation thereof; the derivatives can be used in the therapeutic treatment of infectious diseases in human beings and animals; the derviatives have the general formula

Description

3~

CEPHALOSPORANIC ACID DERIVATIVES ~
_ PROCESSES FOR THE PRF.PARATION THERROF AND
PHARMAC~UTIC~AL (~OMPOSITION COMPRISING THE SAME
The present invention relates to novel cephalos~
poranic acid derivatives and pharmaceutically acceptable salts thereof. More particularly, it relates to novel cephalospoxanic aci~ derivatives and pharmaceutically acceptable .salts thereof, which have ~nti-bacterial activities, to processes for the preparation thereof, to pharmaceutical composition comprising the same, and to a method of using the same kherapeuti.cally in the treatment of infectious diseases in human beings and animals.
Accordingly, one object of the present invention is to provide novel cephalosporanic. acid derivatives and pharmaceutically accep~able salts thereof, which are highly active against a number of pathogenic bacteria.
; : : 15 Another objec~ of the present invention is to provide processes for the preparation of novel cephalosporanic acid derivatives and pharmaceutically acceptable salts thereof.
A further ohject of the pxesent inventi~n is to provide pharmaceutical composition comprising, as an active ingredient, said cephalosporanic acid derivatives ~: or its pharmaceutically acceptable salts.
Still further object of ~he pxesent invention is to provide a method for the treatment of infectious diseases by pathogenic bacteria in human beings and animals.
The object cephalosporanic acid derivatives can be ' ~1 .

., :,;
: ' : ' ':

` represented by the following general formula ~

Rl-X-CoNH ~_ ~ S R3 ~ (I) wherein Rl is a group of the formula -Rb Rc Ra t ~ - , in which Ra is hydrogen, amino or a protected amino group, Rb and Rc are each hydrogen, halogen, lower alkoxy or ~ arylthio 3 and
2 Z is N or CH, R is hydrogen or lower alkoxy, R is hydrogen or lower alkyl, R~ is hydrogen, halogen~ carbamoyloxymetllyl, ; lower alkyl, lower alkoxy, lower alkanoyloxymethyl, lower alkanoylthiome~hyl, or heterocyclic-thiomethyl which may have suitable substituen~s), R5 is carboxy or its derivative, and X is Iower alkylene or a group of the formula: :
-C- in which-R6 is hydrogen or an : ll organic residue which may have l R6 suitable substituent(s~, and non-toxic, pharmaceutically acceptable salts thereof.
In the object compounds ~I) and the corresponding . starting compounds (III) of Process l mentioned below, the partial structure represented by the formula:
Rl ~c g R6 ~ ~ 2 ,' ` `
-is to be understood to include both of the geometrical structures repres~nted by the formula:

Ra ~_o_~6 Ra ~--R6-o N -(A) syn form (A') anti form Accordingly, with regard to the compounds having the above mentioned partial structure, the compounds having the geometrical structure shown by the formula ~A) are referred to as "syn isomer" and the other com-pounds having the alternative one shown by the formula ; (A') as "anti isomer" in this specificatlon.
Suitable pharmaceutically accep~able salts of theobject compounds (I) are conventional non-toxic salts and may include an inorganic salt, for example, a metal salt such as an alkali metal salt ~e.g., sodium saltr potassium salt, etc.) and an alkaline earth metal salt (e.g., calcium salt, magnesium salt, etc.), and an ammonium salt etc.; an organic salt, for example~ an organic amine salt (e.g., trimethylamine salt, triethyl-amine salt, pyridine salt, picoline saIt, dicyclohexyl-amine saltj N,N'-dibenzylethylenediamine salt, N-methylglucamine salt, diethanolamine salt, triethanol-amine salt, tris(hydroxymethylamino)methane salt, etc.) etc.; an organic carboxylic or sulfonic acid addition salt (e.g.~ formate, acetate, maleate, tartrate, methanesulfonate, benzenesulfonate, toluenesulfonate, etc.); an inorganic acid addition salt (e.gU ~ hydro-chloride, hydrobromide, sulfate, phosphate, etc.); a salt with a basic or acidic amino acid (e.g., arginine, aspartic acid, glutamic acid, etc.), and the like.

S~

According to the present invention, the object compounds (I) and the pharmaceutically acceptable salts thereof can be prepared by the processes as illustrated .by the following schemes.
Process 1:
.

H N ~ S ~ 3 ~N~R4 Rs or its reactive derivative at the amino group or a salt there-of Rl-X~CH (II) : 20 ; or its reactive derivative at the carboxy group or a salt thereof Rl_x_coN ~ ~ R4 ~I) Rs or a salt thereof Process 2 :

R '-X-CONH ~ S R3 (Ia~
~ ~ R' Rs or a salt thereof Elimination reaction of the amino-protective group \ ~ ':

R~ X-CONH ~ ~ ~ R (Ib) ~ ~ ~ R4 Rs or a salt thereof 2~ /

, ~ /

.

S~5 ., Process 3 :

R - X _ CON ~ ~ ~ 4 (Ic) 10 or a salt thereof ¦ Elimination reaction of the amino-protective group r in Ra R~
Rl-X--CONH~ R3 ( Id) ~N~J--Rb nS

or a salt thereof ~,~
/

$

. .
' Process 4 Rl_XCON~ ~ S ~ R3 (Ie) N ~ R4 R~
or a salt thereo Elimination reaction of the ~ carboxy-protective group : : :
:

.

-X - CONH ~ ~ ~If) :~ R
: OOH
~: 25 or a salt thereof . .

~: 30 : ~ :
' /~
.

.~ ~7 . .

~.
- . . ~. ~, , ~ . .
3~'~3 Process 5:
-Rl-X-CONH ~ S R3 ~Ig) R
or a salt thereof ; H-R7 ~IV) or a reactive derivative thereof Rl X CONH ~ S ~ R3 (Ih) ~-- N ~ CHz-R
R . :
or a salt thereof h i ~1 R~ R3 R4, R5 and X are each as defined above, and Rl is a group of the formula:
R~ Rl Ra t~ ~ ~ in which Rl is a protected amino group, and Rb~ Rc and Z are each as deined above~
R is a group of the formula:
R~ R
H2N t~ in which Rb, RlC and Z are N each as defined above, R4 is heterocyclic-thiomethyl having a protected amino(lower3alkyl group, Rg is heteTocyclic-thiomethyl having a amino-(lower)alkyl group, ~ -8 . ~ . ~ . .

.:

2~ ~ ~ 3 Ra is a protected carboxy group, R7 is heterocyclic-thio which may have suitable substituents, and Y is a conventional group which is capable to be replaced by ~he residue t-R7) of the compound of the formula: HR7 in which R7 is as defined above.
; Some of the starting compound (m) in Process l are novel and can be prepared, for example, from the known compounds (A-l), (B-l), (c-la) and~(n-la) by the ProcesseS A to Qas illustrated by the following reaction schemes or a similar manner thereto.
The compounds (A-l),(B~l), tc-la) and ~D-la) are disclosed, for example, in the following literatures.
; 15 Compound (A~
.
H2N - C - COOC2Hs ~Journal of Organic IIH Chemistry, Vol.27, paye 360~) .~ .

Compound (B-l C2HsO - CH = CH-C-OC2Hs(Journal of the American ¦I Chemical Society, Vol.69, NH
page 2657 (1949)~

Compound (C-la~

~ (Chemical Abstract Vol.54, H2N~N COOC~3 6709) ~1 ~ 3 .

: . ~

.
.

~ COOCH3 (Chemical Abstraet Vol.52, H2 ~ J 7313g~

COOCH3 (Chemieal A~stract Vol.53, 7162c).

~N3 H ~ournal ~ux Pxaktisehe ehemie Reihe 4, Vol.13, 15~N ~ COOCH3 page 58F 1961 Compound (D-la) __ ; 20 OH

; H~N ~ CH2COOC2Hs (Abstraets of the 9th . Congress of Heterocyelie Chemistry, page 146, FukuoXa, Japan, 1916) , ~ , .
: 30 : 35 ':

Process A:

HzN C l CH =C-CN , HzN~ R9 or a salt thereof or a salt thereof (A~ A-2) (~-3) Process B~
H2N-C-R9 ~ R10- OCH=CH-C-OR10 ~ H2NJ~N,~LR9 NH NH
or a salt thereof or a salt thereof or a salt thereof ~B-l) (A~ -2) lS Process C:

H2N ~ C~13 H2N ~ CH2COOH
or a salt thereof . or a salt thereof 2~ ~C-l) . ~C-2) Process D:
Q
OH R
I Halogenating ~ N
H2N ~ ~ CH2-R9 AgentH2N-~ J CH2-R : `

or a salt thereof or a salt thereof : (D-l) (D-2) Process E-1 . Dehalogenative f CH -R9 RedUction 1~ ~ N g a t~N ~ 2 __~Ra ~ N ~ CH2 R

(E~ E-2) S ~ ~ ~

, Process F:
R8 Rl 1 N R14 Nucleophile or ,~ N
H2N t ~xl ~ H2N~ ~Xl-Rl4 `N a salt thereof N
or a salt thereof or a salt thereof ~F~ F-2) Process G:
12 Introduction f R12 R a carboxy-z ~ protective group 1 Z ~ 9 Rla ~N~cH2cooH ~ Ra t~ ~CH2 R

or a salt thereof or a salt ~hereof : ~G-l) (G-2) Process H:

Rl' Z ~ R9 R SCH2SOR10 Rl ~ ~ COCH
N t a N ~sRlo ~ 20 ~H-l) (H-2) : Process I:
~: Acid and/or 10 acid anhydride Ra t~ ~ CCH~SR10 a ~ COCOSR10 (H-2) (I-l) Process J:
1 Rl Elimina~ion of 1 Rl R~ c the carboxy- Rb c ~ 1' Z ~ g protective group 1' Z ~
30Ra t N ~ X2 R : ~ Ra t~ ~ X2-COOH

(J-l) or a salt thereof (J-2 ~ ~ l 2 . . "

, . , - .

.

Process K:

b ~ c Introduction of Rb Rl ~ R13 an amino- 1' Z ~ 13 2 ~N ~ protective group~ Ra t~N ~ R

(K~ K-2) Process L:

I Rl ~ CH~-R9 ~ Rl ~ CO-R

(L-l) (L-2) ~: 15 Process M:
Rl Rc Rh . Rc Rl _ ~ 14 R6-ONH~ Rl ~ -R14 : or a salt N
20or its hydrate, thereof ~R6 or a salt thereof or a salt thereof (M-l) ~M-2) Process N:
Rl Rl Elimination of Rb Rc : ~ / the amino- ~
Ra ~ X3-R14 protectlve H N t ~ 3-R14 or a salt thereof or a salt thereof (M-l) (N-2) Process 0:

1 Z ~ 14 Nitrosation ~ R-l Z ~ 14 Ra ~ N CH2-R a t N N-R
(0-1) (0-2) OH

S ~, 3 . ..
.
.
.

:

Process P:

~ ~/ c Substitution of z ~
Rl -~ ~ ~C Rl4 hydrogen to R6 Rl_t~ ~ C R14 N N
OH o_RG
or a salt thereof or a salt thereof (P-l~ (P-2) Process Q.

~alogenation? R1 ~ C R14 Ra t~ N ~ C-Rl - a t`N ~ 11 ; N N
o_R6 o-R6 or a salt thereof or a salt thereof (Q~ Q-2) wherein Ra ~ Rl, Rc, R~ and Z are each as defined above, and R6 is an organic residue which may have ; suitable substituent(s), R8 is halogen, R9 is a protected carboxy group, R10 is lower alkyl, :~ Rll is lower alkoxy or arylthio~
R12 is hydrogen or lower alkyl, R13 is a protected carboxy group, or a group of the formula x4.R14 or -C-R14 N

in which X4 is lower alkylene, .:

.

~ 3 ~

R6 is as defined above and R14 is as defined below7 R14 is carboxy or a protected carboxy group, R15 is hydrogen or halogen, Xl is lower alkylene or a group of the formula:
-C- in which R6 is as N defined above, b_R6 X2 is lower alkylene, or a group of the formula:
-CO- or -C-N

O-R
in which R6 is as defined : above, and X3 is a group of the formula :
-CO- or -C-N
o RS, in which R6 is as deined above.

In the above and subsequent description o the present specification~ suitable examples and illustra-tion of the various definitions which the present in-vention intends to include within the scope thereof are __~
--.
.
.. , explained in detail as follows.
The term "loweri' is intended to mean a group hav-ing 1 to 6 carbon atoms, unless otherwise provided.

S Suitable "protective group" in the terms "a pro-tected amino group" and "a protected amino(lower)-alkyl group" may include an acyl and the other co~ven-tional protective group such as ar(lower)alkyl (e.g., benzyl, trityl, diphenylme-thyl, etc.), substituted lG phenylthio ~e.g. 2-nitrophenylthio, etc.)0 substituted aralkylidene (e.g. 4-nitroben2ylidene, etc.), substituted alkylidene (e.g. l-methoxycarbonyl-2-propylidene, etc.~, substituted lower cycloalkylidene (e.g. 2-ethoxycarbonyl-cyclohexylidene, etc.), and the like. And suitable 1~ acyl group may be the ones derived from carboxylic, sulfonic or carbamic aci.., and more particularly sub-stituted or unsubstituted carbamoyl, allphatic acyl, and acyl h~ving an aromatic ring (referred to as aroma-tic acyl) or heterocyclic ring (referred to as hetero cyclic acyl.~
Suitable examples of the aliphatic acyl may be lower alkanoyl (e.g., formyl, acetyl, propionyl, butyryl, isobutyryl, lsovaleryl, oxalyl, succinyl, pivaloyl, etc.);
lower cycloalkanecarbonyl (e.g. cyclopentanecarbonyl, cyclohexanecarbonyl, etc.);
lower alkoxycarbonyl (e.g., methoxycarbonyl, ethoxycarbon-yl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, tert-pentyloxy-carbonyl, hexyloxycarbonyl, etc.); lower cycloalkyl-(lower~alkoxycarbonyl (e.g., l-cyclo~ropylethoxycarbony, etc.); lower alkoxyalkahoyl (e.g., methoxyacetyl, etho-xyacetyl, methoxypropionyl, etc.); and lower alkanesulfonyl (e.g., mesyl, ethanesulfonyl, pro-panesulfonyl, butanesulfonyl, etc.).
Suitable examples of the aromatic acyl may be ar-- , . -, ' ' ', ~ ~
.
.

9~

(lower)alkanoyl (e.g., phenylacetyl, phenylpropionyl, etc.); ar(lower)alkoxycarbonyl (e.g., benzyloxycarbonyl~
phenethyloxycarbonyl, etc.);
arenesulfonyl (e.g., benzenesulEonyl, tosyl, etc.); and aroyl (e;g., benzoyl, toluoyl, naphthoyl, phthaloyl, indancarbonyl, etc.).
Suitable ex~mples of the heterocyclic acyl may be heterocyclic(lower)alkanoyl (e.g., thienylacetyl, furylacetyl, pyrrolylacetyl, thiadiazolylacetyl, tetra~
zolylacetyl, piperazinylacetyl, etc.); heterocyclic-oxycarbonyl (e.g. 8-quinolyloxycarbonyl, etc.);
heterocycliccaxbonyl (e.g., thenoyl, furoyl, nicotinoyl, - isonicotinoyl, pyrrolecarbonyl, pyrrolidinecarbonyl, tetrahydropyrancarbonyl, etc.); heterocyclic~(lower) alkoxycarbonyl (e.g. 2-pyridylmethoxycarbonyl, etc.).
Suitable substituted or unsubstituted carbamoyl may include carbamoyl, lower alkylcarbamoyl (e.g., methylcarbamoyl, ethylcarbamoyl, etc.), arylcarbamoyl (e.g., phenylcarbamoyl, etc.), ar~lower)alkylcarbamoyl (e.g., benzylcarbamoyl, tritylcarbamoyl, etc.), lower alkanoylcarbamoyl (e.g., formylcarbamoyl, acetylcarbamoyl, etc.), mono(or di or tri)halo(lower)alkanoylcarbamoyl (e.s., chloroacetylcarbamoyl, trichloroacetylcarbamoyl, etc.), and the like.
The "acyl" as stated above may optionally have 1 to 3 suitable substituent(s) such as halogen (Q .g. ~
chlorine, bromine, iodine or fluorine), hydroxy, cyano, nitro, lower alkoXy, lower alkyl, lower alkenyl, acyl[preferable mono(or di or tri)halo(lower)alkanoyl (e.g.) chloroace~yl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, etc.)], aryl (e.g., phenyl, tolyl, etc.), or the like.
Preferable examples of said "protective group" in the terms "a protected amino group" and "a protected amino(lower)alkyl group" are acyl, and more preferably .
."~ .

~3 lower alkanoyl (e.g., formyl, acetyl, propionyl, butyryl, isobutyryl, isovaleryl, oxalyl, succinyl, pivaloyl, etc.), mono(or di or tri)halo(lower)-alkanoyl (e.g., chloro-acetyl, dichloroacetyl, trichloroacetyl, tri~luoroacet e-tc.) and lower alkoxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl~
tert-pentyloxycarbonyl, hexyloxycarbonyl, etc.).

Suitable "lower alkyl" may include straight or branched saturated aliphatic hydrocarbon residue such as methyl, ethyl, propyl, isopropyl, butyl, isobutyll tert-butyl, pentyl, neopentyl, tert pentyl, hexyl, and the ; like, and preferably one having 1 to 4 carbon atoms.
Suitable "organic residue which may have suitable substituent(s)" may include :
lower alkyl (e.g., methyl, ethyl, propyl, isopro-pyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl, tert-pentyl, hexyl, etc.);
; mono(or di or tri)halo(lower)alkyl (e.g., chloro-methyl, dichloromethyl, trichloromethyl, bromomethyl, chloroethyl, dichloroethyl, trichloroethyl, fluoroethyl, trifluoroethyl, etc.);
lower alkenyl (e.g., vinyl, l-propenyl, allyl, l-methylallyl, 1 or 2 or 3-butenyl, 1 or 2 or 3 or 4-pentenyl, 1 or 2 or 3 or 4 or 5-hexenyl, etc.);
lower alkynyl (e.g., ethynyl, l-propynyl, propargyl, l-methylpropargyl, 1 or 2 or 3-butynyl, 1 or 2 or 3 or
4-pentynyl, 1 or 2 or 3 or 4 or 5~hexynyl, etc.);
aryl (e.g., phenyl, tolyl, xylyl, cumenyl, naphthyl, etc.~;
ar(lower?alkyl such as phenyl(lower)alkyl (e.g., benzyl, phenethyl, phenylpropyl, etc.); and the like.
halo(lower)alkanoyl(e.g. chloroacetyl, dichloroacetyl, etc.); and the like.

'~:
..

Suitable "lower alkoxy" may be straight or branched and include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy, pentyloxy, neopentyloxy, hexyloxy and the like, and preferably one having l to 4 carbon atoms.

Suitable "halogen" may be chlorine, bromine, iodine or fluorine.

Suitable "lower alkanoyloxylmethyl" may include acetoxymethyl, propionyloxymethyl, butyryloxymethyl, isobutyryloxymethyl, valeryloxymethyl, isovaleryloxy-methyl, pivaloyloxymethyl, hexanoyloxymethyl and the like.
Suitable "lower alkanoylthiomethyl" may include acetylthiomethyl, propionylthiomethyl, butyrylthiomethyl, isobutyrylthiomethyl, valerylthiomethyl, isovalerylthio-methyl, pivaloylthiomethyl, hexanoylthiomethyl, and the like.

Suitable "heterocyclic moietyl' in the terms "hetero-cyclicthiomethyl which may have suitable substituent(s)"
and "heterocyclic-thio ~ilich may have suitable substitu-entts)li may be one containing at least one hetero atomselected from nitrogen, suIfur and oxygen atom, and may include saturated or unsaturated, monocyclic or poly-cyclic heterocyclic group, and preferable heterocyclic group may be ~-containing heterocyclic group such as unsaturated 3 to 6 membered hetexomonocyclic group con-taining l to 4 nitrogen atoms, for exampIe, pyrrolyl, pyr-rolinyl, imidazolyl, pyrazolyl, pyridyl and its N-oxide, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl ~e.g., 4H 1,2,4-triazolyl, lH-~1,2,3-triazolyl, 2H 1,2,3-triazolyl, etc.), tetrazolyl (e.g., lH-tetrazolyl, 2H~tetrazolyl, S ~ ~ 3 .

- , . `

.

etc.), etc.;
saturated 3 to 6-membered heteromonocyclic yroup con-taining 1 to 4 nitrogen atoms ~e.g., pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl, etc.);
unsaturated condensed heterocyclic group con-taining 1 to 5 nitrogen atoms, for example, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, lndazolyl, benzotriazolyl, tetrazolopyridazinyl ~e.g., tetrazolo[l,5-b~pyridazinyl, etc.), etc.;
unsaturated 3- to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.), etc.;
saturated 3 to 6-membered heteromonocyclic group con-taininy 1 to 2 oxygen atoms and 1 to 3 ni~rogen atoms (e.g., morpholinyl, etc.);
unsaturated condensed heterocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms (e.g., benzoxazolyl, benzoxadiazolyl, etc.);
unsaturated 3 to 6-membered heteromonocyclic group con-taining 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl, thiadiazolyl (e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2~5-thiadiazolyl, etc.), etc.;
saturated 3 to 6-membered heteromonocyclic group con-taining 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms (e.y., thiazolidinyl, etc.);
; unsaturated condensed heterocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms (e.g., benzothiazolyl, benzothiadiazolyl, etc.) and the like;
wherein said heterocyclic yroup may have 1 to 4 suitable substituents selected from lower alkyl or lower cyclo-alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, cyclopentyl, hexyl, cyclohexyl, etc.);

~ ~V

.

lower alkenyl ~e g. vinyl, allyl, 1 or 2 or 3~propenyl, 1 or 2 or 3 or 4-butenyl, 1 or 2 or 3 or 4 or 5-pentenyl, etc.); amino(lower)alkyl (e.g.~ aminomethyl, 2-amino-ethyl, 2-aminopropyl, 3-aminopropyl, 4-aminobutyl, 5-aminopentyl, 6-aminohexyl, etc.); a pro-tected amino-(lower)alkyl group such as lower alkoxycarbonylamino-(lower)alkyl (e.g. tert-butoxycarbonylaminomethyl, etc.);
carboxy(lower)alkyl (e.g., carboxymethyl, 2-carboxyethyl~
2-carboxypropyl, 3-carboxypropyl, 4-carboxybutyl, S-carboxypentyl,6 -carboxyhexyl, etc.); sulfo(lower)alkyl (e.g., sulfomethyl, 2-sulfoethyl, 2-sulfopropyl~ 3-sulfopropyl, 4-sulfobutyl, 5-sul~open~yl, 6-sulfohexyl, etc.); phenyl which may have 1 to 3 halogen atom(s) (e.g. phenyl, 2 or 3 or 4-chlorophenyl, 2 or 3 or 4-bromophenyl, etc.); and lower alkylamino(lower)alkyl ~e.g., N-methylamirlomethyl, N,N-dimethylaminomethyl, 2-(N-methylamino)ethyl~ 2-(N,N-dimethylamino)ethyl, 2-(N-methyl-N-ethylamino)ethyl, 3-(N-methylamino)propyl, 3-(N,N-dimethylamino)propyl, 3-(N,N-diethylamino)propyl, 4-(N-methylamino)butyl , 4-(N,N-dimethylamino)butyl, 4-~N-methyl-N-ethylamino)butyl, 5-(N-methylamino)pentyl,
5-(N,N-dimethylamino)pentyl, 6-(N,N-diethylamlno)hexyl,
6-(N,N-dimethylamino)hexyl, etc.).
And pre~'era~le examples of said "heterocyclic moiety" are:
thiadiazolyl (e.g., 1,2,4-thiadiazolyl, 1;3,4-thiadiazolyl, 1,2,5-thiadiazolyl, etc.) which may have a substituent selected from the groups consisting of lower alkyl(e.g., methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, etc.), amino(lower)alkyl ~e.g., aminomethyl, aminoethyl, aminopropyl, etc.) and lower alkoxycarbonylamino(lower)alkyl (e.g., methoxycarbonyl~
aminomethyl, tert-butoxycarbonylaminomethyl, ethoxy-carbonylaminoethyl, etc~);
oxadiazolyl ~e.g., 1,2,4-oxadiazolyl, 1,3,4-:, . :

.

oxadiazolyl, 1,2;5-oxadia~olyl, etc.) which may have halophenyl(e.g., 2-chlorophenyl,4-chlorophenyl,4-bromophenyl,etc.);
tetrazolyl(e.g., lH--tetrazolyl, 2H-tetrazolyl,) which may have a substituent selected rom the groups consisting o~ lower alkyl (e.g., me-thyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, etc.)/ carboxy(lower)-alkyl(e.g., carboxymethyl, carboxyethy:l, carboxypropyl, etc.~ and lower alkenyl (e.g., vinyl, allyl, etc.);
pyrazinyl; and tetrazolopyridazinyl (e.g., tetrazolo~l,5-b]pyrid-azinyl, etc.).
"Heterocyclic" moiety in the terms "heterocyclic-thiomethyl having a protected amino(lower)alkyl group"
and "heterocyclic-thiomethyl ha~ing an amino(lower~-alkyl group" may be the same as exemplified above, and thus defined heterocyclic moiety is preferably lower alkoxycarbonylamino(lower)alkylthiadiazolyl and amino (lower)alkyLthiadiazolyl as aforementioned, respective ly.
Suitable "lower alkylene" may include methylene, ethylene, trimethylene, l-methylethylene, etc:, pre-ferably one having 1 to 3 carbon atoms, more preferably one having 1 to 2 carbon atoms and the most preferably methvlene.
Suitable "carboxy derivative" includes protected carboxy such as esterified carboxy. And suitable examples of said ester may be the ones such as lower alkyl ester (e.g., methyl ester, ethyl ester, propyl ester, isopropyl ester, bu~yl ester, isobutyl ester, t-butyl ester, pe~tyl ester, t-pentyl ester, hexyl ester, 1 cyclopropylethyl ester, etc.);
; lower alkenyl ester (e.g., vinyl ester, allyl ester, etc.);
lower alkynyl ester (e.g., ethynyl ester, propynyl S ~2 .

ester, etc );
lower alkoxyalkyl ester ~e.g., methoxymethyl ester, ethoxymethyl ester, isopropoxymethyl ester, 1-methoxyethyl ester9 l-ethoxyethyl ester, etc.);
lower alkylthioalkyl ester (e.g., methylthiomethyl ester, ethylthiomethyl ester3 ethylthioethyl ester, isopropylthiomethyl ester, etc.);
mono~or di or tri)-halo(lower)alkyl ester (e.g., 2-iodoethyl ester, 2,2,2-trichloroethyl ester, etc.);
lower alkanoyloxytlower)alkyl ester (e.g., acetoxy-methylester, proionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethyl ester, pivaloyloxymethyl ester, hexanoyloxymethyl ester, 2-acetoxyethyl ester, 2-propionyloxyethyl ester, etc.);
lower alkanesulfonyl(lower)alkyl ester ~e.g., mesyl-methyl ester, 2-mesylethyl ester etc.);
ar~lower)alkyl ester, for example, phenyl~lower)alkyl ester which may have one or more suitable substituentts) (e.g., benæyl ester, 4-methoxybenzyl ester, 4-nitro-benzyl ester, phenethyl ester, trityl ester, diphenyl-methyl ester, bis~methoxyphenyl)methyl ester, 3,4-dimethoxybenzyl ester, 4-hydroxy-395-di-t-butylbenzyl ester, etc.);
aryl ester which may have one or more suitable substi-tuent~s) such as substituted or unsubstituted phenyl ester (e.g., phenyl ester, tolyl ester, t-butylphenyl ester, xylyl ester, mesityl ester, cumenyl ester, 4-chlorophenyl ester, 4-methoxyphenyl ester, etc.), tri ~lower)alkyl silyl ester;
lower alkylthioester (e.g. methyl~hioester, ethylthio-ester, etc.) and the like.
Suitable "a protected carboxy group"

may include esterified carboxy as aforementîoned.
; 35 Suitable "a conventional group which is capable ~ "~

~ . - . .
`

Jf4 to be replaced by the residue ~-R7) of the compound of the formula: HR7" in the symbol Y may include halogen ~e.g., chlorine, bromine, etc.), azido, acyloxy such as lower alkanoyloxy (e.g., formyloxy, acetoxy9 propionyloxy~ butyryloxy, etc.), and the like.
Suitable "arylthio" may include phenylthio, tolylthio, xylylthio, mesitylthioJ naphthylthio and the like.
The processes for preparing the object compounds ~I) of the present invention are explained in detail in the following.
Process l:
; The object compound (I) or a salt thereof can be prepared by reacting a 7-aminocephalosporanic acid derivative (II) or its reactive derivative at the amino group or a salt thereof with a- carboxylic acid (III) or its reactive derivative at the carboxy group or a salt thereof.
As to the starting compounds to be used in this process, the 7-aminocephalosporanic acid derivatives (II) have been publicly known and can be prepared by the method known to the art in the cephalosporin field, and the carboxylic acid (III) can be prepared according to a malmer as disclosed in Processes A to Q.
Suitable reactive derivative at the amino group of the compound (II) may include a conventional reactive derivative used in amidation reaction, for example 9 a silyl derivative formed by the reaction of the compound ~II) with a silyl compound such as bis(trimethylsilyl)acetamide, trimethylsilylacetamide, etc.; isocyanato, isothiocyanato, etc.; Schiff's base or its tautomeric enamine type isomer formed by the reaction of the amino group with a carbonyl S - 2 ~

compound such as an aldehyde compound (e.g., acetaldehyde, isopentaldehyde, benzaldehyde, salicylaldehyde, phenylacetaldehyde, p-nitrobenzalde-hyde, m-chlorobenzaldehyde, p-chlorobenzaldehyde~
hydroxynaphthoaldehyde, furfural, thiophenecarbo-aldehyde 9 etc.) or a ketone compound (e.g., acetone, methyl ethyl ketone, /

' ~ ~ 2 ~i methyl isobutyl ~etone, acetylacetone, ethyl aceto-acetate, etc.), and the like.
Suitable derivatives at -the carboxy group o~ the compound (~) and suitable salts of the compound (~) are to be referred to the ones exemplified for the compound (I) r Suitable reactive derivatives at the carboxy group of the compound (m) may include, for example, an acid halide, an acid anhydride, an activated amide, an activated ester, and the like, and preferably an acid chloride and acid bromide;
a mixed acid anhydride with an acid such as substituted phosphoric acid (e.g., dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid, dibenzylphosphoric acid, halogenated phosphoric acid etc.), dialkylphosphorous acid, sulfurous acid, thiosulfuric acid, sulfuric acid, alkyl carbonate (e.g., methyl carbonate, ethyl carbonate, propyl carbonate, etc.), aliphatic carboxylic acid (e.g., pivalic acid, pentanoic acid, isopentanoic acid, 2-ethylbutyric acid, trichloro-acetic acid, etc.), aromatic carboxylic acid (e.g., benzoic acid, etc.~; a symmetrical acid anhydride;
an activated acid amide with a heterocyclic compound contained imino function such as imidazole, 4-substituted imidazole, dimethylpyrazole, triazole or tetrazole;
an activated ester (e.g., cyanomethyl ester, methoxymethyl ester, dimethylaminomethyl ester, vinyl ester, propargyl ester, p-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenyl ester, pen~achlorophenyl ester, mesyl-phenyl ester, phenyla~ophenyl ester, phenyl thioester,p-nitrophenyl thioester, p-cresyl thioester, carboxymethyl thioester, pyranyl ester, pyridyl ester, piperidiny]ester~ 8-quinolyl thioester, or an ester with a N-hydroxy compound such as N,N-dimethylhydroxylamine, l-hydroxy 2-~lH)-pyridone, N-hydroxysuccinimide, .
, .

N-hydroxyphthalimide, l-hydroxybenzotriazole, l-hydroxy 5-chlorobenzotriazole, etc.)', and the like~
The suitable reactive derivative can optionally be selected from the above according to the kind of the compound (II) to be used practicallyO
Suitable salts of the compound (I¢) may include a salt with an i~organic base such as an alkali metal salt ~e.g., sodium or po~assium salt), an alkaline earth metal salt ~e.g , calcium or magnesium sal~j, a salt with an organic base such as trimethylamine, triethylamine, an acid addition salt te.g., hydro-chloride)j and the like.
The reaction is usually carried out in a con~
ventional solvent such as water, ace-tone, dioxane, acetonitrile, chloroform, benzene, methylene chloride, ~thylene chloride, tetrahydrofuran, ethyl acetate, N
N-dime~hylformamide, pyridine or any other organic solvent which does not adversely in~luence the reaction. Among these solvents, hydrophilic solv~nt~
may be used in a mixture with water. The reaction can be usually carried out under cooling.
When the carboxylic acid (II) is used in a form of the free acid or salt in this reaction, the reaction ~ is preferably carried out in the presence of a condens-'~ 25 ing agent such as a carbodiimide compound te.g., N,N'~
dicyclohexylcarbodiimide, N-cyclohexyl-N'-morpholino-ethylcarbodiimide, N-cyclohexyl-N'-(4-diethylamino-~-' cyclohexyl)c rbodiimide, N,N'-diethylcarbodiimide~ NyNI~
diisopropylcarbodiimide, N~ethyl-N'-(3-dimethylamino-propyl)carbodiimide, etc.), a ketenimine compound (e.g., N,N'-carbonylbis(2-methylimidazole), pen-tamethylene-ketene-N-cyclohexylimine, diphenylketene-N~cyclohexyli-mine, etc.); an olefinic or acPtylenic ether compounds i (e.g., ethoxyacetylene), ~-chlorovinylethyl ether, a ~ 35 sulfonic acid ester of N-hydroxybenzotriazole derivative ~ ~27 2.;~

(e.g., 1-(4-chlorobenzenesulfonyloxy)-6-chloro-lH-benzotriazole, etc.), a phosphorus compound (e.g., trialkyl phosphite, ethyl polyphosphate, isopropyl polyphosphate, phosphoryl chloride, phosphorus trichlo-ride, triphenylphosphine, etc.), thionyl chloride,oxalyl chloride, N-ethyl-benzisoxazolium salt, N ethyl-5-phenylisoxazolium-3 -sulfonate, a reagent (referred to as so-called "Vilsmeier reagent") formed by the reaction of an amide compound such as dime-thylformamide, diethylacetamide , N-methylformamide or the like with a halogen compound such as thionyl chloride, phosphoryl chloride, phosgene or the like.
Process 2:
; The object compound ~Ib~ or a salt thereof can be prepared by subjecting the compound (Ia~ or a salt thereof to elimination reaction of the amino-prot2cti~e group.
The elimination reaction is carried out by a con-ventional method such as hydrolysis, reduction or the like These methods may be selected depending on the kind of the protecting group to be eliminated.
The hydrolysis may include a method being conducted in the presence of an acid treferred to as acidic hydroly-sis hereinafter), base (referred to as basic hydrolysis hereinafter), hydrazine, or the like.
Among these methods, acidic hydrolysis is one of the common and preferable method for eliminating the ~ protective group such as substituted or unsubstituted ; 30 alkoxycarbonyl (e.g., t-butoxycarbonyl, t-pentyloxy-carbonyl, trichloroethoxycarbonyl, etc.), substituted or unsubstituted alkanoyl (e.g., formyl, etc.) lower cycloalkoxycarbonyl, substituted or unsubstituted ar (lower)alkoxycarbonyl (e.g., benzyloxycarbonyl, sub-stituted henzyloxycarbonyl, etc.), ar(lower)alkyl (e.g., S ~2&

. ~

ben2yl, trityll etc.), substituted phenylthio, sub-stituted aralkylidene, substituted alkylidene, sub-stituted lower cycloalkylidene, or the like.
Suitable acid for the hydrolysis includes an organic or an inorganic acid, for example, formic acid, tri-fluoroacetic acid, benzenesulfonic acid, p-toluene-sulfonic acid, h~drochloric acid and -the like, Preferable acid is one which can easily be removed from the reaction mixture by a conventional manner such as distillation under reduced pressure, for ex-ample, ~ormic acid, trifluoroacetic acid, hydrochloric acid, etc. The acid suitable for the reaction can be selected according to the kind of protective group to be eliminated, and the elimination reaction can be carried out in the presence or absence of a solvent.
Suitable solvent includes a conventional organic so~-ven-t, water or a mixture thereof. When the hydrolysis is carried out in the presence of trifluoroacetic acid, ; the reaction may be preferably carried out in the presence of anisole.
The basic hydrolysis is preferable applied for eliminating the protective group such as haloalkanoyl (e.g., txifluoroacetyl, etc.), etcO Suitable base in-cludes, or example, an inorganic base such as alkali metal hydroxide (e.g., sodium hydroxide, potassium hydroxide, etc.~, alkaline earth metal hydroxide (e.g., magnesium hydroxide, calcium hydroxide, etc.), alkali metal carbonate (e.g., sodium carbonate, potassium carbonte, etc.), alkaline earth metal carbonate (e.g., magnesium carbonte, calcium carbonate, etc.), alkali metal bicarbonate (e.g., sodium bicarbonate, potassium bicarbonate, etc.), alkaline earth metal phosphate (e.g., magnesium phosphate, calcium phosphate, etc.), alkali metal hydrogen phosphate (e.g., disodium hydrogen phosphate, dipotassium hydrogen phosphate, etc.), or the .

~ ~ 2 'J
: ~ .

;~L~8L;~1J~

like, and an organic base such as alkali metal acetate (e.g., sodi~n acetate, potassium acetate, etc.), alkali metal alkoxide (e.g., sodium methoxide~ sodium ethoxide, sodium propoxide, etc.), trialkylamine (e.g., trimethyl-amine, triethylamine, etc.), picoline, N-methylpyrroli-dine, N-methylmorpholine, 1,5-diazabicyclo[4,3,0]-5-- nonene, 1,4-diazabicyclo[2,2,2]octane, 1,5-diaza~icyclo [5,4,0]-5-undecene or the likec The basic hydrolysis is often carried out in water or a hydrophilic or moistened organic solvent or a mixture thereofO
The hydrolysis using hydrazine is commonly applied for eliminating the protective group such as succinyl or phthaloyl.
~he protecting group can generally be eliminated by hydrolysis as mentioned above or by the other con-ventional hydrolysis. In case that the protective group is halo(lower)alkoxycarbonyl or 8-quinolyloxy-carbonyl, they are eliminated preferably by treating with a heavy metal such as copper, ~inc or the like.
The reductive elimination is generally applied for eliminating the protective group such as halo(lower~
alkoxycarbonyl (e.g., trichloroethoxycarbonyl etc.), f, substituted or unsubstituted aralkoxycarbonyl (e.g., benzyloxycarbonyl, substi~uted benzyloxycarbonyl etc.), 2-pyridylmethoxycarbonyl, benzyL, etc. Suitable re-duction may include, for example, reduction with an alkali metal borohydride (e.g.~ sodium borohydride, ~ etc.j and the like.
; The reaction tempera~ure is no~ critical and may be suitably selected in accordance with the kind of the protective group to be eliminated and the method to be applied, and the present reaction is preferably carried out under a mild condition such as under cool~
ing, at ambient temperature or slightly elevated temper~
ature.

~ () Process_3 The object cQmpound ~Id) or a salt thereof can be prepared by subjecting the compound (Ic) or a salt thereof to elimination reaction of the amino-protective group in Ra.
The present reaction is carried out by conventional method, such as hydrolysis~ reduction or -the like.
The method of hydrolysis and reduction and the reaction conditions (e.g. reaction temperature, solvent, etc.) are substantially the same as those illustrated for the elimination of the protective group of the protected amino group for Ra of the compound (Ia) in the above Process 2 and therefore are to be referred to said ex-planation.
Process 4:
The object compound (If) can be prepared hy s-lb--jecting the compound (Ie) to elimination reaction of a carboxy-protective group.
The present reaction is carried out by conventional method, such as hydrolysis, reduction or the like.
The methods of hydrolysis and reduction and the reaction conditions (e.g., reaction temperature, solvent, etc.) are substantially the same as those illustrated for the elimination of the protective group of the protected amino group for Ra of the compound ~Ia) in the Process 2 and therefore are to be referred to said explanation.
Process 5:
The object compound (Ih) or a salt thereof can be prepared by reacting the compound (Ig) or a salt there-of with the compound (IV) or its reactive derivativeat the mercapto group.
Suitable reactive derivative at the mercapto group of the compound (IV) may include a metal salt such as an alkali metal salt (e.g., sodiu~l salt, potassium salt, etc.) an alkaline earth metal salt (e.g., magne-... .

sium salt, etc.) and the like.
The reaction may be preferably carried out in a solvent such as water, acetone, chloroform, nitro-benzene, N,N-dimethylformamide, methanol~ ethanol, dimethylsulfoxide, or any o-ther organic solvents, which do not adversely influence the reaction and an optional mixture thereo~9 preferably in a rather high polar solvents. The reaction is preferably carried out in around neutral condition. When the compound (Ig) or the compound (IV) is used in a free form, the reaction is preferably conducted in the presence of a base such as alkali metal hydroxide, alkali metal carbonate, alkali metal bicarbonate, trialkylamine or the like. The reaction is usually carried out at ambient temperature or slightly elevated temperature.
The present invention may include, within its scope, the cases that the protected amino group and/or the derivative at the carboxy group are transformed into the corresponding free amino group and/or carboxy group during the reaction or post-treatment in the processes as explained above.
The object compounds ~I) obtained according to the processes 1-5 as explained above can be used without any isolation in the subsequent processes.
Processes A to Q for preparing the starting compounds are explained in detail as follows.
Process A:
.
The compound (A-3) or a salt thereof can be prepared by reacting the compound (A-l) or a salt thereo~ with the compound ~A-2).
The present reaction is usually carried out in the presence of a base as aforementioned in Process 2 in a conventional solvent which does not adversely influence the reaction.

~ w ~r -~æq~.t~

The reaction temperature is not cri~ical and the reaction can be carried out under cooling or at ambient ~emperature.
Process B:
The compound ~B-2) or a salt thereof can be prepared by reacting the compound (A-l) or a salt thereof with the compound (B-l) or a salt thereof.
The present reaction is substantially the same as Process A, and accordingly the reaction conditions (e.g. a base, reaction temperature, solvent, etc.) can be referred to those of Process A.
Process C:
-The compound (C-2) or a salt thereof can be prepared by reacting the compound (C-l) or a salt thereof with carbon dioxide.
The present reaction is usually carried out in the presence of a base such as alkyl lithium ~e.g.
butyl lithium, etc.~ or the like in a conventional solvent which does not adversely in fluence the reaction.
The reaction temperature is not critical and the reaction can be carried out under cooling or at ambient temperature.
Process D:
The compound (D-2) or a salt thereof can be prepared by reacting the compound (D-l) or a salt thereof with an halogenating agent.
Suitable halogenating agent may include a conventional one used for halogenation of hydroxy group such as phosphorus compound ~e.g., phosphoryl ; chloride, phosphorus trichloride, phosphorus tribromide, phosphorus pentachloride, etc.) or the ; like.
The present reaction is usually carried out in a conventional solvent which does not adversely $~ 33 ~ 3 influence the reaction.
The reaction temperature is not critical and the reaction can be carried out under warming to heating.
Process E:
The compound (E-Z) can be prepared by subiecting a compound tE-l) to dehalogenative reduction. The dehalogenative reduction to be used in this process is a conventional one such as a catalytic reduction (e.g., palladium on carbon, palladium black, spongy palladium9 etc,) and the like.
The present reaction is usually carried out in ~ a conventional solvent which does not adversely `~ influence the reaction.
The reaction temperature is not critical and the reaction can be carried out at ambient temperature.
Process F.
The compound (F-2) or a salt thereof can be `
prepared by reacting the compound (F-l) or a salt thereof with a nucleophile selected from alkanol and arenethiol or a salt thereof.
The present reaction is usually carried out in the presence of a base as aforementioned in Process 2 in a conventional solvent which does not adversely influence the reaction.
i 25 The reaction temperature is not critical and ~ the reaction can be carried out under cooling or at ; ~ ambient temperature.
Process G:
The compound ~G-2) or a salt ~hereof can be prepared by reacting the compound ~G-l) or a salt thereof with a carboxy protective agent.
Suitable agent to be used in this reaction may include conventional ones such as lower alkyl halide (e-g- methyl iodide~ etc.) di(lower)alkylsulfate (e.g. dimethylsulfate, etc.), diazo~lower)alkane ~ - 3 ~ -, , .
~ ::
~ :

~e.g. diazomethane, etc.), lower alkanol (e.g. methanol, ethanol, etc.~ or the like.
The present reaction is usually carried out in t}le presence of an acid as a-forementioned in Process Z in a conventional solvent which does not adversely influence the reaction.
The reaction temperature is not critical and the reaction can be carried out under cooling to heating.
Process H:
; 10 The compound ~H-2) can be prepared by reacting the compound ~H-l) with a compound of the formula:

The present reaction is usually carried out in the presence of a base as aforementioned Process 2 in a conventional solvent which does not adversely influence the reaction.
The reaction temperature is not critical and the reaction can be carried out under cooling to under heating.
Process I:
j The compound ~I-l) can be prepared by reacting the compound ~H-2) with an acid and/or acid anhydride such as acetic acid and/or ace~ic anhydride. The reaction can preferably be carried out in the presence of alkali metal perchlorate (e.g. sodium perchlorate, potassium perchlorate, etc.), alkaline earth metal perchlorate (e.g., magnesium perchlorate~ calcium perchlorate, etc.) and ~he like, and an acid such as an organic carboxylic acid (e g. 7 formic acid, etc.) The reaction temperature is not critical and the reaction is preferably carried out under warming to heating.
_ocess J:
The compound (J-2) or a salt thereof can be .;,.

prepared by subjecting the compound ~J-l) to elimination reaction of the carboxy-protective group.
The present reaction can be carried out in substantially the same manner as that of Process ~.
Accordingly, the detailed explanation therefor is to be reerred to said Process 4.
Process K
The compound ~K-2) or a salt thereof can be prepared by reacting the compound (K-l) or a salt thereof with an amino-protective agent. When the amino-protective agent is acylating ag~nt 9 the reaction can be carried out in substantially the same manner as that of Process 1. Accordingly~ the detailed explanation therefor is to be referred to said Process 1.
Process L:
.
The compound ~L-2) can be prepared by oxidizing the compound ~L-l).
The present oxidation reaction is conducted by a conventional method which is applied for the transformation of so-called activated methylene group into carbonyl group. That is, the present oxidation is conducted by a conventional method such as oxidation by using selenium dioxide or the like.
The present reaction is usually carried out in a conventional solvent which does not adversely influence the reaction.
The reaction temperature is not critical and the reaction is preferably carried out under warming to heating.
Process M-The compound (M-2) or a salt thereo:E can be prepared by reacting the compound (M-l) or its hydrate or a salt thereof with a compound of ~he -formula:

R6-ONH2 or a salt thereof.
The present reaction is usually carried out in a conventional solvent which does not adverse~y influence the reaction, and when a salt of the compound of the formula: R6-ONH2 is used in the reaction~ the reaction is preferably carried out in a presence of a base as aforementioned in Process 2.
The reaction temperature is not critical and the reaction can be carried out at ambient temperature.
Process N:
The compound (N-2) or a salt thereof can be prepared by subjecting the compound (N-l) or a salt thereof to elimination reaction of the amino-protective group.
The present reaction can be carried out in substantially the same manner as that of Process 2.
Accordingly, the detailed explanation there~or is to be referred to said Process 2.
Process 0:
The compound (0-2) or a salt thereof can be prepared by reacting the compound (0-1) or a salt thereof with a nitrosating agent.
Suitable nitrosating agent may include a conventional one such as alkali metal nitrite (e.g., sodium nitrite, potassium nitrite, etc.~ and the like.
` The present reaction is usually carried out in a conventional solvent which does not adversely influence the reaction.
The reaction temperature is not critical and the reaction is preferably carried out under cooling or at ambient temperature.
Process P:
The compound (P-2) or a salt thereof can be prepared by reacting the compound (P-l) or a salt S ~5 ~
,, .: , , :, . .
, , ~

~.9~

thereof with a substituting agent capable for substituting a hydrogen atom of the hydroxy in the compound ~P-l) by R6 group.
The present reaction is usually carried out in a conventional solvent which does not adversely influence the reaction.
When the substituting agent is diazo compound, the reac~ion can be carried out under cooling or at ambient temperature.
10 Process Q:
The compound (Q-2) or a salt there of can be prepared by reacting the compound ~Q-l) or a salt thereof with a halogenating agent.
Suitable halogenating agent may include a 15 conventional one used for halogenation of an aromatic ring such as chlorine 7 bromine and the like.
The present reaction is usually carried out in a conventional solvent which does not adversely influence the reaction.
The reaction temperature is not critical and the reaction can be carried out at ambient temperature.

It is to be noted that, in ~he aforementioned reactions and/or the post-treatment of the reaction 25 mixturet the aforementioned geometric isomer may be occasionally transformed into the other geometric isomer and such case is also included in the scope of the present invention.
In case that the object compound (I) haye a 30 free carboxy group at 4 position and/or a free amino group for Ra~ it may be transformed into its pharma-ceutically acceptable salt by a conventional method.
All of the object compounds ~I) and nontoxic pharmaceutically acceptable salt thereof of the 35 present invention are novel and exhibit high antibacterial activity, inhibiting the growth of a wide variety of pathogenic microorganisms including Gram-positive and Gram-negative bacteria and are useful as antibacterial agents. Now, in order to show the utility of the object compounds (I), the test data on the in vitro antibacterial activity of some representative compownds (I) o this invention are shown in the following.
In vitro antibacterial activity:
, Test Method In vitro antibacterial activity was determined by the two-fold agar-plate dilution method as described below.
One loopful of an overnight culture of each test strain in Trypticase-soy broth ~approximately 105 variable cells per ml.) was streaked onheart infusion agar (HI-agar) containing graded concentrations of antibiotics) and the minimal inhibitory concentration ~MIC) was expressed in terminal of ~g/ml after incubation at 37C for 20 hours.
, Test compounds No. 1 7-[2-(4-Aminopyrimidin-2-yl)-2-ethoxyimino-acetamido]-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid ~syn isomer).
No. 2 7-[2-(4-Aminopyrimidin-2-yl)-2-methoxyimino-acetamido]-3-[(1-allyl-lH-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid (syn isomer).
No. 3 7-[2-Allyloxyimino-2-(4-aminopyrimidin-2-yl)acetamido]-3-(1,354-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer).
No. 4 7-[2-(4-Aminopyrimidin-2-yl)-2-propoxyimino-acetamido]-3- (1,3J4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer).
No. 5 7-~2-~6-Aminopyridin-2-yl)-2-(2,2,2-~J

' ' ' '~ ~' '. ' trifluoroethoxyimino)acetamido]-3-[(1-carboxy-methyl-lH-tetrazol-5 yl)thiomethyl]-3-cephem-4-carboxylic acid (syn isomer).
No. 6 7-[2-(6-aminopyridin-2-yl)-2-methoxyimino-acetamido~-3-~1-methyl-lH-tetrazol-5-yl)-thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
No, 7 7-[2-~6-aminopyridin-2-yl)-2-methoxyimino-acetamido]-3-cephem-4-carboxylic acid.
No. 8 7-[2-~6-aminopyridin-2-yl)-2-methoxyimino-acetamido]-3-carbamoyloxymethyl-3-cephem-4-carboxyllc acid ~syn isomer).
No, 9 7-[2-~6-aminopyridin-2-yl)-2-methoxyimino-acetamido]cephalosporanic acid ~syn isomer).
No.lO 7-[2-(2-aminopyrimidin-4-yl)-2-methoxyimino-acetamidol-3-~1-methyl-lH-tetrazol-5-yl)-thiomethyl-3-cephem-4-carboxylic acid.
No.ll 7-[2-(4-aminopyrimidin-2-yl)-2-methoxy-iminoacetamido~-3-(1-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer).
No,12 7-[2-allyloxyimino-2-~6-aminopyridin-2-yl)acetamido]-3-(1-methyl-lH-tetrazol-5-yl-thiomethyl)-3-cephem-4-carboxylic acid (syn isomer).
No.13 7-~2-(6-aminopyridin-2-yl)-2-propargyloxy-iminoacetamido]-3-(1-methyl-lH-tetrazol-5-yl-thiomethyl)-3-cephem-4-carboxylic acid (syn isomer).
No.14 7-~2-(6-aminopyridin-2-yl)-2-ethoxy-- 30 iminoacetamido]-2-methyl-3-cephem-4-carboxylic acid (syn isomer).

~ ~0 .

Test Results ....
MIC (~g/ml.) Micro- vulgaris IAM 1025 aerug nosa mpound No.
~ . _ _ < 0.025 < 1.56 2 0.025 6.25 1~ ~ 3 _ 0.05 < 1.56 A 0.025 1.56 0.025 < 1.56 ~ .._ . , 6 _ 0.025 _ 1.56 . r . _ _ . _ 0.02S 6.25 .__ 0.05 3.13 9 _ 0.025 _ 1.56 . .~ . ~ ~_. _ ~ 10 0.2 6.25 . 20 _ ~ A . . _ . _ _ :~ ~ . _ . ~__. _ _ _ _ 11 _ 0.025 < 1.56 12 O.OS _ 1.56 __ _ .............. _ 13 O.OS _ 1.56 ; 25 14 0.05 1 < ~.56 For therapeutic administration, the object compounds (I) and pharmaceutically acceptable salt thereof of the present invention are used in the form of conventional pharmaceutical preparation which contains said compound, as an active ingredient, in admixture with pharmaceutically acceptable carriers such as an organic or inorganic solid or liquid excipient which is suitable for oral, parenteral or external administration. The pharmaceutical ~ 4i :

: .

3'~3 preparations may be in solid form such as capsuleg tablet, dragee, ointment or suppository, or in liquid form such as solution, suspension, or emulsion.
If needed, there may be included in the above S preparations auxiliary substances, stabilizing agents, wettlng or emulsifying agents, buffers and the other commonly used additives.
While the dosage of the compounds may vary from and also depend upon the age, conditions of the patient, a kind of disease, a kind of the compounds ~I) to be applied, etc. In general, amounts between 1 mg. and about 2000 mg. or even more per day may be administered to a patient. An average single dose of about 50 mg., 100 mg., 250 mg., and 500 mg. o the object compounds ~I) of the present invention may be used in treating diseases infected by pathogenic bacteria.
The following examples are given for the purpose of illustrating the present invention:-, 3~ /

~ ~34 : -;, Example (1) Phosphoryl chloride (0.998 g.) was added to N,N-dimethylformamide (S ml.) and stirred at 40C for 30 minutes. To ~he solution was added a solution of 2-(6-formamidopyridin-2-yl)-2-methoxyiminoacetic acid (syn isaner) ~1.125 g.) in N,N-dimethylformamide (5 ml.} at -15C, and stirred at -10 to -8C for 50 minutes [solution A~.
On the other hand, 7-amino-3-~1-methyl-lH-tetrazol-5-yl)-thiomethyl-3-cephem-4-carboxylic acid (2.007 g.) and trimethylsilylacetamide (7.22 g.) were dissolved in methylene chloride (20 ml.) at 40C and cooled. To the cool solution was added the above solution A at -20 to -15C and stirred at the same temperature for 40 minutes. The resultant solution was poured into a solution of a saturated aqueous solution of sodium bicarbonate ~30 ml.) and water (40 ml.) under ice cooling. The aqueous layerL was separated, washed with ethyl acetate, and then ethyl acetate ~50 ml.) was added to the aqueous layer. The solution was adjusted to pH 3 with 10% hydrochloric acid, and`
extracted with ethyl aceta~e twice. The extract was washed with water and concentrat~d to a small amount under reduced pressure. The appeared precipita~es were collected by filtration, washed with ethyl acetate and dried to give 7- ~2-(6-formamidopyridin-2-yl)-2-me~hoxyiminoacetamido]-3-(1-methyl-lH-tetrazol-5-yl3thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (873 mg.). The same product (126 mg.) was recovered Erom the mother liquor.
~ . 30 Total yield was 999 mg.
4~ j I.R. v mU~ol 3280, 1785, 1728, 16739 1454, 1053 cm~l N.M.R. ~ ppm (DMSO-d6) : 3.62, 3.76 (2H, AB-q, J=18Hz), 3.g0 (3H, s), 3.94 (3H~
s~, 4.24, 4.35 (2H, AB-q, J=16Hz), ~acte tnar k ~3 5.16 ~lH~ d, J=SHz), 5.85 (lH, dd, J=5Hz,8Hz)~ 7.50 (lH, d~ J=8Hz),
7.80 (lHJ t, J=8Hz), 5.00 ~0.3H~
broad s), 6.88 (0.7H, broad d, S J=8Hz)~ 9.28 ~0.7H, broad d, J=lOHz), 8.28 ~0.3H, broad s), 9.50 (lH, broad d, J=8Hz), 10.7 (lH, m, J=lOHz) t2) A mixture of N,N-dimethylformamide ~3 ml.) and phosphoryl chloride (460 mg.) was stirred at 37 ko 40~C for 30 minutes. To the solution were added methylene chloride (3 ml.) and 2-(6-formamidopyridin-2-yl~-2-me~hoxyiminoacetic acid (669 mg.~ at -20 to ; -25C and stirred at -lO to -15C for one hour.
A solution of 4-nitrobenzyl 7-amino-3-cephem-4-c~rboxylate ~670 mg.) and trimethylsilylacetamide (2 g.) in methylene chloride (200 ml.) was added to the above solution at -10 to -15~C, and then stirred at the same temperature for 30 minutes. After the solution was concentrated under reduced pressure, ethyl acetate and water were added to the residue.
The ethyl acetate layer was separated, washed with an aqueous solution of sodium bicarbonate, water and a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was triturated with diethyl ether to give 4-nitrobenzyl 7-~2-(6-formamidopyridin-2-yl)-2-methoxyiminoacetamidoJ-3-cephem-4-carboxylate (730 mg.), mp. 195 to 200C ~dec.).
I.R. v mUxoI : 3350, 3200, 1790, 1725, 1690, 1660 cm The following compounds were prepared in substa~tially the same manner as those of Example 1-(1) and (2).
(3) 7-[2-~6-Formamidopyridin-2-yl)-2-methoxyimino-.
, .
. .

acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl 3-cephem-4-car~oxylic acid (syn isomer), mp. 167 to 169C (dec.).
I.R. v Nu~ol : 3270, 1780, 1670, 1455, 1370, 1252, 1052 cm 1 N.M.R. ~ ppm (DMSO-d6) : 3.65, 3.78 (2H3 AB-q, J=18Hz), 3.97 (3H, s), 4.50, 4.57 (2H, AB-q, J-12Hz), 5.22 ~lH~ d1 J=5Hz), 5.93 (lH) dd, J 5Hz, 8Hz), 6.57 (lH, broad d, J=7Hz), 7.58 ~lH, d, J=7Hz), 7.90 (lH, t, J=7Hz), 9.3 - 9.8 ~2H, m), 9063 (lH, s), 10.62, 10.70 ~lH, m) ~4) 7-[2-~6-Formamidopyridin-2-yl)-2-methoxyimino-lS acetamido]-3-(5-t-butoxycarbonylaminomethyl-1,3,~-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer), mp. 178 to 186C (dec.).
I.R. ~ NmU~ol : 3280, 1785, 1720-1660 ~broad), 1457, 1255, 1162, 1052 cm N.M.R. ~ ppm ~DMSO-d6) : 1.40 (9H, s), 3.63~ 3.78 ~2H, AB-q, J=18Hz~, 3.98 (3H, s), 4.1-4.7 (4H, m), 5.21 (lH, d, J~4.5Hz~, 5.89 ~lH, dd, J=4.5Hz, ; 8Hz), 6.2-8.2~4H, m3, 8.33 ~0.3H, broad s), 9.35 ~0.7H, broad d, J=lOHz), 9.55 ~lH, broad d, J=8Hz), 10.5-10.8 (lH, m) ~S) 7-[2-~6-Formamidopyridin-2-yl)-2-methoxyimino-acetamidolcephalosporanic acid (syn isomer~ ,mp. 191 to 193C (d~c.) .
I.R. ~ Nu~ol : 3250, 1780, 1725, 1665, 1240, 1053 cm N.M.R. ~ ppm ~DMSO-d6) : 2.03 (3H, s), 3.53~ 3.62 t~H, AB-q, J=17Hz), 3.97 t3H, s), 4.70, 5.02 ~2H, AB-q, J=13Hz), 5.18 ~lH, d, J=5Hz), 5.88 ~lH, dd, J=SHz, ~' 8Hz), 6.90 (lH, broad d, J=7Hz), 7.53 (lH, d, J=7Hz) 9 7.82 (lH, t, J=7Hz), 9.3 ~lH, broad d, J-9Hz), 9.54 ~lH, d, J=8Hz), 10.6 (lH, m~ .
(6~ 4-Nitrobenzyl 7-[2-(6-~ormamidopyridin-2-yl)-2-methoxyiminoacetamido]-3-chloro-3-cephem-4-carboxy-late (syn isomer), mp. 162 to 168~C (dec.).
I.R. v NmUjxol : 3200, 1780, 1?35, 1690-1660, 1040 cm N.M.R. ~ ppm (DMSO-d6): 3.70, 4.10 (2H, AB q, J~18Hz), 3.93 ~3H, s), 5.32 (lH, d, J=5Hz), 5.45 (2H, s), 5.98 ~lH, dd, J=5Hz, 8Hz), 6.9 (lH, m), 7.50 (lH, d, J=8Hz), 7.57 ~2H, d, lS J=8Hz), 7.B3 ~lH, m) J 8.26 ~ZH, d, J=8Hz.), 9.30 (lH, m), 9.69 ~lH, d, J=8Hz), lQ.70 (lH, m).
~7) 4-Nitrobenzyl 7- [2-(6-formamidopyridin-2-yl)-2-methoxyiminoacetamido]-3-methoxy-3-cephem-4-carboxylate.
I.R. ~ NmUxol: 3700-3000, 1780, 1710-1640, 1050, 1010 J 640 cm N.M.R. ~ ppm ~DMSO-d6) : 3.7 (2H, broad s), 3.84 ~3H, s), 3.99 (3H, s), 5.25 (lH, d, J=5Hz), 5~36 ~2H, s), 5.77 (lH, dd, J=SHz~ 8HZ) J 6.9 ~1~, m), 7.52 ~lH9 d, J=8Hz), 7.67 ~2H, d, J=8H~), 7.8 ~lH, m), 8.22 (2HJ d, J=8Hz), 9.3 ~lH, m), 9.52 ~lH, d, J--8Hz), 10.7 ~lHs m) ~8) Bellzhydryl 7- ~2 ~6-formamidopyridin-2-yl)-2-methoxyiminoacetamido]-7-methoxy-3-~1-methyl-lH-tetra7ol-S-yl)thiomethyl-3-cephem-4-carboxylate (syn isomer), mp. :L45 to 150C ~dec.).
I.R. v NmUxol :3Z30, 1780, 1725, 1680 cm 1 ~ l , . ~ ..

:
~ .
, . ~ , , Z~3 N.M.R. ~ ppm (acetone-d6) : 3.59 (3H, s), 3.63, 3 73 (2H, AB-q, J=18Hz), 3.83 (3H, s), 3~96 (3H, s~, 4.23, 4.43 (2H, AB-q, J=13Hz), 5.10 (lH, s), 6.86 (lH, s), 7.16-7.80 (13H, m) (9) 7-[2-(6-Formamidopyridin-2-yl~-2-methoxyimino-:` acetamido]-2-methyl-3-cephem-4-carboxylic acid (syn isomer), mp. 198 to 202c (dec.).
10I.R. v mUJol: 3380-30709 179Q, 1735, 1670 cm 1 N .M.R. ~ ppm (DMSQ-d6): 1.47 (3Hg d, J=7Hz~, 3.5-402 (lH, m), 4.00 ~3H, s), 5.20 (lH9 d~ J SHz), 6.05 ~lH, dd, J-5Hz, 8Hz)j, 6.67 (lH, d, 15J=6Hz), 6.9-8.7 (3H, m).
~10) 7-[2-(6-Formamidopyridin-2-yl) -2 -methoxyimino-acetamido)-3-methyl-3-cephem-4-carboxylic acid (syn isomer), mp. 225 to 225.5c (dec.).
I.R. v mUxol: 3400, 3250, 3220, 1773, 1730, 16~0-1650, 1560, 1260~ 1160, 1050 cm 1 N.M.R. ~ ppm (DMSO-d6) : 2.02 (3H, s), 3.3, 3.6 (2H, AB-q, J=18Hz), 3.96 (3H, s), 5.13 ~lH, d, J=4.5Hz), 5.78 (lH, dd, J=4.5E~z, 8Hz), 6.9-8.3 (3H, m), 9.3-9.5 (2H, m), 10.55 (lH, m) (11) 7- [2 - (6-Trifluoroacetamidopyridin-2-yl~ -2-methoxyiminoacetamidolcephalosporanic acid (syn isomer), mp. 151 to 155C.
I.R. v NUxol :~ 3260, 1775, 1730, 1690-1670, 1380, 1160, 1040 cm N.M.R. ~ ppm (DMSO-d6) : 2.00 (3H, s), 3.5 (2H, broad s), 3.98 (3H, s), 4.67, 5.03 (2H, AB-q, J=12Hz), 5.18 ~lH, d, J=5Hz), 5.88 ~lH, dd, J=5Hz~ 8Hz), :`

:: , ,:
, .: `
:

7.5-8.0 ~3H, m), 9.51 ~lH, d, Ja 8Hz), 11.63 (lH, m) ~12) 7-[2-~6-Formamidopyridin-2-yl)-2-methoxyimino-acetamido]-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn isomer), mp. 185 to 190C (dec.).
I.R. v NmU~ol : 3200, 1790, 1700, 1665 cm 1 ; N~M.R. ~ ppm (DMSO-d6) : 3.60, 3.42 ~2H, AB-q,, J=18Hz), 3.98 (3H, s), 4 64, 4 92 ~2H, AB-q, J~12Hz~, 5.20 (lH, d, J=4Hz), 5.90 ~lH, dd, J=4Hz, 9Hz), 6.50 ~2H, s), 6.8-8.0 ~3H, s), 9.58 (lH, d, J=9Hz) (13) 7-E2-(2-Formamidopyrimidin-4-yl)-2-methoxyimino-15 acetamldo]-3-(1-methyl-lH-tetrazol-5-yl~thiomethyl~-3-cephem-4-carboxylic acid, mp. 138 to 155qC(dec.).
I.R. v maxl : 3300, 1787, 1565~ 1408, 1043 cm 1 N.M.R. ~ ppm ~DMSO-d6) : 3.63, 3.76 (2H, AB-q, J=18Hz), 3.92 (3H, s~, 4.02 (3H, ZO s), 4024, 4.35 (2H, AB-q, J=12Hz), 5.16 (lH, d, J=5Hz)g 5.86 (lH, dd, J=5Hz, 9Hz), 7.47 ~lH, d, J=6Hz),
8.63 (lH, d, J=6E~z), 9.37 (lH3 d, J=lOHz), 9.60 (lH, d, J-9Hz), 11.00 (lH, d, J=lOHz) (14~ 7-~2-(6-Formamidopyridin-2-yl)-2-ethoxyimino-acetamido]-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer), mp. 150 ~o 155C (dec.).
I.R. v NUxol : 3200, 1780, 1700, 1660 cm 1 N.M.R. ~ ppm (DMSO-d6) : 1.30 ~3H, t, J-7Hz), 3.65, 3.80 (2H, AB-q, J=16Hz), 3.95 (3H7 s), 4.25 (2H, q, J=7Hz), 4.28 (2H, broad s), 5.18 (lH, d, J=5HZ), 5.90 (lH, dd, J=5Hz, 9Hz), 6.8-8 2 (3H, m), 9.4 (2H, m), 10.6 (lH, broad d) _ .

~15) A solution of pivaloyl chloride (1.07 g.) in methylene chloride (3 ml.) was added to a solution of 2-(6-Formamidopyridin-2-yl)acetic acid (1.6 g.) and 1,5-diazabicyclo[5,4,0]undecene-5(1.35 g.) in me~hylene - 5 chloride (25 ml.) at -20 to -25C, and stirred at the same temperature for one hour ~solution A]. On the other hand, a solution of 7-amino-3-~1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (3.24 g.) and 1,5-diazabicyclo[5,4,0~ndecene-5 (1.35 g.) in methylene chloride (60 ml.) was stirred at room temperature for 10 minutes. To the solution was added the above solution A at -20 to -25C and stirred at the same temperature for 1.5 hours. After removing the solvent from the resultant sclution, ethyl aceta~e, water and sodium bicarbonate were added to the residue. The aqueous layer was separated and washed with ethyl acetate. Ethyl acetate (300 ml.) was added to the aqueous solution, adjusted to pH 2 to 3 with 5% hydrochloric acidg and then shaken ~0 sufficiently. The ethyl acetate layer was separated, washed with water and concentrated under reduced pressure to give 7-[2-(6-formamidopyridin-2-yl)-acetamido]-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (2.2 g.).
I.R. v mU~ol : 3320, 1782, 1690 (broad) cm 1 N.M.R. ~ ppm (DMSO-d6) : 3.68 (4H, broad s), 3.93 (3H, s), 4.33 (2H, broad s~, 5.10 (lH9 d, J=5Hz), 5.72 ~lH, dd, J=5Hz, 9Hz), 6.8, 7.8 (lH~j 7.10 (lH, d, J=8Hz), 7.73 (lH, t, J=8Hz),
9.10 (lH, d, J=9Hz), 8.33, 9~37 (lH, broad s), 10.55 (lH, broad d, J=7HZ) (16) A solution of phosphoryl chloride (2.14 g.~ in N,N-dimethylformamide (14 ml.) was stirred at 37 to - ~ . :

0~2~

40C for 30 minutes. To the solution were added methylene chlorîde (14 ml.) and 2-~6-formamidopyridin-2-yl)-2-dichloroacetoxyiminoacetic acid (syn is~) (4.48 g.) at -20 to -25C and stirred at -10 to -15C for 30 minutes [solution A~. On the other hand, 7-amino-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid ~4.6 g.) was dissolved in a solution of trimethylsilyl-acetamide (14 g.) in methylene chloride ~150 ml.) at 40C, and cooled to -10 to -15C. The solution was added to the above solution A at -10 to -15C and stirred at the same temperature for 30 minutes.
After removing methylene chloride ~o~ the resultant solution under reduced pressure, ice water and ethyl acetate were added to the residue, and adjusted to pH 4 with an aqueous solution of sodium bicarbonat~e.
The aqueous layer was separated, washed with ethyl acetate, adjusted to pH 2 with 10~ hydrochloric acid, and then extracted with ethyl acetate. The extract ~as washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and conceIltrated under reduced pressure. The residue was triturated with diethyl e~her. The precipitates were collected by filtration, washed with diethyl ether and dired to give 7-~2-(6-formamidopyrîdin-2-yl)-2-hydroxyiminoacetamido]-3-~1-methyl-lH-tetrazol-5-yl)-thiomethyl-3-cephem-4-carboxylic acid ~syn isomer) ~5.0 g.), mp. 110 to 115C.
I.R. v NmU~ol : 3z4o9 1780, 1700, 1660 cm 1 N.M.R. ~ ppm ~DMSO-d6) : 3.73 (2H, broad s), 4.00 (3H, s), 4.35 (2H, broad s), 5.20 (lH, d9 J=4Hz)9 5.93 ~lH, dd, J=9Hz, 4Hz), 6.83-8.0 ~3H, m), 9.45 (lH, d, J=9Hz) ~ .

` ~ ~ 20 ~ ~ 3 Example 2 ~1) Conc. hydrochloric acid (127.4 mg.~ was dropwise added to a suspension of 7-[2-(6-formamido-pyridin-2-yl)-2-methoxyiminoacetamido]-3-(1-methyl-lH-tetrazol 5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer, 930 mg.) in methanol (15 ml.) and stirred at room temperature for 4Q minutes. After methanol was removed under reduced pressure from the resultant solution, water (100 ml.) was added to the residue and the solid substance was dissolved by adding 10% hydrochloric acid. Af~er the insoluble material was filtered out, the filtrate was adjusted to pH 3 with an aqueous sodium bicarbonate. The solution was purified by column chromatography on macroporous, non-ionic adsorption resin "Diaion HP-20"
(Trademark, manufactured by Mitsubishi Chemical Industries Ltd.), with an eluent of aqueous methanol.
The eluate was lyophilized to give 7-[2-(6-amino-pyridin-2-yl)-2-methoxyiminoacetamido]-3-~1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (605 mg.), mp. 150 to 154C~
I.R. v NUaJol : 3360, 32Z0, 1780, 1670, 1620, 1585, 15~4, 1042 cm N.M.R. ~ ppm (DMSO-d6) : 3.73 (2H, broad s), 3.75 (3H, s), 3.78 ~3H, s), ; 4.30 and 4.37 (2H, AB-q, J=12Hz), 5.17 ~lH, d, J=5Hz), 5.85 ~lH, dd~
J=5Hz, 9Hz~, 6.53 ~lH, d, J=8Hz), 6.93 ~lH, d, J=8Hz), 7.48 (lH, t, J=8Hz), 9.52 (lH, d, J=9Hz) ~2) A solution of 7-~2-(6-formamidopyridin-2-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid (2.3 g.) in methanolic hydrochloric acid (12 ml., containing hydrochloric acid 6 mmol) was stirred at room temperature for one hour. To the resultant g~3 solution was added diethyl ether, and the precipitates were collected by filtration and dissolved in a mixture of methanol ~50 ml.) and water (10 ml.). The solution was adjusted to pH 3 with an aqueous solution of sodium bicarbonate, trea~ed with activa~ed charcoal ~1 g.) and concentrated to a volume of about 20 ml.
The precipitating crystals were sollected by filtration, washed with water and dried to give 7-[2-~6-amino-pyridin-2-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid ~l.lZ g.), mp. 215 to 220C ~dec.).
The mother liquor and washings were combined and concentrated under reduced pressure. The appeared precipitates were collected by filtration, washed with water and dried to give the same object compound (0.36 g.). Total yield 1.48 g.
I.R. v mUaxol : 3300, 1785, 1730, 1670 cm 1 N.M.R. ~ ppm (DMSO-d6) : 3.64 ~21-l, broad s), 4.06 (3H, s), 5.18 (lH, dd, J=4Hz, 8Hz), 5.85 ~lH, dd, J=4Hz, 8Hz), 6.52 (lH, broad t), 6.78 (lH, d, J=8Hz) ? 7.19 (lH, d, J=9Hz), 7.92 (lH, dd, J=8Hz, 9Hz), 10.0 ~lH, d, J=8Hz) The following compounds were prepared in substantially the same manner as those of Examples 2-(1) and (2).
~3) 7-[2-(6-Aminopyridin-2-yl)-2-methoxyimino-acetamido]-3-~1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid ~syn isomer), mp. 152 to 156C (dec. ) .
I.R. v mUxol : 3400, 3230, 1780, 1670, 1622, 1590, 1550, 1050 cm N.M.R. ~ ppm ~DMSO-d6) : 3.67, 3.73 (2H, AB-q, J=18Hz), 3.83 (3H, s), 4.30, 4.55 (2H, AB-q, J=14Hz), 5.13 ~lH~ d~ J=4Hz), 5.82 (lH9 dd, ~2 .

. .

2~)~2~

J=4Hz, 8Hz), 6.50 ~lH, d, J=8Hz), 6.88 (lH~ d, J=8Hz), 7.45 (lH, t, J=8Hz), 9~50 (lH, d, J=BHz), 9.57 (lH, s) (4) 7-[2-(6-Ami}~opyridin-2-yl)-2-methoxyimino-acetamido3-3-(l-carboxymethyl-lH-tetrazol-5-yl)-thiomethyl-3-cephem-4-carboxylic acid (Sy}l isomer), mp. 169 to 177C (dec.).
I.R. v NmUxol : 3380, 3220, 1780, 1670, 1620, 1050 cm N.M.R. ô ppm (DMSO-d6 + D20~ : 3.679 3.8û (2H7 AB-q, J=14Hz), 3.9g (3H, s), 4.27, 4.50 (2H, AB-q, J=14H~), 5.18 (lH~ d, J=5Hz), S.33 (2H, s), 5.88 (lH, d, J=5Hz), 6.65 ~lH, d, J=8Hz), 6.97 ~lH" d, J=8Hz), 7.60 (lH, t, J=8Hz) (5) 7-[2-(6-Aminopyridin-2-yl)acetamido]-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer), mp. 18~ to 193C (dec.).
I.R. v Na~l: 3600-3080, 1763, 1698, 1663 cm 1 N.M.R. ~ ppm ~D20 + DCQ) : 3.83 (2H, s), 4.03 (2H, s), 4.15 (3H, s~, 4.20, 4.43 (2H, AB-q, J=14Hz), 5.27 (lH, d, J-5Hz~ J
5.73 (lH, d, J=5Hz), 6.g3 (lH, d, J=8Hz), 7.07 ~lH9 d, J=9Hz), 7.98 (lH, dd, J=8Hz, 9Hz) ~6) 7-~2-~6-Aminopyridin-2-yl)-2-methoxyimino-acetamido]-3-chloro-3-cephem-4-carboxylic acid hydro-chloride (syn isomer), yellow pow~er, mp. 170 to 220C (dec.).
Nu~ol : 3300-3100, 1780, 1711, 16 1610, 1540, 1370 cm N.M.R. ~ ppm (DMS0-d6) : 3.57 4~13 (2H, AB-q, J=18Hz), 4.13 (3H, s), 5.37 (lH, d, J~4.5Hz), 355.88 (lH, dd, J=4.5Hz, 8Hz~, - ~3 , . . -. . ` - ` ` ~ . . .

:~Z~ 3 6.77 (lH, d, J=8Hz), 7.21 (lH, d, J=9Hz), 7.97 (lH, dd, J=8Hz, 9Hz), 8.0-9.3 (2H, m), 10.07 (1~13 d, J=8Hz) ~7) 7-[2-~6-Aminopyridin-2-yl)-2-methoxyiminoacet-amido]-3-methoxy-3-cephem-4-carboxylic acid, mp. 175 ~o 182~C~dec.).
I.R. v Nmaxl : 3300, 1775, 1700-1650, 1045 cm 1 N.M.R. ~ ppm ~DMS0-d6) : 3.62 (2H, broad s)~
3.75 ~3H, S)g 3.96 ~3H7 s), 5.15 ~lH, d, J=4.5Hz), 5.60 (lH, dd, J=4.5Hz, 8Hz), 6.70 (lH; ds J=8Hz~, 6.85 (lH, d, J=8Hz), 7.56 (lH, t, J=8Hz), 9.53 (lH, d, J=8Hz) (8) 7-[2-(,6-Aminopyridin-2-yl)-2-me~hoxyimino-acetamido]-7-methoxy-3~(1-methyl-lH-tetrazol-5-yl)-thiomethyl-3-cephem-4-carboxylic a~id (syn isomer), ; mp. 165 to 170C (dec.).
I.R. v Nmaxl : 3300, 1780, 1700, 1680 cm 1 N.M.R. ~ ppm (D20 + NaHC03) : 3.72, 3.58 (2H~
AB-q, J=17Hz), 3.64 (3H, s), 3.98 (3H, s), 4.04 (3H, s), 4.24, 4.06 (2H, AB-qJ J=13Hz), 5.20 (lH, s), 6.74 (lH, d, J=8Hz), 7.10 (lH, d, J=8Hz), 7.56 (lH~
t, J=8~z~
(9) 7-[2-(6-Aminopyridin-2-yl)-2-methoxyiminoacet-amido3-2-methyl-3-cephem-4-carboxylic acid (syn isomer), mp. l99 to 205C (dec.)~
I.R. v NUxol : 3400~3100, 1780, 1730, 1665, 1550, 1295, 1258, 1050 cm N.M.R. ~ ppm (DMSO-d6) : 1.48 ~3H, d, J=9Hz), 3.7-4.2 (lH, m)~ 4.10 (3H, s), 5.20 (lH, d, J=SHz), .

2~1~23 5.92 (lH, dd, J~9Hz, 5Hz~ 9 6.62 ~lH, d, J=6Hz), 6.78 (lH, d, J=8Hz), 7.27 (lH, d, J~9Hz), 8.00 (lH, dd, J=8Hz, 9Hz),
10.00 (lH, d, J=9Hz) (10) 7-[2-(6-Aminopyridin-2-yl)-2-methoxyimino-acetamido~-3-methyl-3-cephem-4-carboxylic acid hydrochloride (syn isomer), mp. 195 to 198C (dee.).
I R. v NmUxol : 3100, 1780, 1682, 1668, 1260, 1050 cm N.M.R. ~ ppm (DMSO-d6) : 2.07 ~3H, s), 3.35, 3.70 (2H, AB-q, J=18Hz), 4.11 (3H, s~, 5.18 (lH~ d, J=4.5Hz), 5.77 ~lH~ dd, J=4.5Hz, 8Hz), 6~80 ~lH, d, J=8~z), 7.20 ~lH, d, J=9Hz), 7.98 ~lH, dd, J=8~1z, 9Hz), 9.95 (lH, d, J=8Hz~, 6-9.3 (2H, m) ~11) 7-[2-(6-Aminopyridin-2-yl)-2-hydroxyimino-acetamidol-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-~-carboxylic acid(syn iso~er~, mp. 165 to 170C (dec ).
I.R. v Na~l : 3300, 1760, 1680 cm 1 N.M.R. ~ ppm (DMSO-d6) : 3.68 (2H, broad s), 3.93 (3H, s), 4.30 (2H, broad s), 5.13 (lH, d, J=4Hz), 5.83 (lH, dd, J=4Hz, 9Hz~, 6.4B (lH9 d, J=8Hz), 6.93 ~lH, d, J=8Hæ), 7.43 (lH, t, J-8H~), 9~37 (lH, d, J=9Hz) (12) 7-[2-(6-Aminopyridin-2-yl)-2-methoxyimino-acetamido]-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn isomer), mp. 190 to 195C ~dec.).
I.R. v mUxol : 3400, 1780, 1720, 1670 cm 1 N.M.R. ~ ppm (DMSO-d~) : 3.60, 3.44 (2H, AB-q, J=17Hz), 3.88 (3H, s), 4.62, 4.88 ~2H, AB-q, J=13Hz), n ~

`
.

L2~ 3 5.13 (lH, d, J=4Hz), 5.80 (lH, dd, J=4Hz, 9Hz), 6.48 (lH, d, J=8Hz), 6.88 (lH, d, J=8Hz), 7.42 (lH, t, J=8Hz), 9.44 (lH, d, J=9Hz) (13) 7-[2-(2-Aminopyrimidin-4-yl)-2-methoxyimino-acetamido]-3-(1-methyl-lH-~etrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid, mp. 181 to 182.5C (dec.).
I.R. v NmUaxol 3440, 3320, 1790, 1693, 1650, 1630, 1525, 1043 cm 1 N.M.R. ~ ppm (DMSO-d6) : 3.68 (2H, broad s), 3.90 (3H, s), 3.93 (3H, s), 4.2S, 4.33 (2H, AB-q, J=14Hz), 5.12 (lH, d, J=5Hz), 5.82 (lH, dd, J=5Hz, 8Hz), 6.85 (lH, d, J=5Hz), 8.27 ~lH, d, J=5Hz), 9.50 (lH, d, J=8Hz) (14) 7-~2-(6-Aminopyridin-2-yl)-2-ethoxyimino-acetamido]-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer), mp. 165 b~ 170C (dec.).
I.R. v NmaU3ol : 3380, 3240, 17807 1670 cm 1 N.M.R. ~ ppm (DMS0-d6) : 1.28 ~3H, ~, J=7Hz)~
3.64, 3.76 ~2H, AB-q, J=18Hz), 3.95 ~3H, s), 4.18 ~2H, q, J=7Hz), 4.24, 4.38 (2H, AB-q, J=14Hz), 5.15 (lH, d, J=5Hz) 3 5.84 ~lH, dd, J=SHz, 8Hz), 6.50 (lH, d, J=8Hz), 6.90 (lH, d, J=8H7), 7.43 ~lH, t, J=8Hz), 9.46 ~lH, d, J=8Hz) (15~ 7-~2-(6-Trifluoroacetamidopyridin-2-yl)-2-methoxyiminoacetamido]cep~lalOsporanic acid (syn i~omer)(380 m~.) was added to a solution of sodium ace~ate (857 mg.) in water (6 ml.), and stirred a~ room te~lperature for 16 hours. The resultant solution was washed with , .
.

, ethyl acetate (5 ml.), adjusted to pH 4 with 10 hydrochloric acid and washed with ethyl acetate.
The solution was concentrated under reduced pressure to 2/3 of the initial volume, and subjected to column chromatogra~hy on macroporous, non-ionic adsorption resin "Diaion HP-20" (Trademark:
manufactured by Mitsubishi Chemical Industries Ltd.) and eluted with 10~ isopropyl alcohol. The eluate was lyophilized to give 7-[2-~6-aminopyridin-2-yl)-2-methoxyiminoacetamido]cephalosporanic acid (syn isomer)(130 mg.), pale yellow powderS mp. 155 to 161C (dec.).
I.R. v NmaU~ol : 3350-3220, 1780, 1740, 1680-1655, 1380, 1040 cm N.M.R. ~ ppm ~DMSO-d6) : 2.00 ~2H, s), 3.5 (2H, broad s), 3.88 (3H, s), 4.67, 5.04 (2H, AB-q, J=12Hz), 5.15 (lH, d, J=5Hz), 5.83 (lH, dd, J=5Hz, 8Hz), 6.45 (lH, d, J=8Hz), 6.88 (lH, d, J=8Hz), 7.43 (lH, t, J=8Hz) 9 9.4 ~lH, d, J=8Hz) :
' ~Z~

~xample 3 A solution of 7-[2-(6-formamidopyridin-2-yl)-2-methoxyiminoacetamido]-3-~5 t-butoxycarbonylamino-methyl-1,3,4-thiadiaz~1-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer)(1.12 g.) in 98~:Eormic aeid ~11 ml.) was stirred at room temp~rature for Z hours. Methanol ~20 ml.) and conc. hydrochloric acid ~0.3 ml.) were added to the resultant solution and then stirred at room temperature for 30 minutes. After the reaction mixture was concentrated in vacuo, water (25 ml.) was added to the residue, and then the solution was adjusted to pH 3 to 4 with a saturated aqueous solution of sodium bicarbonate. The solution was subjected to column chromatography on macroporous, non-ionic adsorption resin ~'Diaion HP-20" ~Trademark, manufactured by Mitsubishi Chemical Industries Ltd.) with an eluent of aqueous methanol. The eluate was concentrated ~mder reduced pressure and lyophilized to give 7-[2-~6-aminopyridin-2-yl)-2-methoxyi~ino-acetamido]-3-~5-aminomethyl-1,3,4-thiadiazol-2-yl)-thiomethyl-3-cephem-4 carboxylic acid (syn isomer) (0.48 g.~, mp. 248 to 251C (dee.).
I.R. v Nma~l : 3500, 3400, 3230, 1770, 1670, 1620, 1040 cm 1 N.M.R. ~ ppm ~DMS0-d6) : 3.53 (2H, broad s), 3.88 ~3H, s), 4.35 (4H, broad s), 5.05 ~lH, d, J=SHz), 5.75 (lH, dd, J=5Hz, 8Hz), 6.48 (lH, d, J=8Hz), 6.88 (lHJ d, J=8Hz), 7.43 ~lH7 t, J=8Hz) ;

Example 4 (1) 10% Palladium on carbon (216 mg.) was added to a solution of 4-nitrobenzyl 7-[2-~6-formamido-pyridin-2-yl)-2-methoxyiminoacetamido3-3-cephem-4-carboxylate (540 mg.) in te~rahydrofuran ~10 ml.), methanol (5 ml.), acetic acid (0.075 ml.), and water ~0.75 ml.). The mixture was subjected to catalytic reduction at ambient temperature under ordinary pressure for 5 hours, and then allowed to stand overnight. After filtered off the catalyst~
the filtrate was concentrated under reduced pressure.
Ethyl acetate and an aqueous solution of sodium bicarbonate were added to the residue, and the aqueous layer was separated. The solution was adjusted to pH 2 with 10% hydrochloric acid. The appeared precipitates were collected by filtration, washed with water and dried to give 7-[2-(6-formamidopyridin-2-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid (300 mg.), mp. 202 to 204C (dec.).
I.R. v maU]ol : 3250, 3200~ 1780, 1720, 1660 cm l N.M.R. ~ ppm ~DMS0-d6 t D20) : 3.56 (2H, broad d), 3.96 ~3H, s~, 5.13 (lH, d, J=5Hz), 5.91 (lH, d, J=SHz), 6.46 ~lH, m), 6.85-8.00 ~3H, m) (2) A mixture of 4-nitrobenzyl 7-[2-(6-formamido-pyridin-2-yl)-2-methoxyiminoacetamido]-3-chloro-3-cephem-4-carboxylate (syn isomer)(l.43 g.), 10% palladium on carbon (0.8 g.), methanol (30 ml.) and ~etrahydrofuran (60 ml.) was subjected to catalytic reduction at ambient temperature under ordinary pressure for 4 hours.
After removing the catalyst by filtration, the filtrate was concentrated under reduced pressure. An aqueous solution of sodium bicarbonate and ethyl acetate were added to the residue, and the aqueous layer was separated~ The aqueous layer was adjusted to pH 6, .,, ~'~

washed with ethyl acetate ? and then adjusted to pH 1 to 2. The aqueous layer was extracted with ethyl acetate The ethyl acetate extract was washed with an aqueous solution of sodium chloride, dried over magnesium sulfate, and concentrated under reduced pressure. Diethyl ether (30 ml.) was added to the residue, stirred for one hour, and then the precipitates were collected by filtration to give 7- [2-(6-formamidopyridin-2-yl)-2-methoxyiminoacetamido]-3-chloro-3-cephem-4-carboxylic acid (syn isomer) (680 mg.), brownish yellow powder, mp. 200 to 204C (dec.).
I.R. v mU~ol: 32ZS, 1780, 1730, 1680-1650, 1550 cm 1 N M.R. ~ ppm (DMSO-d6): 3.65, 4.08 (2H, AB-q, J=18Hz), 4.00 ~3H9 s), 5.30 ~lH, d"
J=4.5Hz), 5.98 (lH, cld, J= 8Hz, 4.5Hz), 6.97 (lH, d, J=8Hz), 7.53 (lH, d, J=8Hz), 7.87 (lH, t, J=8Hz), 9.35 (lH, m), 9.63 (lH, d, J=8Hz), 10.63 (lH, m) The following compounds were prepared in substantially the same manner as that of Example 4-~1) and (2).
(3) 7- [2-~6-Formamidopyridin-2-yl)-2-methoxyimino-acetamido]-3-methoxy-3-cephem-4-carboxylic acid, mp. 173 to 175C (dec.).
I.R. v NaJl: 3300, 1770, 1720-1660, 1040, 810, 620 cm N.M.R. ~ ppm (DMSO-d6) : 3.61 (2H, broad s), 3.73 ~3H, s), 3 95 (3H, s), 5.14 (lH, d, J=5Hz), 5.66 (lH, dd, J=5Hz, 8Hz), 6.9 (lH, m~, 7.48 (lH, d~ J=8Hz), 7.80 (lH, dd, J=8Hz, 9Hz~, 9.3 (lH, m), 9.42 (lH, d, J=8Hz), 10.5 (lH, m) ~9~
-~4) 7-[2-~6-Aminopyridin-2-yl)-2-methoxyimino-acetamido]-3~(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. v NmUxol : 3360, 3220, 1780, 1670~ 1620, S 1585 J 1544, 1042 cm (5) 7-[2-~6-aminopyridin-2-yl)-2-me~hoxyimino-acetamido]-3-cephem-4-carboxylic acid.
; I.R. v mU]ol : 3300, 1785, 1730, 1670 cm 1 : (6) 7-[2-(6-Aminopyridin-2-yl)-2-methoxyimino-acetamido]-3-~1,3,4-thiadiazol-2-yl)thiome~hyl 3-cephem-: 4-carboxylic acid (syn isomer).
I~R~ v NmUxol : 3400, 3230, 1780, 1670, 1622, 1590, 1550, 1050 cm ; (7) 7-~2-(S-Aminopyridin-2-yl)-2-methoxyimino-acetamido]-3-(5-aminomethyl-1,3,4-thiadiazol-2-yl)-thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. v maU]ol : 3500, 3400, 3230, 1770, 1670, 1620, 1040 cm ~8) 7-[2-(6-Aminopyridin-2-yl)-2-methoxyimino acetamido]-3-(1-carboxymethyl-lH-tetrazol-5-yl)-: thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. v NmaUxol : 3380, 3220, 1780, 1670, 1620, 1050 cm ~9) 7-[2-(6-Aminopyridin-2-yl)acetamido]-3-~1-methyl-lH-tetrazol-5-yl~hiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I R. v ~Uxol : 3600-3080, 1763, 1698, 1663 cm 1 ~10) 7-[2-~6-Aminopyridin-2-yl)-2-methoxyimino-acetamiao]-3-chloro-3-cephem-4-carboxylic acid hydrochloride (syn isomer).
I.R. v mUxol : 3300-310Q, 1780, 1710, 1660, 1610, 1540, 1370 cm ~11) 7-[2-~6-Aminopyridin-2-yl)-2-methoxyimino-acetamido]-3-methoxy-3-cephem-4-carboxylic acid.
I.R. v ma]l : 3300, 1775, 1700-1650, 1045 cm 1 z~

~12) 7-[2-t 6-Aminopyridin-2-yl)-2-methoxyimino-acetamido]-7-methoxy-3-~1-methyl-lH-tetrazol-5-yl)-thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. v NmUxol : 3300, 1780, 1700, 1680 cm 1 (13) 7-[2-~6-Aminopyridin-2-yl~-2-methoxyimino-acetamido]-2-methyl-3-cephem-4-carboxylic acid (syn iscmer).
: I.R. v mUaxol : 3400-3100, 1780, 1730, 1665, 1550, 1295, 1258, 1050 cm (14) 7-[2-(6-Aminopyridin-2-yl)-2-methoxyimino-acetamido]-3-methyl-3-cephem-4-carboxylic acid : hydrochloride (syn isomer).
: I.R. v NmU~ol : 31003 1780, 1682, 1668, ; 1260, 1050 cm ~15) 7-[2-(6-Aminopyridin-2-yl)-2-hyd~oxyimino-: 15 acetamido]-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid tsyn lsomer).
I.R. v NUxol : 3300, 1760, 1680 cm 1 (16) 7-~2-(6-Aminopyridin-2-yl)-2-methoxyimino-` acetamido]-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. v mUa]ol : 3400, 1780, 1720, 1670 cm 1 ~17) 7-[2-~2-Aminopyrimidin-4-yl)-2-methoxyimino-acetamido]-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid.
: 25 I.R. v NUaxol : 3440, 3320, 1790, 1693, 1660, 1630, 1525, 1043 cm (18) 7-[Z-(6-Aminopyridîn-2-yl)-2-ethoxyimino-acetamido]-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomerj.
I.R. v NUaxol : 3380, 3240, 1780, 1670 cm 1 ~19) 7-[2-~6-Aminopyridin-2-yl~-2-me~hoxyimino-acetamido]cephalosporanic acid (syn isomer).
I.R. v NmaU~ol : 3350-3220~ 1780, 1740, 1680-1555, 1380, 1040 cm (20) 7-[2-~4-Aminopyrimidin-2-yl)-2-.

: :
.

methoxyiminoacetamido]-3-(1-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (a mixture of syn and anti isomer).
I.R. v NmUaxol : 3380, 32Z0, 1780, 1700-1620, 1240, 1040 cm 1 (21) 7-[2-Allyloxyimino-2-(6-aminopyridin-2-yl)-acetamido]-3-(1-methyl-lH-tetrazol-S-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer).
I.R. v NmauiXol : 3380, 3310, 1780, 1670, 1620 cm 1 (22) 7-[2-~6-Aminopyridin-2-yl)-2-propargyloxy-iminoacetamido]-3-~1-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer).
I.R. v Nmaxl : 3270, 1765, 1690, 1665, 1620, 1580, 1530 cm 1 (23) 7-[2-~2-Amino-6-chloropyrimidin-4-yl)-2-me~hoxy-iminoacetamido]-3-(1-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid hydrochloride.
I.R. v mUaxol : 3300-3100, 1785, 1660, 1390, 1050 cm (24) 7-[2-(4-Aminopyridin-2-yl)-2-methoxyimino-acetamido]-3-(1-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer~.
I.R. v NUxol : 3400, 3230, 1778, 1650, 1600 1380, 1050 cm 1 (25) 7-[2-(6-Aminopyridin-2-yl)-2-propoxyimino-acetamido]-3-(l-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer).
I.R. v ~maxol : 3400) 3250~ 1780, 1670, 1625, 15gO, 1550 cm~l (26) 7-~2-(6-Aminopyridin-2-yl)-2-isopropoxyimino-acetamido~-3-(1-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer).
I.R. v NUaxol : 3380, 3Z40, 1780, 1670, 1620 cm 1 (27) 7-[2-(6-Aminopyridin-2-yl)-2-isobutoxyimino-acetamido]-3-(l-methyl-lH-tetrazol-5-ylthiomethyl)-3-, cephem-4-carboxylic acid ~syn isomer~.
I.R. v Nm~axl : 33709 3220, 178U, 1670, 16Z0 cm 1 (~8) 7-[Z-~2-Aminopyridin-4-yl)-2-methoxyimino-acetamido]-3-~1-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid ~syn isomer).
I.R. v NmUxol : 3200, 1775, 1670, 1600, 1560 cm 1 ~29) 7-[2-(6-Aminopyridin-2-yl)-2-ethoxyimino-acetamido~-2-methyl-3-cephem-4-carboxylic acid ~syn lsomer) .
I.R. v NmUJol : 3350, 3150, 1795, 1730, 1670 cm 1 (30) 7-[2-(6-Aminopyridin-2-yl)-2-propoxyimino-acetamido~-2-methyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. v NmUxol : 3340~ 3150, 1780, 1735, 1670 cm 1 (31) 7-[~-(6-Aminopyridin-2-yl)-2-isopropoxyimino-acetamidol-2-methyl-3-cephem-4-carboxylic acid ~syn isomer).
I.R. v maUxol : 3350, 3150; 1795, 1735, 1670 cm l (32) 7-[2-~6-Aminopyridin-2-yl)-2-butoxyimino-acetamido]-3-(1-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer).
I.R. v NmUxol : 3350, 3200, 1775, 1670, 1620, 1585, 1540 cm ~33) 7-~2-(6-Aminopyridin-2-yl)-2 butoxyimino-acetamido]-2-methyl-3-cephem-4-carboxylic acid (syn ; isomer3.
I.R. v NmUxol : 3400, 3120, 1785, 1660 cm 1 (34) 7-[2-~6-Aminopyridin-2-yl)-Z-isobutoxyimino-acetamidol-2-methyl-3-cephem-4-carboxylic acid ~syn isomer).
I~R. v mUJol : 3300, 1785~ 1735, 1660 cm 1 ~35) 7-~2-Allyloxyimino-2-(6-aminopyridin-2-yl)-acetamido]-2-methyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. v NmaUxol : 3350, 3150, 1795, 1735, 1670 cm 1 ' .; , , ~ ~ Z~ ~ ~ 3 (36) 7-[2-~6-Aminopyridin-2-yl)-2-propargyloxy-iminoacetamido]-2-methyl-3-cephem-4-carboxylic acid (syn isomer~.
I.R. v mUxol : 3350, 1780, 1670 cm 1 (37) 7-[2-(6-Aminopyridin-2-yl)-2-(2,2,2-trifluoro-ethoxyimino~acetamido]-3-~1-methyl-lH-tetrazol-5-ylthio-methyl)-3-cephem-4-carboxylic acid ~syn isomer).
I.R. v mUxol : 3400, 1780, 1690 cm 1 (38) 7-[2-(6-Aminopyridin-2-yl)-2-phenoxyimino-acetamido]-2~methyl-3-cephem-4-carboxylic acid (syn isomer~.
I.R. v mUxol : 3200, 17609 1690, 1670 cm 1 (39) 7-[2-(6-Aminopyridin-3-yl)-2-methoxyimino-acetamido]-3~ methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer).
I.R. v maxl : 3380, 3220, 1780, 1680, 1630, ; 1590, 1550 cm (40) 7-[2-(6-Aminopyridin-3-yl)-2-methoxyimino-acetamido]-3-(1-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (anti isomer).
I.R. v mUaxol : 3350, 3200, 1780, 1680, 1630, 1520 cm (41) 7-[2-(6-Amino-3-chloropyridin-Z-yl)-2-methoxy-iminoacetamido]-3-(1-methyl-lH-te~razol-5-ylthiomethyl)-~ 3-cephem-4-carboxylic acid hydrochloride (syn isomer).
I R. v NmUxol : 3350-3100j 1790, 1670, 1550, 1380, 1235 7 1040 cm (42) 7-[2-(6-Amino-3,5-dichloropyridin-2-yl)-2-methoxyiminoacetamido]-3-(1-methyl-lH-tetrazol-5-yl-thiomethyl)-3-cephem-4-carboxylic acid (syn isomer~.
I.R. v mUaxol : 3300, 1785, 1730, 1660, 1545, 1380, 1235, 1045 cm (43) 7-[2-(4-Aminopyrimidin-2-yl)-2-methoxyimino-acetamido]-3-(1,3,4-thiadiazol-2-yl~hiomethyl~-3-cephem-4-carboxylic acid (syn isomer), mp. 164-171C
(dec.).

: . . ' ~ -:
, ~44) 7-[2-(4-Aminopyrimidin-2-yl)-2-methoxyimino-acetamido]-3-~5-methyl-1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer), mp. 161-167C
(dec.).
~45) 7-[~-~4-Aminopyrimidin-2-yl)-2-methoxyimino-acetamido]cephalosporanic acid ~syn isomer), mp. 149-159C ~dec.).

: ~ :

Example 5 (1) A solution of 7-[2-~-formamidopyridin-2-yl)-2-methoxyiminoacetamido]cephalosporanic acid (syn isomer) (2.10 g.) and disodium 2-(5-sulfido-lH-tetrazol-l-yl)acetate ~2.70 g) in water ~40 ml.) was adjusted to pH 7 with sodium bicarbonate, and stirred at 65C for 6 hours at p~ 7 to 7.4. The resultant solution was washad with ethyl acetate, adjusted to pH 2.5 with 10% hydrochloric acid and stirred. The precipitates were collected by fil-tration, washed with water and diethyl ether in turnto give 7-[2-~formamidopyridin-2-yl)-Z-methoxyimino-acetamido]-3-(1-carboxymethyl-lH-tetrazol-5-yl)-thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (1.27 g.), mp. 166 to 168C (dec.).
IoR~ v Naxl : 3300, 1782, 1737, 1670 (broad), 1577, 1247, 1053 cm N.M.R. ~ppm (DMS0-d6) : 3.60, 3.72 (2H, AB-q, J-18Hz), 3.92 (3H, s), 4.23, 4.45 (2H, AB-q, J=13Hz), 5.12 (lH, d, J=SHz), 5.28 (2H, s)~ 5.83 (lH, dd, J=SHz, 8Hz), 6.88 (lH, broad d, J=8Hz), 7.50 ~lH, d9 J=8Hz), 7.83 (lH, t, J=8Hz), 9.32 (lH~ broad d, J-8Hz), 9.55 (lH, broad d, J=8Hz) 9 lO.S - 10.8 (lH, m).

The following compounds were prepared in sub-stantially the same manner as that of Example 5-(1~.
(2) 7-[2-(6-Aminopyridin-2-yl)-2-methoxyimino-acetamido]-3-~1-methyl-lH-tetrazol-S-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. vmUaxl : 3360, 3220, 1780, 1670, 1620, 1585, 1544, 1042 cm (3) 7-[2-~6-Aminopyridin-2-yl)-2-:' ~ . .

.~3 methoxyiminoacetamido]-3-~1,3,4-thiadiazol~2-yl)-thiomethyl-3-cephem-4-carboxylic acid (syn isomer~.

I.R. v maxl : 3400, 3230, 1780, 1670, 1622, S 1590, 1550~ 1050 cm (4) 7-[2-~6-Aminopyridin-2-yl)-2-methoxyimino-acetamido]-3-(5-aminomethyl-1,3,4-thiadiazol-2-yl)-thiomethyl-3-c0phem-4~carboxylic acid (syn isomer).
I R v NUJol 3500, 3400, 3230, 1770, 1670, 1620, 1040 cm .
~5) 7-[2-~6-Aminopyridin-2-yl)-2-methoxyimino-lS acetamido]-3-(1-carboxymethyl-lH-tetrazol-5-yl)-thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

I.R. v maUxol : 3380, 3220, 1780, 1670J 1620, : 1050 cm ~6) 7-[2-(6-Aminopyridin-2-yl)acetamido]-3-(l-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

I.R. v NU]ol : 3600-3080, 1763, 16989 1663 cm 1 (7) 7-E2-~6-Aminopyridin-2-yl~-2-me~hoxyimino-ace~amido]-7-methoxy-3~ methyl-lH~tetrazol-5-yl)thio methyl-3-cephem-4-carboxylic acid (syn isomer) I.R. v Nlu~ol 3300~ 1780, 170U,1680 cm ~8) 7-[2-(6-Aminopyridin-2-yl)-2-hydroxyimino-acetamido]-3~ methyl-lH-tetrazol-S-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
: 35 . . , : ;
.. :

I.R. v mUJol : 3300, 1760, 1680 cm 1 ~9) 7-[2-~2-Aminopyrimidin-4-yl)-2-methoxyiminoacetamido]-3-~1-methyl-lH-tetrazol-5-yl)-thiomethyl-3-cephem-4 carboxylic acid.

I R v NU]ol : 3440, 3320, 1790~ 1693, 1660, 1630, 1525, 1043 cm~
~10) 7-[2-(6-Aminopyridin-2-yl~2;~thoxyimino-acetamido]-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid tsyn isomer).

I.R. v maJl : 3380, 3240~ 1780, 1670 cm 1 7 [2-~4-Aminopyrimidin-2-yl)-2-methoxyimino-acetamido]-3-~1-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid ~a mixture of syn and anti isomer).

I.R. v ma~l : 3380, 3220, 1780, 1700-1620, 1240 ,1043 cm 1 (12) 7-[2-~Allyloxyimino-2-(6-aminopyridin-2-yl)-acetamido]-3-~1-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid ~syn isomer).

I.R. v NUxol : 3380, 3310, 1780, 1670, 1620 cm 1 (1 3) 7 - L2 - (6-Aminopyridin-2-yl)-2-propargyloxyimino acetamido]-3-~1-me~hyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer).
I R. v NmUJol 3270, 1765, 1690, 1665, 1620, _. _.

:~ .... . ~ .

z~

(14) 7-[2-~2-~mino-6-chloropyri~idin-4-yl)-2-methoxyiminoacetamido]-3-~1-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid hydrochloride.

I R. v mUJol : 3300-3100, 1785, 1660, 1390, 1050 cm~l ~15) 7-[2-~4-Aminopyridin-2-yl)-2-methoxymino-acetamido]-3-~1-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxyllc acid (syn isomer).

I.R. v mUxol : 3400, 3230, 1778, 1650, 1600, 1380, I050 cm 1 ~16) 7-[2-(6-Aminopyridin-2-yl)-2-propoxyi*.ino-acetamido]~ l-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid ~syn isomer).

I.R. v NmUxol : 3400, 3250, 1780, 1670, 1625, ~ 20 1590, 1550 cm ; (17) 7-~2-~6-Aminopyridin-2-yl)-2-isopropoxyimino-acetamido]-3-~1-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acld ~syn isomer).
I.R. v mUJol : 3380, 3240, 1780, 1670, 1620 cm 1 (18) 7-[2-(6-Aminopyridin-2-yl~-2-isobutoxyimino-acetamido]-3-~1-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer).

I.R. v Nmaxl : 3370, 3220, 1780, 1670, 1620 cm 1 (19) 7-[2-t2-Aminopyridin-4-yl)-2-methoxyimino-acetamido]-3-(1-methyl-lH-tetrazol-S-ylthiomethyl)-71~ :
~; :"

. ~, - . ~ . . .. . . . .
...

.. . . .. ... .. . . ..
. ` . . .. . . . . - .
. . . .. , . ` . ~, `. ~ . , ` . . .. ..

~ 3 3-cephem-4-carboxylic acid ~syn isomer).

I.R. v mUaJol : 3200, 1775, 1670, 1600~ 1560 cm 1 ~20) 7-[2-(6-Aminopyridin-2-yl)-2-butoxyimino-acetamido]-3-(1-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer~.

I.R. v NaUxol : 3350, 3200, 1775, 16709 1620, 1585, 1540 cm 1 (21) 7-[2-(6-Aminopyridin-2-yl)-2-(2,2,2-trifluoro-ethoxyimino)acetamido3-3-(1-methyl-lH-tetrazol-5-ylthio-methyl)-3-cephem-4-carboxylic acid (syn isomer).
I .R . v Nmllxol : 3400, 1780, 1690 cm 1 (22) 7-[2-(6-Aminopyridin-3-yl)-2-methoxyimino-acetamido]-3-(1-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer).

I.R. v maJl : 3380, 3220, 1780, 16~0~ 1630, 1590, 1550 cm~

(23) 7- ~2-(6-Aminopyridin-3-yl) -2-methoxyimino-acetamido]-3-~1-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid tanti isomer).

I.R. v mU~ol : 3350~ 3200, 1780, 1680, 1630, 1520 cm 1 (2~) 7-[2-(6-Amino-3-chloropyridin-2-yl)-2-methoxy-iminoacetamido]-3-(1-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid hydrochloride ~syn isomer).

_ _ 7~

; , . i .
..... ~ .
. .

~v~

I.R. v mU~ol : 3350-3100, 1790, 1670, 1550, 1380, 1235, 1040 cm (25) 7-L2-(6-Amino-3,5-dichloropyridin-2-yl)-2-methoxyiminoacetamido]- 3- (l-methyl-lH-tetrazol-- 5-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer).

I.R. v Nmaxl : 3300, 1785, 1730, 1660J
1545 7 1380 7 1235, 1045 cm 1 ~263 7- [2-(4-Aminopyrilllidin-2 yl)-2-me~hoxyimino-acetamido~-3-(1,3~4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer) J mp 164 -171C ~dec.~.

~2 7) 7-L2-~4-Aminopyrimidin-2-yl)-2-methoxyimino-acetamido]- 3- (5 -methyl-l, 3, 4-thiadiazol-2-ylthio-methyl)-3-cephem-4-carboxylic acid (syn isomer), mp 161-167C ~dec.).

'~1 ~, ~, . . , , . , :

:. : : : .
.
: ~ . .

:

Example 6 To phosphoryl chloride (2.6 g~) was added N~N-dimethylformamide ~4 ml.) and the mixture was stirred at 40 to 50C for 30 minutes, and then methylene chloride ~20 ml.) was added thereto. To this mixture was added 2-(4-formamidopyrimidin-2-yl)-2-methoxyiminoacetic acid tl.9 g.) under cooling at -20 to -15C with stirring~ and the stirring was continued at the same temperature for ~ 30 minutes.
On the other hand, 7-amino-3-~1 methyl-lH-tstrazol-5-ylthiomethyl~-3-cephem-4-carboxylic acid and trimethyl-silylacetamide ~11 g.) were added to methylene chloride (66 ml.) and the mix~ure was stirred at ambient temperature for an hour, and to this solution was added all at once the above activated solution of 2-~4-formamidopyrimidin-2-yl)-2 methoxyiminoacetic acid under cooling at ~20c with stirring, and the stirring was continued at the same temperature for an hour and at ambient temperature for additional an hour.
The reaction mixture was concentrated under reduced pressure and then ethyl acetate and an aqueous solution of sodium bicarbonate were added to a~just the solution ~o pH 7 to 8.
After the aqueous layer was separated out, a proper quantity of ethyl acetate was added thereto. The mixture was adjusted to pH 1 to 2 with dilute hydrochloric acid and then salted out. The ethyl acetate layer was separated out, washed with an aqueous solution of sodium chloride and dried over magnesium sulfate, and then evaporated to dryness under reduced pressure. The resultant foamy substance was pulverized in ethyl ether, collected by filtration and then dried to give 7-[2-(4-formamidopyrimidin-'~ 3 .

9~3 2-yl)-2-methoxyiminoacetamido]-3~ methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid ~2.9 ~g.). Thus obtained produc~ ~0.6 g.) was dissolved in a mixed solution of methanol and ethyl acetate (5 ml.)~2:1 by volume), and the solution was poured into ethyl ether (40 ml.) and then ~he mixture was allowed to stand for a while. The precipitates were collected by filtration to give purified pale-yellowish powder o~ 7-L2-(4-ormamidopyrimidin-2-yl)-2-methoxyiminoacetamido~-3 (1-methyl-lH-tetrazol-5-ylthio-methyl)-3-cephem-4-carboxylic acid (a mixture of syn and anti isomers) (0.5 g.).
I.R. ~ NaU3ol 3300, 1785, 1650-1730, 1570, 1240, 1175, 1040, 720 cm 1 N.M.R. ~ppm (DMSO-d6): 3.70 (2H, m) 3.g2 (3~, s) 3.92 (s) } (3~) 3.g9 (s) 4.20 and 4.30 ~2H, ABq, J=15Hz) 5.05 (d, J=5Hz) } (lH) 5.15 (d, J=5Hz) 5.60 (m) } (lH) 5.80 (d,d, J=5Hz, 9Hz) 6.90-7.60 (lH, m) 8.61 (lH, d, J=5Hz) 8.76 (d, J=9Hz) } (lH) 9.51 (d, J=9Hz~
11.10 (lH, broad s) To phosphoryl chloride (1.6 g.) was added i~,N-dimethylformamide (8 ml.) and the mixture was s tirred at .
~.- -,- . ` , .
.~ .
s ~ ` ~
~ .

~ L2~9~

40C for 30 minutes. To this mixture was added a solution of 2-allyloxylmino-2-(6-formamidopyridin-2-yl)acetic acid ~syn isomer) (2.0 g.~ in N~N-dimethylformamide (8 ml.) under cooling at -15QC with stirring and the stirring was S continued at -10 to -8C for an hour.
On the other hand, 7-amino-3-(1-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (3.2 g.) and trimethylsilylacetamide (11.5 g.) were added to methylene chloride (35 ml.), and the mixture was stirred at 30C
till it became a solution and then cooled to -i5C.
To this solution was added the above obtained .:
N,N-dimethylformamide solution under cooling at -15C with stirring, and the stirring was continued at the same temperature for an hour. After the reaction mixture was poured into an aqueous solution ~80 ml.) of sodium bicarbonate (3.2 g.), the aqueous layer was separated out?
washed with ethyl acetate. To the aqueous solution was ~added ethyl acetate and the mixture was adjusted to pH 3 to 4 with 5~ hydrochloric acid. The ethyl acetate layer was separated out and the remaining aqueous solution was extracted twice with ethyl acetate. The ethyl acetate solution and these extracts were combined together, `
dried and then evaporated to dryness under reduced pressure.
The residue was crystallized from water, collected by filtration and then dried to give 7-[2-alIyloxyimino-2-~6-formamidopyridin-2-yl)acetamido]-3-~1-methyl-lH-~; tetrazol-S-ylthiomethyl)-3-cephem-4-carboxylic acid ~syn isomer) (1.81 g.~, mp. 132 - 135C (dec.) I.R. v NmaJl : 3300, 1785, 1670, 1580, 1545 cm 1 ; 30 N.~.R. ~ ppm [acetone-d6 and D2O]: 3.83 (2H, broad s) ,7 ~

4.00 (3H, s~, 4.43 ~2H9 broad s), ; 4.70-4.87 (2H, m), 5.27 ~lH, d, J=5Hz), 5.13-5.60 ~2H, m), 5.83-6.27 (2H, m), 7.00-8.00(3H~ m) Example 8-(1) To phosphoryl chloride ~1.6:L g.) was added N,N-dimethylformamide t8 ml.~ and the m;xture was stirred at 40C for 30 minutes. To this mixture was added a solution of 2-~6-formamidopyridin-2-yl)-2-propargyloxyiminoacetic acid (syn isomer) ~2.0 g.) in N,N-dlmethylformamide (8 ml.) under cooling at -15C with stirring, and the stirring was continued at -10 to -8C for 40 minutes.
On the other hand, 7-amino-3-(1-methyl-lH-tetrazol-S-ylthiomethyl)-3-cephem-4-carboxylic acid lS (3.25 g.) and trimethylsilylacetamide (10.5 g.) were added to methy~ene chloride (40 ml.), and the mixture was stirred at 30C till it became a solution.
To the solution was added the above obtained N,N-dimethylformaide mixture under cooling at -15C with stirring, and the stirring was continued at the same temperature for an hour. After the reaction mixture was poured into an aqueous solution (~0 ml.~ of sodium bicarbonate (4.0 g.); the aqueous layer was separated out.
The remaining methylene chloride solution was extracted with an aqueous solution of sodium bicarbonate. Thus obtained aqueous layer and extract were cc,mbined together, and adjusted to pH 2 with 10% hydrochloric acid and then ~ extracted with ethyl acetate. The extract was washed ; with water9 dried and then e.vaporated to dryness ~mder reduced pressure. The residue was puiverizcd in water, :

collected by filtration and then dried to give 7-[2-(6-~ormamidopyridin-2-yl~-2-propargyloxyiminoacetamidol-3-(1-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem 4-carboxylic acid (syn isomer) ~2.41 g.~, mp. 123 - 125C (dec.) I.R. v NmaUJol : 3300, 1780, 1670, 1575, 1540 cm 1 N.M.R. ~ ppm (acetone-d~ and D2O) 3.07 (lH, t, J-2Hz!, 3.83 ~2~1, s)j 4.00 (3~, s), 4.43 ~2H, s), 4.87 t2H, d, J-2Hz), 5.27 ~lH, d, J=5Hz), 6.07 (lH, d, J=5Hz), 7.00-8.07 ~3H, m) ; The following compounds were obtained according to similar manners to those of Examples ~ to 8-(1).
(2) 7-[2-(2-Formamidopyridin-4-yl)-2-methoxy-iminoacetamido]-3-(1-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid ~syn isomer), mp. 138-140C (dec.).
I.R. v Nmaxl : 3250, 1780, 1680~ 1610, 1550 cm 1 N.M.R. ~ ppm (DMSO-d6) : 3.73 (2H, broad s), 3.97 (3H, s), 4.03 (3H, s), 4.40 (2H, broad s), 5.23 ~lH, d, J=5Hz), 5.90 (lH, d,d, J=5Hz, 81-lz), ~ 7.13-8.53 (3H, m), 9.87 (lH, d, J=8Hz), ; ~ 10 73 ~lH, d, J=6Hz) ; ~3) 7-~2-~4-Formamidopyridin-2-yl)-2-methoxy-iminoacetamido]-3-~1-methyl-lH-tetrazol-5-ylthiomethyl~-3-cephem-4-carboxylic acid (syn isomer), mp. 160-166C ~dec.).
I R v Nujol: 3300, 1780, 1690, 1590, 1520, 1380, 1040 cm N.M.R. ~ ppm ~DMSO-d6) : 3.70 ~2H, m), 3.95 (6H, s), 4.32 ~2H, broad s), 5.15 ~lH, d, J=4.5 Hz) 5.85 ~lH, d,d, J=4.5 Hz, 8.0 Hz), - : .
; ~:

8.10-8.50 (4H, m), 9.52 (lH, d, J=8Hz) (4) 7~ ~2-(6-Chloro-2- Eormamidopyrimidin-4-yl)-2-methoxyiminoacetamido]-3~ methyl-lH-tetrazol-5-ylthio-methyl)-3-cephem-4-carboxylic acid tsyn and anti mixture).
5I.R. v NmaU~ol: 3200-3300, ~780, 1700, 1680, 1550, 1380) 1040 cm 1 N.M.R. ~ ppm (DMSO-d6): 3.75 (2H, m~
3.98 (3H, s) 4.01 (3H, s) lO4.35 (2H, m) 5.20 (lH, d, J=4.5Hz~
S.90 ~lH, m) 6.80 (s) } ~lH) 6-90 (s3 9.41 ~d, J=8Hz) } ~lH) 9.69 (d, J=8Hz) ` 9.45 ~lH, d, J=lOHz) 11.05 (d, J=lOHz) } (lH) 11.43 (d9 J=lOHz) (5) 7- [2-(3-Chloro-6-formamidopyridin-2-yl)-2-methoxyiminoacetamido]-3-(1-methyl-lH-tetrazol-5-ylthio-. ~ - methyl~-3-cephem-4-carboxylic acid ~syn isomer~, mp.
~ 165-172~C (dec.).
-~ I.R. V NU~Q1: 3300, 1790, 1710, 1670~ 1645, 1370, 1270, 1050, 725 cm 1 N.M.R. ô ppm (DMSO-d6) : 3.68 ~2H, m), 3.94 (3H, s), 3.98 (3H, s), 4.20, 4.38 t2H, ABq, J=14Hz), 5.14 (lH, d, J=4.5Hz), 5.82 (lH, d,d, J=4.5Hz, 8Hz), 6.90(lH, m), 7.94 (lH,d, J=8Hz), : ~ 8 " :`~

.
.. . :
-. . . ' ~ ~

~3~3~

9.22 (lH, m), 9.52 ~lH, d, J=8Hz), 10.72 (lHJ d, J=8Hz) ~6) 7-[2-~3,5-Dichloro-6-formamidopyridin-2-yl)-2-methoxyiminoacetamido]-3-(1-methyl-lH-tetrazol-5-ylthio-methyl)-3-cephem-4-carboxylic acid ~syn isomer), mp. 149-155C (dec.)~
I.R. v NUxol : 3250, 1785, 1705, 1688, 1665, 1420, 1255, 1200, 1073J 1050 cm 1 N.M.R. ~ ppm tDMSO-d6~ : 3.70 (2H, m), 3.95 (3H, s), 4.01 ~3H, s), 4.33 (2H, broad s), 5.17 (lH, d, J=4.5Hz), 5.87 (lH, d,d, J=4.5Hz, 8Hz), 8.31 (lH, s), 9.18 ~lH, d, J-8Hz), 9.57 ~lH, d, ` J=8Hz), 10.65 (lH, d, J=8Hz) (7) 7-[2-Ethoxyimino-2-(6-formamidopyridin-2-yl)-acetamido]-2-methyl-3-cephem-4-carboxylic acid ~syn isomer) J
mp. 183-186C ~dec.).
I.R. v NmUjxol : 3350, 3300, 1790, 1730~ 1670 cm 1 N.M.R. ~ ppm ~DMSO-d6~ : 1.25 (3H, t, J=7Hz), 1.40 (3~1, d, J=7Hz), 3.75 (lH, m), 4.15 ~2H, q~ J=7Hz~, 5.10 tlH, d, J=4Hz), 5.90 (lH, d,d, J=8Hz, 4Hz), 6.50 ~1~l, d, J=6Hz), 6.70-8.20 ~3H, m) (8) 7-[2-t6-Formamidopyridin-2-yl)-2-propoxyimino-acetamido]-3-~1-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid ~syn isomer).
I.R. v NmaU~ol : 3300, 1785, 1680, 1580, 1550 cm 1 N.M.R. ~ ppm ~acetone-.d6 and D2O) : 0.96 (3H, t, J=7Hz~, 1.64-1.84 ~2H, m), 3.72, 3.82 (2H, AB~, J-18Hz), '~

:
" ' ~ .;

3.96 t3H, s), 4.16 (2H, t, J=7Hz), 4.40 ~2H, broad s}, 5.20 (lH, d, J=5Hz), 6.00 (l}lp d, J=5Hz), 6~88-8.20 (3H, m) (9) 7- [2-Isopropoxyimino-2- (6-ormamidopyridi.n-2-yl)acetamido~-3- (1-methyl-lH-tetlazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer).
I.R. v NmUxol : 3300, 178S, 1680, 1580, 1540 cm 1 N.M.R. ~ ppm ~acetone-d6 and D2O) : 1.32 (6H, d, J=6Hz), 3.76, 3.88 (2H, ABq~ J=18Hz), 3.98 ~3H, s), 4.40 (2H, broad s), 4.36-4.64 ~lH, m), 5.24 tlH, d, J-5Hz), 6.04 (lH, d, J=5Hz), 6.92-8~20 (3H, m) ` lS ~ 7-[2-(6-Formamidopyridin-2-yl)-2-propoxyimino-; acetamido]-2-methyl-3-cephem-4-carboxylic acid (syn isomer~, mp. 145-150C (dec.).
I.R. v ma3l : 3300, 179Q, 1680 cm 1 N.M.R. ~ ppm (DMSO-d6) : 0.95 ~3H, t, J=8Hz), ~ 1.45 ~3H, d, J=7Hz), 1.40-1.90 (2H, m), 3.83 ~lH, m), 4.17 ~2H, t, J-6Hz), 5.17 ~lH, d, J=4Hz), 6.00 ~lH, d,dp J=4Hz, 8Hz)~
6.58 ~lH, d, J=6Hz), 6.80-8.20 ~3H, m~
~11) 7-~2-Isopropoxyimino-2-t6-formamiaopyridin-2-yl)-acetamido]-2-methyl-3-cephem-4-carboxylic acid ~syn isomer), mp 160-163C.
I.R v maU~ol : 3300, 1790~ 1735, 1670 cm 1 N.M.R. ~ ppm (DMSO-d6) : 1.30 (6H, d, J=6Hz), 1.45 ~3}1, d, J=7Hz), 3.80 (lH, m), .~

. ' ' , ~ ~

4.45 (lH, m) J 5.15 (lH9 d, J=4Hz), 6.00 (lH, d,d, J=4Hz, 8Hz~ 9 6.58 ~lH~ d, J=6Hz), 6.80-8.20 (3H3 m)
(12) 7- [2-Butoxyimino- 2-~6-formamidopyridin-2-yl)-acetamido]-3- tl-methyl-lH-te'crazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer), mp. 153-155C (dec.).
I.R. ~ mUJol : 3300, 1785, 1670, 1580, 1550 cm l N.M.R. ~ ppm (acetone-d6 and D20) : 0.80-1.07 ~3H, m), 1.23-1.83 (4H, m)~ 3.83 (2H, broad s), 10 - 3.97 (3H, s), 4.23 (2H, t, J=6Hz~, 4.43 ~2H, broad s)~ 5.27 ~lH, d, J=5Hz~ 7 6~10 ~lHp d; J=5Hz), 6.97-8.00 (3H, m) ~13) 7 ~2-t6-Formamidopyri~in-2-yl)-2-isobutoxyimino-acetamido]-3-(1-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid ~syn isomer), mp. 118-120C ~dec.).
I.R. ~ NaUJol : 3500, 3300, 1785, 1680~ 1580~ 1550 cm 1 ; N.M.R. 8 ppm ~DMSO-d6) : O.g3 ~6H, d, J=6Hz~, 1.77-2.17 ~lHp m), 3.70 ~2H, broad s), .20 3.93 (3H, s), 4.00 t2Hp d, Js6Hz), 4.33 ~2H, broad s), 5~18 ~lH, d, J-5Hz), ~ .
; 5.90 (lH, d,d, J=5Hz, 9Hz), ~ 6O83-8~00 (3Hp m~
.
(14) 7-[2-Butoxyimino-2-~6-formamidopyridin-2-yl)-acetamido]-2-methyl-3-cephem-4-carboxylic acid ~syn isomer), mp.155-160C (dec.).
I.R. v maJl : 3300, 1790, 1680 cm 1 N.M.R. 8 ppm (DMSO-d6) : 0~83-1~83 (lOH, m), 3~67-4~00 ~lH, m~, 4.27 ~3H, t, J=4Hz~, 5.22 (lH, d, J-4Hz), 6.03 ~lH, d,d, ~ J-4Hz, 8Hz), ~ 8 ~ :
. . .

6.62 ~lH, d, J=6Hz), 7.00-8.50 (3H, m) ~ 15) 7-[2-(6-Formamidopyridin-2-yl~-2-isobutoxy-iminoacetamido.]-2-methyl-3-cephem-4-carboxylic acid (syn isomer), mp. 152-154C ~dec.).
v Nu~ol 3300, 1790, 1675 cm N.M.R. 8 ppm ~DMSO-d6) : 0.90 ~6H, d, J=6Hz), 1.42 (3H, d, J=6Hz), 2.00 (lH, m), 3.80 ~lH" m), 3.90 ~2H, d, J-6Hz), 5.10 ~lH, d, J=4Hz) 9 5.95 (lH, d,d, J=4Hz, 8Hz) 3 6.50 (lH~ d, J=6Hz), 6.80-8.20 (3H, m) tl6) 7-[2-Allyloxyimino-2-~6-formamidopyridin-2-yl)-acetamido]-2-methyl-3-cephem-4-carboxylic acid (syn isomer) mp. 128-132C (dec.).
I.R. ~ maU]ol: 3300~ 1790, 1730, 1670 cm 1 N.M.R. ~ ppm (DMSO-d6~ : 1.45 (3H) d, J=7Hz), ;~ 3.85 (lH, m~, 4.70 (2H, d, J-SHz), 5.20 (lH, d, J=4Hz), S.20-S.S0 ~2H, m), 5.80-6.20 (lH, m), 6.00 ~lH, d,d9 J=4Hz, 8Hz), 6.S0 ~lH, d, J=6Hz~, 6.80-8.20 ~3H~ m) (1 7) 7-[2-(6-Formamidopyridin-2-yl)-2-propargyloxy-iminoacetamido~-2-methyl-3-cephem-4-carboxylic acid (syn isomer), mp. 134-137C (dec.).
I.R. v NaU~ol: 3300, 1790, 1730, 1670 cm 1 N.M.R. ~ ppm (DMS0-d6) : 1.45 (3H, d, J=7Hz), 3.50 (lH, t, J=2Hz), 3.80 (lH, m), 4.85 (2H, d, J=2Hz), 5.15 (lH, d, J=4Hz), 6.00 (lH9 d,d, J=4Hz9 8Hz), _ _ . ~ :

., 6.58 ~lH, d; J=6Hz), 6.80-8.20 (3H, m) (18) 7-[2-(2J2,2-Trifluoroetho~yimino)-2-(6-formamidopyridin-2-yl)acetamido]-3-~1-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer), mp. 165-170C (dec.).
I.R. v NUjxol : 3300, 1790, 1690 cm l N.M.R. ~ ppm ~DMS0-d6~ : 3.70 (2H, broad s), 3.93 C3H, s)~ 4.32 (2H, broad s), 4.70, 4.95 ~2H, ABqJ J=9Hz), 5.15 (lH, d, J=4Hz) 9 5.88 (lH, d,d, J=4Hz, 8Hz)~ 7.00-8.0G
(3H, m), 9.33 (lH, m), 9.67 (lH, d, J~8Hz), 10.60 (lH, m) ~19) 7-[2-~6-Formamidopyridin-2-yl)-2-phenoxyimino-acetamido]-2-methyl-3-cephem-4-carboxylic acid (syn isomer~
mp. 150-155C ~dec.).
I.R. v ma3l : 3250; 1780, 1720, 1650 cm 1 N.M.R~ ~ ppm ~DMSO-d6) : 1.50 ~3H, d, 3-7Hz), ~; 20 3.90 ~lH, m), 5.25 (lH, d, J=4Hz) 9 6~10 (lH, d,d, J=4Hz, 8Hz), 6.60 (lH, d, J=6Hz), 7.0-8.2 (8H3 m), 9.86 (lH, d, J=8Hz), lQ.73 (lH, d, J=8Hz) (20) 7-[2-(6-Formamidopyridin-3-yl)-2-methoxyimino-acetamido]-3-(1-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer).
I.R. v Najxl : 3250, 1780, 1680, 1250, 1175 1035 .cm 1 N.M,R. ~ ppm (DMSO-d6~ : 3.75 (2H, broad s~, : ` ~3 , . ~:

:

3.98 (6H1 s), 4.35 ~2H, broad s), 5.22 (lH, d, J=5Hz), 5.87 ~lH, d,d, J=SH2, 8Hz), 7.8-8.5 (3H, m), 9.83 (lH, d, J=8Hz), 10.87 (lH, d, J=7Hz) ~21) 7-~2-(6-Forma}nidopyridin-3-yl)-2-methoxyimino-acetamido~-3-(1-methyl-lH-tetrazol-5-ylthiomethyl3-3-cephem-4-çarboxylic acid (anti isomer).
I.R. ~ maU~ol: 3300~ 17~0, 1680-1710, 1600, 1240, 1050 cm 1 N.~.R. ~ ppm (DMS0-d6) : 3.74 (2H, broad s)~
3.9~ (3H, s), 4.00 (3H, s~
4.00, 4028 (2H, ABq, J=13Hæ), 5~1~ (lH, d, Ja5Hz), 5.72 (lH, IS d,d, J=5Hz, 8Hz~, 7.80-8.50 t3H, m) 9 9.28 (1~l, d, J=8Hz), 10.80 (lH~ d, J=6Hz~

Example 9 (l~ Phosphoryl chloride (500 mg~) was added dropwise to a suspension of 2-(4-aminopyrimidin-~-yl)-2-methoxyiminoacetic acid ~syn isomer) (250 mg.) in ethyl ~ acetate ~S ml.) at 0 to 6C with stirring and the stirring ; ~was continued at the same ~emperature for 45 minutes.
To this solution was added dropwise N,N-dimethylformamide ~0.7 ml.) over a period of 6 minutes at 0 to 6C with stirring, and the stirring was continued at the same temperature for 40 minutes. To the resultant solution was added all at once a solution of 7-amino-3-(1-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid ~3~5 mg.) and trimethylsilylacetamide ~1.5 g.) in ethyl :. ~
~, :

.

~ D~2 ~

acetate ~7 ml.) under cooling at -20C, and the mixture was stirred at 0 to 6C for an hour. The reaction mixture was poured into water ~20 ml.) and adjusted to pH 4 with an aqueous solution of sodium bicarbonate. The aqueous layer was separated ou~ and the remaining organic layer was extracted with water. The aqueous layers were combined together and the ethyl acetate remained in the aqueous solution was removed therefrom under reduced pressure. The aqueous solution was subjected to column chromatography on a non-ionic adsorption resin/ "Diaion HP 20" (Trade Mark, manu~actured by Mitsubishi Chemical Industry Ltd.) ~2Q ml.). After the column was washed with water, elution was carried out with 5-10% aqueous methanol ~100 ml.), 20~ aqueous methanol (150 ml.) and ; 15 20 to 30% aqueous methanol ~150 mlO) in turn, and the fractions containing the desired compound~ere collected and evaporated to dryness under reduced pressure. The ; resultant residue was lyophilizedto give 7-E2-(4-amino-pyrimidin-2-yl)-2~methoxyiminoacetamido]-3-tl-methyl-lH-tet~azol-5-ylthiomethyl)-3-cephem-4-carboxylic acid tSYn isomer) (110 mg.), mp. 155 to 158C.
I.R. v NuJol : 3380~ 3220, 1780, 1630-1690, 1590, 1040 3 840 cm 1 N.M.R. ~ ppm (DMSO-d6~ : 3.65 (2H9 m), 3.94 ~3H, s), 4.32 (2H, broad s), 5.11 ~lH, d, J-5Hz), 5.80 elH, d,d, J=5Hz, 8Hz), 6.44 ~lH, d, J=6Hz), 7.04 ~2H, broad s), 8.10 ~lH~ d, J=6Hz), 9.43 51H, d, J=8Hz) The ollowing compounds were obtained according _.

, .

to similar manner to that of Example 9-(l).
(2) 7-[2-Allyloxyimino-2-~6-aminopyridin-2-yl)-acetamido]-3-(1-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer), mp. 149-151C
~dec.).
~3) 7-[2-(6-Aminopyridin-2-yl)-2-propar~yloxy-iminoacetamido~-3-~1 methyl-lH-tstrazol-5~ylthiomethyl)-3-cephem-4-carboxylic acid tsyn isomer), mp. 163-165C
~dec.).
(4) 7-~2-~2-Aminopyridin-4-yl)-2-methoxyimino-acetamido]-3-(1-methyl-lH-~etrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer), mp. 175-177C
(dec.).
(5) 7-[2-~4-Aminopyridin-2-yl)-2-methoxyimino-acetamido]-3-(1-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer), mp. 163-167C
(dec.).
(6) 7-[2-(2-Amino-6-chloropyTimidin-4-yl)-2-methoxyiminoacetamido]-3-(1-methyl-lH-tetrazol-5-ylthio-methyl)-3-cephem-4-carboxylic acid hydrochloride, mp. 170-180C.
(73 7-[2-(6-Amino-3-chloropyridin-2-yl)-2-methoxyiminoacetamido]-3-(1-methyl-lH-tetrazol-5-ylthio-methyl)-3-cephem-4-carboxylic acid hydrochloride ~syn 2S isomer), mp. 155-160C (dec.).
(8) 7-[2-(6-Amino-3~5-dichloropyridin-2-yl)-2-methoxyiminoacetamido]-3-(1-me~hyl-1l~-tetrazol-5-ylthio-methyl)-3-cephem-4-carboxylic acid (syn isomer), mp.
139-144~C (dec.).
~9) 7-[2-(6-Aminopyridin-2-yl)-2-ethoxyiminoacetamido]-, . .~ .
' ~ 2~

2-methyl-3-cephem-4-carboxylic acid (syn isomer), mp.
190-195C (dec.).
(10) 7-~2-(6-Aminopyridin-2-yl)-2-propoxyimino-acetamido]-3~ methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic ac;d (syn isomer)j 138-140C (dec.).
~11) 7-[2-(6-Aminopyridin-2-yl)-2-isopropoxyimino-acetamidoJ-3-(1-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer), mp. 149 151C
(dec.).
(12) 7-[2-(6-Aminopyridin-2-yl)-2-propoxyimino-acetamidoJ-2-methyl-3-cephem-4-carboxylic acid (syn isomer), mp. 190-195C ~dec.).
(13) 7-[2-~6-Aminopyridin-2-yl)-2-isopropoxyimino-acetamidol-2-methyl-3-cephem-4-carboxylic acid (syn isomer) mp~ 185 188C (dec.). -~
(14) 7-[2-(6-Aminopyridin 2-yl)-2-butoxyiminoacetamido~-3-(1-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer), mp. 108-110C (dec~.
(15) 7-[2-(6-Aminopyridin-2-yl)-2-isobutoxyimino-; 20 acetamido]-3-(1-methyl-lH-tetrazol-5-yl~hiomethyl)-3-cephem-4-carboxylic acid ~syn isomer), mp~ 140-142C ~dec.).
(16) 7-[2-(6-Aminopyridin-2-yl)-2-butoxyiminoacetamido]-2-methyl-3-cephem-4-carboxylic acid (syn isomer), mp.
200-205C (dec.).
(17) 7-~2-(6-Aminopyridin-2-yl)-2-isobutoxyimino-acetamido]-2-methyl-3-cephem-4-carboxylic acid (syn isomer}, mp. 175-180C (dec.).
~18) 7-[2-Allyloxyimino-2-(6-aminopyrydin-2-yl)-acetamidoJ-2-methyl-3-cephem-4-carboxylic acid (syn isomer)~
mp. 168-173C ~dec.).
~7 .

~L~L~9~3 (19) 7-[2-~6-Aminopyridin-2-yl)-2-propargyloxy-iminoacetamido]-2-methyl-3-cephem-4-carboxylic acid (syn isomer), mp. 165-170C tdec.).
~20) 7-~2-~6-Am;nopyridin-2-yl)-2-(2,2,2-trifluoro-ethoxyiminoacetamido]-3-(1-methyl-lH-tetrazol-5 ylthio-methyl)-3-cephem-4-carboxylic acid ~syn isomer), mp.
165-170C ~dec.).
; ~21) 7-~2-~6-Aminopyridi.n-2-yl)-2-phenoxyimino-acetamido]-2-methyl-3-cephem-4-carboxylic acid ~syn isomer), mp. 145-147C ~dec.).
t22) 7-[2-(6-Aminopyridin-3-yl)-2-me~hoxyimino-acetamido]-3-(1-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer), mp. 165-167C (dec.).
~23) 7-~2-~6-Aminopyridin-3-yl)-2-methoxyimino-acetamido~-3-~1-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (anti isomer), mp. 153-155C ~dec.).
`~ t24) 7~[2-(4-~ninopyrimidin-2-yl)--2-methoxyimino-acetamido]-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic aeid (syn isomer), mp 164-171C (dee.).
I.R. ~ NaU~ol : 3380, 3220, 1780, 1620-1690, 1585, 1540, 12S0, 1060, 1040, 895, 830, 720 cm 1 N-~-R- ~ ppm tDMSO-d6) : 3.73 (2H, broad s), 3.95 (3H, s), 4.28, 4.65 (2H, ABq, J=13Hz), 5.18 (lH, d, J=5E~z), 5.87 (lH, d, d, J=5Hz, 8Hz~, 6.48 (lH, d, J=7Hz), 7.05 (2H, broad s), 8.15 (lH, d, J=7Hz), 9.47 (lH, d, J=8Hz), 9.63 (lH, s) (25) 7-~2-(4-Aminopyrimidin-2-yl)-2-methoxyimino-acetamido]-3-~5-methyl-1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer), mp 161-167C (dec.).

I.R. ~ Nu~ol : 3380, 3220, 1780, 1620-1690, 1585, 1250, 1045, 840, 720 cm 1 N.M.R. ~ppm (DMSO-d6) : 2.70 (3H, s~, 3.70 (2H, broad s), 3.97 (3H, s), 4.21, 4.58 (2H, ABq, J=13Hz), 5.22 (lH, d, J=5Hz), 5.81 (lH, d, d, J=5Hz, 8Hz), 6.47 (lH, d, J=7Hz~, 7.05 (2H, broad s), 8.i2 ~lH, d, J=7Hz), 9.47 (lH, d, J=8Hz) (26) 7-~2-(4-~ninopyrimidin-~2-yl)-2-methoxyimino-acetamido]cephalosporanic acid (syn isomer), mp 149-159C (deG.).
I.R. ~ Nu~ol : 3370, 3220, 1780, 1730, 1630-1680, 1040, 725 cm N.M.R. ~ ppm (DMSO-d6) : 2.03 (3~1, s), 3.36, 3.62 (2H, AB~, J=18Hz), 3.93 (3H, s), 4.7, 5.0 (2H, ABq, J=12Hz), 5.10 (lH, lS d, J-4.5Hz), 5.77 (lH, d, d, J=4.5Hz, ~; 8.0Hz), 6.43 (lH, d, J=6.0Hz), 8.10 (lH, d, J-6.0Hz), 9.40 (lH, d, J=8.0Hz) ~3 r3 ~27) 7-[2-(6-Aminopyridin-2-yl~-2-methoxyimino-acetamido]-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

I.R. v Nmaxl : 3360, 32Z0, 1780, 1670, 1620, : 1585~ 1544, 1042 cm~

~28) 7-~2-(6-Aminopyridin-2-yl)-2-methoximino-acetamido]-3-cephem-4-carboxylic acid.
' I.R. v Naxl : 33nO, 1785, 1730, 1670 cm 1 (29) 7-[2-~6-Aminopyridin-2-yl)-2-methoximino-acetamido]-3-~1,3,4-thiadiazol-2-yl~thiomethyl-3-15 cephem-4-carboxylic acid (syn isom~r) .

I.R. v mUaxol : 3400, 3230, 1780, 1670, 1622, 1590, 1550, 1050 cm~

20 (30) 7-[2-(6-Aminopyridin-2-yl)-2-methoxyimino-acetamido]-3-(5-aminomethyl-1,3~4-thiadiazol-2-yl)-thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

I.R. v mNUxol : 3500, 3400, 3230, 1770, 1670, 1620, 1040 cm 1 ` (31) 7-[2-(6-Aminopyridin-2-yl)-2-methoximino-acetamido]-3-(1-carboxymethyl-lH-tetrazol-5-yl~-thiome~hyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. v NUaxol : 3380, 3220, 1780, 1670, 1620, lOS0 cm 1 ~32) 7-[2-~6-Aminopyridin-2-yl)acetamido]-3-_ .
9~

` - . . ~ . .
.
i ~ :

~z~

~l-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

I.R. v NmUa~ol : 3600 3080, 1763, 1698, 1663 cm 1 (33} 7-[2-(6-Aminopyridin-2-yl)-2-methoxyimino-acetamido]-3-chloro-3-cephem-4-carboxylic acid hydrochloride (syn isomer).

I.R. v NUxol : 3300-3100~ 1780, 171Q, 1660, 1610 J 1540, 1370 c~ 1 (34) 7-[2-(6-Aminopyridin-2-yl)-2-methoxyImino-acetamido~-3-methoxy-3-cephem-4-carboxylic acid.
I.R. v mUJol : 3300~ 1775, 1700-1650, 1045 cm 1 (35) 7~[2~(6-Aminopyridin-2-yl)-2-methoxyimino-acetamido]-7-methoxy-3-(1-methyl-lH-tetrazol-5-yl~-thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

I.R v mUaxol : 3300, 1780~ 1700, 1680 cm 1 (36) 7-[2-(6-Aminopyridin-2-yl)-2-met}loxyimino-acetamido~-2-methyl-3-cephem-4-carboxylic acid.(syn isomer).

I.R. v NmUxol : 3400-3100, 1780, 1730, 1665, 1550, 1295, 1258, 1050 cm~

(37) 7-[2-(6-Aminopyridin-2-yl)-2-methoxyimino-acetamido]-3-methyl-3-cephem-4-carboxylic acid hydrochloride (syn isomer).

I.R. v mUa~ol : 3100, 1780, 1682 9 1668, 1260, 1050 cm 9~

.
:. :
..
~ ' ,.

(38) 7-[2-(6-Aminopyridin-2-yl)-2-hydroximino-acetamido]-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

I.R. v ma~l : 3300, 1760, 1680 cm 1 (3~) 7-[2-~6-Aminopyridin-2-yl)-2-methoxyimino-acetamido3-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. v NUa]ol : 3400, 1780, 1720, 1670 cm 1 ~40) 7-[2-~2-Aminopyrimidin-4-yl)-2-methoxyimino-acetamido]-3-~1-methyl-lH-tetrazol-5-yl)thiomethyl- ~:
3-cephem-4-carboxylic acid.

I.R. v NUxol : 3440, 3320, 1790, 1693, 1660, : 1630~ 1525, 1043 cm~

~41) 7-[2-~6-Aminopyridin-2-yl)-2-ethoxyimino-acetamido]-3-~1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid gsyn isomer).

I.R. v maxl : 3380, 3240, 1780, 1670 cm 1 ~42) 7-[2-(6-Aminopyridin-2-yl)-2-methoxyimino-; acetamldo]cephalosporanic acid (syn isomer).

I.R. v maxl : 3350-3220~ 1780S 1740, 1680-1655, 13809 1040 cm .

9~

: : :
. ` -Example 10 Conc.hydrochloric acid ~0.36 ml) was added to a solution of 7-[2-~4-formamidopyrimidin-2-yl)-2-methoxyiminoacetamido]-3-~1-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid ~1.9 g) in methanol (38 ml), and the mixture was stirred at ambient temperature for 5.5 hours. The reaction mixture was concentrated~ and the concentrate was diluted with water and then washed with ethyl acetate.
After the ethyl acetate in the aqueous solution was removed by distillation, the aqueous solution was subjected to column chromatography on a macroporous~
non-ionic adsorption resin, "Diaion HP-20" (Trade mark, manufactured by Mitsubishi Chemical In~ustries I,td.) ~110 ml). Elution was carried out with water (400 ml), 9 ~

- ~ , "
. ~ .
.

10% aqueous methanol ~100 ml.), 20% aqueous methanol (200 ml.)-and then 30% aqueous methanol (2 Q.), and the fractions containing the desired compound were collected. The combined fractions were evaporated to dryness under reduced pressure to give powders ~1.0 g.) of 7-[2-(4-aminopyrimidin-2-yl~-2-methoxyiminoacetamido]-3-tl-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (a mixture of syn and anti isomer), mp. 150-160C (dec.).
I.R. ~ NUxol: 3380, 3220, 1780, 1620-1700, 1240, 1040 cm 1 N.M.R. ~ ppm (DMSO-d6) : 3.72 (2H, broad s), 3.98 (6H, s~
4.34 ~2H, broad s) 5.08 ~d, J=4H) } ~lH) 5.15 (d, J=4Hz) 5.60-6.00 ~lH9 m) 6.4S ~lH, d, J=6Hz) 7.00 (2H, m) 8.12 ~lH, d, J=6Hz) 8.87 ~d, J=8Hz) } (lH~
9.43 (d, J=8Hz) Example 11 Conc. hydrochloric acid (0.31 ml.) was added to a solution of 7-~?-allyloxyimino-2-(6--formam;dopyridin-2-yl)acetamido]-3-(1-methyl-lH-tetrazol-S-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer) (1.75 g.) in methanol (7 ml.), and the mixture was stirred at ambient temperature for 30 minutes. The methanol was removed by distillation from the reaction mixture, and the remaining aqueous solution was diluted with water (80 ml.) 9 '~

and then adjusted to pH 2-3 with an aqueous solution of sodium bicarbonate. The aqueous solution was subjected to column chromatography on a macroporous, non-ionic adsorption resin "Diaion HP-20" (Trade Mark, manufactured by Mitsubishi Chemical Industries Ltd.) (50 ml.). After the column was washed with water ~1 ~.), elution was carried out with 50~ aqueous methanol ~lQ.) and fractions containing the desired compound were collected. The methanol was removed by distillation from the combined fractions under reduced pressure and the resultant aqueous solution was lyophilized to give 7-[2-allyloxyimino-2-(6-aminopyridin-2-yl)acetamido]-3-~1-methyl-lH-tetrazol-5-ylthiomethyl~-3-cephem-4-carboxylic acid ~syn isomeT) ~1.13 g.), mp. 149-151C (dec.).
I.R. ~ NUixol : 3380, 3310J 1780, 1670, 1620 cm 1 N.M.R. ~ ppm ~3MSO-d6) : 3.70 (2H, broad s), 3.93 (3H, s~, 4.33 ~2H9 broad s), 4.67 (2H, d, J=SHz), 5.17-5.57 ; (2H, m), 5.10 ~lH~ d, J=5Hz), 5.80 ~lH, d,d, J=5Hz, 3Hz3, 5.83-6.27 ~lH, m), 6050 ~lH, d, J=8Hz), 6.90 (lH, d, J=8Hz), 7.43 (lH, t, Ja8Hz), 9.47 ~lH, d, J=9Hz) Example ~
Conc. Hyd~ochloric acid tO.43 ml.) was added to a solution of 7 ~2-(6-formamidopyridin-2-yl)-2-propargyloxyiminoacetamido~-3-(1-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid ~syn isomer) (2.35 g.) in methanol ~15 ml.), and the mixture was stirred 9 ~

.
: . :

at am~ient temperature for 30 minutes. The methanol was removed by distillation under reduced pressure from the - reaction mixture, and the remaining aqueous solution was diluted with water ~100 ml.) and then adjusted to pH 2 with an aqueous solution of sodium bicarbonate. The precipitating crystals were collected by filtration, washed with water and then dried to give 7-[2-~6-aminopyridin-2-yl)-2-propargyloxyiminoacetamido]-3-(1-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid ~syn isomer~ (1.05 g.3, mp. 163-165C (dec.).
I R v Nu~ol 3270, 1765, 1690, 1665, 1620, 1580; 1530 cm 1 N.M.R. ~ ppm (DMS0-d6) : 3.48 (lH, t, J=2Hz) D
3.62, 3.76 (2H, ABq, J=18Hz), 3.90 (3H, s), 4.26, 4.34 (2H, ABq, J-13Hz), 4.76 ~2H, d, J=2Hz), 5.12 (lH, d, J-5Hz), 5.80 ~lH, d,d, J=5Hz, 9Hz), 6.52 (lH, d, J=8Hz), 6.88 (1~, d, J=8Hz), 7.42 (lH, t3 J~8Hz), 9.54 (lH, d, J=9Hz) ExampIe 13~
, ~ Conc. hydrochloric acid (242 mg.) was added to a solution of 7-[2-(6-chloro-2-formamidopyrimidin-4-yl)-2-methoxyiminoacetamido]-3-(l-methyl-lH-tetrazol-S-ylthi-~ethyl)-3-cephem-4-carboxylic acid (1.2 g.) in methanol (12 ml.)g and the mixture was stirred at ambient temperature for S hours. The reaction mixture was e~aporated to dryness under reduced pressure to give a foamy residue 9 which was pul~erized with ethyl ether. This powder (1.1 g.) 9 ~

,~
.

was dissolved in methanol (6 ml.), and to ethyl ether ~50 ml.) was added dropwise the methanol solution. The precipitates were collected by filtration and then dried to give 7-[2-(2-amino-6-chloropyrimidin-4-yl)-2-methoxy-iminoacetamido]-3-(1-methyl-lH tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid hydrochloride (0.95 g.).
I.R. v Na3l : 3100~3300, 1785, 1660, 1390, ; lOS0 cm N.M.R. ~ ppm (DMSO-d6) : 3.75 (2H, m), 3.95 (3H, s), 4.00 ~3H, s), 4.24, 4.40 (2H, AB
J=14Hz), 5.18 ~lH, d, J=4.5Hz), 5.79 (lH, d,d, J=4.5Hz, 8.0Hz), 6.28 (lH, s), 8.00-10.00 (2H, broad s), 9.96 (lH, d, J=8Hz) The following compounds were obtained according to similar manners to those of ExampleslO and 13-(l).
(2) 7-~2-~4-Aminopyridin-2-yl)-2-methoxyimino-acetamido]-3-~1-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer), mp. 163-167C ~dec.~.
I.R. v Nu~ol 3400, 3230, 1778, 1650, 1600, 1380, 1050 cm 1 N.M.R. ~ ppm (DMSO-d6 and D2O~ : 3.64 (2H, m), ; 3-97 t6~, s)7 ~.32 ~2H, broad s), 5.12 tlH, d, J=4.5Hzi), 5.80 (lH, d,d, J=4.5Hz, 8Hz), 6.60 (lH, d,d, J=2Hz;
7Hz), 6.97 (lH, d, J=2Hz), 8.00 (lH7 d, J=7Hz), 9.52 (lH, d9 J=8Hz) (3) 7-[2-(6-Aminopyridin-2-yl)-2-propoxyiminoacetamido]-3-(1-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer), mp. 138-140C (dec.).

I.R. v Nu~ol: 340û, 3250, 1780, 1670, 1625~ 1590, 1550 cm~
N.M.R. ~S ppm tDMSO-d6) : 0.9 (3H, t, J=8Hz), 1.67 (2H, m), 3.7 (2H, broad s), 3.93 (3H, s), 4.07 (2H, t, J=8Hz), 4.30 (2H, broad s), 5.13 (lH, d, J=5Hz), 5.83 (lH, d,d, J=5Hz, 9Hz), 6.50 (lH, d, J=8Hz), 6.90 (lH, d, J=8Hz), 7.47 {lH, t , J=8Hz), 9.30 ~lH, d, J=9Hz) ~43 7- ~2- ~6-Aminopyridin-2-yl) -2 isopropoxyimino-acetamido]-3-(1-methyl-lH-te~razol-5-ylthiomethyl) 3-cephem-4-carboxylic acid (syn isomer), mp. 149-15:LC
~dec.).
I.R. v Nlu~ol 3380, 3240, 1780, 1670, 1620 cm 1 N.M.R. ~ ppm ~DMSO-d6): 1.27 (6H, d, J=6Hz), 3.70 (2H, broad s), 3.97 (3H, s), 4.33 ~2H , broad s), 4.35 (lH, m), 5.17 ~lH, d, J=5Hz), 5.87 (1~, d,d, J=5HzJ 9Hz), 6.50 (lH, d, J=8Hz), 6.93 (lH, d, J=8Hz), 7.47 (lH, t, J=8Hz~; 9.43 (lH, d, J=9Hz~
~5) 7-[2- (6 -Aminopyridin- 2 -yl) - 2- isobutoxyimino-: acetamido]-3-(1-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer), mR. 140-142C ~dec.).
I.R. v mUa~ol : 3370, 3220, 1780, 1670, 1620 cm 1 N.M.R, ~ ppm ~DMSO-d6) : 0.88 (6H, d, J=7Hz~, 1.96 ~lH, m), 3.68 (2H, broad s), 3.88 t2H, d, J=7Hz), 3.92 (3H9 s), 4.24, 4.36 (2H, ABqJ J=13Hz), _, :
9~

,, . .

5.12 ~lH, d, J=5Hz), 5.84 (lH, d,d, J=SHz, 9Hz), 6.48 (lH, d, J=8Hz), 6.88 ~lH, d, J=8Hz), 7.40 (lH, t, J=8Hz), 9.44 (lH, d~ J=9Hz) ~6) 7-E2 ~2-Aminopyridin-4-yl)-2-methoxyimino-acetamido]-3-~1-methyl-lH-tetrazol-5-ylthiomethyl~-3-cephem-4-carboxylic acid (syn isomer), mp. 175-177~C (dec.).
I.R. v maJl: 3200~ 1775, 1670, 1600, 1560 cm 1 N.M.R~ ~ ppm (DMS0-d6) : 3. 73 ~2H, broad s), 3.98 (6H, s)~ 4O35 (2H, broad s), 5.18 ~lH, d, J=SHz), 5.83 (lH, djd, J=SHz, 8Hz) 3 6.67-6.80 (2H~ m), 8.00 (lH9 d, J=6Hz), 9.79 (lH, d, J= 8Hz) ;~ 15 (7) 7-[2-(6-Aminopyridin-2-yl)-2-ethoxyimino-acetamidoJ-2-methyl-3-cephem-4 carboxylic acid (syn isomer), mp. 190-195C (dec.).
I.R. v mUjxol: 3350~ 3150, 1795, 1730, 1670 cm 1 N.M.R. ~ ppm (DMSû-d6) : 1.33 (3H9 t, J=7Hz), 1.43 (3H, d, J=7Hz), 3.90 ~lH, m~, 4.35 (2H, q, J=7Hz), 5.17 (lH, d, J=4Hz) , 5 .92 (lH, d,d, J=4E~z, 8Hz), 6.58 ~lH, d, J=6Hz), 6.73 (lH, d, J=7Hz), 7.17 (lH, d, J=8Hz), 7.95 (lH, d9d, J=7Hz7 8H~), 9.93 (lH, d, J=8Hz) (~) 7-[2-(6-Aminopyridin-2-yl)-2-propoxyiminoacet-amido]-2-methyl-3-cephem-4-carboxylic acid (syn isomer), mp . l90- 195C (dec.).
I R v Nu~ol 334o9 3150, 1780, 1735, 1670 cm N.M.R. ~ ppm (DMSO-d~) : 0.85 (3H, t, J=8Hz), 1.40 ~3H, d, J=7Hz), 1.70 (2H, m), ~; 3.80 (lH, m) 9 4.15 (2H, t, J=6Hz) 9 5.10 (lH, d~ J=4Hz), 5.gO (lH, d,d, J=4Hz, 8Hz), 6.54 (lH, d, J=6Hz), 6.74 ~lH, a, J-7Hz), 6.85 (lH9 d3 J=7Hz)~ 7.68 tlH, t, J=7Hz), 9.68 ~lH, d, J=8EIz) (9) 7-~2-~6-Aminopyridin-2-yl)-2-isopropoxyimino-~10 acetamido]-2-methyl-3-cephem-4-carboxylic acid (syn isomer), mp. 185-188C ~dec.).
I.R. v NmUaJol: 3350, 3150, 1795, 1735, 1670 cm 1 N.M.R. ~ ppm (DMSO-d6): 1.37 (6H 9 d, J=6Hz), 1.47 (3H, d9 J=6Hz), 3.92 (lH, m)~
4.58 (lH, m), 5.20 (lH, d, J=4Hz)9 5O93 (lH, d,d, J=4Hz, 8Hz~, 6.60 (lH, d, J=6Hz), 6.77 ~lH, d, J-7Hz), 7.08 (lH, d, J=8Hz~, 7.90 (lH, d,d, J_7Hz9 8Hz), 9.87 ~lH~ a9 J=8Hz) 7-~2-(6-Aminopyridin-2-yl)-2-butoxyimino-acetamido]-3-~1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer), mp. lOB-110C (dec.).
I.R. v ma~l: 3350~ 3200, 17759 1670, 1620, 1585, 1540 cm 1 N.M.R. ~ ppm ~DMS0-d6) : 0.90 (3H, t, J=7Hz), 1.80-1.16 t4H, m), 3.70 (2H, broad s), 3.92 (3H, s), 4.16 (2H, t, J=7Hz), 4.30 ~2H, broad s), 5014 (lH, d9 J=5Hz), 5.78 (lH, d,d, J=5Hz, 9Hz), - .
, .

6.58 (lH, d, J=8Hz), 6.86 ~lH, d, J=8Hz), 7.48 (lH, t, J=8Hz), 9.50 (lH, d, J-9Hz) ~11) 7-~2-~6-Aminopyridin-2-yl)-2-butoxyimino-acetamido~-2-methyl-3-cephem-4-carboxylic acid (syn isomer), mp. 200-205C (dec.).
I.R. ~ NUxol: 3400, 3120, 1785, 1660 cm~l N.M.R. ~ ppm ~DMSO-d6): O.9D ~3H, t, J~7Hz), 1.45 ~3H~ d, 3=6Hz), 1.20-1.80 (4H, m), 3.85 ~lH, m), 4.25 ~2H, t, J=6Hz~/ 5.12 (lH, d, J-5Hz), 5~90 ~lH, d,d, J=SHz, 8Hz), 6.56 (lH, d, J=5Hz), 6.70 ~lH, d, J-7Hz), 7.05 ~lH, d, J=7Hz), 7.82 ~lH, t, J=7Hz), 9.80 (lH, d, 3=8Hz) ~12) 7-[2-~6-Aminopyridin-2-yl)-2~isobutoxyimino-: acetamido]-2-methyl-3-cephem-4-carboxylic acid ~syn isomer), mp 175-180~C ~dec.).
I.R. v mU~ol: 3300~ 1785, 1735, 1660 cm 1 N.M.R. ~ ppm (DMSO-d6) : 0.95 (6H, d, J=6Hz), 1.48 (3H, d, J=7Hz), 2.08 ~lH, m), 3092 (1~, m)9 4.08 ~2H, d9 J=7Hz), 5.20 ~IH, d, J-4Hz), 5.95 (lH9 d,d, J=4Hz, 8Hz), 6.62 ~lH~ d, J=6Hz), 6.80 (lH, d, J=7Hz), 7.07 (lH, d, J=8Hz), 7.88 (lH, d,d, J=7Hz, 8Hz), 9~87 (lH, d, J=8Hz) ~133 7-[2-Allyloxyimino-2-(6-aminopyridin-2-yl)-; 30 acetamido]-2-methyl-3-cephem-4-carboxylic acid (syn isomer~, ~ , , ' , ;, ~

mp. 168-173C (dec.).
I.R. v Nu~ol 3350, 3150, 1795, 1735, 1670 cm 1 N.M.R. ~ ppm (DMSO-d63 : 1.47 ~3H, d, J=7Hz), 3O90 (lH, m), 4.83 (2H, d, J=5Hz), S 5.20 (lH9 d, J=~Hz), 5.23-5.66 (2H7 m), 5.95 tlH, d,d, J=4Hz, 8Hz), 5.83-6.30 (lH, m~, 6.60 (lH, d, J=6Hz~, 6.77 ~lH, d, J=7Hz), 7.10 (lH, d, J=7Hz)~ 7.93 ~lHp t, ; 10 J-7Hz)p 9.93 ~lH, d, J-8Hz) (14) 7-[Z-t6-Aminopyridin-2-yl)-2-propargyloxy-iminoacetamido]-2-methyl-3-cephem-4-carboxylic acid (syn isomer)9 mp. lS5-170C (dec.).
I.R. v NmUaxQl: 3350j 17~, 1670 cm 1 N.M.R, ~ ppDI (DMSO-d6) : 1.47 (3H, d, J=7Hz), 3.58 (2H, t, J=2Hz), 3.87 (lH, m), 4.88 ~lH, d, J=2Hz), 5.17 (lH, d, J=4H2), 5.93 (lH~ d,d~ J=4Hzj 8Hz), 6.58 ~lH, d, J=6Hz)g 6.66 (lH, d, J=BHz) 9 6.70 (lH, a, J=8Hz), 7.68 (lH, t, J=8Hz), 9.77 (lH, d, J=8Hz) (ls~ 7-[2-(6-Amlnopyridin-2-yl~-2-(2~2,2-trifluoro-ethoxyimino)acetamido3-3-(1-me~hyl-lH-tetra~ol-5-ylthio-methyl)-3-cephem-4-carboxylic acid (syn isomer)~ mp.
165-170C ~dec.).
I.R. v mU]ol: 3400, 1780, 1690 cm 1 N.~l.R. ~ ppm (DMSO-d6) : 3.72 (2H, broad s), 3.95 (3H, s), 4.32 (2H, broad s), 4.66, 4.92 ~2H, ABq, J=9Hz) ?

1 ~ '3 . ~.. ,,. . ~.
~ .

5.17 (lH, d, J=4Hz), 5.83 ~lH, d,d~
J=4Hz, 8Hz), 6.32 (lH, d, J-8Hz), 6.90 (lH, d, J-8Hz), 7O55 (lH, t, J=8Hz), 9.68 (lH, d, J-8Hz) (16) 7-[2-(6-Aminopyridin-2-yl)-2-phenoxyimino-acetamido3-2-methyl~3-cephem-4-carboxylic acid (syn isomer) mp. 145-147C ~dec.).
I.R. v mU~ol: 3200, 1760, 1690, 1670 cm 1 N.M.R. ~ ppm (DMS0-d6) : 1.50 (3H, d, J=7Hz), 3~90 (lH7 m), 5.23 (lH9 d, J=4Hz), 6.05 (lH, d,d, J=4Hz, 8Hz), 6.60 ~lH~ d, J=6Hz), 6.73 ~lH, d, J=7.5Hz), 7.13 (lH, d, J=7.5Hz), 7.00-7.50 (5H, m), 7.63 ~lH, d, ; lS J-7.5Hz), 9.~8 ~lH, d, J=8Hz) tl7) 7-[2-(6-Aminopyridin 3-yl)-2-methoxyimino-acetamido~-3-(1-methyl-lH-tetrazol-5-ylthlomethyl)-3-cephem-4-carboxylic acid (syn isomer)~ mp. 165-167C (dec.).
I.R. ~ NaJ~l: 3380, 3220, 1780, 1680, 1630, 1590, 1550 cm 1 N.M.R. ~ ppm ~DMS0-d6) : 3.75 (2H, broad s), 3.~0 (3H, s), 3.97 (3~, s), 4.35 (2H, broad s), 5.17 (lH, d~
J=5Hz), 5.82 (iH, d,d, Ja5Hz, 8Hz), ~5 6.57 (lH, d, J=9Hz), 7.67 ~lH, d,d, ; J-2Hz, 9Hz), 8.03 ~lH~ d, J=2Hz), 9.73 (lH, d, J=8Hz)
(18) 7- L2- (6-Alninopyridin-3-yl)-2-methoxyimino-acetamido]-3-(1-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (anti isomer~, mp 153-155C ~dec.).

. .
~ ~ 3 : : . - -I.R. v Nu~ol 335o9 3200, 1780, 16809 1630, 1520 cm 1 N~M~Ro ~ ppm (DMSO-d6) : 3.73 (2H, broad s~ 9 3.97 (6H, s), 4.35 (2H, broad s), 5.17 (lEI, d, J=5Hz), 5.72 ~lH, d,d, J=SHz, 8Hz), 6.62 (lH, dJ J=9Hz~, 7.75 (lH, d,d, J-2Hz, 9Hz), 8.25 ~lH~ d, J=2Hz), 9.25 (lH, d9 J=8Hz)
(19) 7-[2-~6-Amino-3-chloropyridin-2-yl)-2-methoxy-iminoacetamido]-3-(1-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4~carboxylic acid hydrochloride (syn isomer), mp~ 155-160C (dec.).
I.R. v NuJol 3100-3350, 1790, 1670, 1550, 13~0, 1235,1040 cm 1 N.M.R. ~ ppm (DMSO-d6) : 3.70 (2H, m), 3.94 (3H~ s), 4.03 (3H, s), 4.21, 4.37 (211, AB
J=14Hæ), 5.14 (lH, d, J=4.5Hz), 5.80 (lH, d,d, J=4.5Hz, 8Hz), 6.97 (lH, d, J=lOHz)9 7.80 ~lH~ d, J=lOHz), 7.50-9.00 ~2H, m), 9.70 (lH, d, J=8Hz)
(20) 7-[2-~6-Amino-3,5-dichloropyridin-2-yl)-2-~ methoxyimlnoace~amido]-3~ methyl-lH-tetrazol-5-ylthio-; methyl)-3-cephem-4-carboxylic acid (syn isomer), mp.
139-144C (dec.).
I~R~ v mU~ol: 339 1785, 1730, 1660, 1545, 1380, 12359 1045 cm 1 N.M.R. ~ ppm (DMSO-d6) : 3.73 (2H, m), 3.98 (6H9 s), 4.35 (2H, broad s), 5.17 (lH, d, J=4.5 }1z), 5.81 (lH, d,d, J=4.5Hz, 8Hz~9 7.87 (lH, s)9 7.50-8.20 (2H, m), 9 43 (lH, d9 J=8Hz~
1 ~ ~

.
, . . :

9~
(21) 7-[2-(4-Aminopyrimidin-2-yl)-2-methoxyiminoacetamido]-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer), mp 164 171C (dec.).
(22~ 7-[2-~4-Aminopyrimidin-2-yl)-2-methoxyiminoacetamido~-3-(5-methyl-1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid ~syn isomerl, mp 161-167C ~dec.).
(23) 7-[2-(4-Aminopyrimidin-2-yl)-2-methoxyiminoacet~ o]-cephalosporanic acid (syn isomer), mp 149-159C (dec.).

~ ~o lS

1 ~3 e3 ~.

Example 14 (1) A mixture of N,N-dimethyl fonnamide (12mQ) and phosphoryl chloride (1.84g) was stirred for 30 minutes at ambient temperature. To the mixture were added methylene chloride (12mQ) and 2-ethoxyimino-2-(4-formamidopyrimidin-2-yl)acetic acid (syn isomer) ~1.9lg) at -5 to 0C, and then the reaction mixture was stirred for an hour at the same temperature.
On the other hand, a mixture of 7-amino-3-(:L/3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid (4.36g) and trimethylsilyl acetamide (12g) in methylene chloride (120mQ) was warmed to make a clear solution.
lS The solution was cooled to -10C and added to the activated acid solu~ion obtained above.
The reaction mixture was stirred for 40 minutes at 0C, and then poured into a cold aqueous solution of sodium bicarbonate. The aqueous layer was separated out, adjusted to pH 2 with 10~ hydrochloric acid and extract-ed with ethyl aceta~e. The extract was dried over anhydrous magnesium sulfate and evaporated to dryness.
The residue was triturated with diethyl ether to give ;~ 25 an amorphous precipitate l3.6g) of 7-~2-ethoxyimino-2-~4-formamidopyrimidin-2-yl)acetamido]-3-(1,3,4~thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer).
, .
I.R.v Nm~ 3250, 1780, 1660, 1570cm~l.

N.M.R. ~ppm (~MSO-d6): 1.30 (3H,t,J=7Hz), 3.72 (2H, board s), 4.27 (2H,q,J=7Hz), 4.30, 4.57 (2H,A~q,J=13Hz), 5.18 (lH,djJ=5Hz), 5.88 (lH, dd, J=5Hz, 8Hz), 7.1-7.5 (lH,m), 8.67 (l~I,d,J=6Hz), 8.9-9.2 ,..

. ~ . , , ~

~, `` ;~ 3 (lHIm), 9.45 (lH,d,J=8Hz), 9.52 (lH,s), 11.10 (lH,d,J=7Hz).
The following compounds were obtained according to the sïmilar manner to that of Example 14-(1).
S (2~ 7-12-(4-E'ormamidopyrimidin-2-yl)-2-propoxyi-minoacetamido]-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer), mp 17V -175C (dec.).

I.R.v Nm~xl: 3250, 3100, 1780, 1710, 1670, 1615, 1580cm~~.
N.M.R. ~ppm (DMSO-d6): 0.93 (3H,t,J=7~z), 1.4-1.9 (2H,m), 3.72 (2H,broad s)l 4.20 (2EI/t,J=7Hz), 4.33, 4.58 (2H, ~B~, J=13Hz), 5.20 (lH,d,J=6Hz), 5092 (lH, d,d,J=5Hz,8Hz), 7.0 -; 7.7 (lH,m), 8.67 (lH,d,J=6Hz), 8.8-9.2 (lH,m), 9.47 (lH,d,J=8Hz), 9.53 (lH,s), 11.23 (lH,d,J=6Hz).
(3) 7-[2-Allyloxyimino-2-(4-formamidopyrimidin-2-yl)acetamido~-3~(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer), mp 130-133~C
(dec.).
I.R.v Nmaxl : 3250, 1780, 1720, 1660, 1570cm~~
N.M.R. ~ppm (DMSO-d6): 3.73 (2H,broad s), 4.80 (2H,d,J=5Hz), 5.20 (lH,d, J=5Hz), 5.1 5.6 (2H, m), 5.90 (lH,d,d,J=5Hz, 8Hz), 5.7--6.3 (lH, m), 7.0-8.7 (lH,m), 8.68 (lH,d, J=6Hz), 8.8-9.3 (lH,m), 9.53 (lH, d,J=8Hz), 9.57 (lH,s), 11.23 (lH, d, J=6Hz).
(4) 7-12-Benzyloxyimi~o-2-(4-formamidopyrimidin-2-~7 , ~, ~

~l~Z~ 23 yl)acetamido]-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid ~syn isomer), mp 143-145C (dec.).
I.R.vNm~xl : 3300, 178S, 1720, 1670, 1575cml.
N.M.R. ~ppm (DMSO-d6): 3.63 (2H, broad ~), 4.28,`4.52 (2H,ABq,J=13Hz), 5.13 (lH,d,J=5Hz), 5.27 (2H,s), 5~85(1H,d,d,J=5Hz,8Hz), 7.32 ~5H,~), 7.2-7.6 (lH,m), 8.60 (lH,d,J=6Hz), 8.8-9.2 (lH,m), 9.52 (lH,s), 9.SS (lH,d,J=8Hz), 11.30 (lH,d,J=6Hz).
(5) 7-[2-(6-Formamidopyridin-2-yl)-2-methoxyimino-~ acetamido~-3-[1-allyl-1~-tetrazol-5-yl)thiomethyl~
; 15 -3-cephem-4-carboxylic acid (syn isomer).
R~UNm~xl : 3300, 1785, 1700-1670, 1580, 1380, 1260, 815cm~l.
N.M.R. ~ppm (DMSO-d6): 3.72 ~2H, broad s);
3.95 (3H,s), 4.20, 4.50 (2H, ABq, ~=13~z), 4.9-6.6(7H,m), 6~85-9.42(5H,m1, lO.S(lH,m~.
(6) ~ 7-[2-(2,2,2-Trifluoroethoxyimino)-2-(6-; formamidopyridin-2-yl)acetamido]cephalosporanic acid (syn isomer), which starts to decompose at ~5 120C.
I.R~v m~xl : 3310, 1788, 17i8, 1673 cm~l~ ;
N.M.R. ~ppm ~DMSO-d6): 2.00 ~3H,s), 3.53 ~2H, broad s), 4.5-5.0 (4H,m), 5.15 ~ (lH,d,J=SHz), 5.88 (lH,d,d, J=5Hz, 8Hz), 6~7-8~1 (3H,m), 9.27 (lH,broad d, J=lOHz), 9~62 (lH,d,J=8Hz), 10~40-10.85 ~lH, m).
(7) 7-[2-Allyloxyimino-2~6-formamidopyridin-2-yl) acetamidol-3-~5-tert-butoxycarbonylaminomethyl-l~

: ~ . :.

~ , 3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer), mp. 170-180C (dec.) I~R~VNm~X~ : 3300/ 1788, 1720-1680 cm~l.
N.M.R. ~ppm ~DMSO-d6): 1.43 (9H,s), 3.72 (2H, broad s), 4.1-4.9 (6H~m), 5.1 -6.3 (5H,m), 6.75 - 8.1 ~3H,m), 9.1 9.5 ~lH,m), 9.58 (lH,d,Ja8~z), 10.4-10.8 (lH,m).
(8) 7-[2-(6-Formamidopyridin-2-yl)~2-propargyloxyi-minoacetamido}-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer), mpl52-156C
~dec.).
.vNmaI : 3300, 1780, 1670, 1580cm~l.
N.M.R. ~ppm (DMSO-d6): 3.5 (lH,m), 3.7 (2H,m), 4.25, 4062 (2H,ABq,J=13Hz), 4.8 (2I~,m), 5.17(1H,d,J=4.5Hz), 6.22 (lH,d,d,J=4.5Hz,8Hz), 7.0-9.4 (2H, m), 7.5 (lH,d,J=7Hz), 7.85 (lH,t, J=7Hz), 9.57(1H,s), 9.4-9.5 (lH, m), 10.6 (lH,m).
9)~ 7-~2-(4-Formamidopyrimidin-2-yl)-2-methoxyimino acetamido]-3-(tetrazolo[1,5-b]pyridazin-6-ylthio-methylj-3-cephem-4-carboxylic acid (syn isomer).
I.R.VNmaxl : 3250, 1780, 1710, 1680, 1570cm ~.
~10) 7-[2-(4-Formamidopyrimidin-2-yl)-2-methoxyimino acetamido]cephalosporanic acid (syn isomer), mp 150-154C (dec~3.
I.R.vNm]xl :~3250, 1780, I700, 1670, 1590cm~l.
N.M.R.~ppm ~DMSO-d6): 2.05 ~3H,s), 3.58 (2H, broad s), 4.00 (3H,s), 4.73, 5.00 (2H,ABq,J-13Hz), 5.20 (lH,d,J=4Hz), 5.90 (lH,d,d,J=4Hz,8Hz), 7.40 (lH, broad s), 8.68 (lH,d,J=5Hz), 9.07 i (lH,broad s), 9.53 (lH,d,J=8Hz), 11.23 (lH,d,J=8Hz).
_ .
:t~ ~
, .
: .
`, `
, . . .

- ., `

z~

~11) A mixture of N,N~dimethylformamide (14mQ~ and phosphoryl chloride (2.5g) was stirred for 30 minut-es at 40C. To the mi~ture were added methylene chlaride ~14mQ) and 2-(2,2-dichloroaceto~yimino~-2-~6-formamidopyridin-2-yl)acetic acid (syn isomer) ~S.3g) at -20C, and then the reaction mixture was stirred for 30 minutes at -15 to -10C.
On the other hand, a mixture of 7-amino-3-[~ l-hexyl-lH-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid (5.89g) and trimethylsilyl acet-amide (16g) in methylene chloride (150mQ) was warm-ed to make a clear solution. The solution was cooled to -15C and added all at once to the activa~-ed acid solution prepared above. The reaction mix-ture was stirred for 30 minutes at -15 to 0C and ~or additional 30 minutes at ambient temperature.
The solvent was removed by distillation from the reaction mixture under reduced pressure to give a residue, to which ethyl acetate (15OmQ) and water ~ tlOOmQ) were added, and then the mixed solution was adjusted to pH 3 with an aqueous solution of sodium bicarbonate. The organic layer was separat-ed out, washed two times with an aqueous solution of sodium chloride and dried over magnesium sul-fate, and then evaporated to dryness to give a brownish oil. This oil was washed three times with diethyl ether ~70mQ) and triturated with diisopropyl ether to give a powder of 7-[2-(6-formamidopyridin-2-yl) 2-hydroxyiminoacetamido~-3 - (l-hexyl-lH-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid (syn isomer), mp 74 84C (dec.).
I.R.~U3xl : 3300, 1785, 1700-1675, 1580, 1380, 1260, 810cm~l.
N.M.R.~ppm (DMSO-d6) : 0.8-1.8 (llH,m), 3.7 (2H,m~, 4.3 (4H,m), 5.18 (lH,d, .

J=4.5E~z), 5.95 ~lH,d,d,~=4.5~z, 8Hz), 7.5-9.43 (5H,m), 10.6 (lH,m).
The following compound was obtained according to the similar manner to that of Examp:Le 14- (11).
(12) 7-[2-(6-Formamidopyridin-2-yl)-2-hydroxyimino-acetamido]-3-~(1-allyl-lH-tetrazol-5-yl~thiomethyl]-3-cephem-4-carboxylic acid (syn isomer~, mp 88-91C
(dec.).
; I.R.vNUal : 3300, 1785, 1700-1660, 15~0, 1380, 1260~ 815cm~l.
N.M.R.~ppm (DMSO-d6~ : 3.63 (2H, broad s), 4.13, 4.43 t2H, ABq,J~13Hz), 4.93 (2H,m), 5.0-5.2 (lH,m~, 5.25 ~2H,m), 5.67-6.16 (2H,m), 6.38-8.08 (3H,m), 9.3 (lH,d, J-8Hz), 10.55 (lH,m).
(13) A mixture of 2-(4-aminopyrimidin-2-yl)~2-methoxyiminoacetic acid dihydrate (syn isom~r) (1.6~g) and phosphoryl chloride (4.3g) i~ methylene chloride (lOmQ) was stirred for 30 minutes at O
to 5C. To the above mixture was added dropwise N,N-dimethylformamide (5.3mQ) and the resultant mixture was stirred for 30 minutes at O to 5C.
On the other hand, a mixture of 7-amino-3-~ allyl-11l-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid (2.5g) an~ trimethylsilyI acet-- amide (lOg) in methylene chloride (35mQ) was warm-ed to make a clear solution. The solution was cooled to -5C and added to the activated acid solution obtained above.
The reaction mixture was stirred for 30 minutes at 5 to 10C and for additional 30 minutes at ambient temperature and then poured into a cold aqueous solution of sodium bicarbonate. The aqueous layer was separated out, adjusted to pH 3 with 10%

- ' ' ~

.

hydrochloric acid, washed with ethyl acetate and then subjected to column chromatography over nonionic adsorption resin, "Diaion HP20" (Trade Mark, manufactured by Mitsubishi Chemical Industries Ltd~ (70mQ). The column was washed with water and eluted with 3Q% a~ueous methanol. The eluent con-taininy a desired compound was evaporated to re-move the methanol under reduced pressure and then lyophilized to give 7-[2 (4-aminopyrimidin-2-yl)-2-methoxyimino-acetamido]-3-El-allyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (1.58g), mp 151-156C (dec.).
I.R.~Nmal 3370, 3220, 1730, 1680 ~ 1640cm 1.
N.M.R.~ppm (DM5O-d6) : 3.7 (2H,m), 3.95 (3H, s), 4~23, 4.48 (2H,ABq,J-13Hz), 4.8-5.4(5H,m), 5.7-6.2 (2H,m), 6.45 (}H,d,J=7Hz), 7.05 ~2E~, broad s), 8.10 (lH,d,J=7H2), 2a 9.45 (lH,d,J=8Hz).
(14) A mixture of 2-(4-aminopyrimiain-2-yl)-2-methoxyiminoacetic acid (syn isomer) (2.32g) and phosphoryl chloride (4.6g) in methylene chloride ; '~15mQ) was stirred for 30 minutes at 3~C. To the mixture was added dropwise a solution of N,N-dimethylformamide (3.0mQ) in methylene chloride (15mQ) and stirred for 40 minutes at 3C.
A solution of 4-nitrobenzyl 7-amino-3-cephem-4-carboxylate (3.02g) and trimethylsilyl acetamide (15g) in methylene chloride ~60m~) was cooled to -5C and added to the activated acid solution obtained above. The mixture was stirred for 30 minutes at 3 to 5C and for additional 30 minutes at ambient temperature. The solvent was evaporated to dryness and the residue was dissolved in ethyl ~L~2 ;

acetate (200mQ~. The solution was washed with an aqu20us solution of sodium bicarbonate and water, dried over anhydrous magnesium sulfate and evaporated to dryness. The residue was washed with diethyl ether to give 4-nitrobenzyl 7-~2-(4-amino~
pyrimidin-2-yl)-2-methoxyiminoacetamido]-3-cephem~
4-carboxylate (syn isomer) (3.1g) as a powder, mp 125-131C (dec.).
I.R.vNm~xl : 3500, 3400, 3250, 1790, 1720, 1690, 1640, 1525, 1040, 855, 740cm~l .
; The following compounds were obtained accord-ing to the similar manner to those of Examples `~
(13) and (14).
(15) 7~[2-(4-aminopyrimidin-2-yl)-2-methoxyimino acetamido]-2-methyl-3-cephem-4-carboxylic acid (syn isomer), mp 175-181C (dec.).
I.R.VNm~xl : 3400, 3300, 1780, 1665, 1635, 1590 cm~l.
N.M.R.~ppm ~DMSO-d6) : 1.45 (3H,d,J=7Hz), 3.78 (lH,d,J=7Hz), 3.95 (3H,s), 5.10 ~lH,d,J=4.5Hz), 5.93 (lH, d,d,J=4.5Hz,8Hz), 6.45 (lH,d, J=7Hz), 6.57 (lH,d,J-6Hz), 7.05 (2H, broad s), 8.10 (lH,d, J=6Hz), 9.41 (lH,d,J=8Hz).
6? 7~2-(4-Aminopyrimidin-2-yl)-2-methoxyimino acetamido3-3-methyl-3-cephem-4-carboxylic acid `~ ~syn isomer), mp 169-175C (dec.).
I.~.VNm~ol 3350, 3210, 1765, 1680-1630, 1580, 1375, 1040, 920, 720cm~l.
N.M.R.~ppm (DMSO-d6) : 2.03 (3H,s), 3.25, 3.66 (2H, A~q, J=18Hz), 3.95 (3H,s), 5.08 (lH,d,J=4.5Hz), 5.76 (lH,d,d,J=4.5HZ,8.0Hz), .

, ~ , ~: -; , , , -.
" , :
, , , -. .
. . . .
. . :

V.9~3 6.43 ~lH,d,J=7Hz), 7.03(2H, broad s), 8.10 (lH,d,J=7Hzj, 9.37 (lH,d,J=8.0Hz~
(17) 7-~2-(4-Aminopyrimidin-2-yl)-2-methoxyimino-acetamidol-3-carbomoyloxymethyl-3-cephem 4~carboxy-lic acid (syn isomer), mp 200-204C (dec.).
I.R.vN~l : 3370, 320Q, 1775, 1710, 1670-1630, 1400, 1320, 1040, 985, 720cm~1.
`N.M.R.~ppm (DMSO-d6) . 3.38, 3.61 (2H,ABq,J-18Hz), 3.94 (3HIs), 4.62, 4.90 (2H,ABq,~=13Hz), 5.15(lH,d,J=
4.5Hz~, 5.80 (lH,d,d,J-4.5Hz, 8.0Hz), 6.44 (lH,d,J=7.0Hz), 6.58 ~2H,s), 7.03 (2H,broad s), 8.10 (lH,d,J=7.0Hz), 9.41 (lH, d,J~8.OHz).
(18) 7-~2-(4-Aminopyrimidin-2-yl)-2 methoxyimino-;~ acetamido] 3-acetylthiomethyl-3-cephem-4-carhoxylic acid (syn isomer), mp 168-173C (dec.).
I.R.VNu~ol : 3400, 3240, 1780, 1680-1630cm~~.
N.M.R.~ppm (DMSO-d6) : 2.33 (3Hjs), 3.2, 3.7 (2H, ABq,J=18Hz), 3.92 (3H,s), 3.9-4.2 52H,m), 5.10 (lH,d,3~
4.5Hz), 5~78 (lH,d,d,J=4.5Hz,8Hz), 6.40 (lH,d,J=6Hz),7.02 (2H,broad s), 8.08 (lH,d,J=6Hz~, 9.37 (lH, d,J=8Hz).
~19) 4-Nitrobenzyl 7-~2-(4-aminopyrimidin-2-yl)-2-methoxyiminoacetamido]-3-chloro-3-cephem-4-carboxy-late (syn isomer), mp 100-108C (dec.).
I.R.vNmal : 3370, 3210, 1780, 1740, 1680, 1630, 1520, 1375, 1350, 1220, 1040, 850, 735cm~10 N.M.R.~ppm (DMSO d6) : 3.75~ 4.07 (2H,ABq, 35 J=18Hz), 3.93 (3H,s), 5.30 (lH, : : , : , ' d,J=4.5Hz), 5.45 t2H,s), 5-95 ; (lH,d,d,J=4.5Hz,8.0Hz), 6.42 (lH,d,J-7.0Hz), 7.06 (2H, broad s), 7.68 (2H,d,J=8.0Hz), 8.22 (2H,d,J=8.0Hz), 8.08 (lH,d,J=
7.0Hz), 9.53 (lH,d,J=8 0Hz).
~20) Sodium 7-[2-(4-Aminopyrimidin-2-yl)-2-methoxy iminoacetamidol-3-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-ylthiomethyl]-3-cephem-4-carboxylate (syn isomer), mp 211-221C (dec.).
I.R.vNmaxl : 3370, 3220, 1765, 1670-1600, 1400, 1090, lQ40, 835, 728cm~~.
N.M.R. 8ppm (DMSO-d6): 3.3-3.7 (2H,m), 3.90 ~3H,s), 4.4 (2H,m), 5.00 ~lH,d, J=4.5Hz), 5.6 (lH,m), 6.45 (lH, d,J=7Hz), 7~05 (2H,broad s), 7.5 -8.1 (4H,m), 8.I0 (lH,d,J-7~z), .~
9~3 (lH,m).
(21) 7-~2-(4-~mino-6-chloropyrimidin-2-yl)~2-methoxyiminoacetamidoj-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3~cephem-4-carboxylic acid (syn isom-er~, mp 173-178C (dec.).
I.R.vNU~l : 3400, 3280,~1780, 1680, 1630, 1575, 1530, 138~, 1040, 900, 800 cm~~.
N.M~R.~ppm (DMSO-d6) : 3.72 (2H,broad s), 4.00 (3H,s), 4.28, 4.63 (2H, ABq, J=13Hz), 5.17 (lH,d,J=4.5Hz), 5.85 ~lH,d,d,J=4.5HZ, 8.0Hz), 6.50 (lH,s), 7.4 (2H,broad s), 9.50 (lH,d,J=8.0Hz), 9.58 (lH,s~.
(22) 7-[2-(4-Aminopyrimidin-2-yl)-2-ethoxyimino-acetamido]-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-car~oxylic acid (syn isomer).
I.R.vNUaxl : 3350, 3250, 1780, 1660, 1585cm~1.

_..

; . ~ . -- : : :.

.

^~ Z3
(23) 7-12-(4~Aminopyrimidin-2~yl~ 2-propoxyimino-aeetamido]-3-(1,3,4-thiadiazol-2-ylthiomethyl~-3-eephem-4-carboxylic acid (syn isomer).
I.R.vNmaxl: 3375, 3225, 1780, 1660, 1590, 1540cm~~.
~24) 7-[2-AllyIoxyimino-2-(4-aminopyrimidin-2-yl) ; aeetamido]-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-eephem-4-carboxylic aeid (syn isomer).
I.R.vNmaxl: 3380, 3230, 1780, 1660, 1585, 1540cm~l.
~25) 7-12-(4-Aminopyrlmidin-2-yl)-2-benzyloxyimino-aeetamido]-3-(1,3,4 thiadiazol-2-ylthiomethyl)-3-eephem-4-earboxylic aeid (syn isomer).
; I~R~VNmaXl 3370, 3230, 1780, 1660, 1590, 1540cm 1 (26) 7-[2-(6-Aminopyridin-2-yl)-2-hydroxyimino-acetamidol-3-[5l-hexyl-lH-tetrazol-5-yl)thiomethyl]
3-eephem-4-carboxylie acid (syn isomer~.
I.R.VNm~Xl: 3200, 1780, 1670, 1620, 810, 725em l.
(27) 7-12-(6-Aminopyridin-2-yl)-2-hydroxyimino-acetamido~-3-[1-allyl-lH-tetrazol-5-yl)thiomethyl]-3-cephem-4-earboxylic aeid (syn isomer).
I.R.vNm~l: 3350, 3200, 1775, 1665, 1620, 1250, 990, 805em~ .
(28) 7-[2~(6-Aminopyridin-2-yl)-2-methoxyimino-acetamido~-3-[1-allyl-lH-tetrazol-5-yl~thiomethyl]-3-cephem-4-carboxylie acid (syn isomer).
I.R.VNuaxol: 3380, 3240, 1780, 1670, 1620cm 1.
(29) 7-[2-(6-Aminopyridin-2-yl)-2-(2,2,2-trifluoro ethoxyimino)acetamido~-3-[(1-carboxymethyl-lH-tetrazol-5-yl)thiomethyl]-3-cephem 4-carboxylic acid (syn isomer).
I.R.VN~iol 3440, 3320, 1778, 16~8, 1665, 1623, 1552 cm~l~

1 ~ ~

(30) 7-[2~(6-Aminopyridin-2-yl)-2-propargyloxyi-minoacetamido]-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer).
I.R.vNU~l : 3300, 3200, 216G, 1775, 1735, 1670, 1630, 1085, 1025cm~l.
(31) 7-[2-(4-~minopyrimidin-2-yl)-2-methoxyimino~
acetamido]-3-cephem-4-carboxylic acid (syn isomer).
I.R.v~U3l : 3380, 3240, 1780, 16aO-1630, 1585, 1378, 1040, 985, 725cm~l.
~32~ 7-[2-(4-Aminopyrimidin-2-yl)-2-methoxyimino-acetamido~-3-chloro-3-cephem-4-carboxylic acid - (syn isomer).
~`~ I.R.vN~l~l : 3460l 3400, 3260, 1773, 1680-1650, 1620, 1570, 1380, 1270, 1095, 1040, 860cm~l.
~; (33) 7-~2-(4-Aminopyrimidin-2-yl)-2-methoxyimino-acetamido}-3-(pyrazin-2-ylthiomethyl)-3-cephem-4-caroxylic acid (syn isomer).
I.R.vNmaxl : 3350, 3250, 1780, 1660, 1590cm~l.
(34) 7-12-(4-Aminopyrimidin-2-yl) 2-methoxyimino acetamido]-3-(tetra2O1O~1,5-b]pyridazin-6-ylthio-me~hyl)-3-cephem-4-carboxylic acid (syn isomer~.
I~R.~Nmal : 3350, 1770, 1660, 1530cm 1.
(35) 7-[2-(4-Amino-6-methoxypyrimidin-2-yl)-2-` methoxyiminoacetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid, mp 161 - 163C (dec.).
I-R- ~max : 3400, 3250, 1783, 1675, 1620, 1580, 1380, 1040 cm N.M.R. ~ppm~DMSO-d6): 3.73(2H, broad s), 3.83(3H,s), 3.97(3H,s), 4.27,4,63(2H, ABq,J=13Hz~, 5.l7(lH~d~J=4-5Hz)~ 5.73 (lH,s), 5.87(1H,d,d,J=4.5Hz,8Hz), 6.77 (2H,broad s), 9.45(1H,m), 9.57(1H,s?.
(36) 7-[2-(4-Amino-6-phenylthiopyrimidin-2-yl)-2-methoxyiminoacetamido~-3-(1,3,4-thiadiazol-2-yl)-_ :: ` i ": : ` :
::

' thiomethyl-3-cephem-4-carboxylic acid, mp 148 -160C(aec.).
I.R. ~Nu~ol: 3370, 3250, 1780, 1680, 1630, 1570, 750, 722 cm 1 N.M.R. ~ ppm(DMSO-d6): 3.7(2H,m), 3,95 (3H,s), 4.28,4.60(2H,ABq,J=13Hz), 5.16 (lH,d,J=4.5Hz), 5.8(2H,m), 6.98(2H, broad s), 7.60(5H,s), 9.47(1H,d,~=8Hz), 9.59 (lH,s).

:; :

~ ~ 25 .

~: :

~: , ~ -: , :, .

;~

Example 15 ~1) A ~olution of 7-[2-ethoxyimino-2-(4-formamidopyri-midin-2~yl)acetamido]-3-(1,3,4-thiadiazol~2-ylthio-methyl)-3-cephem-4-carboxylic acid (syn isomer) t3~9?g) and concentrated hydrochloric acid (0.73m~) in methenol (80mQ) was stirred for 1.5 hours at ambient temperature. The solvent was evaporated to dr~ness and the residue was dissolved in water (lOOmQ). The aqueous solution was washed with ethyl acetate and adjusted to pH 3 with an aqueous solution of sodium bicarbonate and then subjected to column chromatography over nonionic adsorption resin, "Diaion HP 20". The column was washed with water and eluted with 50% aqueous methanol.
The eluent containing a desired compound was eva~
porated to remove the methanol and then lyophilized ~ to give 7-~2-(4-aminopyrimidin-2-yl)-2-ethoxyimino-; acetamido]-3-(1,3,4-thiadiazol-2-ylthiomethyl)~3-cephem-4-carboxylic acid ~syn isomer) (1.75g), mp 155-160C (dec.).
I.R.vNm~l : 3350, 3250, 1780, 1660, 1585cm~~.
N.M.R.~ppm (~MSO-d6) : 1.27 (3H,t,J=7Hz), 3.72 (2H, broad s), 4.22 (2H,q, 3=7Hz), 4.33, 4.58 (2H,ABq, J=13Hz), 5.17 (lH,d,J=SHz), 5.87 ~$ (lH,dd,J=5 Hz, and 8 Hz), 6.45 (lH,d,J-6Hz), 7.03 (2H, broad s), 8.12 (lH,d,J=6Hz), 9.37 ~lH,d, J=8Hzl, 9.57 (lH,s).
The following compounds were obtained according to 30 *he similar manner to that of Example 15-(1).
(2) 7-12-(4-Aminopyrimidin-2-yl)-2-propoxyimino-acetamido]-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid ~syn isomer), mp 145-150C
tdec.).
~35 I.R.VNm~xl : 3375, 3225, 1780, 1660, 1590, .

--, ' ~

~ . , .
:

~ ~3~g~3 ' ` .

1540cm~
N.M.R.~ppm (DMSO-d6) : 0.90 (3H,t,J=7Hz), 1.4-1.8 (2H,m~, 3.58, 3.74 (2H, ABq,J-18Hzj, 4.08 (2H,t,J=7Hz), 4.26, 4.54 (2H, ABq,~=13Hz), 5.12 (lH,d,J=5Hz), 5.80 (lHId,d, J=5Hz,8Hz), 6~40(1H,d,J=6Hz), 7.00 (2~,s), 8.06 (lH,d,J=6Hz), 9.36 (lH,d,J~8Hz~, 9.52 (lH,s).
(3) 7-[2-Allyloxyimino~2-~4-aminopyrimidin-2-yl) acetamido~-3-(1,3,4-thiadiazol-2-ylthiomethylj-3-cephem~4-carboxylic acid (syn isomer), mp 150-153C
(dec.).
I.R.vNU~l : 3380, 3230, 1780, 1660, 1585, 1540cm~~.
i N.M.R.~ppm (DMSO-d6) : 3.7 (2H,broad s), 4.30, 4.57 (2H,ABq,J=13Hz), 4.68 ~2H,d,J=5Hz), 5.13 (lH,d, J=5Hz)~ 5.0-5~6 (2H,m), 5.85 (lH,d,d~J=5Hz,8Hz), 5.7~6.2(1H/m~, 6.42 (lH,d,J=6Hz), 7.02 (2H, broad s), 8.10 (lH,d,J=6Hz), 9.43 (lH,d,J=8Hz), 9.57 (lH,s).
~4) 7-~2-(4-Aminopyrimidin-2-yl)-2-benzyloxyimino-acetamido]-3~ 3~4-th}adiazol-2-ylthiomethyl]-3-~ cephem-4--carboxylic acid (syn isomer), mp 145-150C
: ~ tdec. ) .
I.R.vNmaxl : 3370, 3230, 1780, 1660, 1590, 1540cm-1.
N.M.R.~ppm (DMSO-d6~ : 3.5 (2H,broad s), 4.33, 4-57 t2H, ABq,J=13Hz), 5.15 (lH, d,J=5Hz), 5.28 (2H,s), 5.87 (lH, d,d,J=5Hz,8Hz), 6.47 (lH,d,J=6Hz) r 7.0-7.3 (2H,m), 7.40 (5H,s), 8.13 (lH,d,J=6Hz),9.55 (lH,d,J=8Hz), .

~2~

- ~-. .

~ ,- .. .,- .. .
.. . . -, . . .. ..

... .
. .. .

9.60 (lH,s).
(5~ 7-~2-(6-Aminopyridin-2-yl)-2-hydroxyimino-aeetamido~-3~ hexyl-lH tetrazol-5-yl~thiomethyl]
-3-cephem-4-carboxylic acid (syn isomer~, mp 148-153C (dee.).
I.R.vNmaxl : 3200, 1780, 1670, 1620, 810 725cm~l.
N.M.R.~ppm (~MSO-d6): 0.8-~1.8 (llH,m), 3.73 (2H, broad s~, 4.4 (4H,m), 5.17 (lH,d,J=4.5Hz), 5.87 (lH, d,d,J=4.5Hz,8Hz), 6.63 (lH,d,J=
8Hz), 6.88 (lH,d,J=8Hz), 7.53 ~lH,t,J=8Hæ), 9.45 ~lH,d,J=8Hz).
~6) 7-[2-(6-Aminopyridin-2-yl)-2-hydroxyimino-aeetamido]-3-[(1-allyl-lH-tetrazol-5-yl)thiomethyl-3-eephem-4-carboxylie aeid (syn isomer), mp 168-171C (dec.).
I~R~VNmaxl : 3350, 3200, 1775, 1665, 1620, 1250, 990, 805cm~l.
N.M.R.~ppm (DMSO-d6) : 3.75 (2H, broad s), 4.20, 4.52 (2H,ABq,J=14Hz), 5.0 (2~1,m), 5.06 (lH,d,J=4.5Hz), 5.3 (2H,m), 5.8-5.9 (2H,m), 6.65 ~lH,d,J=8Hz), 6.91 (lH,d,J=8Hz), 7~50 (lH,t,J=8Hz), 9.4 (lH,d, J= 8HZ ) .
(7) 7-[2-(6-Aminopyridin-2-yl)-2-methoxyimino-aeetamido]-3-[(1-allyl-lH-tetrazol-5-yl)thiomethyl]-3-cephem-4-~arboxylie aeid (syn isomer), mp 148-149C (dec.).
I~R~VNuaxl : 3380, 3240, 1780, 1670, 1620cm~l.
N.M.R.~ppm (DMSO-d6): 3073(2H,broad s~, 3.93 (3H,s), 4.21/ 4.54 (2H,ABq,J=14Hz), 5.0 (2H,m), 5.15 (lH,d,J=4.5Hz), 5.3 (2H,m), 5.8 (lH,m), 5.85 (lH,d,d,J=4.5Hz,8Hz), 6~51 (lH,d,J=8Hz) 7 ~ ~ ,3!
:

-: ' , , :
.
' : : ,, , 6.91 (lH,d,J=8Hz), 7.48 (lH,t, J=8Hæ), 9.5 (lH,d~J=8Hz).
( 8 ) 7 - E 2-(6-Aminopyridin-2-yl~-2~ 2~2-trifluoro ethoxyimino)acetamido3-3-~ carboxymethyl-lH-tetrazol-5-yl)thiomethyl]-3-cephem-4-earboxylic aeid (syn isomer3, mp 178C (dee.).
I.R.VNma~l : 3440, 3320, 1778, 1688, 1665, 1623, 1552cm~l.
N.M.R.~ppm (DMSQ-d6) : 3.60,3.74 (2~I,ABq, J=19Hz), 4.22,4.48 (2H,ABg,J=
14Hz), 4.68, 4.34 (2H,ABq,J=9Hz), 5.12 (lH,d,J=5Hz), 5.30 (2H,s), 5.83 (lH,d,d,J=5Hz,8Hz), 6.56 ; (lH,d,J=8Hz), 6.90 (lH,d,J=8Hz), 7.48 (lH,t,J=8Hz)~ 9.66 (lH,d, J-8E~z).
~ (9) 7-[2-(6-Aminopyridin-2-yl)-2-propargyloxyi-; minoaee~amido~-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-eephem-4-earboxylie aeid (syn isomer), mp 168-175C (dee.).
I.R.~NMal : 3300, 3200, 2160, 1775, 1735, 1670, 1630, 1085, 1025em~l.
; - N.M.R.~ppm lDMSO d6) : 3.6 ~3H,m), 4.30, 4.60 ~2H,ABq,J=13Hz), 5.00 (2H/s~, 5.22 (lH,d,J=4.5Hz), 5.83 (lH, d,d,J=4 5Hz,8.0Hzj, 6.80 (lH,d, J=6Hz~, 7.16 (lH,d,J=6Hz), 7.90 (lH,t,J=6Hz), 9.60 (lH,s), 10.01 (lH,d,J=8Hz).
30(10) 7-[2-(4-Aminopyrimidin-2-yl)-2-methoxyimino-acetamido]-3-[(1-allyl-lH-tetrazol-5-yl)thiomethyll-3-eephem-4-earboxylie aeid ~syn isomer)~
I.R.~Nmaxl : 3370j 3220, 1~80, 1680-1640em~l.
3 (11) 7-[2-(4-Aminopyrimidin-2-yl)-2 methoxyimino-acetamido3-3-cephem-4-carboxylic acid (syn isomer).

_ , : 1~

- .

.:

I.R.vNUaxl : 3380, 3240, 1780, 1680-1630, 1585, 1378, 1040, 985, 725c~
(12) 7-~2-~4-Aminopyrimidin-2-yl)-2-methoxyimino aeetamido]-2-methyl-3-cephem-4-carboxylic acid (syn isomer).
IdR.vNm~xl : 3400, 3300, 1780, 1665, 1635, lS9 0cm~ l .
: (13) . 7-12- (4-Aminopyrimidin 2-yl) -2-m~thoxyimino aeetamido3-3-methyl-3-cephem-4-earboxylie acid ~syn isomer).
I.R.vNm~xl ~ 3350, 3210l 1765, 1680-1630, 1580,-1375, 1040~ 920, 720cm~l.
(14) 7-[2-(4-Aminopyimidin-2-yl)-2-methoxyimino-aeetamido]-3-earbamoyloxymethyl~3-eepyem-4-earboxylie aeid (syn isomer).
I~R~VNmaxol : 3370, 3200, 1775, 1710, 1670-1630, 1400, 1320, 1040, 985, 720cm~l.
~15) 7- L2- (4-Aminopyrimidin-2-yl)-2-methoxyimino-aeetamido]~3-aeetylthiomethyl-3-cephem-4-earboxylie aeid (syn isomer) I.R.vNmal : 3400, 3240, 1?80, 1680-1630em 1 (163 7-[2-(4-Aminopyrimidin-2-yl)-2-methoxyimino-aeetamido3-3-ehloro-3-cephem-4-earboxylie aeid (syn isomer).
I.R.VNm~Xl : 3460, 3400, 3260, 1773, 1680-1650, 1620, 1570, 13~, 1270, 1095, 1040, 860 em~l.
; (17) Sodium 7-[2-(4-Aminopyrimidin-2-yl)-2-me~hoxy-iminoaeetamido3-3-15 (4-ehlorophenyl)-1,3,4-oxadia-zol-2-ylthiomethyl]-3-cephem-4-carboxylate (syn isomer).
I.R.vNU~xl : 3370, 3220, 1765, 1670-1600, 1400, 1090, 1040, 835, 728cm~l.
(18) 7-[2-(4-Amino-6-chloropyimidin-2-yl)-2-methoxyiminoaeetamido3-3-(1,3,4-thiadiazol-2-,~ , .
. .
: ~23 :
`
.;, . ~ .
~, ...
.. .~ ~ `
;. ~.
:

ylthlomethyl) 3-cephem-4-carboxylic acid (syn isomer).
I.R.vNm~xl ~ 3400, 3280, 1780, 1630, 1630, ~575, 1530, 1380, 1040, 900, 800cm~l.
519) 7-[2-t4-Aminopyrimidin-2-yl)-2-methoxyimino-aeetamido]-3-(pyrazin-2-ylthiolnethyl)-3-eephem-4-earboxylie aeid ~syn isomer).
I.R.VNmaol : 3350, 3250, 1780, 1660, 1590em~l.
~20) 7-[2-(4~minopyrimidin-2-yl)-2~methoxyimino-aeetamidoJ-3-(~etrazolo L 1~; 5-b]pyridaæin-6-ylthio-methyl)-3-eephem-4-earhoxylie aeid (syn isomer).
X.R.vNU~xl : 3350, 1770, 1660, 1530cm 1.
(21) 7-[2-(4-Amino-6-methoxypyrimidin-2-yl)-2-methoxyiminoaeetamido]-3-(1,3,4-thiadiazol-2-yl)thio-methyl-3-eephem-4 carboxylie aeid.
I.R. ~ ma~l: 3400~ 3250, 1780, 1675, 1620, 1580, 1380, 1O40 em 1.
(22) 7-[2-(4~Amino-6~phenyl~hiopyrimidin 2-yl)~2-methoxyiminoacetamido]-3-(1,3,4-thiadiazol-2-yl) thiomethyl-3-eephem-4-carboxylie aeid.
I.R. ~mUxol 3370~ 3250, 1780, 1680, 1630, 15~0, 750, 722 em 3~

~ 2 ~

`. - .
.

~;
':

~ 9~3 Example 16 A solution of 7-~2-allyloxyimino-2-(6-formamidopyridin-2 yl)acetamido]~3-(5-tert-butoxycarbonylaminomethyl-1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4~carboxylic acid (sym isomer) (2.7g) in formic acid (27mQ) was ~ 5 stirred for 2 hours at ambient temperature and evaporat-; ed to dryness. To the residue were added methanol ~SOmQ) and concentrated hydrochloric acid (0782g), and the mixture was stirred for an hour at ambient temper-ature. The solvent was evaporated and the residue was dissolved in water (SOmR), adjus~ed to pH 4 to 5 with an aqueous solution of sodium bicarbonate, treated with ~` an activated charcoal and then su~jected to column chromatography over noniomc adsorption resin, "Diaion HP 20" t80mQ). The column was washed with water and eluted with 50~ aqueous methanol. The eluent contain-ing a desired compound was evaporated to remove the methanol and then lyophilized to give 7-[2-allyloxyimino-2-(6-aminopyridin-2-yl)acetamido~-3-(5-aminomethyl-1,3, 4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer) (0.6g), mp 180C (dec.).
I~R.VNmaxl : 3400, 3250, 1770, 1670, 1620cm~1.
N.M.R.~ppm (DMSO-d6~D20): 3.63 (2H, broad s)~
4.2 4.8 (6H,m), 4.8-6.3 (5H,m), 6.53 ~IH,d,J=8Hz), 6.90 (lH,d,J=8Hz), 7.47 (lH,t,J=8Hz).

12~

-.

Example 17 (1) A mixture of 4-nitroben2yl 7-[2-(4-aminopyrimidin-2-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate (syn isomer) (3.0g) and 10% palladium on carbon ~1.5g) in 50% aqueous tetrahydrofuran ~90mQ) was stirred under hydrogen atmosphere for 3 hours at ambient temperature. The catalyst was removed by filtration and the filtrate was concentrated to ; half of the original volume. The remaining aqueous solution was diluted with water (lOOmQ), washed with ethyl acetate, adjusted to pH 3 with 10%
hydrochloric acid and subjected to column chromato-graphy over nonionic adsorption resin, "Diaion HP20"
The column was washed wi~h water and eluted with 10% methanol. The eluent containing a desired compound was evaporated to remove the methanol in vacuo and then lyophili~ed to give 7-~2-(4-amino-pyrimidin-2-yl)-2-methoxyiminoacetamido~-3-cephem-4~carboxylic acid (syn isomerj (750 mg), mp 191-; 197C (dec.).
I.R.vNUaxl : 3380, 3240, 1780, 1680-1630, 1585, 1378, 1040, 985, 725cm~l.
N.M.R.~ppm (DMSO-d6) : 3.6 (2H,m), 4.00 (3H, S~ t 5.13 ~lH,d,J=4.5Hz), 5.91 (lH,dd,J=4.5Hz,8Hz), 6.50(1H,d, ; 25 J=7Hz), 6.6 (lH ,m), 7.03 (2H, broad s), 8.17 (lH,d,J=7Hz), 9.47 d,J=8Hz).
The following compounds were obtained according to the similar manner to that of Example 17-(1).
(2) 7-[2-(4-Aminopyrimidin-2-yl~-2-methoxyimino-acetamido]-3-chloro-3-cephem-4-carboxylic acid (syn isomer), mp 200-205C (dec.).
I.R.VNuiol : 3460, 3400, 3260, 1773, 1680-1650, max 1620, 1570, 1380, 1270, 1095, 1040, 860cm~l.

- . ..
~ 2 6 :

N.M.R.~ppm (DMSO-d 6 ) : 3.60, 4.03 (2H,ABq, J-18Hz), 3.95 (3H,s), 5.25 (lH,d,J=4.5Hz), 5.85 (lH,d,d, J=4.5Hz, 8.0Hz), 6.4~ ~lH,d,J=
7Hz), 7.03 (2H, broad s), 8.11 (lH,d,J=7.0Hz), 9.50 ~lH,d,J=
8.OHz).
(3) 7-~2-(4~Aminopyrimidin-2-yl)-2-methoxyimino-aeetamido]-3-[1-allyl-lH-tetrazol-5-yl)thiomethyl~-3-eephem-4-carboxylie aeid (syn isomer).
I.R.vNuiol : 3370, 3220, 1780, 1680-1640em~~.
max ~4) 7-[2-t4-Aminopyrimidin-2-yl)-2-methoxyimino-acetamido]-2-methyl-3-eephem-4-earbQxylie aeid (syn isomer).
I.~.vNm~xl : 3400, 3300, 1780, 1665, 1635, l59Oem~l.
(5) 7-[2~(4-Aminopyrimidin-2-yl)-2-methoxyimino-aeetamido]-3-methyl-3-cephem-4-carboxylie aeid ~syn isomer).
I~R~VNmaXl : 3350, 3210, 1765, 1680-1630, `1580, i375, 1040, 920, 720em-1.
(6) 7-[2-(4-Aminopyrimidin-2-yl)-2-methoxyimino-acetamido]-3-earbamoyloxymethyl-3-eephem-4-earboxylie aeid (syn isomer).
I.R.VNmaol : 3370, 3200, 1775, 1710, 1670-` ~ 1630, 1400, 1320, 1040, 985, 7 2 0 cm~ 1 .
~ (7) 7-[2-(4-~minopyrimidin-2-yl~-2-methoxyimino-; aeetamido]-3-acetylthiomethyl-3-eephem-4-carboxylie aeid (sym isomer).
I.R.VNmaXl : 3400, 3240, 1780, 1680-1630em~l.
(8) Sodium 7-[2-(4-Aminopyrimidin~2-yl)-2-methoxy iminoacetamidol-3-~5-(4-chlorophellyl)-1,3,4-~; oxadiazol-2-ylthiomethyl]-3-cephem 4-carboxylate (sym isomer).
.
.
~2 7 ,, . .: . . -- . . . . , . . ... i . .
~, - ; - .
` .. ,. ~;. . ~ . .
,~
, . .. . . .. . .

I.R.vNUaxl : 3370, 3220, 1765, 1670-1600, 1400, 1090, 1040, 835, 728cm 1.
(9) 7-~2-(4-Amino-6-chloropyrimidin-2-yl)-2-methoxyiminoacetamido]-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer).
I.R. ~Nu~xl 3400, 3280, 1780, 1680, 1630, 1575, 1530, 1380, 1040, 900, 800cm~l.
10~10) 7-l2-~4-Aminopyrimidin-2-yl)-2-ethoxyimin acetamido~-3-(1,3,4 thiadiazol-2-ylthiomethyl3-3-~ephem-4-carboxylic acid (syn isomer).
I.R. vNUaol: 3350, 3250, 1780, 1660, 1585cm~
(11) 7-[2-~4-Aminopyrimidin~2--yl)-2-propoxyimino-acetamido]-3-~1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer)~
I.R. vNU~xl: 3375, 3225, 1780, 1660, 1590, : 1540cm ~.
(12) 7-[2-Allyloxyimino-2~(4-aminopyrimidin-2-yl) acetamido]-3-(1,3,4-thiadiazol-2-ylthiometyl)-3- .
cephem-4-caxboxylic acid (syn isomer).
I.R. ~Nm~oxl 338G, 3230, 1780, 1660, 1585, ~ 1540cm~l.
; (13) 7-~2-(4-Aminopyrimidin-2-yl)-2-benzyloxyimino-acetamido]-3-~1,3,4-thiadiazol-2-ylthiomethyl~-3-cephem-4-carboxylic acid (syn isomer).
I.R. vNm~Xl: 3370, 3230, 1780, 1660, 1590, 1540cm~ .
(14) 7-[2-(6-~mlnopyridin-2-yl)-2-hydroxyimino-acetamido]-3-~(1-hexyl-lH-tetrazol-5-yl)thiomethyl]-3~ceplem-4-carboxylic acid (syn isomer).
I.R. ~NU~oxl 3200, 17R0, 1670, 1620, 810, 725cm~ .
(15) 7-12-(6-Aminopyridin-2-yl)-2-hydroxyimino-acetamido]-3~ -allyl~lH-tetrazol-5-yl)thiomethyl]

, .
~9~ ~

':

.

3-cephem-4-carboxylic acid ~sym isomer).
I.R. vNU~xl : 3350, 32ao, 1775, 1665, 1620, 1250, 990, 805cm~l.
~16) 7-[2-(6-Aminopyridin-2-yl)-2-methoxyimino-acetamido]-3-[(1-allyl lH-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid (syn ïsomer).
I.R. vNm~Xol : 3380, 3240, 17%0, 1670, 1620cm~~
(17) 7-[2-(6-Aminopyridin-2-yl)-2-~2,2,2-trifluoro ethoxyimino)acetamido~3-[(1-carboxymethyl-lH-tetrazol-5-yl)thiome~hyl~-3-cephem-4-carboxylic acid (syn isomer).
l.R. ~Nuaxl : 3440, 3320, 1778, 1688, 1665, 1623, 1552cm~l.
(18) 7-[2-~6-Aminopyridin-2-yl)-2-propagyloxyimino acetamido~-3-~1,3,4~thiadiazol-2-~lthiomethyl)-3-cephem-4-carboxylic acid ~syn isomer).
I.R. vNUiol : 3300, 3200, 2160, 1775, 1735, max 1670, 1630, 1085, 1025cm-~.
(19) 7-[2-(4-Aminopyrimidin-2-yl)-2-methoxyimino-acetamido~-3-tpyrazin-2-ylthiomethyl)-3-cephem-4 carboxylic acid (gyn isomer).
I.R. vNUaol : 3350, 3250, 1780, 1660, 1590cm~~.
t20~ 7-[2-4-Aminopyrimidin-2-yl)-2-methoxyimino-acetamido]-3-~tetrazolo~1,5-b]pyridazin-6-ylthiome-thyl)-3-cephem-4-carboxylic acid ~syn isomer).
I.R. vNUaxl ~ 3350, 1770, 1660, 1530cm~~.
(21) 7-[2-~4-Amino-6-me~hoxypyrimidin-2-yl) 2-methoxyiminoacetamido]-3-[1,3,~-thiadiazol~2-yl)-3~ thiomethyl-3-cephem-4-carboxylic acid.
I.R.l~Nm~l : 3400, 3250, 1780, 1675, 1620, 1580, 1380, 1040cm (22) 7-[2-(4-Amino-6-phenylthiopyrimidin-2-yl)-2-methoxyiminoacetamido]-3-(1,3,4 thiadiazol-2-yl)-thiomethyl-3-cephem~4-carboxylic acid.
' 2~
.

, ` ,. . , ~

:

- ~!Z~Z3 :

I.R. 1) Nu~ol: 3370, 3250, 1780, 1680, 1570, 750, 722cm ~23) Benzhydryl 7- [2-~6-Eormamidopyridin-2-yl)-2-methoximinoacetamido]-7-methoxy-3-(1-methyl-lH-tetrazol-5-yl~thiomethyl-3-cephem-4-carboxylate (1.1 g) was added to a cooled mixture of trifluoro-acetic acid (10 ml) and anisole (2 ml), and stirred under ice cooling for 30 minutes. After removing the solvent from the resultan~ solution, the residue was triturated with diethyl ether. The precipitates were collected by filtration and washed with diethyl ether to give 7-~2-~6-formamidopyridin-2-yl)-2-methoxyiminoacetamido]-7-methoxy-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (900 mg) 7 mp 124 to 128C ~dec.).

I.R. v NaUJol: 3400-3200, 1780t 17009 1670 cm 1 N.M.R. ~ppm (aceton-d6) : 3.59 (3H, s), 3.63, 3,76 (2H, AB-q, J=18Hz), 4.00 ~6H, s), 4.36 (2H, broad s), 5.13 (lHg s), 6,90-8.10 ~3H, m).

~ ~3 ~3 ~, .. , .~

Z~3 Example 18 (1) A mixture of 7-~2-(2,2,2-trifluoroethoxyimino~-2-~6-formamidopyridin-2-yl)acetamido]cephalosporanic acid (4.7g), disodium salt of 2 (5-mercapto-lH-tetrazol-1-yl)acetic acid (2.3g) and sodium bicarbo-; 5 nate (0.72g) in phosphate buffer (pH6.4, 150mQ) was stirred for 3 hours at 60 to 65C and -then for 2 hours with an additional disodium salt of 2-(5 mercapto-lH-tetrazol-l-yl)acetic: acid (0.88g) at the same temperature. The reaction mixture was cooled in an ice bath, adjusted to pH4.5 with 0%
hydrochloric acid and washed with ethyl acetate.
The aqueowssolution was acidified to pH 1 with 10%
hydrochloric acid and extracted with ethyl acetate.
The extract was washed with wa~er, dried over anhydrous magnesium sulfate and evaporated to dry-ness. The residue was triturated with diethyl ether and washed with the same solvent to give crude 7-[2-(2~2~2-trifluoroethoxyimino)-2-16-formamido-pyridin-2-yl)acetamido]-3-[(1-carboxymethyl-lH-tetra-~0 ~ol-5-yl)thiomethyl~-3-cephem-4-carboxylic acid (syn isomer) (2.3g).
This compound was identified by transforming it to 7-12-(2~2,2-trifluoroethoxyimino)-2-(6-amino-pyridin-2-yl)acetamido~-3-[(1-carboxymethyl-1~-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid (syn isomer) according ~o the similar manner to that of Example 2-(g)~
I.R. vNmaXl : 3440, 3320, 1778, 1688, 1665, 1623, 1552cm~l.
~ The following compound was obtained according to ; the similar manner to that of Example 18-(1).
(2) 7-[2-~4-Formamidopyrimidin-2-yl)-2-methoxyimino acetamido]-3-(tetrazolo[1,5-blpyridazin-6-ylthio-methyl)-3-cephem-4-carboxylic acid (syn isomer), mp 170-175C (dec.).

13~

. . .
.
,~ i . `
~ . . . .
-- ~L9,'Z~3 I.R. vNU]l : 3250, 1780~ 1710, 1680, 1570cm 1.
N.M.R.~ppm (DMSO-d 6): 3.76 (2H,broad, s), 4.00 ~3~,s~, 4.27, 4.63 (2H, ABq,J=14~z), 5.20 (lH,d/J=4Hz~, 5.90 (lH,d,d,J=4Hz,8Hz),7.43 (lH, broad s), 7.77 (lH,d,J=
lOHz), 8.58 (lH,d,J=lOHz~, 8.70 (lH,drJ=4Hz)~ 9.10 (lH,broad s), 9.5 ~lH,d,J=8Hz).
(3) A mixture of 7-[2-(4-formamidopyrimidin-2-yl)-2-methoxyiminoacetamido3-3~acetoxymethyl-3-cephem-4-carboxylic acid (syn isomer) (2.8g3, 2-mercatopyra-zine (0.853g~ and ~odium bicarbonte (1.48g) in phosphate buffer (pH 6.86/ 12QmQ) was stirred ~or 3 hours at 70C. The reaction mixture was cooled in an ice bath and adjusted to pH2 with 10~ hy-drochloric acid. A resultant solid was filtered and the filtrate was washed three times with ethyl acetate. The solid was dissolved in a mixture of ethyl acetate, acetone and water, and then the aqueous layer was separated out. The filtrate and the aqueous layer wera combined, concentrated in vacuo to remove ace~one and ethyl acetate andjthen subjected to column chromatography over nonionic adsorption resin, "Diaion ~P 2Q".
The column was washed with water and 20~ aqueous methanol and eluted with 50~aqueous methanol.
The eluent was evaporated to remove the methanol in vacuo and then lyophilized to give 7 [2-(4 amino-pyrimidin-2-yl)-2-methoxyiminoacetamido]-3-(pyrazin-2-yl-thiomethyl)-3-cephem-4-carboxylic acid (syn isomer) (0.9g), mp 175-180C (dec.).
I.R. vNujol 335Q, 3250, 1780, 1660, 1590cm~1.
N.M.R.~ppm (DMSO-d6): 3.55,3.73(2H,ABq,J=18~z), 4.00 (3H/s~, 4.10, 4.62 (2H,ABq, , ~3~

.
- . ,~
. . . . . .

~Z~9~3 ' ;~ J=13Hz) 5.17 (l~I,d,J=4H~), 5.83 (lH,d,d,J=4Hz,8Hz~, 6.48 ~lH,d,J=6Hz), 7.10 (2~,s), 8.15 ~lH,d,J=6Hz), 8.30-8.67 (3H,m)~ 9.45 (1H,d,J=8Hz) The following compounds wsre obtained according to the similar manner to that of Example 5-(3).
(4) 7-~2-(4-~minopyrimidin-2-yl)-2-methoxyimino-acetamido]-3~ allyl-lH-tetrazol-5-yl)thiomethyl~
,~ ~ 10 -3-cephem-4-carboxylic acid ~syn isomer).
~ Ro vNU]ol : 3370, 3220, 1780, 1680-1640cm~l.
i (5) Sodium 7-~2-(4-Aminopyrimidin-2-yl)-2-methoxy-iminoacetamido]-3-~5-~4-chlorophenyl)-1,3,4-oxa-diazol~2-ylthiomethyl3-3-cephem-4-carboxylate (syn isomer).
I.R. ~Nu~ol : 3370, 3220, 1765, 1670-1600, 1400, 1090, 1040, 835, 728cm~l.
(6) 7-[2-(4-Amino-6-chloropyrimidin-2-yl)-2-methoxyiminoacetamido]-3-~1,3,4-thiadiazol-2-~ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer).
I.R. vNU~oxl : 3400, 3280, 1780, 1680, 1630, 1575, 1530, 1380, 10~0, 900, ~` 800cm 1.
~ , (7) 7-[2-(4-Aminopyrimidin-2-yl)-2-ethoxyimino-~ acetamido]~3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer~.
I.R.~vNUal O 3350, 3250, 1780, 1660, 1585cm~l.
(8) 7-~2-(4-Aminopyrimidin-2-yl)-2-propoxyiminoace-tamido]-3-(1,3,4-thiadiazol-2-ylthiomethyI)-3~ -cephem-4-carboxylic acid ~syn isomer).
I.R. vNU~l : 3375, 3225, 1780, 1660, 1590, '; ~ 154ûcm-1~
~9) 7-[2-Allyloxyimino-2-~4-aminQpyrimidin-2-yl) acetamido]-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer).

3 3 ~ ~

- ~ . ~ . ., . . ` .
-~ . . ~ , ... ... ... .. . . .
- . . . , .
..

V~

I.R. vNmaXl : 3380, 3230, 1780, 1660, 1585, 154Ocm 1.
(10) 7-~2-(4-Aminopyrimidin-2 yl)-2-benzyloxyimino-acetamido~-3-(1,3,4-thiadiazol-2-ylthiomethyl~-3-cephem-4-carboxylic acid (syn isomer).
I.R. vNmal : 3370, 3230, 1780, 1660, 1590, 1540cm~l.
~11) 7-~2 (6-Aminopyridin-2-yl)-2-hydroxyimino-acetamido]-3-~(1-hexyl-lH-tetrazol-5-yl)thiomethyl~-3-cephem-4-carboxylic acid (syn isome~).
- I.R. vNUiol : 3200, 1780, 1670, 1620, 810, max 725cm~ .
(12) 7-~2-(6-~minopyridin-2-yl~-2-hydroxyimino-acetamino]-3-[(1-allyl-lH-tetraæol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid (syn isomer).
I.R. VNujol 3350, 3200, 1775, 1665, 1620, ~` 1250, 390, 805cm~l.
~13) 7-[2-(6-Aminopyridin-2-yl)-2-methoxyimino-acetamido]-3-[(1-allyl-lH tetrazol-5-yl)thiomethyl~-3-cephem-4-caxboxylic acid (syn isomer).
I.R. vNmal : 3380, 3240, 1780, 1670, 1620cm~l.
(14) 7-[2-(6-Aminopyridin-2-yl)-2-(2,2,2-trifluoro ethoxyimino)acetamido]-3-~(1-carboxymethyl-lH-tetrazol~5-yl)thiomethyll-3-cephem-4-carboxylic ~;~ 25 acid (syn isomer).
I.R. vNmaxl : 3440, 3320, 1778, 1688, 1665, 1623, 1552cm~l.
(15) 7-~2-(6-Aminopyridin-2-yl)-2-propargyloxyimino-acetamido]-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer).
I.R. vNU3xl : 3300, 3200, 2160, 1775, 1735, 1670, 1630, 1085, 10~5cm~l.
(16) 7-[2-(4-Aminopyrimidin-2-yl)~2-metnoxyimino ; acetamido]-3-(tetrazolo~1,5-b]pyridazin-6-ylthio-methyl)-3-cephem-4-carboxylic acid (syn isomer), - .
1 3~

:. , :

mp 200-203C (dec.~.
I.R. ~Nujol : 3350, 1770, 1660, 1530cm - max N.M.R. ~ppm (DMSO-d6) : 3.63, 3.77 (2H,ABq, ~ ~=18~z), 3.93 (3H~s), 4.23, 4.60 ~2H,ABq,J=14Hz), 5.12(1H,d,J=4Hz), 5.85 (iH,d,d,3=4Hz,8Hz), 6.45 (lH,d,J-6Hz), 7.10 (2H,s), 7.75 ~lH,d,J=lO~z), 8.12 (lH,d,J=6EIz),.
8.60 (lH,d,J=lOHz), 3.43(1H,d, - J-8Hz).
(17) 7-[2-(4-Amino-6-methoxypyrimidin-2-yl)-2-methoxyiminoacetamido]-3-~1,3,4-thiadiazol-2-yl)-thiomethyl-3-cephem-4-carboxylic acid.
I;R. ~Nmaxl . 3400, 3250, 1780, 1675, L620, ;~ 15 1580, 1380, 1040cm (18) 7-[2-(4-Amino-6-phenylthiopyrimidin-2-yl)-2-methoxyiminoacetamidol-3-(1,3,4-thiadiazol-2-yl)-~ thiomethyl-3-cephem-4-carboxylic acid.
; ~ I.R. ~Nmal~ : 3370, 3250, 1780, 1680, 1630, 157n, 750, 722cm~l.

j .
~:

, .. ..

: _ .
: ~ 13~ : :

. , . ~ . . ;

, llZ09Z3 ;

.

Example 19 7-[2-~4-Aminopyrimidin-2-yl)-2-methoxyimino-acetamido]-3-[1-(2-tert-butoxycarbonylaminoethyl3-lH-tetrazol-5-yl]~hiomethyl-3-cephem-4-carboxylic acid (syn isomer~ was obtained by reacting 7-amino-3-[l-~2-tert-butoxycarbonylaminoethyl)-lH-tetrazol 5-yl]-thiomethyl-3-cephem-4-carboxylic acid, which can be prepared from 7-aminocephalosporanic acid and 1-(2-tert-butoxycarbonylaminoethyl)-lH-tetrazole-S-thiol, with 2-(4-aminopyrimidin-2-yl)-2-methoxyiminoacetic acid (syn isomer) in substantially the same manner as that o~ Example 14-~1).
Physical constant of 7-amino-3-[1~(2-tert-butoxycarbonylaminoethyl)-lH-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid:
mp 185 - 189.C (dec.) I.R. ~ Nu301 : 3420, 3200,1810, 1700, 1620, 1525, 1290, 1175 cm N.M.R. ~:ppm (NaHCO3~D203 : 1.33 ~H, s), 3.3-3.9 (4H, m), 4.20, 4.40 ~2H, ABq, J=13Hz), 4.5-4.9 (2H~ m), 5.10 ~1~, d~ J=5Hz), 5.51 ~lH, d, J=SHz) .

.

.

~ 9 ~ 3 Physical constant of 7-[2-(4-aminopyrimiclin-2-yl)-2-methoxyiminoacetamido]-3-~1-(2-tert-butoxy-carbonylaminoethy~ H-tetrazol-5-yl]thiomethyl-3 cephem-4-carboxylic acid (syn isomer);

I.R. v mUa~ol : 3400, 3220, 1790, 1720-1640, 1530, 1260, 1175, 1055, 725 cm 1 .

N.~.R. ~ppm (DMSO-d6+D2O) : 1.66 ~9H, s), 3.0-3.7 ~2H~ m), 3.7 ~2H, m), 4.12 ~3HI s), 4.4 (4H, m), 5.19 (lH, d, J-5Hz~, 5.86 ~lH, d, J=5Hz~, 6.90 (lH, d, J=7Hz), 8.23 ~lH, d, J=7Hæ) Example 20 7-~2-~4-Aminopyrimidin-2-yl)-2-methoxyimino-acetamido]-3-[1~2-aminoethyl)-lH-tetrazol-S-yl]-thiomethyl-3-cephem-4-carboxylic acid ~syn isomer) was obtained from the object compound in Exan!pl~ 19 in substantially the same manner as that of Example 3, mp 183-195C ~dec.).
~`
I. R. v NUa3ol : 3400, 3220, 1770, 1660, 1630, 1590, ~540, 1180, 1040 cm N.M.R.~ ppm ~DMS0-d6~D2O~ ~, 3.i-3.8 ~4H, m), 3.99 ~3H, s), 4.3 (2H, m), 4.7 ~2H~ m~, 5.12 (lH, d, J=5Hz), 5.82 ~lH, d, J=5Hz), 6.61 (lH, d> J=7Hæ), 8.28 (lH, d, J=711z).

, ..
~ 3 7 Preparation of the starting compounds ; ~reparat~.on 1 (1) A 15% n-hexane solution ~636 g.) of n-butyllithium was added to a solution of 6-amino-2-methylpyridine (64.8 g.) in tetrahydrofuran ~500 ml.) at -20 to -30C over one hour, and stirred at -8 to -10C for 30 minutes. To the solution was added trimethylsilylchloride (161.7 g.) at -15 to -5C
over 40 minutes, and the resultant solution was stirred at room temperature overnight. The solution was filtered through by a column packed with silica gel (180 g.), washed with tetrahydrofuran and then the filtrate was concentrated under reduced pressure. The residue was purified by frackional distillation to give 6-EN,N-bisttrimethylsilyl)-; amino-2-methylpyridine ~117.6 g.)p b.p. 95 to 97C/5-6 mm.
N.M.R. ~ppm (CCQ4) : 0.13 (18H, s), 2.35 ~3H, s)~
6.43 (lH, d, J=8Hz), 6.60 ~lH, d, ~=8Hz~, 7.25 ~lH, t, J=8Hz) (2) A 15% n-hexane solution ~33806 g.) ~f n-butyllithium was dropwise added to a solution of 6-[N,N-bis~trimethylsilyl~amino]-2-methylpyridine ~100 g.) in anhydrous tetrahydrofuran (300 ml.~ at -20 to -30C over one hour and the solution was stirred at 20 to 23C for one hour. The resultant solution was added in small portions to crush~ed dry ice ~1 kg.) under stirring, and stirred till a room tempera~ure. After removing tetrahydrofuran from the solution under reduced pressure, absolute ethanol ~1 Q) was added to the residue. 30% Ethanol solution (660 ml.) of hydrochloric acid was dropwise added to the solution at -5 to -10C, and further hydrogen chloride gas was bubbled at 0 to 5C for 30 minutes and then the solution was stirred at 10C overnight. After removing ethanol from the resultant solution, the residue was dissolved in water, _ : 13 ~ ' and washed with ethyl acetate 3 times. The solution was adjusted to pH 7 to 8 with sodium bicarbonate and extracted with ethyl acetate. The ethyl acetate extract was washed with a saturated aqueous solution of sodium chloride, dried and concentrated under reduced pressure to give the crude product (54 g.) The product was purified by colum~ chromatography on silica gel (l kg.) with an eluent ~ethyl acetate + benzene) to give ethyl 2-(6-aminopyridin-2-yl)acetate (3002 g.), mp 66 to 68C.
I.R. ~ Nm~a~l : 343a, 3340, 3200, 1730, 1645, 1480, 1190 cm 1 N.M.R. ~ppm tCDCQ3) : 1.25 ~3H, t, ~6Hz), 3.67 ~2H, s), 4.20 (2~, q, J=6Hz), 5.33 (2H, broad s), 6.43 (lH, d, J=8Hz), 6.62 (lH, d, J=8Hz), 7.40 (lH, t, J=8Hz~.
.
~3) Acetic anhydride ~16.6 ml.) and 98% formic acid ~7.32 ml.) were mixed at room temperature and stirred at 50 to 66C for 30 minutes. The solu~ion was dropwise added to a solution of ethyl 2-(6-aminopyridin-2-yl)acetate (26.5 g.) in ethyl acetate (250 ml.) a* 20 to 23C over ~0 minutes, and stirred at the same temperature for one hour. Cool water was added to ~he resultant solution and shaked sufficiently. The ethyl acetate layer was separated, washed with water/ an aqueous solution of sodium bicarbonate and water in turn, dried and concentrated under reduced pressure to give ethyl 2-(~-formamidopyridin-2-yl)acetate (28 g.), mp 35 to 38C.

.

- , ~ .

I. R. v Nma3l : 3250, 3100, 1738, 1690, 1580, 1460, 1305, 1277 cm 1 N.M.R. ~ppm (IlMS0-d~) : 1.17 (3H, t, J=8Hz), 3 75 (2H, s)~ 4.08 ~2H, q, J=8Hz), 6.85 ~O.SH9 b-road d, J=8Hz), 7.95 ~0.5H, broad s), 7.08 ~lH, d, J=8Hz), 7.73 ~lH9 t, J=8Hz), 8.33 (0.5H, broad s) 9 9.25 (0.5H, broad d), 10.58 ~lH, broad s)O

(4) To a solution of ethyl 2-~6-formamidopyridin-2-yl)acetate (26 g.) in dioxane ~260 ml.) was added selenium dioxide ~16.65 g.) in small portions at 85 to 90C o~er on~ hour and stirred at the same temperature or one hour.
After cooling the resultant solution the dioxane layer was separated and concentrated under reduc~d pressure and then ; the residue was dissolved in ethyl acetate. The solution was washed with water, dried over magnesium sulfate and treated with acti~ated charcoal and ~hen concentrated ~u~der reduced pressure. The residue was triturated with diethyl ether to give ethyl 2-(6-formamidopyridin-2-yl)glyoxylate . (14.3 g.), mp 124 to 126C.

1. R. v max O 32209 31009 1737, 1720, 1690, 12737 1233 cm N.M.R. ~ppm (DMSO~d6): 1.34 (3H, t, J=8Hz}, 4.44 ~2H, q, J=8Hz), 7.33 (0.65H, broad 5~ J 7.8 - 8.2 (0.35H), 7.84 ~lH, d, J=8Hz), 8.09 (lH, t, J=8Hz?, 8.44 ~0.35H, broad s), 9.22 (0.65H, broad s)~ 10.85 (lH, broad s).

:
. ` ' , . ~

~b L~

(5) 2N Sodium hydroxide solution [solvent:water ~1 part) + ethanol (4 parts)] ~14.87 ml.) was added to a solution of ethyl 2-~6-formamidopyridin-2-yl)glyoxylate (6.00 g.) in ethanol ~180 ml.) at room temperature and stirred at the same temperature for 20 minutes.
Me*hoxyamine hydrochloride (2.71 g.) was added to the resultant solution, stirred at room temperature for 1.5 hours and then concentrated to a small volume under re-duced pressure. The precipitates were collected by fil-teration washed with ethyl acetate and water, dissolved in methanol and then treated with activated charcoal. The solution was concentrated under reduced pressure and then the precipitates were colleçted by filtration to give 2-~6-ormamidopyridin-2-yl)-2-methoxyiminoacetic acid (3.63 g.), mp 170 to 171C (dec.).

R. ~ NUxol : 3230, 3132, 1745, 1680, 15759 1450 ~ 1320 ? 1208, 1032 cm 1 N.M.R. ~ppm (DMS0-d6) : 3.70 (3H, s)~ 6.90 (0.6H, ~; 2~ broad d)9 7.9 (0.4H, broad s), 7.10 (lH, d, J=8Hz), 7.75 ~lH, t, J-8Hz), 8.38 (0.4H, broad s), 9.25 (0.6H, broad d) - 10.58 ~lH~ broad d).

(6) To a solution of ethyl 2-(6-formamidopyridin-~-yl)acetate (4.4 g.) in ethanol (44 ml.) was added 2N sodium hydroxide solution [solvent:water (1 part~ + ethanol (4 parts] (15.9 ml.) a~ 18 to 20C over 30 min~tes, and then the solution was stirred at room temperature for one hour.
After lN hydrochloric acid (31.7 ml.) was added to the ,. ~fl ~

.~ , .

~ 9 ~ 3 solution, the solution was concentrated under reduced pressure. The residue was extracted with hot ethyl ; acetate ~500 ml.) and the extract was concen~rated under reduced pressure. The residue was washed with ethyl acetate to gi~e 2-(6-formamidopyridin-2-yl)acetic acid (2.5 g.), mp 125 to 126C (dec.).

I.R. v NuJol : 3270, 1720, 1655, 1575, 1460 cm 1 N.M.R. ~ppm (DMSO-d6~D20) : 3.70 (2H, s), 6.9 and 7.9 (lH, m), 7.10 (lH, d, J=8Hæ), 7.75 (lH, t, J=8Hz), 9.25 and 8.38 (lH, ~ broad s).
-(7) A suspension o~ 2(6-formamidopyridin-2-yl)-2-methoxyiminoacetic acid ~1.5 g.) and conc.hydrochloric acid tO-77 g.) in methanol t30 ml.) was stirred at room tem-perature for 45 minutes. After concentrating the Tesultant solution under reduced pressure, ~he residue was washed with diethyl ether. The precipitates were collected by filtration to give 2-~6-aminopyridin-2-yl)-2-methoxyimino-acetic acid hydrochloride (1.63 g.), mp 100 to 105C.

R ~ NuJol : 3~00 - 3150, 1730, 1670, 12459 1050, 803 cm 1 N.M.R. ~ppm ~DMS0-d6) : 4.13 (3H, s~, 6.B9 (lH, d, J=8Hz), 7.22 ~lH, d, J=8.5Hz), 7.95 (lH, dd, J=8.5Hz, 8Hz).

t8) Bis(trimethylsilyl)~cetamide tI.61 g.) was added 1 ~

~; :

~ J~ 3 to a stirred suspension of 2-(6-aminopyridin-2-yl)-2-methoxyiminoacetic acid hydrochloride (410 mg.) in ethyl - acetate ~5 ml.) all at once, and stirred at 40C for 50 minutes. Trifluoroacetic anhydride tl.3 g.) was dropped into the solution at -10 to -5C over 30 minutes, and then the solution was stirred at the same temperature for 3 hours. Ethyl acetate ~10 ml.) and.water ~3 ml.) were added to the resultant solution. ~he solution was washed with water and a saturated aqueous solution of sodium bicarbonate in turn 9 dried over magnesium sulfate, and concentrated under reduced pressure to give 2-~6-trifluoroacetamidopyridin-~-yl~-2-methoxyiminoacetic ac;d (470 mg.), mp 194 to 195C.

I. R. v NmUaxol : 3350, 1680-lG70, 1600, 1380, 1040, 850, 810 cm 1 (9) lN Sodium hydroxide (27.5 ml.) was added to a stirred solution of ethyl 2-~6-formamidopyridin-2-ylj-' glyoxylate ~5.55 g.) in ethanol (lO0 ml.) a~ room temperature, and the solution was stirred at the same temperature for 3n minutes. To the solution was added hydroxylamine hydrochloride (1.9 g.) all at once 9 and the solution was stirred at room temperature for 2 h~urs. Af~er removing ethanol from the resultant solution under reduced pressure, ethylacetate was added to the residue, and then the so~ut-ion was adjusted to pH 7 with an aqueous solution of sodium bicarbonate. The aqueous layer was separated and adjusted to pH 2 with 10% hydrochloric acid. The precipitates were collected by filtration, washed with water and dried to 1~

.. ..

~ ~ 2~ 3 give 2-(6-foTmamidopyridin-2-yl)-2-hydroxyiminoacetic acid t3.6 g.), mp 190 to 192C (dec ).

I. R.~ v NUaxol : 3120, 1700, 1665, 1620 cm 1 (103 A mixture of 2-~6-formamidopyridin-2-yl)-2-hydroxyiminoacetic acid (3.6 g.), dichloroacetyl chloride ~7.6 g.) and methylene chloride tlO0 ml.) was stirred at room temperature for 5 hours. The precipitates were col-lected by filtration, washed with diethyl ether and dried to give 2-~6-formamidopyridin-2-yl)-2-dichloroacetoxyimino-~ . .
acetic acid (4.6 g.~, mp 88 to 90C.

I. R. v NuJol : 1800, 1720, 1620 cm 1 Prep~ration 2 1) A mixture of acetic anhydride (32.7 g.) and formic acid tl6.2 g.~ was stirred at 50 to 60C for 30 minutes. The solution was added ~o a suspension of methyl 2-~2-aminopyrimidin-4-yl~acetate (17.93 g.) ln ethyl acetate t300 ml.) at room temperature over 10 minutes, and the solution was stirred at room temperature for 3 hours.
; After remo~ing the insoluble substance by filtration, water (300 ml.~ was added to the filtrate, and then the mixture was adiusted to pH 7 with sodium bicarbonate. The aqueous layer was separated and extracted with ethyl acetate. The extract and the organic layer were combined~ washed with a saturated aqueous solution of sodium chloride~ dried over magnesium sulfate, treated with activated charcoal~ and then concentrated under reduced pressure. The residue was ' , , ~riturated with diethyl ether to give methyl 2-(2-formamidopyrimidin-4-yl)acetate tl4.62 gO)~ mp 103 to 107C.

I.R. v NUa~ol : 3000-3400 (multiple), 174Q, 1703, 1600, 1567 cm 1 N.M.R. ~ppm (DMSO-d6) : 3.70 (3H, s), 3.90 (2H, s), 7.25 (lHg d3 J=5Hz), 8.60 (lH, d, J-5Hz), 9.43 (lH, d, J=lOHz), 11.07 (lH, broad d~ J=lOHz) . .
:..
:~ (2) Selenium oxide t9^g2 g.) was added to a solution of methyl 2-(2-formamidopyr.imi~in-4-yl)acetate ~14.52 g.) in dioxane (20Q ml.) at 90 to 95C over 20 minutes, and stirred at the same temperature for an hour. After cool-ing the resultant solution, the solution was filtered : through a column packed with silica gel (20 g.), washed with dioxane and concentrated under reduced pressure.
: The residue was dissolved in acetone and filtered, and then the flltrate was concentrated under reduced pressure.
The residue was triturated with chloroform to give a ;: crude product ~8.2 g ). The product was added to ethyl . . acetate9 heated and an insoluble material was filtered out. The filtrate was cooled, and the precipitates were collected by filtration to give methyl 2-(2-formamido-pyrimidin 4-yl)glyoxylate (5.55 g.). The product was recrystallized from ethyl acetate (saturated with water) to give mono hydrate thereof, mp 143 to 144~C.
. Anal. Calcd- for C8H7 N34 H2 . .
.

C H N
Calcd. 42.30 3.99 18.50 found 42.22 3~95 18.34 I Rv Nu~ol : 3270, 32009 1750, 1710, 1597, S 1585, 1416, 1233 cm 1 .N.M~R. ~ppm (DMSO-d6) : 3.65 ~3H, s)~ 7.30 (2H, s), 7.40 ~lH, d, J=5Hz), 8.63 (lH, d, J=SHz), 9-33 tlH, d, J=lOHz), 10.95 ~lH, bd9 J=lOHz).

~3) 4N sodium hydroxide tlQ.85 ml.~ was added to a solution of methyl 2-(2-formamidopyrimidin-4-yl)glyoxylate -~
mono hydrate ~4.55 g.~ in methanol (60 ml.), and the solut-ion was stirred for an hour.
i To the solution was added methoxylamine hydrochloride (1.82 ~.) little by little, and the solution was stirred at room .~ .
- tempeTature or 30 minutes, and then under ice cooling for 30 minutes. The p~ecipi~ates were collected by filtration, and dissolved in water. The insoluble substance was fil-:, .
tered out. The fi~trate was adjusted to pH l with 10%
hydrochloric acid and extracted with ethyl acetate. The :
extract was washed with a saturated aqueous solution of ~ sodium chloride, and conentrated under reduced pressure.
; ~ The precipitates were collected by filtration to give 2-(2-formamidopyrimidin-4-yl)-2-methoxyiminoacetic acid ~0.63 g.). The methanol solution obtained above was concentrated under reduced pressure, and the residue was dissolved in water. The aqueous solution was treated with activated ~harcoal, adjusted to pH 1 with 10% hydrochloric acid and e.xtracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and ' ' ', concentrated under reduced pressure. The precipitates were collected by filtration to give the same object compound (0.73 g.), total yield 1.36 g, mp 180 to 182~C (dec.~.
I. R. ~maU~ol : 3300-2400 (multiple), 1750, 1670, ~ ` 1590, 1573, 140~, 1240, 1048 cm~
N.M.R. ~ppm (DMSO-d6) 4.00 (3M, s), 7.47 (lH, d, J=5Hz~, 8.60 (lH, d, J=5Hz), 9.23 (lH, d, J=lOHz), 11.02 (lH, broad d, J=lOHz).
Pre~aration 3 !
(1) lN Sodium hydroxide solution ~.5 ml.) w~s added to a stirred solution of ethyl 2-(6-formamidopyridin-2-yl3-glyoxylate (1.9 g.) in ethanol (30 ml~) at room temperature and stirred at the same temperature for 30 minut~s. A~ter adding ethoxylamine hydrochloride (912 mg.~ to the solution, the solution was ~tirred at room temperature ~or 4 hours.
- The resultant solution was concentrated under reduced pres-sure, and ethyl acetate and an aqueous solution of sodium bicarbonate were added to the residue. The aqueous layer was separated and ethyl acetate was addbd to the solution. The solution was adjusted to pH 1 with 10% hydrochloric acid.
The ethyl acetate layer was separated, dried over magnesium ; sulfate and concentrated under reduced pressure. The resi-due was triturated wit'n a mixture of diethyl ether and petroIeum ether to give 2-(6-formamidopyridin-2-yl)-2-ethyoxyiminoacetic acid (920 mg.), mp. 155 to 156C (dec.).
~ NU]ol 3250, 1740, 1650 cm N.M.R. ~ppm (DMSO-d6) : 1.3 ~3H, t, J=7Hz), 4.3 (2H, q, J=7Hz), 6.8-8.2 (3H,m), 9.4 (IH, broad d), 10.5 (lH, broad d) j~ .

.

.

:
.. ~ .

~ 3 Preparation 4 ~13 A mixture of formic acid ~20 g.) and acetic S anhydride (41.3 g.) was stirred for 30 minutes at 50C and thereto was added methyl 4-amino-2-pyridinecarboxylate tll gO) at ambient temperature, ancl then the mixture was stirred for 2 hours at 70-75C. After the removal o the sol~ent from the reaction mixture, the residue was recrystallized from ethanol ~160 ml.) to give a pale yeIlow powder of methyl 4-formamido~2-pyridinecarboxylate (8.3 g.~, ; mp. 185 to 186.5C.
I.P~ v NmUa~ol: 3200-3300, 1690, 1675, 1585, 1570, 1495, 1420, 1260, 990, 8609 840 cm 1 t~) To a mixture of methyl 4-formamido-2 pyridine-carboxylate ~9.9 g.~, methyl methylthiomethyl sulfoxide ~6.82 g.) and N9N-dimethylformamide ~200 ml.) was added 50~ sodium hydride t7-92 g.) with stirring at 10C and the stirring was continued for further 10.5 hours at 45C.
After the removal of N,N-dimethylformamide from the reaction mixture, to the residue was added a cold mixture of ethyl acetate and diluted hydrochlor;c acid. The ethyl acetate layer was separated and the remaining aqueous layer was further extracted with ethyl acetate. The combined extract was washed with an aqueous solution o sodium chloride, dried over magnesium sulfate and the solvent was distilled off. The residue ~6.0 g.) was washed with a mixture of ethyl aceta~e and die~hyl ether, collected by filtratlon and then dried to give the ~rownish yellow powder of 4-formamido-2-(2-methanesulfinyl-2-methylthioacetyl)pyridine : - -. `' ~' ' ' ~ ' `

3g~3 :-`` -.
tl.96 g.), mp. 132 to 132.5C. After the concentration of the filtrate, the precipitates were collected by filtration,washed with diethyl ether and then dried to give the same compound (1.11 g.). Total yield : 3.07 g.
I.R. v NUaJol: 3200-3225, 1680, 1580~ 1290, 1170, 1020, 845 cm 1 ~3) After stirring a mixture of acetic anhydride (14 ml.) and formic acid ~136 ml.) for 10 minutes at 40 to 50C, 4-formamido-2-(2-methanesulfinyl-2-methylthio-acetyl)pyridine (3.7 g.) was added thereto~ and then the .
; stirring was continued at 65C for 30 minutes. To the mîxture was added sodlum periodate (0.872 g.), and the mixture was stirred for 15 minutes. After the removal OlC the solvent from the reaction mixture, the residue was dissolved in ethyl acetate. The solution was washed with an aqueous solution of sodium bicarbonate, aqueous svdium thiosulfate and water successively~ and then dried over anhydrous magnesium sulfate. The solvent was distilled off and the resldue was washed with diethyl ether, collected by fil~cration and then dried to give a pale yellow powder of S-methyl 2-~4-formamidopyridin -2-yl)-thiogiyoxylate (1.96 g.), mp. 145 to 148C.
I.R. v NUa~ol: 3150-3300, 1690, 1670) l5g5, 1570, 1500, 1420, 1265, 990, 860~ 835, 745 cm 1 (4) A mixture of S-methyl 2-(4-formamidopyridin-2-yl)thioglyoxylate (1.07 g.), methanol (20 ml.) and lN
aqueous solution of sodium hydroxide (5.7 ml~) was stirred for 50 minutes at ambient temperature to give a solutions containing 2- (4-formamidopyridin-2-yl)glyoxylic acid.

..

, ' ', 32~

To the solution was added 0-methylhydroxylamine hydrochloride (438 mg.), and the mixtùre was stirred for an hour at ambient temperature. After the removal o the solvent from the reaction mixture, to the residue was added water (5 ml.), and the mixture was washed with ethyl acetate and then water was distilled off. The remaining water in the residue was ` azeotropically removed with ethanol and benzene in ; turn to give a pale brown powder of 2-(4-formamidopyridin-2-yl~-2-methoxyiminoacetic acid ~syn isomer) (960 mg.).
N.M.R. ~ ppm (DMS0-d6+D20):3.93 (3H, s), 7.6 (lH, broad) 8.1 (broad s) ) ~lH) 8,55 ~broad s) 8.45 tlH, broad s) Preparation 5 (1) A mixture of formic acid (559.3 g.) and acetic anhydrlde (1033.4 g.~ was stirred for 30 minutes at 40 to 50C and thereto was added methyl 6-amino-2-pyridinecarboxylate (616 g.) at 40C, and then the mixture was stirred for l hour at 80C. After the removal of the solvent from the reaction mixture, the residue was dissolved in a mixture of benzene and n-hexane and then fil~ered. Thus obtained precipitates were recrystallized from benzene (2 ~.) to give methyl 6-formamido-2-pyridinecarboxylate (647.8 g.3, mp. 134 to 136C.

- ' . ' , ~lement analysis:
` ` C N H
~ Calcd (%) 53.334.48 15.55 ; Found (%) 53.374.40 15.58 ~` 5 I.R. v NaJl : 3200, 1740, 1700 cm 1 ,,''. ~ :
~; t2) To a mixture of methyl 6-formamido-2-pyridinecaxboxylate (435.7 g.), methyl methylthiomethyl sulfoxide (300 g.) and N,N-dimethylformamide ~2.2 Q.) -was added 50% sodium hydride (348 g.) with stirring under ice-cooling, and the mixture was stirred for 30 :`
~` minutes at ambient temperature. To the reaction mixture was added benzene (4.4 Q.) under ice-cooling and the precipitates were collected by filtration. The pre-cipitates were added to a mixture of methylene chloride t3 Q.)~ ice (2 kg.) and concentrated hydrochloric acid ~730 ml.). The mixture was adjusted to pH 7 with - ~ sodium bicarbonate and then extracted with methylene chloride. The extract was dried over magnesium sulfate and the solvent was distilled off. The residue was crystallized in diethyl ether, collected by filtration and then dried to give 6-~ormamido-2-(2-methanesulfinyl-2-methylthioacetyl~pyridine (430 g.), mp. 130 to 132C.
I.R. v maUJol : 3250, 3150, 3050, 17]0, 1690, 1600, 1510 cm 1 N.M.R. ~ ppm ~d6-acetone ~ D2O) : 2.30 ~3H9 s), 2~88 ~3H, s), 6.00 (lH, s) 9 7.7-8.2 (3H, m) .

~3) A mixture of 6-formamido-2-(2-; methanesulfinyl-2-methylthioacetyl)pyridine t424 g.), sodium periodate ~100 g.) in acetic acid (2.1 ~.) was stirred for 30 minutes at 70C. After the ~emoval of the solvent from the reaction mixture 9 to the residue were added water ~5 Q.) and sodium thiosulfate (116 g.)~
and then the mixture was adjusted to pH 7 with sodium bicarbonate. The precipitates were collected by filtration, washed with water and then dried to give S-methyl 2-(6-formamidopyTidin-2-yl)thioglyoxylate (2~6.4 g.), mp. 163 to 165C. Further, the same compound tl2 g.) was obtained from the aqueous layer by 2xtraction with ethyl acetate.

R. v mUaxol : 3250, 3150~ 30809 1700; 1670, 1595, 1580, 1510 cm 1 ~ - N.M.R. ~ ppm (acetone-d6 ~ D2O) : 2.57 (3H, s), ; 7.77 - 8.27 (3H, m) (4)-a) A mixture of S-methyl 2-(6-formamidopyridin-2-yl)thioglyoxylate t4.48 g.), methanol (20 ml.) and lN
aqueous solution of sodium hydroxide (20 ml.) was stirred for 50 minutes at ambient temperature to give a solution containing 2-(6-formamidopyridin-2-yl)glyoxylic acid.
To the solution was added O-propylhydroxylamine hydrochloride .. , _ ~ .

. .

(2.23 g.), and the mixture was stirred for 35 minutes at the same temperature. The reaction mixture was adjusted to pH 7 with hydrochloric acid and the methanol was distilled off. The remaining aqueous mixture was washed with ethyl acetate, and ethyl acetate was added thereto and then adjusted to pH 1 with 10~ hydrochloric acid.
The ethyl acetate layer was separated, washed with water, dried over magnesium sulfate, treated with activated charcoal and then the solvent was distilled off. Thus obtained product was washed with a mixture of diethyl ether and diisopropyl ether and then dried to give 2-t6-formamidopyridin-2-yl)-2-propoxyiminoacetic acid (syn isomer) (1.76 g.), mp. 140 to 142C (dec.).
I R ~ NuJol 3250, 3100, 2600, 1755, 1670, 1620, 1580 cm 1 N.M.R. ~ ppm ~acetone-d6 ~ D20) : 0.96 ~3H, t, J=7Hz), 1.56-1.84 ~2H, m), 4.2 (2H9 t, J=7Hz)~
7.0-8.32 ~3H, m) Similarly,~he following compounds were obtained.
(4)-b) 2-(6-Formamidopyridin-2-yl3-2-(2,2,2-trifluoro-ethoxyimino)acetic acid ~syn isomer), mp. 183 to 184C
(dec.) I.R. v ~ol: 3220, 1760, 1680 cm 1 N.M.R~ ~ ppm (DMS0-d6) : 4.78, 5.07 (2H, ABq, J=9Hz), 7.0-8.2 ~3H, m), 9.0-9.3 (lH, m), 10.76 (lH, m) (4~-c~ 2-(6-Formamidopyridin-2-yl)-2-isopropoxy-iminoace~ic acid ~syn isomer)~ mp. 140 to 150C (dec.).
.~

, ~' :

``

I.R. v Nu~o~: 3300, 2600, 1750, 1670, 1620, 1580, 1510 cm N.M.R. ~ ppm (acetone-d6 ~ D2O) : 1.3 (6H, d, J=6Hz), 4.36-4.64 ~lH, m), 6.92-8.28 ~3H, m) ' (4)-d) ~-Allyloxyimino-2-(6-formamidopyridin-2-yl~
acetic acid (syn isomer), mp. 140C ~dec.).
I.R. v NuJol 32509 3100, 2600, 1760, 1670, 1620, 1580 cm l N.M.R. ~ ppm ~acetone-d6 ~ D2O) : 4 67-4.9 ~2H, m), 5.17-5.6 (2~, m), 5.8-6.52 (1~, m), 7.0-8.33 ~3H, m) (4)-e) 2-(6-Formamidopyridin-2-yl) 2-propargylQxy-iminoacetic acid (syn isomer), mp. 145 to 150C (dec.).
I.R. v mUaJol: 3350~ 3250, 3100, 2600~ 1755, 16857 1620, 1580, 1510 cm 1 N.M.R. ~ ppm ~acetone-d6 + D2O) : 3.04 (lH, t9 J=2Hz~, 4.88 ~2H, d, J=2Hz), 7.0-8 28 (3H, m) (4)-f~ 2-Butoxyimino`-2-(6-formamidopyTidin-2-yl)-acetic acid (syn isomer~, mp. 129 to 131~G (dec.).
I.R. ~ Nu~ol: 31503 1755, 1670 cm l N.M.R.~ ppm (DMSO-d6~ : 0.7-1.9 ~7H, m) 9 4.20 ~2H, t, J=6Hz~, 7.0-8.1 ~3H, m), 10.7 ~lH, ~ broad d) (4)-g) 2-Isobutoxyimino-2-(6-formamidopyr:idin-2-yl)-acetic acid ~syn isomer), mp. 153 to 155C ~dec.).
I.R. v maJl: 3250, 3150, 1750, 1680, 1620, 1580 cm 1 N.M.R. ~ ppm ~acetone-d6 ~ D2O): 0.96 ~6H, d, J=6Hæ), 1.88-2.16 ~lH, m), 4.0 (2H9 d, J=6Hz), 7.0-8.28 (3H, m) 1~

(4)-h) ~-(6-FoTmamidopyridin~2-yl)-2-phenoxyimino-acetic açid (syn isomer), mp. 148 to 150C ~dec.).
I.R. v mUaxol: 1730, 1660, 1560 cm 1 N.M.R. ~ ppm ~DMSO-d6) : 6.80-8.2 (8H, m), 10.80 (lH, d, J=~H~) ~reparatiOn 6 (1) Methyl 6-Eormamido-3-pyridinecarboxylate, mp. 218 to 220C was obtained according to the similar ; manner ~o that of the ~reparation 4-(1).
I.R. ~ NUa~ol: 3100~ 3020, 1710, 1605, 1540 cm 1 N.M.R. ~ ppm (DMSO-d6 ~ D2O) : 3.84 (3H, s), 8.12-8.84 ~3H, m) (2) 2-Formamido-5-(2-methanesulfinyl-2-methylthio-acetyl)pyridine, mp. 125 to 127C was obtained according lS to the similar manner to that of Preparation 4-~2).
I.R. v mUxol: 3200, 1710, 1660, 1600, 1545 cm 1 ~3) S-Methyl 2-(6-formamidopyridin-3-yl)thioglyoxylate, mp. 152 to 154C was obtained according to the similar manner to that of the Preparation 4-(3) by using acetic acid instead of acetic anhydride and formic acid.
I.R. v ma~l: 3250~ 3150, 3050, 1730, 1680, 1600, 1590, 1510 cm 1 N.M.R. ~ ppm (acetone-d6 + D2O) : 2.47 ~3H, 5), 8 35-9.17 (3H, m) (4) A mixture of S-methyl 2-(6-ormamidopyridin-3-yl)thioglyoxylate ~13 g.)l methanol ~50 ml.), lN aqueous solution of sodium hydroxide (58 ml.) and water (150 ml.
was stirred at ambient temperature for 30 minutes.
To the mixture was added O-methylhydroxylamine hydrochloride (4.85 g.) and then stirred fOT an hour. The reaction 1 ~ ~

.. .
,. , .. , .
: .
,~, . . ~ ::

< ,.~ 3 , ^
. .

mixture was adjusted to pH 7 with an aqueous solution of sodium bicarbonate~ and the methanol was removed by distillation,under reduced pressure. The rcmaining ` a~ueous solution was washed with ethyl acetate and thereto was added ethyl acetate. The resultant mixture was adjusted to pH 2 with 10% hydrochloric acid and theret was added sodium chloride, and the mixture was stirred for a while. The precipitateswere collected by filtration washed with diisopropyl ether and then dried to give 2-(2-formamidopyrldin-3-yl)-2-methoxyiminoacetIc acid (syn isomer) (2.0 g.), mp. 159 to 161~ (dec.).
I.R. v NUa~ 1735, 1665, 1590, 1550 cm 1 N.M.R. ~ ppm (DMSO-d6) : 4.00 ~3H, s), 7.8-8.5 ~3EI, m), 10.87 (lH, d, J=6Hz) ' On the other hand~ the ethyl acetate layer was separated from the filtrate and the remaining aqueous layer was further extracted with ethyl acetate.
The ethyl acetate layers were combined together, dried over magnesium sul~ate and then the solvent was distilled off to give powder of 2-~6-formamidopyridin-3-yl)-2-methoxyiminoacetic acid ~a mixture of syn and anti isomers).
Thus obtained powder was dissolved in an aqueous solution of sodium bicarbonate and then adjusted to pH 2 to 3 with 10% hydrochloric acid. The precipitates were collected by filtration and then dried to gi~e 2-(6-formamidopyridin-3-yl)-2-methoxyiminoacetic acid (anti isomer) (1.45 g.) ! mp. 168 to 170C (dec.).
I.R. ~ mUa~ol: 1705, 1605, 1535 cm 1 N.M.R. ~ ppm (DMSO-d6,) : 4.00 (3H, s), 7.8-8.5 (3H, m), 10.80 (lH, d9 J=7H~) ~ :, ' Further, the mother liquor was adjusted to pH 3 to 4 with an aqueous solution vf sodium bicarbonate.
The resultant solution was washed with ethyl acetate~
adjusted to pH 2 with 10% hydrochloric acid and then extracted with ethyl acetate. The extract was dried over magnesium sulfate and then the solvent was distilled off to ~ive further 2-(6-formamidopyridin^3-yl)-2-methoxyiminoacetic acid (syn isomer) (2.5 g.).
Pre~aration 7 (1~ Methyl 2-formamido-4-pyridine mp. 196 to 197C was obtained according to the similar manner to that of the Preparation4 -(1).
I.R. ~ NaUxol: 31007 1740, 1710, 1580, 1540 cm l N.M.R. ~ ppm (DMS0-d6) : 3.92 (3H, s), 7.48-8.6 ~5 (3H, m) (2) 2-Formamido-4-~2-methanesulfinyl-2-methyl-thioacetyl)pyridine, mp. 123 to 125C was obtained according to the similar manner to that of the Preparation 4-~2).
I.R. v m~a~l: 3150, 3050, 1690, 1610~ 1565 cm l (3) S-Methyl 2-(2-formamidopyridin-4-yl)thio-glyoxylate, mp. 165 to 167C was obtained according to the similar manner to tha~ of the Preparation 4-(3) by using acetic acid instead of acetic anhydride and formic acid~
I.R. v mU~ol: 3250, 3100, 1710, 1680, 1610, 1565, 1520 cm N.M.R. ~ ppm (CDCQ3 + D20~ : 2.48 (3H~ s~, 7.5-8.6 t3H, m) (4) 2-~2-Formamidopyridin-4-yl)-2-methoxyiminoacetic acid (syn isomer) ? mp. 170 to 172C (dec.) was obtained ' ...... ~. , . ~;

:

~ Z 3 according to the similar manner to that of the Preparation 4-~4) via 2-(2-formamidopyridin-4-yl)-glyoxylic acid.
IoR~ v NUa]ol 2500~ 1710~ 1640~ 1615~ 1600 1520 cm 1 N.M.R. ~ ppm (DMSO-d6 ~ D2O) : 4.02 ~3H, s), 7.0-8.6 (3H, m) Preparation 8 (1) A mixture of ethyl 2-(4-amino-6-hydroxy-pyrimidin-2-y~)acetate (15~8 g~) and phosphoryl chloride t75 mlO) was stirred for 4 hours under heating at 80 to 9dC. The resultant solution was allowed to cool and phosphoryl chloride was distilled off. The remaining oily substance was poured into a mixture o ice-water ~200 ml.) and ethyl acetate (200 ml.). The resultant mixture was neutralized with an aqueous solution of ammonia and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and then the solvent was distilled off. The resultant residue was washed with diisopropyl ether and then dried to give pale brown crystals of ethyl 2-~4-amino-6-chloro-pyrimidin 2-yl)acetate (8.1 g.), mp. 127 to 128C.
I.R. v mUa~ol: 3250-3400, 17009 1650, 1520-1580, 1320~ 1160-1210, 860, 840 cm l (2) Ethyl 2-(6-chloro-4-formamidopyrimidin-2-yl)-acetate (oil) was obtained according to the similar manner to that of the Preparation 4~(1).
I.R. v Falm : 2800-3600, 1680-1730, 1560, 1140-1190, 1020 cm 1 N.M.R. ~ ppm ~CDCQ3) : 1.30 (3H9 t, J=8Hz), _ .

, ~ .
, 3.92 (2H, s), 4.23 (2H, q, J=8Hz), 8.3-9.3 (lH9 broad)~ 9.4-10.4 (ZH, broad) (3) To a solution of ethyl 2-(6-chloro-4-formamido-S pyrimidin-2-yl)acetate (2.3 g.) and sodium acetate (0.93 g.) in 80% ethanol (50 ml.) was added 10~ palladium on carbon (0.2 g.), and the mixture was stirred under a hydrogen atmosphere for 8 hours at ambient temperature. The reaction mixture was filtered and the filtrate was concentrated. To the residue were added ethyl acetate and a small amount of water and the ethyl acetate layer was separated. The remaining aqueous layer was extracted with ethyl acetate. The ethyl acetate layers were combined together, washed with water and dried over magnesium lS sulfate and then the solvent was distilled off. Thus obtained oily substance (2.2 g.) was purified by column chromatography on silica gel (40 g.) using a mixture of benzene and ethyl acetate as an eluent to give a pale brown solid of ethyl 2-(4-formamidopyrimidin-2-yl)acetate (1,3 g.), mp. 80 to 93C.
I.R. v NUa~ol : 1710~ 1670, 15309 1310, 1170, 840 cm 1 N.M.R. ~ ppm (CDCQ33: 1.23 (3H, t9 J=8Hz), 3.78 (2H, s), 4.33 ~2H, q, J=8Hz)~
6.5-8.3 ~lH, broad), 8.37 (lH, d9 J=5Hz)~ 9.15 (lH, broad s), 9.45 (lH9 broad s) (4) To a solution of ethyl 2-(4-formamidopyrimidin-2-yl3acetate (7.0 g.)in acetic acid ~34 ml.) was added dropwise a solution of sodium nitrite ~4.1 g.) in water (12 ml.) over a 15 minutes period with stirring at 10C, .
1 ~3 ~

.

~ 3 and the stirring was continued at the same temperature for an hour and at ambient temperature for another an hour.
After cooling the reaction mixture in an ice bath, water (50 ml.) was added theretoO The precipitates were collected by filtration and washed successively with water and diethyl ether and then dried to give a quantitative yield oF a powder of ethyl 2-(4-formamidopyrimidin-2-yl~-2-hydroxyiminoacetate, mp. 164 to 180C (dec.).
~.M.R.~ ppm ~DMSO-d6): 1.30 (3H, t, J=BHz), 4.40 (2H, q, J-8Hz), 7.5 (lH, broad), B.73 ~lHJ d, J=6Hz), 9.05 (lH3 broad s) (5) Ethyl 2-~4-formamidopyrimidin-2-yl)-2-hydroxyiminoacetate (7.0 g.) was dissolved in dioxane (200 ml.) under heating and the resultant solution was cooled to ambient tempera~ure in an ice bath~ and then thereto was added a solution of diazomethane in diethyl ether with stirring until complete consumption of ~he starting materials. The reaction mixture was concentrated to give a brown oil, which was purified by column chrornatography on silica gel (140 g.) using benzene as an developing solvent and a mixture of benzene and ethyl acetate (3:1) as an eluent to give a pale brown semisolid of ethyl 2-~4-formamidopyrimidin-2-yl)-2-methoxy-iminoacetate (4.4 g.).
I.R. vmaxm : 3500-3600 (shoulder), 2900-3400, 1680-1740, 1560, 1500, 1250, 10207 840 cm 1 N.M.R. ~ppm (CDCQ3~: 1.40 (3H, t, J=8Hz), 4.17 (3H~ s~, 4.47 (2H, q, J=8Hz), 7.5-8.6 ~lH, broad), , .

8.73 (lH, d, J=6Hz), 8.9 (lH, broad~
(6~ A mixture of ethyl 2-(4-formamidopyrimidin-2-yl)-2-methoxyiminoacetate ~4.3 g.) and lON aqueous solution of sodium hydroxide (6.1 ml.) in ethanol (100 ml.) was stirred for 3 hours at ambient temperature. To the reaction mixture was gradually added concentrated hydrochloric acid with stirring 9 where~y said mixture was adjusted to pH 3. The precipitates ~ere collected by filtration and washed successively with ethanol and dîethyl ether and then dried to give white crystals of 2-~4-aminopyrimidin-2-yl)-2-methoxyiminoacetic acid.
I.R. v ~Nujol): 2500-3300~ 1550-1650, 1240, 1000-1040 cm 1 N.M.R. ~ ppm (D20-NaHC03) : 4.05 (3H~ s), 6.67 ~lH, dl J=6Hz), 8.18 (lH, d, J=6Hz) The filtrate and washings are combined together and the solvsnts were dis~illed off. The residue was pulverized in diethyl ether, collected by filtration and then dried to give further the same compound.
(7) 2-(4-Formamidopyrimidin-2-yl)-2-methoxyimino-acetic acid (brown powder) 7 mp. 64 to 70~ (dec.) was o~tained according to the similal~ manner to that of the Preparation 4-(1).
N.M.R. ~ ppm (DMS0-d6): 4.02 (3H, s), 7.1-7.9 (lH, broad) 8.73 (lH? d, J=6Hz), 8.9 (lH, broad) :

~ : :

Preparation 9 (1) A mixture of ethyl 2-~4-formamidopyrimidin-2-yl)acetate (2.95 g.), selenium dioxide (1.73 g.) in dimethylsulfoxide (30 ml.) was stirred under heating at 50 to 52C or an hour and at 70 to 72C for another 0.5 hours. The reaction mixture was cooled to ambient temperature and ~iltered, and then the filtered precipitates were washed with ethyl acetate. The filtrate and washings were combined together and concentrated to the volume o about 5 ml. under reduced pressure below 100C. The residue was poured into water (50 ml.~, and the mixture was stirred for 10 minutes.
The resultant mixture was filtered and the filtered precipitates were washed with water. The filtrate and washings were combined together and adjusted to pH 7 with an aqueous solution of sodium bicarbonate. The mixture was washed with ethyl acetate and saturated with sodium chloride and then extracted with a mixture of ethyl acetate and ethanol (2:1). The extract was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and then the solvent was distilled off to give a deep yellow oil of a mixture of ethyl 2-(4-formamidopyrimidin-Z-yl)glyoxylate and its monohydrate, i.e. ethyl 2-(4-formamidopyrimidin-2-yl)-2,2-dihydroxyacetate ~2.4 g.).
(2) A mixture of ethyl 2-~4-formamidopyrimidin-2-yl)acetate ~2.95 g.), selenium dioxide ~1 R7 g.) and N9N-dimethyl formamide (15 ml.) was stirred for an hour under heating at 70C. The reaction mixture was cooled to ambient temperature and filtered and then the filtered ' ' ', precipitates were washed with a small amount o N,N
dimethylformamide. The filtrate and washings were combined together and the solvent was distilled of~.
The residue was poured into water (60 ml.) and the resulting mixture was stirred for :LO minutes. The mixture was adjusted to p~l 6 to 7 w;th an aqueous soluti~
of sodium bicarbonate and filtered to separate insoluble substances, which were washed with water. The filtrate and washings were combined ~ogether and washed successively with diethyl ether and ethyl acetate. The aqueous mixture was saturated with sodium chloride and then extracted wlth a mixtur2 of chloroform and ethanol ~1:1) (60 ml. x 4). The extract was dried over magnesium sul-Eate and the solvent was distilled of. The resulting oily substance ~2.2 g.) lS was dissolved in ethyl acetate (10 ml.) and subjected to column chromatography on silica gel (15 g.) using ethyl acetate as an eluent. The eluates containing the desired compound were collected and then the solvent ` was distilled off. The resulting oily substance (1.5 g.) W2S dissolved in a small amount of ethyl acetate and then crystallized from diisopropyl ether to give pale yellow crystals of a mixture of ethyl 2-~4-formamidopyrimidin-2-yl)-glyoxylate and its monohydrate, i.e. ethyl 2-(4-formamido-pyrimidin-2-yl)-2 3 2-dihydroxyacetate (0.6 g.), mp. 74 to 78~C.
I.R. v mUaxol: 3200-3400, 1755, 1690-1710, 1595, 15~07 1280, 125,0, 1215, 1135, 1100, 1030, 850 cm 1 N~M~Ro 6 ppm (DMSO-d6) : 1.16 (1.8H, t, J=7Hz), 1.26 (1.2H~ t, J=7Hz~, 4.10 (1.2H,q7J=7~z) ~L ~ 3 9~

4.42 (0.8H, q, J=7Hz), 6.97 (1.2H, broad s), 7.0-7.8 (lH, m), 8.64 (0.6H, d, J=6Hz~ 7 8.90 (0.4H, d, J=6Hz)9 8~8-9.6 ~lH9 m), 11.15 (lH, broad s) (3) A mixture Qf ethyl 2-(4-ormamidopyrimidin-2-yl)glyoxylate and its monohydrate obtained in Preparation 6-(l) was dissolved in ethanol (30 ml.) and there~o was added dropwise lN ethanol solution of potassium hydroxide (11 ml.) under ice-cooling with stirring, and then stirring was continued for 2 hours at ambient temperature.
The reaction niixture was filtered and the filtered precipitates were washed successively with a small amount of ethanol and diethyl ether and then dried to give a brown powder of potassium 2-~4-aminoprimidin-2-yl)~
glyoxylate (0.4 g.). The filtrate and washings were combined together and concentrated to the volume of about 15 ml, and to the residue was added diethyl ether (20 ml.~. The precipitates were collected by filtration and washed successively with a small amount of ethanol and diethyl ether to give further a pale brown powder of a mix~ure of potassium 2-(4-aminopyrimidin-2-yl)-glyoxylate and its monohydrate (0.8 g.).
Total yield : 1.2 g.
~S I.R. v mUa~ol : 3380, 3200, 1715, 1665, 1600, 1245, 940, 750 cm 1 N.M.R. ~ ppm (D2O): 6~54 (d, J=6Hz) } (lH) 6.74 (d; J=6Hz) 8 13 ~d, J-6Hz) } (lH) 8.24 (d, J-6Hz) .
' . ~ ' ~ 2 3 (4) To a solution o~ O-methylhydroxylamine hydro-chloride (0.25 g.) in methanol (6 ml.) was added a mixture of potassium 2-(4-aminopyrimidin-2-yl)glyoxylate and its monohydrate with stirring at ambient temperature, and the mixture was stirred for 4 hours. The reaction ~ixture was allowed ~o stand overnight at ambient temperature, filtered, and the filtered precipitates were washed with ethanol. After the filtra~e and washings were combined together, the solvents were distilled o.
The resultant oily substance was pulverized in acetone (15 ml.~ and collected by filtration. Thus obtained powder was washed successively with acetone and diethyl ether and then dried to give a pale brown powder o 2-(4-aminopyrimidin-2-yl)-2-methoxyiminoacetic acid (syn isomer) (290 mg.).
I.R. v mUa~ol: 3100-3400, 2500-2~00, 1540-1660, 1250~ 990-1040 cm 1 N.M.R. ~ ppm (D2O~NaHCO3): 4.05 (3H3 s), 6.63 (lH9 d, J=6Hz) 3 - 20 8.13 (lH, d, J=6Hz) Preparation lo (1) Methyl 2-(2-formamido-6-chloropyrimidin-4-yl)acetate (crystal) was obtained according to the similar manner to that of the Preparation 4~
I.R. ~ m~a~l: 3200, 3140, 1730, 1700, 1540-1580, 15009 1420, 13~0, 1350, 1270, 1240, 1140, 840, 770, 740 cm 1 (2) Methyl 2-(2-ormamido-6-chloropyrimidin-4-yl) 2-hydroxyiminoacetate, mp. llO to 112C was obtained according to the similar manner to that of the Preparation &-(4~.

~: .

' ..

NUJol: 3200, 174G~ 1700, 1675.
13gO, 1270, 1240, 1180, 1045, 860, ; 810, ~50 cm 1 N.M.R. ~ ppm ~DMSO-d6): 3.90 (3H, s), 7.57 (lH, s}
9.23 ~lH~ d, J=9Hz), 11.40 ~lH, d, J=9Hz), 13.28 (lH, s) t3) Methyl 2-(2-formamido-6-chloropyrimidin-4-yl)-2-methoxyiminoacetate (powder), mp. 165 to 17~.5C was obtained according to the similar manner to that of the Preparation 8-(5).
I.R. ~ Na~ 1 3150, 1750, 1700, 1670, 1645, 1420, 1380, 1270, 1250, 1040, 955~ 795, 735 cm~l N.M.R. ~ ppm (DMSO-d6) : 3.93 and 4.14 (6H~ s), 7.59 ~lH, s), 9.26 ~lH, d, J=9Hz), 11.50 ~lH, d, J=9Hz) ~4) 2-(2-Amino-6-chloropyrimidin-4-yl)-2-methoxy.-iminoacetic acid (powder) was obtained according to the ; simiIar manner to that of the Preparation 8-(6~.
I.R. v NUa~ol: 3350, 3200, 1695-1740, 1660, 1365, 1030 cm N.M.R.~ppm (DMSO-d6 + D2~): 3.80 (3H, s)~
6.16 (s) } (lH~
6.77 (s) (5~ 2-~2-Formamido-6-chloropyrimidin-4-yl)-2-methoxyiminoacetic acid ~powder), mp. 138 to 142C (dec.) was obtained according to the simtlar manner to that of Preparation 4~
I.R. v mUa~ol: 3400, 3325, 3200, 1740~ 1695, 1670, 1550, 1385, 1250, 1040, 820 cm 1 f ~' ' - ' ' "'~' ' , N.M.R. ~ ppm ~DMSO-d6): 4.05 (3HJ S) 6.87 (s)~
) ~lH) 6.93 (s) ~.38 (lH, d, J=9Hz) 11.11 (lH, d, J=9H~) Pre~aratiOn 11 (1) A 15% n-h0xane solution ~636 g.) of n-butyl-lithium was added to a solution of 2-amino-6-methylpyridin (64.8 g.) in tetrahydrofuran (S00 ml.) at -20 to -30C
over one hour, and stirred at -8 to -lO~C for 30 minutes.
To the solution was added trimethylsilylchloride (161.7 g.) at -15 to -5C over 40 minutes, and the resultant solution was stirred at room temperature overnight. The solution was filtered through by a column packed with silica gel ~180 g.), washed with tetrahydrofuran and then the filtrate was concentrated under reduced pressure. The residue was purified by fractional distillation to give a 2-[N,N-bls(trimethylsilyl)amino]-6-methylpyridin~
7.6 g.), b.p. 95 to 97C/5-6 mmHg.
N.M.R. ~ppm (CCQ4): 0.13 (18H, s)l 2.35 (3H, s), 6.43 (lH, d, J=8Hz), 6.60 (lH, dg J=8Hz), 7.25 ~lH, t~ J=8Hz) (2) A 15% n-hexane solution (338.6 g.) of n-butyllithium was dropwise added to a solution of 2-~N,N-bis(trimethylsilyl)amino]-6-methylpyridine (100 g.) in anhydrous tetrahydrofuran (300 ml.) at -20 to -30~C over one hour and the solution was stirred at ~0 to 23C for one hour. The resultant solution was added in small portions to crushed dry ice (1 kg.) under stirring, and stirred till a room temperature. After removing 1~'7 , "

, ~. ., tetrahydrouran from the solution under reduced pressure, absolute ethanol ~1 Q.~ was added to the residue.
30~ Ethanol solution (660 ml.) of hydrochloric acid was dropwise added to the solution at -5 to -10C, and -further hydrogen chloride gas was bubbled at 0 to 5C or 30 minutes and then ~he solution was stirred at 10C overnigh~
Ater removing ethanol from the resultant solution, the residue was dissolved in water, and washed with ethyl acetate 3 times. The solution was adjusted to pH 7 to 8 with sodium bicarbonate and extracted with ethyl acetate.
The ethyl acetate extract was washed with a saturated aqueous solution of sodium chloride, dried and concentrated under reduced pressure to give the crude product ~54 g.). The product was purified by column chromatography on silica gel (1 kg.) with an eluent (cthyl acetate ~ benzene~ to give ethyl 2-(6-aminopyridin-2-yl)acetate (30.2 g.), mp. 66 to 68C.
I.R. v mUJol: 3430- 3340, 3200, 1730~ 1645, 1480, 1190 cm 1 N.M;R. ~ ppm (CDCQ3): 1.25 ~3H, t, J=6Hz), 3.67 ~2H, s), 4.20 (2H, q, J=6Hz)~
5.33 (2H, broad s), 6.43 (lH, d, J=8Hz), 6.62 ~lH, d, J=8Hz), 7.40 (lH, t 7 J=8Hz) ~3) Ethyl 2-(6-formamidopyridin-2-yl)acetate, mp. 35 to 38C was obtained accord;ng to the similar manner to that of the Preparation 4-(1).
I.R. v mUaJol: 3250, 3100, 1738, 1690, 1580, 1460, 1305, 1277 cm 1 N.M.R. ~ ppm ~DMSO-d6): 1.17 ~3H, t, J=8Hz), 3,75 ~2H~ s), 4.08 ~2H, q, J=8Hz~
6.85 (0~5H~ broad d, J=8Hz), 7.95 (0.5H, broad s), 7.08 (lH, d3 J=8Hz), 7.73 (lH, t, J=8Hz), 8.33 (0.5H~ broad s), ~.25 (0.5H, broad d), 10.58 (lH, broad s~.
~4) To a solution of ethyl 2-(6-formamidopyTidin-2-yl)acetate (26 g.) in dioxane (260 ml.) was added selenium dioxide (16.65 g.) in small portions at 85 to 90~C over one hour and stIrred at the same temperature for one hour. After cooling the resultant solutlon the dioxane layer was separated and concentrated under reduced pressure and then the residue was dissolved in ethyl acetate. The solution was washed with water, dried 15~ over ma~nesium sulfate and treated with activated charcoal and then concent~ated under reduced pressure. The residue was triturated with diethyl ether to give ethyl 2-~6-formamidopyridin-2~yl~glyoxy~ate (14.3 g.), mp. 124 to 126C.
I.R. v Nu~ol 3220, 3100, 1737, 1720, 1690, 1273 3 1233 cm ~ ;
;` N.M.R. ~ ppm tDMSO-d6): 1.34 (3H, t, J=8Hz), 4.44 ~2II, q, J=8Hz)l 7.33 ~0.65H3 broad s), 7.8-8.2 ~0.35H3, 7.84 ~lH, d, J~8Hz), 8.09 (lH, t, J=8Hz), 8044 ~0.35H, broad s), 9.22 ~0.65H, broad s), 10.85 ~lH, broad s) (53 2-(6-Formamidopyridin-2-yl)-2-methoxyimino-acetic acid (syn isomer), ~p. 170 to 171C (dec.) was obtained according to the sim;lar manner to that of the ; ~

Preparation ~-~4) via 2-~6-~ormamidopyridin^2-yl)-glyoxylic acid.
I.R. v NUa~ol: 3230, 3132, 1745, 1680, 1575, 1450, 1320, 1208) 1032 cm 1 N.M.R, ~ ppm (DMSO-d6): 3.70 (3Hg s~, 6.90 (0.6H, broad d), 7.9 tO.4H~ broad s), 7.10 (lH~ d, J=8Hz) 3 7.75 (lH, ~, J-8Hz)~ 8.38 ~0.4H, broad s), ~ 9.25 (0.6H, broad d), 10.58 ~lH, broad d) (5) A mixture of 2-(6-formamidopyridin-2-yl)-2-methoxyiminoacetic acid ~syn isomer) (5.0 g.) and concentrated hydrochloric acid (2.34 g.) in methanol t50 ml.) was stirred for 40 minutes at ambient temperature.
After the removal o- methanol from the reaction mixture under reduced pressure~ the residue was pulverized in diethyl ether, collected by filtration and then dried to gi~e a pale brown powder of 2~6-aminopyridin-2-yl)~2-methoxyiminoacetic acid hydrochloride (syn isomer) (5.2 g.).
N.M.R. 8 ppm (DMSO-d6 -~ D20): 4010 ~3H, s), 5.84 ~lH, d, J=7Hz)~ 7.23 (lH, d, J-lOHz), 7.99 (lH, dd, J=7Hz, lOHz~
~7) To a mixture af 2-~6-aminopyridin-2-yl)-2-methoxyiminoacetic acid hydrochloride (syn isomer), acetic acid (350 ml.) and water (10 ml.) was introduced chloride gas for 1.5 hours. After the removal of the excess of the chlorine gas by bubbling air into the reaction mixture, the solvent was distilled off. The residue was pulverized in diethyl ether and collected by filtration. After the addition of water and ethyl acetate to the resultant ~ 7~3 `:
`
. .
`

I

~ Z 3 powder ~9.8 gO)~ the aqueous layer was separated and washed with ethyl acetate. The ethyl acetate layer and washings were combined together, and further extracted with water.
The aqueous layers were combined together and adjusted to pH 4 with lN aqueous solution of sodium hydroxide, and then the solvent was distilled off under reduced pressure.
The remaining water in the residue was azeotropically removed with benzene three times to yield brownish powder which was dried in a desiccator to give 2-(6-amino-3-chloropyridin-2-yl)-2-methoxyiminoacetic acid ~syn isomer) ~3.27 g ?.
N.M.R. ~ ppm ~DMSO-d6 ~ D2O): 3.81 (3H, s), 6.50 (lH, d, J=9Hz), 7.48 ~lH, d, J=9H~) Further the remaining ethyl acetate layer was drled over magnesium sul-fate and the solvent was distilled of The residue was washed with die~hyl ether and then dried to give 2-(6-amino-3,5-dichloropyridin-2-yl)-2-methoxyiminoacetic acid (syn isomer) (2.4 g.)$ mp. 139 to 1~4C.
N.M.R. ~ ppm ~DMSO-d~): 3.96 ~3H, s), 6.2-~.1 (2H, broad), 7.83 (lH, s) (8)-a~ 2-(3-Chloro-6-formamidopyridin-2-yl)-2-methoxyiminoacetic acid (syn isomer) (powder), mp. 151 to 154C was obtained according to the similar manner to that of the Preparation 4-(1).
I.R. v NU]ol: 3200, 1740, 1680, 1580, 1290, 1250, 1140, 1050, 840 cm 1 (8)-b) 2-(3,5-Dichloro-6-formamidopyridin-2-yl)-2-methoxyiminoacetic acid (syn isomer) (powder), . ~ ~

.
`' ' -mp. 164 to 165C was obtained according to the similar manner to that of the Preparation 4-(1).
I.R. ~ NUa~ol: 3250, 2300-2600, 1712, 1565, 1410, 1250, 1035 cm 1 N.M.R. ~ ppm (DMSO): 4.02 (3H, s.~, 8.29 (lH, S) r 9.05 (1~l, d, J=lO~lz), 10.77 (lH, d, J=lOHz) .

: 15 1 7 ,~

~ . .. ~, 13.~ 3 Preparatio _ 2 To a solution of ethyl 3-e~hoxyacrylimidate hydro-chloride (4.0g) and l-ethoxycarbonylformamidine hydro-bromide (4.4g) in methanol (llOmQ) was added dropwise a solution of sodium metal (lg) in methanol ~llOmQ~ at 0C. The reaction mixture was stirred ~or an hour at O to 5C and for additional 4 hours at ambient temper ature. The solution was evaporated to dryness and the residue was dissolved in a mixture of ethyl acetate and an aqueous solution of sodium chlorideu The organic layer was separated out and the aqueous layer was ex-tracted with ethyl acetate five times. All organic layers were combined, dried over anhydrous magnesium sulfate and evaporated to dryness. The residue was triturated with diethylether to give methyl 4-amino-pyrimidine-2-carboxylate (1.33g), which was recrystalliz-ed from ethyl acetate, mp. 140-142.5C.
I.R. vNU~xol : 3450, 3300, 3180, 1730, 1630, 1585, 1540cm~l.
N.M.R.~ppm ~DMSO-d6) : 3.81 (3H,S), 6.54 (lH,d,J=
6Hz), 7.23 (2H,S~, ~.16 (lH,d,J=
6Hz).
Preparation 13 (1) To a solution of 2-chloroacrylonitrile (437mg) and l-ethoxycarbonylformamidine hydrobromide (985mg) in ethanol (5m~) was added dropwise triethylamine ll-Olg) at 0C. The reaction mixture was stirred for 4 hours at ambient tempera~ure and evaporated to dryness. The residue was dissolved in a mixture of ethyl acetate and water,and extracted with ethyl acetate three times. The combined extracts were dried over anhydrous magnesium sulfate and 1 ~3 evaporated to dryness. The residue was triturat-ed with diethyl ether to give ethyl 4-aminopyrimidine-2-carboxylate t480mg), which was recrystallized from a mixture of ethyl acetate and benzene, mp.
S 101-104C.
I.R. vNUal : 3450, 3300, 3180, 1730, 1630, 1580, 1540cm~~.
N.M.R.~ppm (DMSO-d6) : 1.30 t3H,t,J=7Hz), 4.30 (2H,q,J=7Hz), 6.60 (lH,d, J=6Hz~, 7.3- (2H, Sl, 8.20 (lH, d, J=6Hz).
- ' Th~ following compound was obtained according to the similar manner to that of Preparationl3-(1) by us-ing triethylamine or sodium carbonate as a base.
(2) Methyl 4-aminopyrimidine-2-carboxylate.
I.R. vNmaxl : 3450, 3300, 3180, 1730, 1630, 1585, 1540cm~l.

20 Preparation la (1~ A mixture o~ formic acid (lOOg) and acetic ; anhydride (204g) was stirred for half an hour at ambient temperature. To the solution was added ethyl 4-aminopyrimidine-2-carboxylate (30g) and the mixture was stirred for 1.5 hours at 70 to ` 75C and then evaporated to dryness. The residue ; was triturated with ethanoI, collected by filtration and washed with ethanol to give ethyl 4-formamido-pyrimidine 2-carboxylate (20.0g), mp 205-206C.
I.R. vNmaxl : 31GO, 1720, 1630, 1570, 1520cm N.~.R. ~ppm (DMSO-d6) : 1.37 ~3H,t,J=7Hz), 4.40 (2H,q,J=7Hz), 7.73 (lH, broad s), 8.83 (lH, d,J=4Hz~, 9.00 (lH,~road s), 11.40 (lH, broad s) ~ ~i7~1 :.

:. :

` ~.'~9'~3 The following compound was obtained according to the similar manner to that of Preparation 14-(1).
(2) Methyl 4-formamidopyrimidine-2-carbOXylater mp 234-236C.
I.R. vNm~xl : 3100, 1735, 1710, 1640, 1570, 1530, 1510cm ~.
N.M.R. ~ppm ~DMSO-d63 : 3.93 (3~t,s~, 7.73 (lH~
broad s), g.82 (lHrd,J=5~1z), 9.00 ~lH, broad s), 11.40 (lH, broad s~

Preparation 15 (1) To a solution of methyl 4-formamidopyrimidine-2-carboxylate (1.3g) and methyl methylthiomethyl sulfoxide (0.89g) in NIN-dimethylformamide (lOmQ) was added 50~ sodium hydride ~l.Og) at 10C under stirring and the stirring was continued for 1.5 hours at ambient temperature. The mixture was cooled in an ice bath and thereto was added methy-; 20 lene chloride (30 mQ).
The precipitate which was co]lected by filtration was added portionwise to a mixture of methylene chloride t50mQ), ice water and concentrated hydro-chloric acid ~2.1m~) under stirring~ The methylene chloride layer was separated out and the aqueous layer was extracted with methylene chloride.
The combined extracts were dried over anhydrous magnesium sulfate and evaporated to dryness.
The residue was triturated with diethyl ether, filtered and washed with diethyl ether to give 4-formamido-2-(2-methanesulfinyl-2-methylthioacetyl) pyrimidine (1.2g).
I.R. VNm~xl : 1690, 1560, 1450, 1370cm-l.
N.M.R. ~ppm (DMSO-d6) : 2 2303 ~s)}(3H)' ,:

2.73 (s)~ 3H 5-95 (s~}(lH
2.93 ~s) ( )' 6.07 (s) )' 7.67 (lH, broad s), 8.92 (lH,d,J=5Hz), 9.17 (lH, broad s), 11.40 (lH, broad s) ; 5 The same compound as the object compound of Pre-parationl~(l) was obtained from the following compound according to the similar manner thereto.
~2) Ethyl 4-formamidopyrimidine-2-carboxylate.

~reparation 16 A mixture of formic acid ~4.82g) and acetic anhyd-ride (9.7g) was stirred for half an hour at ambient temperature.
To the solution was added 4~formamido-2~(2-methanesul-finyl-2-methylthioacety~pyrimidine (2.6g) and the mix-ture was stirred for 1.5 llours at 50C and then for an hour with an addition of sodium periodate (610mg) at the same temperature. The mixture was evaporated to dry-ness and the residue was dissolved in a mixture of ethyl acetate (50m~) and an aqueous solution (20mQ) of sodium chloride. The organic layer was separated out and the aqueous layer was extracted with ethyl acetate three times~ The combined organic layers were dried over anhydrous magnesium sulfate and evaporated to drynessO The residue (2.0g) was subjected to column c~romatography over silica gel (13g) using a mixture of ethyl acetate and benzene (1:1 by volume) as an eluent.
The fractions containing a desixed compound were collect-ed, evaporated to dryness an~ crystallized from a small amount of ethyl acetate to give pure product of S-methyl 4-formamidopyrimidine-2-thioglyoxylate (840mg), mp 112-114C.
I.R. vNmaxl : 3480, 3380, 1715, 1680, 1585cm-1.
N.M.R. ~ppm (DMSQ-d~) : 2.17 (3H,s), 7.20 (lH, broad s), 8.12 (lH,d,~=6Hz), 9.17 (lH, ~road s), ~ '7~

. .. `
. , .

11~08 (lH,d,J-7Hz).

Preparation 17 (1) To a suspension of S-methyl 4-formamidopyri-midine-2-thioglyoxylate (3.0g) in water (26mQ) was added dropwise lN aqueous solution (12mQ) of sodium hydroxide at ambient temperature and the mixture was stirred for half an hour at the same temperature.
To the solution was added an aqueous solution of etho~yamine prepared by ethoxyamine hydrochloride (1.3g), water (lOm~ and sodium bicarbonate (1.12g).
The reaction mixture was stirred for half an hour at ambient temperature and adjusted to pH 4 with lN hydrochloric acid (1.5mQ). The solution was stirred for 10 minuteis at ambient temperature and adjusted to pH 3 with lN hydrochloric acid and then wa3hed with ethyl acetate. The aqueous layer was salted out, adjusted to pH 1 with 10~ hydro-chloric acid and extracted with ethyl acetate.
The extract was dried over magnesium sulfate and evaporated to dryness. The crystalliæed residue was washed with n-hexane to give 2-ethoxyimino-2-~4-~o~mamidopyrimidin-2-yl)acetic acid (syn isomer) ~2.22g), mp. 130-135C(dec.~.
I.R. vNU~xl : 3250, 1720, 1630, 1605, 1570cm~l.
.M.R. ~ppm (DMSO-d6) : 1.28 (3H,t,J=7~z), 4.32 (2H,q,J=7Hz), 7.4-7.7 (lH, m)~ 8.72 (lH,d,J=6Hz~, 8.8-9.1 (lH,m), 11.37 (lH,d,J=6Hz).
The following compounds were obtained accordiny to the similar manner to that of PreparatiOn 17-(1).
(2) 2-(4-Formamidopyrimidin-2-yl)-2-methoxyimino-acetic acid (syn isomer), mp. 165-166C (dec.).
I R vNUiol : 3400, 3250, 3150, 1740, 1700, max 1570cm~l-, -N.M.R. ~ppm (DMSO-d6) : 4.00 (3~IIs), 7.53 (lH, broad s), 8.72 (lH,d, J-6Hz~, 8.87 ~lH,broad s), 11.23 (lH/~,J=6~
S (33 2-(4-Formamidopyrimidin-2-yl)-2-propoxyimino-acetic acid (syn isomer), mp 145-148C (dec.).
I.R. vNm~Xol : 3150, 3100, 3050, 1750, 169Q, 1615, 1570, 1540cm~~.
; (4) 2-Allyloxyimino-2-(4 formamidopyrimidin-2-yl) acetic acid (syn isomer), mp 120-122C (dec.).
I.R. vNm~xl : 3250, 3100, 1710, 1630, 1570, 151Scm~l.
(5) 2-Benzyloxyimino-2-(4-formamidopyrimidin-2-` yl)acetic acid (syn isomer), mp 75-77C.
I.R. vNmaXl : 3250, 3050, 1720, 1630, 1570 cm~l.

Preparation 18 A mixture of ethyl 2-(6-chloro-4-Eormamidopyrimidin-2-yl)acet~te (24.3g~ and selenium dioxide (16065g) in ~ N,N-dimethylformamide (243mQ) was stirred for an hour ; at 70 t~ 75C. The precipitated solid was filtered off, and the filtrate was concentrated in vacuo.
The residue was dissolved in ethyl acetate t5Q0mQ), washed with water and an a~ueous solution of sodium chloride, dried over anhydrous magnesium sulfate and evaporated to dryness. ~he residue was triturated with di1so~p~opyl ether to give a powder of ethyl 6-chloro-4-formamidopyrimidin-2-ylglyoxylate (17.74g).
This product (lg~ was recrystallized from ethyl acetate (lOmQ) to af~ord the puri~ied product ~570mg), mp 114-117C.
I.R. vNujol : 3400, 3230-310Q, 1760, 1720-1680, max 1580-1550, 1250, 1200, 850, 730cm-1.

, `:
. , : , , . :

: ~ :
, Preparation 19 To a mixture of ethyl 6-chloro-4-foxmamidopyrimidin-2-ylglyoxylate (10.6g) and methoxyamine hydrochloride (3.34gj in ethanol (200mQ3 was added an aqueous solution (60mQ) of sodium bicarbonate (3.36g) and the mixture was stirred for 2 hours at ambient temperature~
After evaporation o the solventJ the residue was dis-solved in ethyl acetate. The solution was washed with water, dried over anhydrous magnesium sulfate and evaporated to give oily product (10.8g).
This product was subjected to column chromatography over silica gel (]18g) using be.nzene as an eluen~.
The fractions contained a desired compound were collect-ed, and evaporated, and the resultant oily product (5.6g) was crystallized from diethyl ether to give ethyl 2-(6-chloro 4-formamidopyrimidin-2-yl)-2-methoxyi-minoacetic acid (syn isomer~, mp. 116-119C.
I.R. ~uaol : 3400, 1750, 1725, 1665, 1495, 1270, 103Ocm~l.
N.M.R. ~ppm (CDCQ3) : 1.35 (3H,t,J=7Hz), 4.0~ (3H, s), 4.~0 ~2H,q,J=7Hz~, 6.5-8.3(1H~
broad), 8.3-9.0 (lH,broad), 9.2 (lH, broad s).

Preparation ~o A mixture of ethyl 2-(4-formamidopyrimidine-2-yl) acetate (50.0g) and selenium dioxide (31.87g) in N,N-dimethylformamide ~240mQ) was stirred for an hour at 70 to 75C and cooled to ambient temperature.
The precipitated solid was filtered off and the filt-rate was evaporated in vacuo to give an oily product.
The oil was added to water (750mQ) under stirring, ad-justing to p~7 with an aqueous solution of sodium bicarbonate. The precipitated yellow substance was filtered off and washed with water. The filtrate and washings were combined and thereto was added methoxya-mine hydrochloride (19.95g). The mixture was adjust-ed to pH4 with an aqueous solution of sodium bicarbo-nate and stirred for 3 hours at ambient temperature.
The aqueous reaction mixture was extracted with ethyl acetate and the extract was washed with an aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and evaporated to give ethyl 2-(4-formamidopyrimidin-2-yl)-2-methoxyiminoacetate (syn isomer) ~31g) a~ a brownish oil.
N.M.R. ~ppm (CDCQ3) : 1.36 (3H,t,J=7Hz), 4.12 (3~/s), 4.42 (2H,q,J=7Hz), 6.5-8.2 (lH, broad), 8.66 (lH,d,J=6Hz), 8.8 -10.0 (2H, broad) Preparation 21 (1) To a solution of ethyl 2-(4-formamidopyrimi-din-2-yl)-2-methoxyiminoacetic acid (syn isomer) (30.8g) in ethanol (308mQ3 was added lN alcoholic solution (550mQ) of potassium hydroxide ancl the - mixture was stirred for 3.5 hours at ambient temperature. The reaction mixture was cooled in an ice bath and adjusted to pH 3 with concentrat-ed hydrochloric acid (53mQ). The resultant solid ; was filtered and washed with ethanol (60m~), water (lOOmQ), acetone (lOOm~) to give a crude product (28.Bg). This product (lg) was recrystallized from water (lOmQ) to give a purified product of 2-(4-aminopyrimidin-2-yl)-2-methoxyiminoacetic acid (dihydrate,syn isomer) (0.4g), mp. 178-183C (dec~).
The following compound was obtained according to the similar manner to that of Preparation 21-(1).
(2) 2-(4-Amino-6-chloropyrimidin-2-yl)-2-methoxyi-minoacetic acid (syn isomer).

:.

~ .
.. , ~ :
: :

I.R. vNm~l : 3480, 3380, 3200l 1640, 1610-1580, 1530, 1040, 720cm~l.
N.M.R. ~ppm (D20) : 4.10 ~3H,s), 6.76 ~lH,s).

Preparation 22 To a solution of ethyl 2-(4-chloro-6-formamido-pyrimidin-2-yl)-2-methoxyiminoacetate (syn isomer) ~17g) in ethanol ~255mQ) was added dropwise phosphoryl chloxide (14.7g) under cooling in an ice bath.
The mixture was stirred for 1.5 hours at ambient temper-ature and evaporated to dryness.
~ The residue was dissolved in a mixture of ethyl aceta~e -~ and water and adjusted to pH 7 with an aqueous solution of sodium bicarbonat~. The organic layer was separated out, dried over anhydrous magnesium sulfate and eva-porated to dryness. The residue was triturated with n-hexane to give ethyl 2-(4-amino-6-chloropyrimidin-2-;~ yl)~2-methoxyiminoacetate ~syn isomer~ (9.99g), mp 136-2C.
~.R. vKBar : 3500, 3380, 3200, 1735, 1640, 1575, 1535~ lO~Ocm~l.
N.M.R. ~ppm (DMSO-d6) : 1.30 t3H,t,J=7HZ), 4.03 (3H,s), 4.30 (2H,q,J-7Hz), 6.53 (lH,s), 7~5 (2H, broad s) . . .

~: ~ ' ' . " ` ' ,, , : , 3l~ 23 Preparation 23 (1) To a solution of ethyl 2-(4-amino-6-chloropyrimidin-2-yl)acetate (21~5 g) in methanol (200 ml) was added a solution of sodium metal (7.25 g) in methanol (130 ml) and the mixture was refluxed for 3.5 hours.
The reaction mixture was cooled in an ice-salt bath and saturated with dry hydrogen chloride and then allowed to stand overnight at ambient temperature.
The mixture was evaporated to dryness and the residue was dissolved in a mixture of ethyl acetate and a cold aqueous solution of sodium bicarbonate.
The organic layer was separated ~ut, washed with water, dried over anhydrous magnesium sulfate~
and evaporated to give methyl 2-(4-amino-6-methoxy-pyrimidin-2-yl)acetate (14.2 g), mp 91-~4~.

I.R.~mUa~l : 3480, 3390, 3210, 1738, 1660, 1600cm N.M.R. ~ppm (DMSO-d6): 3.66 (5H, 5) , 3.82(3H, s), 5.68 (lH, s~, 6.66 (2H, broad s).

~2) To a solution of thiophenol (2.55 g) in N,N-dimethyl-formamide (20 ml) was added 50 % sodium hydride (1.1 gj under cooling in an ice bath and the mixture was stirred for 20 minutes at 0C to 5C. To the mixture was added ethyl 2-(4-amino-6-chloropyrimidin-2-yl)-2-methoxyiminoacetate (2.0 g) and the mixture was stirred for 6 hours at ambient temperature.
The resultant mixture was poured into cold water, adjusted to pH 7 with diluted hydrochloric acid and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate .. i ;:
. :
~ . . . .

and evaporated to dryness. The residue was subjected to column chromatography on silica gel (50 g) using a mixture of chloroform and ethyl acetate (3:1 by valume) as an eluent. The fractions containing the object product were collected and evaporated to give ethyl 2-(4-amino-6-phenylthio~
pyrimidin-2-yl)-2-methoxyiminoacetate (syn isomer) (460 mg), mp 154-156C

I.R.~mU]l : 3450, 3280, 3160, 1720, 1620, 1550, 1520, 1300, 1040, 1025, 700cm 1 .

N.M.R. ~ppm (CDC13): 1.34 (3H, t, J=7Hz), 4.05 (3H, s), 4.27 (2H, q, J=7Hz) 5.2 (2H, broad s), 5.84 (lH, s), 7.2-7.7 (5H, m).

Preparation 24 .
Methyl 2-(4-formamido-6-methoxypyridin-2-yl)acetate (13.9 g) was obtained by reacting methyl 2-(4-amino-6-methoxypyrimidin-2-yl)acetate (14 g) with formic acid (14.7 g) and acetic anhydride (30.4 g) accarding to the similar manner to that of Preparation 14-(1), mp 61-63C.

N.M.R. ~ppm (DMSO-d6): 3.73 (3H, s), 3.87 (2H, s), 3.96 (3H, s), 6.1-7.8 (lH, broad), 8.1-9.8 (lH, broad), 10O87 (lH, d, J=6Hz).

Preparation 25 _ Methyl 2-(4-formamido-6-methoxypyrimidin-2-yl)-2-methoxyiminoacetate (syn isomer) (12.47 g) was obtained :L~3 J~
`` ' 5~Z~

by reacting methyl 2-(4-formamido-6-methoxypyrimidin-2-yl)acetate (12.24 g) with selenium dioxide (6.94 g) and then methoxyamine hydrochloride (4.51 g) according to the semilar manner to that of Prepara-tion 20, I.R.~ malm : 3300, 1750, 1720, 1660, 1590, 1565, 1210, 1035cm Preparation 26 (1) 2-(4-Amino-6-methoxypyrimidin-2-yl)-2-methoxyimino-acetic acid (syn isomer) (8.22 g) was obtained by reacting methyl 2-(4-formamido-6-methoxypyrimidin-2-yl)-2~methoxyiminoacetate (syn isomer) (12.0 g) with lN ethanolic solution (187 ml) of potassium hydroxide according to the similar manner to ~hat of Preparation 21, mp 127-129C (dec.).

I.R. ~NUx 1 : 3420, 3380, 1650, 1615, 1590 1250, 1050, 1025cm N.M.R. ~ppm (DMSO-d6 + D20): 3.78 (3H,s ), 3.95 ~3H,s )~ 5.78 (lH,s ) ; (2) 2-(4-Amino-6-phenylthiopyrimidin-2-yl)-2-methoxy-iminoacetic acid (syn isomer) (130 mg) was obtained by reacting ethyl 2-(4-amino-6-phenylthiopyrimidin-2-yl~-2-methoxyimino acetate (syn isomer) (247 mg) with lN aqueous solution (1.8 ml) of sodium hydroxide according to ~he similar manner to that of Preparation 21, mp 136-138C (dec.).

I.R. ~mU~ol : 3300, 1650, 1600, 1560, 1150, 1040, 750cm 1 ;, . , .

SUPPLEMENl`ARY DISCLOSURE
This disclosure and the Pxincipal Disclosure are concerned with novel cephalosporanic acid derivatives, pharmaceutically acceptable salts thereo~, and their preparation.
The derivatives are represented by the formula (I), as defined in the Principal Disclosure.
The following examples further illustrate the invention~

' .

!~

' .
Example S.D

(1) Methylene chloride (15 ml) was added to a Vilsmeier reagent, which was prepared ~y phosphoryl chloride (0.75 g) and N,N-dimethylformamide (0.75 ml) in a conventional manner.
To this mixture was added 2-(4-formamidopyrimidin-2-yl)-2-phenoxyiminoacetic acid (syn isomer) (1.0 g) at -20C, followed by stirring at -15 to -13C for half an hour. To ~his solution was added a solu~ion sf 7-amino-3-(1,3,4-thiadiazol-2-ylthio-methyl)-3-cephem-4-carboxylic acid (1.27 g) and trimethylsllyl-acetamide (4.6 g) in methylene chloride (14 ml) at -20C with stirring, and the stirring was continued at -15 to -13C for half an hour and at ambient temperature for additional half an hour. The reaction mixture was evaporated to give a residue, to which ethyl acetate and then an aqueous solution of sodium bicarbonate were added. To the separated aqueous solution was added ethyl acetate and then adjusted to pH 1 to 2 with hydro-chloric acid.

After addition of a small amount of acetone, the organic layer was separated, washed with water and an aqueous solution of sodium chloride, dried over magnesium sulfate, and then evaporated.
The residue was pulverized with diethyl ether to give 7-~2-(4-formar!lidopyrimidin-2-yl)-2-phenoxyiminoacetamido]-3-(1,3,4-, thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer) (1-~5 g)-,;':
I.R. v ma~l : 1780, 1710, 1660, 1570, 121G, 1060, 1000, 760 cm 1 1 ~ ~ ; - . .

9~;3 N.M.R. ~ppm (D~lSO-d6~: 3.73 ~2H, m), 4.27, 4.67 (2H, ABq, J=12Hz), 5.27 ~lH, d, J=5Hz), 5.97 (lH, dd, J=5Hz, 8Hz), 6.9-7.6 (5H, m), 7.7-8.2 (lH, m), 8.77 (lH, d, J=6Hz), 9.10 (lH, m), 9.54 (lH, s3, 9.83 (lH, d, J=8EIz), 11.10 (lH, d, J=7Hz) 12) 7-r2-(4-Formamidopyrimidin-2-yl)-2-phenoxyiminoacetamid 3-[1-(2-tert-butoxycar~onylaminoethyl)~lH-tetrazol-5-ylt~io-methyl]-3-cephem-4-carboxylic acid (syn isomer) (1.8 g) was obtained by reacting 7-amino-3-[1-(2-~ert-butoxycarbonylamino-ethyl)-lH-tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid (2.12 g) with an activated acid prepared from 2-(4 formamido-pyrimidin-2-yl)-2-phenoxyiminoacetic acid (syn iso~er) (1.1 g), phosphoryl chloride ~0.83 g) and N,N-dimethylformamide (0.8 ml), in substantially the same manner as that of Example 1-(1)~

I.R. v mNaJl 3300-3100, 1770, 1715-I660, 1570, 1250, 1210, 1160, 990, 850, 760 cm 1 N.M.R. ~ppm (DMSO-d6): 1.25 (9H, s), 3.23 ~2H, m), 3~70 t2H, m), 4.27 (4H, m), 5.17 (lH, d, J=5Hz), 5.90 (lH, m), 6~8-7.6 (5H, m), 7.90 ~lH, m), 8.73 (lH, d, J=

6Hz), 9.83 (lH, d, J=8Hz), 11.20 (lH, d, J=7~z) `

:' Example S~D~2 (1) A solution of 7-[2-(4-formamidopyrimidin-2-yl)-2-phenoxyiminoacetamido]-3-(lr3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer~ (1.40 g) and coc.
hydrochloric acid (0.23 ml) in methanol (20 ml) was stirred at ambient temperature for 1.5 hours.
The reaction mixture was poured into diethyl ether (150 ml) with stirring, followed by the precipi~ates were collected by filtration, washed wi~h diethyl ether and dried ~o give a pale yellow powder ~1.2 g). TQ this powder was added wate:r (6 ml) and the suspension was stirred for 20 minutes. ~he remaining powder was collected by filtration, washed with water and then dried in vaccuo to give a pale yellow powder ~0.96 g) of hydrochloric acid salt of 7-[2-(4-aminopyrimidin-2--yl)-2-phenoxyiminoacetamido]-3-~1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer), mp 155-161C (dec.).

I.R. v Na~l : 3300, 3160, 1770, 1650, 1580, 1200, 1060, 1000, 980, 760 cm 1 N.M.R. ~ppm (D~SO-d6 + D2O): 3.76 (2H, m), 4.11, 4.64 (2H, ABq, J=13Hz), 5.28 (lH, d, ; J=5Hz), 5.95 (lH, d, J=5Hz), 6.73 (lH, d, J=6Hz~, 7.0-7.6 (5H, m), 8.30 (lH, d, J=6Hz), 9.63 (lH, s) ~:

~2) A solution of formic acid salt of 7-[2-(4-formamido-pyrimidin-2-yl)-2-phenoxyiminoacetamido]-3-[1-(2-aminoethyl~-lH-tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid (syn isomer) (1.5 g) and concO hydrochloric acid (0.45 ml) in methanol (20 ml) was stirred at ambient temperature for 1.5 hours. The reaction ~ix~ure was concentrated till the prec~pitates appeared therein, and to the concentrate was added water (double volume of said concentrate).
The aqueous solution was chromatographed on non-ionic adsorp-tion resin "Diaion HP-20" (Trade Mark: maker Mitsubishi Chemical Industries Ltd.) (6Q ml) with 20 % aqueous methanol (500 ml), 30 % aqueous methanol (300 ml) and then 60 % aqueous methanol (500 ml) as an eluent, and the fractions containing a desired compound were collected. These fractions were concentrated to a volume of 150 ml and the concentrate was lyophilized to give a pale yellow powder (0. 55 g) of 7- [2- (4-aminopyrimidin-2-yl)-2-phenoxy-iminoacetamido3-3-[1-(2-aminoethyl)-lH-tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid (syn isomer) r mp 217-227 C (dec.)O

I.R. v Nail : 3300, 3160, 1760, 1660, 1620, 1580r 1200, . 9801 950, 760 cm 1 .. . .
N.M.R. ~ppm (DMSO-d6 -~ D2O): 3.1-3.8 (4~1, m), 4.27 (2~, m), 4.69 (2H, m~, 5.17 (lH, d, J=5EIz), 5.87 (lH, d, J=5Hz~, 6.60 (lH, d, J=6Hz~, 7.0-7.7 (5H, m), 8.27 (lH, d, J=6Hz~

g~
~ ~ -;' ' - , . .

, ~ '~ : .

Example S~D~3 To 7~~2-(4-formamidopyrimidin-2-yl)-2-phenoxyimino-acetamido]-3-[l-(2-tert-bu~oxycarbonylaminoethy~ H-tetrazol-5-ylthiomethylJ-3-cephem-4-carboxylic acid (syn isomer) (1.7 g) was added ~ormic acid (17 ml) and the solution was stirred at ambient temperature or 4 hours. After the reaction mixture was evaporated, the resi~ue was pulverized with ethyl acetate to give a brown powder (1.5 g) of formic acid 1. 10 salt of 7-[2~4-formamidQpyrimidin-2-yl)-2-pheIloxyiminoacetamido~-3-~l-(2-aminoethyl)-lH-tetrazol-5-ylthiomethyl]-3-cephem-4 carboxylic acid ~syn isomer).

I.R. v maj1 : 3200, 1770, 1710, 16~G, 1570, 1210, 990, 760 cm 1 ,..

~ 25 1~.'2~3 , Preparation S.D.l .

To a suspension of S-methyl (4-formamidopyrimidin-2-yl)-thioglyoxylate (6.7 g) in water (60 ml) was added dropwise lN aqueous solution of sodium hydroxide ~26.8 ml) over a period of 15 minutes with stirring, and -the stirring was continued at ambien-t temperature for 20 minutes.
On the other hand, an ethanolic solution (50 ml) of N-phenoxyphthalimide (9.26 g) and hydrazine monohydrate (1.84 g) was refluxed under heating for 5 minutes and the precipitates were removed by filtration. The resultant solution was added to the aqueous solution obtained above, followed by stirring for 5 minutes. After adjustiny to pH 3 to 4 with 6N hydrochloric acid, the stirring was continued at ambient temperature Eor additional 3 hours. The ethanol was removed by evaporation from the reaction mixture, and the remaining aqueous solution was adjusted to p~ 7 to 8 with 5 % aqueous solution o~ sodium bicarbonate and ~hen washed with ethyl acetate. To the aqueous solution was added ethyl acetate and then adjusted ~o pH 1 to 2 with hydrochloric acid. The separa~ed ethyl acetate layer was washed with water, dried over magnesium sulfate and evaporated to dryness. The residue was pulverized with diisopropyl ether to give a brownish powder (2.2 g) of 2-(4-formamido-pyrimidin-2-yl)-2-phenoxyiminoacetic acid (syn isomer), mp 131-133 C (dec.~.

I.R. v ma~l : 3150, 1740, 1680, 1660, 1575, 1540, 1440, 1310, 1205, 980, 760 cm 1 ~j 11 ~3~

.

2~3 `

;.
N.M.R. ~ppm (DMSO-d6): 7.1-7.9 (5H, m), 8.15 (lH, m), 8 . 97 (lH, d, J=6Hz~, 9 . 23 (lH, m), 11. 57 (lH, d, J=6Hz~

.

; 10 ~ ..

:

... ...

- .,

Claims (356)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:
1. A process for preparing a compound of the formula:

(I) wherein R1 is a group of the formula:

in which R? is amino or a protected amino group, R? and R? are each hydrogen, halogen, lower alkoxy or arylthio, and Z is N or CH, R2 is hydrogen or lower alkoxy, R3 is hydrogen or lower alkyl, R4 is hydrogen, halogen, carbamoyloxymethyl, lower alkyl, lower alkoxy, lower alkanoyloxymethyl, lower alkanoylthiomethyl, or hetero-cyclic-thiomethyl which is unsubstited or substituted by a substituent selected from the group consisting of lower alkyl, carboxy(lower)alkyl, amino(lower)alkyl, a protected amino(lower)alkyl, halophenyl and lower alkenyl, R5 is carboxy or a derivative thereof, and X is lower alkylene or a group of the formula:

in which R6 is hydrogen, lower alkyl, mono, di- or tri-halo(lower)alkyl, lower alkenyl, lower alkynyl, aryl, ar(lower)alkyl or halo(lower)alkanoyl, or a pharmaceutically acceptable salt thereof which comprises:
(1) reacting a compound of the formula:

(II) wherein R2, R3, R4 and R5 are each as defined above, or a reactive derivative thereof at the amino group or a salt thereof, with an acylating agent of the formula:

R1-X-COOH (III) wherein R1 and X are each as defined above, or a reactive derivative thereof at the carboxy group, or a salt there-of, to give a compound of the formula:

(I) wherein R1, R2, R3, R4, R5 and X are each as defined above, or a pharmaceutically acceptable salt thereof;
or (2) subjecting a compound of the formula:

(Ia) wherein R1' is a group of the formula:

in which is a protected amino group, and R?, R? and Z are each as defined above, and R2, R3, R4, R5 and X are each as defined above, or a salt thereof, to an elimination reaction effective to eliminate the amino-protective group in R?, to give a compound of the formula:
(Ib) wherein R1" is a group of the formula:

in which R?, R? and Z are each as defined above, and R2, R3, R4, R5 and X are each as defined above, or a pharmaceutically acceptable salt thereof; or (3) subjecting a compound of the formula:

(Ic) wherein R? is heterocyclic-thiomethyl having a pro-tected amino(lower)alkyl group, and R1, R2, R3, R5 and X are each as defined above, or a salt thereof, to an elimination reaction effective to eliminate the amino-protective group in R? to give a compound of the formula:

(Id) wherein R? is heterocyclic-thiomethyl having an amino-(lower)alkyl group, and R1, R2, R3, R5 and X are each as defined above, or a pharmaceutically acceptable salt thereof; or (4) subjecting a compound of the formula:

(Ie) wherein R? is a protected carboxy group, and R1, R2, R3, R4 and X are each as defined above, or a salt thereof, to an elimination reaction effective to eliminate the carboxy-protective group in R? to give a compound of the formula:

(If) whereln R1, R2, R3, R4 and X are each as defined above, or a pharmaceutically acceptable salt thereof; or (5) reacting a compound of the formula:

(Ig) wherein Y is a conventional group which is capable to be replaced by the residue (-R7) of the compound of the formula: H-R7, in which R7 is heterocyclic-thio which is unsubstituted or substituted by a substituent selected from the group consisting of lower alkyl, carboxy(lower)alkyl, amino(lower)alkyl, a protected amino(lower)alkyl, halophenyl and lower alkenyl, and R1, R2, R3, R5 and X are each as defined above, or a salt thereof, with a compound of the formula:

R7 - H (IV) wherein R7 is as defined above, or a reactive derivative thereof, to give a compound of the formula:

(Ih) wherein R1, R2, R3, R5, R7 and X are each as defined above, or a pharmaceutically acceptable salt thereof, and if desired, converting the resulting compound to a corresponding pharmaceutically acceptable salt.
2. A process for preparing a compound of the formula:

(I) wherein R1 is a group of the formula:

in which R? is amino or a protected amino group, R? and R? are each hydrogen, halogen, lower alkoxy or arylthio, and Z is N or CH, R2 is hydrogen or lower alkoxy, R3 is hydrogen or lower alkyl, R4 is hydrogen, halogen, carbamoyloxymethyl, lower alkyl, lower alkoxy, lower alkanoyloxymethyl, lower alkanoylthiomethyl, or hetero-cyclic-thiomethyl which is unsubstited or substituted by a substituent selected from the group consisting of lower alkyl, carboxy(lower)alkyl, amino(lower)alkyl, a protected amino(lower)alkyl, halophenyl and lower alkenyl, R5 is carboxy or a derivative thereof, and X is lower alkylene or a group of the formula:

in which R6 is hydrogen, lower alkyl, mono, di- or tri-halo(lower)alkyl, lower alkenyl, lower alkynyl, aryl, ar(lower)alkyl or halo(lower)alkanoyl, or a pharmaceutically acceptable salt thereof which comprises:
reacting a compound of the formula:

(II) wherein R2, R3, R4 and R5 are each as defined above, or a reactive derivative at the amino group or a salt thereof with an acylating agent of the formula:

R1-X-COOH (III) wherein R1 and X are each as defined above, or a reactive derivative thereof at the carboxy group or a salt thereof, and if desired converting the resultant compound to a pharmaceutically acceptable salt thereof.
3. A process according to claim 2, in which R?
is amino or acylamino, R? and R? are each hydrogen, halogen, lower alkoxy or phenylthio, R4 is hydrogen, halogen, carbamoyloxymethyl, lower alkyl, lower alkoxy, lower alkanoyloxymethyl, lower alkanoylthiomethyl, unsaturated 5 to 6-membered heterocyclic-thiomethyl in which the heterocyclic moiety contains two nitrogen atoms and one sulfur atom and is unsubstituted or substituted with a substituent selected from the group consisting of lower alkyl, amino(lower)alkyl and lower alkoxycarbonylamino(lower)alkyl, or unsaturated 5 to 6-membered heterocyclic-thiomethyl in which the hetero-cyclic moiety contains two nitrogen atoms and one oxygen atoms and may have a halophenyl, or unsaturated 5 to 6-membered heterocyclic-thiomethyl in which the hetero-cyclic moiety contains four nitrogen atoms and is unsubstituted or substituted by a substituent selected from the group consisting of lower alkyl, carboxy(lower)-alkyl amino(lower)alkyl, lower alkoxycarbonylamino-(lower)alkyl and lower alkenyl, or unsaturated 5 to 6-membered heterocyclic-thiomethyl in which the hetero-cyclic moiety contains two nitrogen atoms or tetra-zolopyridazinylthiomethyl, R5 is carboxy or an esterified carboxy group, and X is lower alkylene or a group of the formula:

in which R6 is hydrogen, lower alkyl, trihalo(lower)-alkyl, lower alkenyl, lower alkynyl, phenyl or phenyl-(lower)alkyl.
4. A process according to claim 3, wherein R?
is amino, lower alkanoylamino or trihalo(lower)alkanoyl-amino, R4 is hydrogen, halogen, carbamoyloxymethyl, lower alkyl, lower alkoxy, lower alkanoyloxymethyl, lower alkanoyl-thiomethyl, thiadiazolylthiomethyl which is unsubstituted or substituted with a substituent selected from the group consisting of lower alkyl, amino(lower)alkyl and lower alkoxycarbonylamino(lower)-alkyl, halophenyloxadiazolylthiomethyl, tetrazolyl-thiomethyl which is unsubstituted or substituted with a substituent selected from the group consisting of lower alkyl, carboxy(lower)alkyl, amino(lower)alkyl, lower alkoxycarbonylamino(lower)alkyl and lower alkenyl, pyrazinylthiomethyl or tetrazolopyridazinyl-thiomethyl, and R5 is carboxy, nitrophenyl(lower) alkoxycarbonyl or diphenyl(lower)alkoxy-carbonyl.
5. A process according to claim 4, wherein X
is said group of the formula:

such that said compound of formula (I) is in the syn form.
6. A process according to claim 5, wherein R1 is a group of the formula:

in which R? is hydrogen, halogen, lower alkoxy or phenyl-thio and R2 is hydrogen.
7. A process according to claim 6, wherein R5 is carboxy.
8. A process according to claim 7, wherein R? is hydrogen, chloro, methoxy or phenylthio, R3 is hydrogen or methyl, R4 is hydrogen, chloro, carbamoyloxymethyl, methyl, acetoxymethyl, acetylthiomethyl, 1,3,4-thiadiazol-2-ylthio-methyl, 5-methyl-1,3,4-thiadiazol-2-ylthiomethyl, 5-(4-chlorophenyl)-1,3,4-oxadiazol-2-ylthiomethyl, 1-methyl-1H-tetrazol-5-ylthiomethyl, 1-allyl-1H-tetrazo-5-ylthiomethyl, 1-tert-butoxycarbonylaminomethyl-1H-tetrazol-5-ylthiomethyl, 2-pyrazinylthiomethyl or tetrazolo[1,5-b]pyridazin-6-ylthiomethyl and R6 is methyl, ethyl, propyl, allyl or benzyl.
9. A process according to claim 8, wherein R?, R3 and R4 are each hydrogen and R6 is methyl.
10. A process according to claim 8, wherein R? and R4 are each hydrogen and R3 and R6 are each methyl.
11. A process according to claim 8, wherein R? and R3 are each hydrogen, R4 is acetoxymethyl and R6 is methyl.
12. A process according to claim 8, wherein R? and R3 are each hydrogen, R4 is carbamoyloxymethyl and R6 is methyl.
13. A process according to claim 8, wherein R? and R3 are each hydrogen, R4 is 1,3,4-thiadiazol-2-ylthiomethyl and R6 is methyl.
14. A process according to claim 8, wherein R? and R3 are each hydrogen, R4 is 1,3,4-thiadiazol-2-ylthiomethyl and R6 is ethyl.
15. A process according to claim 8, wherein R? and R3 are each hydrogen, R4 is 1,3,4-thiadiazol-2-ylthiomethyl and R6 is propyl.
16. A process according to claim 8, wherein R? and R3 are each hydrogen, R4 is 1,3,4-thiadiazol-2-ylthiomethyl and R6 is allyl.
17. A process according to claim 8, wherein R? and R3 are each hydrogen, R4 is 5-methyl-1,3,4-thiadiazol-2-ylthiomethyl and R6 is methyl.
18. A process according to claim 8, wherein R? and R3 are each hydrogen, R4 is 1-methyl-1H-tetrazol-5-ylthiomethyl and R6 is methyl.
19. A process according to claim 8, wherein R? and R3 are each hydrogen, R4 is 1-allyl-1H-tetrazol-5-ylthiomethyl and R6 is methyl.
20. A process according to claim 8, wherein R? and R3 are each hydrogen, R4 is tetrazolo[1,5-b]pyridazin-6-yl-thiomethyl and R6 is methyl.
21. A process according to claim 8, wherein R? and R3 are hydrogen and R4 and R6 are methyl.
22. A process according to claim 8, wherein R? and R3 are hydrogen, R4 is acetylthiomethyl and R6 is methyl.
23. A process according to claim 8, wherein R? and R3 are hydrogen, R4 is chloro and R6 is methyl.
24. A process according to claim 8, wherein R? and R3 are hydrogen, R4 is 5-(4-chlorophenyl)-1,3,4-oxadiazol-2-ylthiomethyl and R6 is methyl.
25. A process according to claim 8, wherein R? is chloro, R3 is hydrogen, R4 is 1,3,4-thiadiazol-2-ylthio-methyl and R6 is methyl.
26. A process according to claim 8, wherein R? and R3 are hydrogen, R4 is 1,3,4-thiadiazol-2-ylthiomethyl and R6 is benzyl.
27. A process according to claim 8, wherein R? and R3 are hydrogen, R4 is 2-pyrazinylthiomethyl and R6 is methyl.
28. A process according to claim 8, wherein R? is methoxy, R3 is hydrogen, R4 is 1,3,4-thiadiazol-2-ylthio-methyl and R6 is methyl.
29. A process according to claim 8, wherein R? is phenylthio, R3 is hydrogen, R4 is 1,3,4-thiadiazol-2-yl-thiomethyl and R6 is methyl.
30. A process according to claim 8, wherein R? and R3 are hydrogen, R4 is 1-(2-tert-butoxycarbonylaminoethyl)-1H-tetrazol-5-ylthiomethyl and R6 is methyl.
31. A process according to claim 6, wherein R? and R3 are hydrogen, R4 is hydrogen or chloro, R5 is 4-nitrobenzyl-oxycarbonyl and R6 is methyl.
32. A process according to claim 5, wherein R1 is a group of the formula:

in which R? is hydrogen or halogen, R2 and R3 are hydrogen, R4 is tetrazolylthiomethyl substituted by lower alkyl, R5 is carboxy and R6 is lower alkyl.
33. A process according to claim 32, wherein R? is hydrogen, R4 is 1-methyl-1H-tetrazol-5-ylthiomethyl and R6 is methyl.
34. A process according to claim 32, wherein R? is chloro, R4 is 1-methyl-1H-tetrazol-5-ylthiomethyl and R6 is methyl.
35. A process according to claim 5, wherein R1 is a group of the formula:

in which R? and R? are hydrogen or halogen.
36. A process according to claim 35, wherein R5 is carboxy.
37. A process according to claim 36, wherein R? and R? are hydrogen or chloro, R2 is hydrogen or methoxy, R3 is hydrogen or methyl and R4 is hydroyen, chloro, carbamoyloxy-methyl, methyl, methoxy, acetoxymethyl, 1,3,4-thiadiazol-2-ylthiomethyl, 5-aminomethyl-1,3,4-thiadiazol-2-ylthiomethyl, 1-methyl-1H-tetrazol-5-ylthiomethyl, 1-carboxymethyl-1H-tetrazol-5-ylthiomethyl, 1-hexyl-1H-tetrazol-5-ylthiomethyl or 1-allyl-1H-tetrazol-5-ylthiomethyl and R6 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, trifluoro-ethyl, allyl, propargyl or phenyl.
38. A process according to claim 5, wherein R1 is a group of the formula:
R2 and R3 are hydrogen, R4 is tetrazolylthiomethyl substi-tuted by lower alkyl, R5 is carboxy and R6 is lower alkyl.
39. A process according to claim 38, wherein R4 is 1-methyl-1H-tetrazol-5-ylthiomethyl and R6 is methyl.
40. A process according to claim 5, wherein R1 is a group of the formula:

R2 and R3 are hydrogen, R4 is tetrazolylthiomethyl substi-tuted by lower alkyl, R5 is carboxy and R6 is lower alkyl.
41. A process according to claim 40, wherein R4 is 1-methyl-1H-tetrazol-5-ylthiomethyl and R6 is methyl.
42. A process according to claim 5, wherein R1 is a group of the formula:

R2 and R3 are hydrogen, R4 is tetrazolylthiomethyl substi-tuted by lower alkyl, R5 is carboxy and R6 is lower alkyl.
43. A process according to claim 42, wherein R4 is 1-methyl-1H-tetrazol-5-ylthiomethyl and R6 is methyl.
44. A process according to claim 5, wherein R1 is a group of the formula:

in which R? is lower alkanoylamino and R2 is hydrogen.
45. A process according to claim 44, wherein R? is formamido, R3 is hydrogen, R4 is acetoxymethyl, 1,3,4-thiadiazol-2-ylthiomethyl, 1-methyl-1H-tetrazol-5-ylthio-methyl or tetrazolo[1,5-b]pyridazin-6-ylthiomethyl, R5 is carboxy and R6 is methyl, ethyl, propyl, allyl or benzyl.
46. A process according to claim 5, wherein R1 is a group of the formula:
in which R? is formamido and R? is hydrogen or chloro, R2 is hydrogen, R3 is hydrogen, R4 is 1-methyl-1H-tetrazol-5-ylthiomethyl, R5 is carboxy and R6 is methyl.
47. A process according to claim 5, wherein R1 is a group of the formula:

in which R? is lower alkanoylamino or trihalo(lower)alkanoyl-amino.
48. A process according to claim 5, wherein R? is formamido or trifluoroacetamido, R? and R? are hydrogen or chloro, R2 is hydrogen or methoxy, R3 is hydrogen or methyl, R4 is hydrogen, methyl, chloro, carbamoyloxymethyl, acetoxy-methyl, methoxy, 1,3,4-thiadiazol-2-ylthiomethyl, 5-tert-butoxycarbonylaminomethyl-1,3,4-thiadiazol-2-ylthiomethyl, 1-methyl-1H-tetrazol-5-ylthiomethyl, 1-hexyl-1H-tetrazol-5-ylthiomethyl or 1-allyl-1H-tetrazol-5-ylthiomethyl, R5 is carboxy, 4-nitrobenzyloxycarbonyl or benzhydryloxycarbonyl, and R6 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, 2,2,2-trifluoroethyl, allyl, propargyl, phenyl or benzyl.
49. A process according to claim 5, wherein R1 is a group of the formula:
R2 and R3 are hydrogen, R4 is 1-methyl-1H-tetrazol-5-ylthio-methyl, R5 is carboxy and R6 is methyl.
50. A process according to claim 5, wherein R1 is a group of the formula:

R2 and R3 are hydrogen, R4 is 1-methyl-1H-tetrazol-5-ylthio-methyl, R5 is carboxy and R6 is methyl.
51. A process according to claim 5, wherein R1 is a group of the formula:

R2 and R3 are hydrogen, R4 is 1-methyl-1H-tetrazol-5-ylthio-methyl, R5 is carboxy and R6 is methyl.
52. A process according to claim 4, wherein R1 is a group of the formula:

in which R? is amino or formamido, R2 and R3 are hydrogen, R4 is 1-methyl-1H-tetrazol-5-ylthiomethyl, R5 is carboxy and X is a group of the formula:

such that said compound of formula (I) is in the syn form.
53. A process according to claim 3, wherein X is lower alkylene.
54. A process according to claim 53, wherein R? is amino or formamido, R2 and R3 are hydrogen, R4 is 1-methyl-1H-tetrazol-5-ylthiomethyl and X is methylene.
55. A process for preparing a compound of the formula:

(Ib) wherein R1" is a group of the formula:

in which R? and R? are each hydrogen, halogen, lower alkoxy or arylthio, and Z is N or CH, R2 is hydrogen or lower alkoxy, R3 is hydrogen or lower alkyl, R4 is hydrogen, halogen, carbamoyloxymethyl, lower alkyl, lower alkoxy, lower alkanoyloxymethyl, lower alkanoylthiomethyl, or heterocyclic-thiomethyl which is unsubstituted or sub-statuted by a substituent selected from the group con-sisting of lower alkyl, carboxy(lower)alkyl, amino(lower)-alkyl, a protected amino(lower)alkyl, halophenyl and lower alkenyl, R5 is carboxy or a derivative thereof, and X is lower alkylene or a group of the formula:

in which R6 is hydrogen, lower alkyl, mono-, di- or tri-halo(lower)alkyl, lower alkenyl, lower alkynyl, aryl, ar-(lower) alkyl or halo(lower) alkanoyl, or a pharmaceutically acceptable salt thereof comprising subjecting a compound of the formula:

(Ia) wherein R1' is a group of the formula:

in which is a protected amino group, and R?, R? and Z
are each as defined above, and R2, R3, R4, R5 and X are each as defined above, or a salt thereof, to an elimination reaction effective to eliminate the amino-protective group in .
56. A process according to claim 55, wherein R1' is a group of the formula:

in which is lower alkanoylamino and R? is hydrogen, halogen, lower alkoxy or phenylthio, R1" is a group of the formula:
in which R? is as defined above, R2 is hydrogen, R4 is hydrogen, halogen, carbamoyloxymethyl, lower alkyl, lower alkanoyloxymethyl, lower alkanoylthiomethyl, thiadiazolyl-thiomethyl which is unsubstituted or substituted by lower alkyl, halophenyloxadiazolylthiomethyl, tetrazolylthiomethyl substituted by lower alkyl or lower alkenyl, pyrazinylthio-methyl, or tetrazolopyridazinylthiomethyl, R5 is carboxy, and X is a group of the formula:

such that the compound of formula (Ib) is in the syn form, in which R6 is lower alkyl, lower alkenyl or phenyl(lower)-alkyl, and, if desired, converting the resultant compound to a pharmaceutically acceptable salt thereof.
57. A process according to claim 56, wherein is a formamido, R? is hydrogen, chloro, methoxy or phenylthio, R3 is hydrogen or methyl, R4 is hydrogen, chloro, car-bamoyloxymethyl, methyl, acetoxymethyl, acetylthiomethyl, 1,3,4-thiadiazol-2-ylthiomethyl, 5-methyl-1,3,4-thiadiazol-2-ylthiomethyl, 1-methyl-1H-tetrazol-5-ylthiomethyl, 1-allyl-1H-tetrazol-5-ylthiomethyl, 5-(4-chlorophenyl)-1,3,4-oxadiazol-2-ylthiomethyl, 2-pyrazinylthiomethyl or tetra-zolo[1,5-b]-pyridazin-6-ylthiomethyl, and R6 is methyl, ethyl, propyl, allyl or benzyl.
58. A process according to claim 57, wherein R? and R3 are hydrogen, R4 is 1-methyl-1H-tetrazol-5-ylthiomethyl, and R6 is methyl.
59. A process according to claim 57, wherein R? and R3 are hydrogen, R4 is 1,3,4-thiadiazol-2-ylthiomethyl and R6 is methyl.
60. A process according to claim 57, wherein R? and R3 are hydrogen, R4 is 5-methyl-1,3,4-thiadiazol-2-ylthio-methyl and R6 is methyl.
61. A process according to claim 57, wherein R? and R3 are hydrogen, R4 is acetoxymethyl and R6 is methyl.
62. A process according to claim 57, wherein R? and R3 are hydrogen, R4 is 1,3,4-thiadiazol-2-ylthiomethyl and R6 is ethyl.
63. A process according to claim 57, wherein R? and R3 are hydrogen, R4 is 1,3,4-thiadiazol-2-ylthiomethyl and R6 is propyl.
64. A process according to claim 57, wherein R? and R3 are hydrogen, R4 is 1,3,4-thiadiazol-2-ylthiomethyl and R6 is allyl.
65. A process according to claim 57, wherein R? and R3 are hydrogen, R4 is 1,3,4-thiadiazol-2-ylthiomethyl and R6 is benzyl.
66. A process according to claim 57, wherein R? and R3 are hydrogen, R4 is 1-allyl-1H-tetrazol-5-ylthiomethyl and R6 is methyl.
67. A process according to claim 57, wherein R?, R3 and R4 are hydrogen and R6 is methyl.
68. A process according to claim 57, wherein R? and R4 are hydrogen and R3 and R6 are methyl.
69. A process according to claim 57, wherein R? and R3 are hydrogen and R4 and R6 are methyl.
70. A process according to claim 57, wherein R? and R3 are hydrogen, R4 is carbamoyloxymethyl and R6 is methyl.
71 A process according to claim 57, wherein R? and R3 are hydrogen, R4 is acetylthiomethyl and R6 is methyl.
72. A process according to claim 57, wherein R? and R3 are hydrogen, R4 is chloro and R6 is methyl.
73. A process according to claim 57, wherein R? and R3 are hydrogen, R4 is 5-(4-chlorophenyl)-1,3,4-oxadiazol-2-ylthiomethyl and R6 is methyl.
74. A process according to claim 57, wherein R? is chloro, R3 is hydrogen, R4 is 1,3,4-thiadiazol-2-ylthio-methyl and R6 is methyl.
75. A process according to claim 57, wherein R? and R3 are hydrogen, R4 is 2-pyrazinylthiomethyl and R6 is methyl.
76. A process according to claim 57, wherein R? and R3 are hydrogen, R4 is tetrazolo[1,5-b]pyridazin-6-ylthio-methyl and R6 is methyl.
77. A process according to claim 57, wherein R? is methoxy, R3 is hydrogen, R4 is 1,3,4-thiadiazol-2-ylthio-methyl and R6 is methyl.
78. A process according to claim 57, wherein R? is phenylthio, R3 is hydrogen, R4 is 1,3,4-thiadiazol-2-yl-thiomethyl and R6 is methyl.
79. A process according to claim 55, wherein is a group of the formula:
in which is lower alkanoylamino and R? is hydrogen or halogen, R1" is a group of the formula:

in which R? is as defined above, R2 and R3 are each hydrogen, R4 is tetrazolyl having lower alkyl, R5 is carboxy, and X is a group of the formula:
such that the compound of formula (Ib) is in the syn form, in which R6 is lower alkyl.
80. A process accordlng to claim 79, wherein is formamido, R? is hydrogen, R4 is 1-methyl-1H-tetrazol-5-ylthiomethyl and R6 is methyl.
81. A process according to claim 79, wherein is formamido, R? is chloro, R4 is 1-methyl-1H-tetrazol-5-yl-thiomethyl and R6 is methyl.
82. A process according to claim 55, wherein is a group of the formula:
in which R? is lower alkanoylamino or trihalo(lower)-alkanoylamino and R? and R? are hydrogen or halogen, R1"
is a group of the formula:

in which R? and R? are hydrogen or halogen, R4 is hydrogen, halogen, carbamoyloxymethyl, lower alkyl, lower alkanoyloxy-methyl, thiadiazolylthiomethyl, or tetrazolylthiomethyl which may have lower alkyl, carboxy(lower)alkyl or lower alkenyl, R5 is carboxy, and X is a group of the formula:

such that the compound of formula (Ib) is in the syn form, in which R6 is hydrogen, lower alkyl, trihalo(lower)alkyl, lower alkenyl, lower alkynyl or phenyl.
83. A process according to claim 82, wherein is formamido or trifluoroacetamido, R? and R? are hydrogen or chloro, R4 is hydrogen, chloro, carbamoyloxymethyl, methyl, acetoxymethyl, 1,3,4-thiadiazol-2-ylthiomethyl, 1-methyl-1H-tetrazol-5-ylthiomethyl or 1-carboxymethyl-1H-tetrazol-5-ylthiomethyl, 1-allyl-1H-tetrazol-5-ylthiomethyl, R6 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, 2,2,2-trifluoroethyl, allyl or propargyl.
84. A process according to claim 55, wherein R1' is a group of the formula:

in which is lower alkanoylamino, R1" is a group of the formula:

R2 and R3 are hydrogen, R4 is tetrazolylthiomethyl substitu-ted by lower alkyl, R5 is carboxy, and X is a group of the formula:

such that the compound of formula (Ib) is in the syn form, in which R6 is lower alkyl.
85. A process according to claim 84, wherein is formamido, R4 is 1-methyl-1H-tetrazol-5-ylthiomethyl and R6 is methyl.
86. A process according to claim 55, wherein R1' is a group of the formula:

in which is lower alkanoylamido, R1" is a group of the formula:

R2 and R3 are hydrogen, R4 is tetrazolylthiomethyl substi-tuted by lower alkyl, R5 is carboxy, and X is a group of the formula:
such that the compound of formula (Ib) is in the syn form, in which R6 is lower alkyl.
87. A process according to claim 86, wherein is formamido. R4 is 1-methyl-1H-tetrazol-5-ylthiomethyl and R6 is methyl.
88. A process according to claim 55, wherein is a group of the formula:

in which is lower alkanolyamino. R1" is a group of the formula:

R2 and R3 are hydrogen, R4 is tetrazolylthiomethyl substi-tuted by lower alkyl, R5 is carboxy, and X is a group of the formula:

such that the compound of formula (Ib) is in the syn form, in which R6 is lower alkyl.
89. A process according to claim 88, wherein is formamido, R4 is 1-methyl-1H-tetrazol-5-ylthiomethyl and R6 is methyl.
90. A process according to claim 55, wherein R1' is a group of the formula:

in which is lower alkanoylamino. R1" is a group of the formula:
R2 and R3 are hydrogen, R4 is tetrazolylthiomethyl substi-tuted by lower alkyl, R5 is carboxy, and X is a group of the formula:

such that said compound of formula (Ib) is in the anti form, in which R6 is lower alkyl.
91. A process according to claim 90, wherein is formamido, R4 is 1-methyl-1H-tetrazol-5-ylthiomethyl and R6 is methyl.
92. A process according to claim 55, wherein R1' is a group of the formula:

in which is lower alkanoylamino, R1" is a group of the formula:

R2 and R3 are hydrogen, R4 is tetrazolylthiomethyl substi-tuted by lower alkyl, R5 is carboxy, and X is lower alkylene.
93. A process according to claim 92, wherein is formamido, R4 is 1-methyl-1H-tetrazol-5-ylthiomethyl and X
is methylene.
94. A process for preparing a compound of the formula:

(Id) wherein R1 is a group of the formula:

in which R? is amino or a protected amino group, R? and R?
are selected from hydrogen, halogen, lower alkoxy and aryl-thio, and Z is N or CH, R2 is hydrogen or lower alkoxy, R3 is hydrogen or lower alkyl, Rb is heterocyclic-thiomethyl substituted by amino(lower)alkyl group, R5 is carboxy or a derivative thereof, and X is lower alkylene or a group of the formula:

in which R6 is hydrogen, lower alkyl, mono-, di- or tri-halo(lower)alkyl, lower alkenyl, lower alkynyl, aryl, ar-(lower)alkyl or halo(lower) alkanoyl, or a pharmaceutically acceptable salt thereof comprising subjecting a compound of the formula:

(Ic) wherein R4 is heterocyclic-thiomethyl having a protected amino(lower) alkyl group, and R1, R2, R3, R5 and X are each as defined above, or a salt thereof, to an elimination re-action effective to eliminate the amino-protective group in R4a, and if desired converting the resultant compound to a pharmaceutically acceptable salt thereof.
95. A process according to claim 94, wherein R1 is a group of the formula:

in which R1a is amino or lower alkanoylamino, R2 and R3 are hydrogen, R4a is thiadiazolylthiomethyl having lower alkoxy-carbonylamino(lower)alkyl or tetrazolylthiomethyl substi-tuted by lower alkoxycarbonylamino(lower)alkyl, R? is thia-diazolylthiomethyl substituted by amino(lower)alkyl or tetrazolylthiomethyl substituted by amino(lower)alkyl, R5 is carboxy, and X is a group of the formula:

such that said compound of formula (Id) is in the syn form, in which R6 is lower alkyl or lower alkenyl.
96. A process according to claim 95, wherein R? is formamido, R? is 5-tert-butoxycarbonylaminomethyl-1,3,4-thiadiazol-2-ylthiomethyl, R? is 5-aminomethyl-1,3,4-thia-diazol-2-ylthiomethyl and R6 is allyl.
97. A process according to claim 95, wherein R? is amino, R? is 1-(2-tert-butoxycarbonylaminoethyl)-1H-tetrazol-5-ylthiomethyl, R4 is 1-(2-aminoethyl)-1H-tetra-zol-5-ylthiomethyl and R6 is methyl.
98. A process according to claim 94, wherein R1 is a group of the formula:

in which R? is lower alkanoylamino, R2 and R3 are hydrogen, R? is thiadiazolylthiomethyl substituted lower alkoxycar-bonylamino(lower)alkyl, R? is thiadiazolylthiomethyl sub-stituted by amino(lower)alkyl, R5 is carboxy, and X is a group of the formula:

such that the compound of formula (Id) is in the syn form, in which R6 is lower alkyl.
99. A process according to claim 98, wherein R1a is formamido, R4a is 5-tert-butoxycarbonylaminomethyl-1,3,4-thiadiazol-2-ylthiomethyl, R4b is 5-aminomethyl-1,3,4-thiadiazol-2-ylthiomethyl and R6 is methyl.
100. A process for preparing a compound of the formula:

(If) wherein R1 is a group of the formula:

in which R1a is amino or a protected amino group, R1b and R1c are each selected from hydrogen, halogen, lower alkoxy and arylthio, and Z is N or CH, R2 is hydrogen or lower alkoxy, R3 is hydrogen or lower alkyl, R4 is hydrogen, halogen, carbamoyloxymethyl, lower alkyl, lower alkoxy, lower alkanoyloxymethyl, lower alkanoylthiomethyl, or heterocyclic-thiomethyl which is unsubstituted or substituted by a sub-stituent selected from the group consisting of lower alkyl, carboxy(lower)alkyl, amino(lower)alkyl, a protected amino(lower)alkyl, halophenyl and lower alkenyl, and X
is lower alkylene or a group of the formula:

in which R6 is hydrogen, lower alkyl, mono-, di- or tri-halo(lower)alkyl, lower alkenyl, lower alkynyl, aryl, ar(lower)alkyl or halo(lower)alkanoyl, or a pharmaceutically acceptable salt thereof, comprising subjecting a compound of the formula:

(Ie) wherein R5a is a protected carboxy group, and R1, R2, R3, R4 and X are each as defined above, or a salt thereof, to an elimination reaction effective to eliminate the carboxy protective group in R5a to give said compound of formula (If), and if desired, converting the resultant compound to a pharmaceutically acceptable salt thereof.
101. A process according to claim 100, wherein is a group of the formula:

in which R? is hydrogen, halogen, lower alkoxy or phenylthio, R2 is hydrogen, R4 is hydrogen, halogen, carbamoyloxymethyl, lower alkyl, lower alkanoyloxymethyl, lower alkanoylthiomethyl, thiadiazolylthiomethyl which is unsubstituted or substituted by lower alkyl; halo-phenyloxadiazolylthiomethyl, tetrazolylthiomethyl which is unsubstituted or substituted by lower alkyl or lower alkenyl, pyrazinylthiomethyl, or tetrazolopyridazinyl-thiomethiomethyl, R? is nitrophenyl(lower)alkoxycarbonyl, and X is a group of the formula:

such that said compound of formula (If) is in the syn form, in which R6 is hydrogen, lower alkyl, lower alkenyl or phenyl(lower)alkyl.
102. A process according to claim 101, wherein R?
is hydrogen, chloro, methoxy or phenylthio, R3 is hydrogen or methyl R4 is hydrogen, chloro, carbamoyloxymethyl, methyl, acetoxymethyl, acetylthiomethyl, 1,3,4-thiadiazol-2-ylthiomethyl, 5-methyl-1,3,4-thiadiazol-2-ylthiomethyl, 5-(4-chlorophenyl)-1,3,4-oxadiazol-2-ylthiomethyl, 1-methyl-1H-tetrazol-5-ylthiomethyl, 1-allyl-1H-tetrazol-5-ylthiomethyl, 2-pyrazinylthiomethyl or tetrazolo-[1,5-b]pyridazin-6-ylthiomethyl, and R6 is hydrogen, methyl, ethyl, propyl, allyl or benzyl.
103. A process according to claim 102, wherein R?
and R3 are hydrogen, R4 is 1-methyl-1H tetrazol-5-ylthio-methyl and R6 is methyl.
104. A process according to claim 102, wherein R?
and R are hydrogen, R4 is 1,3,4-thiadiazol-2-ylthio-methyl and R6 is methyl.
105. A process according to claim 102, wherein R?
and R3 are hydrogen, R4 is 5-methyl-1,3,4-thiadiazol-2-ylthiomethyl and R6 is methyl.
106. A process according to claim 102, wherein R?
and R3 are hydrogen, R4 is acetoxymethyl and R6 is methyl.
107. A process according to claim 102, wherein R?, R3 and R4 are hydrogen and R6 is methyl.
108. A process according to claim 102, wherein R?
and R3 are hydrogen. R4 is chloro and R6 is methyl.
109. A process according to claim 102, wherein R?
and R3 are hydrogen, R4 is 1-allyl-1H-tetrazol-5-ylthio-methyl and R6 is methyl.
110. A process according to claim 102, wherein R?
and R4 are hydrogen and R3 and R6 are methyl.
111. A process according to claim 102, wherein R?

and R3 are hydrogen and R4 and R6 are methyl.
112. A process according to claim 102, wherein R?
and R3 are hydrogen, R4 is carbamoyloxymethyl and R6 is methyl.
113. A process according to claim 102, wherein R?
and R3 are hydrogen, R4 is acetylthiomethyl and R6 is methyl.
114. A process according to claim 102, wherein R?
and R3 are hydrogen, R4 is 5-(4-chlorophenyl)-1,3,4-oxadiazol-2-ylthiomethyl and R6 is methyl.
115. A process according to claim 102, wherein R?
is chloro, R3 is hydrogen, R4 is 1,3,4-thiadiazol-2-ylthiomethyl and R6 is methyl.
116. A process according to claim 102, wherein R?

and R3 are hydrogen, R4 is 1,3,4-thiadiazol-2-ylthio-methyl and R6 is ethyl.
117. A process according to claim 102, wherein R?

and R3 are hydrogen, R4 is 1,3,4-thiadiazol-2-ylthiomethyl and R6 is propyl.
118. A process according to claim 102, wherein R?
and R3 are hydrogen, R4 is 1,3,4-thiadiazol-2-ylthio-methyl and R6 is allyl.
119. A process according to claim 102, wherein R?

and R3 are hydrogen, R4 is 1,3,4-thiadiazol-2-yl-thio-methyl and R6 is benzyl.
120. A process according to claim 102, wherein R?
and R3 are hydrogen, R4 is 2-pyrazinylthiomethyl and R6 is methyl.
121. A process according to claim 102, wherein R?
and R3 are hydrogen, R4 is tetrazolo[l,5-b]pyridazin-6-ylthiomethyl and R6 is methyl.
122. A process according to claim 102, wherein R?
is methoxy. R3 is hydrogen, R4 is 1,3,4-thiadiazol-2-ylthiomethyl and R6 is methyl.
123. A process according to claim 102, wherein R?
is phenylthio, R3 is hydrogen, R4 is 1,3,4-thiadiazol-2-ylthiomethyl and R6 is methyl.
124. A process according to claim 100, wherein R1 is a group of the formula:

in which R? is hydrogen or halogen, R2 and R3 are hydrogen, R4 is tetrazolylthiomethyl substituted by lower alkyl, R? is nitrophenyl(lower)alkoxycarbonyl, and X is a group of the formula:

such that said compound of formula (If) is in the syn form in which R6 is lower alkyl.
125. A process according to claim 124, wherein R?
is hydrogen, R4 is 1-methyl-1H-tetrazol-5-ylthiomethyl, R? is 4-nitrobenzyloxycarbonyl and R6 is methyl.
126. A process according to claim 124, wherein R?
is chloro, R4 is 1-methyl-1H-tetrazol-5-ylthiomethyl, R? is 4-nitrobenzyloxycarbonyl and R6 is methyl.
127. A process according to claim 100, wherein R1 is a group of the formula:

in which R? is amino or lower alkanoylamino, and R? and R? are hydrogen or halogen, R4 is hydrogen, halogen, carbamoyloxymethyl, lower alkyl, lower alkoxy, lower alkanoyloxymethyl, thiadiazolylthiomethyl which may have amino(lower)alkyl, or tetrazolylthiomethyl which is unsubstituted or substituted by lower alkyl, carboxy-(lower)alkyl or lower alkenyl, R? is nitrophenyl(lower)-alkoxycarbonyl or diphenyl(lower)alkoxycarbonyl, and X is a group of the formula such that said compound of formula (If) is in the syn form in which R6 is hydrogen, lower alkyl, lower a1kenyl, trihalo(lower)alkyl, lower alkynyl or phenyl.
128. A process according to claim 127, wherein R?
is amino, R? and R? are hydrogen or chloro, R2 is hydrogen or methoxy, R3 is hydrogen or methyl, R4 is hydrogen, chloro, carbamoyloxymethyl, methyl, methoxy, acetoxymethyl, 1,3,4-thiadiazol-2-ylthiomethyl, 5-aminomethyl-1,3,4-thiadiazol-2-ylthiomethyl, 1-methyl-1H-tetrazol-5-ylthiomethyl, 1-hexyl-1H-tetrazol-5-ylthio-methyl or 1-carboxymethyl-1H-tetrazol-5-yl-thiomethyl, R? is 4-nitrobenzyloxycarbonyl, and R6 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, allyl, propargyl, 2,2,2-trifluoroethyl or phenyl.
129. A process according to claim 127, wherein R?
is formamido, R?, R? and R3 are hydrogen, R2 is hydrogen or methoxy, R4 is hydrogen, chloro methoxy or 1-methyl-1H-tetrazol-5-ylthiomethyl, R? is 4-nitro-benzyloxycarbonyl or benzhydryloxycarbonyl and R6 is methyl.
130. A process according to claim 100, wherein R1 is a group of the formula:

R2 and R3 are hydrogen, R4 is tetrazolylthiomethyl substituted by lower alkyl, R? is nitrophenyl(lower)-alkoxycarbonyl, and X is a group of the formula:
such that said compound of formula (Ie) is in the syn form, in which R6 is lower alkyl.
131. A process according to claim 130, wherein R4 is 1-methyl-1H-tetrazol-5-ylthiomethyl, R? is 4-nitro-benzyloxycarbonyl and R6 is methyl.
132. A process according to claim 100, wherein R1 is a group of the formula:

R2 and R3 are hydrogen, R4 is tetrazolylthiomethyl substituted by lower alkyl, R? is nitrophenyl(lower)-alkoxycarbonyl, and X is a group of the formula:

such that the compound of formula (If) is in the syn form in which R6 is lower alkyl.
133. A process according to claim 132, wherein R4 is 1-methyl-1H-tetrazol-5-ylthiomethyl, R? is 4-nitro-benzyloxycarbonyl and R6 is methyl.
134. A process according to claim 100 wherein R1 is a group of the formula:

R2 and R3 are hydrogen, R4 is tetrazolylthiomethyl sub-stituted by lower alkyl, R? is nitrophenyl(lower)alkoxy-carbonyl, and X is a group of the formula:
such that the compound of formula (If) is in the syn form, in which R6 is lower alkyl.
135. A process according to claim 134, wherein R4 is 1-methyl-1H-tetrazol-5-ylthiomethyl, R? is 4-nitro-benzyloxycarbonyl and R6 is methyl.
136. A process according to claim 100, wherein R1 is a group of the formula:

R2 and R3 are hydrogen, R4 is tetrazolylthiomethyl sub-stituted by lower alkyl, R? is nitrophenyl(lower)-alkoxycarbonyl, and X is a group of the formula:

such that said compound of formula (If) is in the anti form, in which R6 is lower alkyl.
137. A process according to claim 136, wherein R4 is 1-methyl-1H-tetrazol-5-ylthiomethyl, R? is 4-nitro-benzyloxycarbonyl and R6 is methyl.
138. A process according to claim 100, wherein R1 is a group of the formula:

R2 and R3 are hydrogen, R4 is tetrazolylthiomethyl, sub-stituted by lower alkyl, R? is nitrophenyl(lower)alkoxy-carbonyl and X is lower alkylene.
139. A process according to claim 138, wherein R4 is 1-methyl-1H-tetrazol-5-ylthiomethyl, R? is 4-nitro-benzyloxycarbonyl and X is methylene.
140. A process for preparing a compound of the formula:

( Ih ) wherein R1 is a group of the formula:

in which R? is amino or a protected amino group, R? and R? are each selected from hydrogen, halogen, lower alkoxy and arylthio, and Z is N or CH, R2 is hydrogen or lower alkoxy, R3 is hydrogen or lower alkyl, R5 is carboxy or its derivative, R7 is heterocyclic-thio which is unsub-stituted or substituted by a substituent selected from the group consisting of lower alkyl, carboxy(lower)alkyl, amino(lower)alkyl, a protected amino(lower)alkyl, halo-phenyl and lower alkenyl, and X is a lower alkylene or a group of the formula:

in which R6 is hydrogen, lower alkyl, mono-, di- or tri-halo(lower)alkyl, lower alkenyl, lower alkynyl, aryl, ar(lower)alkyl or halo(lower)alkanoyl, or a pharmaceutically acceptable salt thereof, comprising reacting a compound of the formula:

wherein Y is a conventional group which is capable of being replaced by the residue (-R7) of a compound of the formula:

in which R7 is as defined above or a salt thereof, with a compound of the formula:
R7-H (IV) wherein R7 is as defined above, or a reactive derivative thereof, and if desired converting the resultant com-pound to a pharmaceutically acceptable salt thereof.
141. A process according to claim 140, wherein R1 is a group of the formula:

in which R? is amino or lower alkanoylamino, and R? is hydrogen, halogen, lower alkoxy or phenylthio, R2 and R3 are hydrogen, R5 is carboxy, R7 is thiadiazolylthio which is unsubstituted or substituted by lower alkyl, tetrazolylthio substituted by lower alkyl or lower alkenyl, halophenyloxadiazolylthio, pyrazinylthio or tetrazolopyridazinylthio, X is a group of the formula such that said compound of formula (Ih) is in the syn form, in which R6 is lower alkyl, lower alkenyl or phenyl-(lower)alkyl and Y is lower alkanoyloxy.
142. A process according to claim 141, wherein R?
is amino or formamido, R? is hydrogen, chloro, methoxy or phenylthio, R7 is 1,3,4-thiadiazol-2-ylthio, 5-methyl-1,3,4-thiadiazol-2-ylthio, 1-methyl-1H-tetrazol-5-ylthio, 1-allyl-1H-tetrazol-5-ylthio, 5-(4-chlorophenyl)-1,3,4-oxadiazol-2-ylthio, 2-pyrazinylthio or tetrazolo[1,5-b]-pyridazin-6-ylthio, R6 is methyl, ethyl, propyl, alkyl or benzyl and Y is acetoxy.
143. A process according to claim 142, wherein R?
is amino, R? is hydrogen, R6 is methyl, and R7 is 1-methyl-1H-tetrazol-5-ylthio.
144. A process according to claim 142, wherein R?
is amino, R? is hydrogen, R6 is methyl and R7 is 1,3,4-thiadiazol-2-ylthio.
145. A process according to claim 142, wherein R?
is amino, R? is hydrogen, R6 is methyl and R7 is 5-methyl-1,3,4-thiadiazol-2-ylthio.
146. A process according to claim 142, wherein R?
is formamido, R? is hydrogen, R6 is methyl and R7 is tetrazolo[l,5-b]pyridazin-6-ylthio.
147. A process according to clairn 142, wherein R?
is formamido, R? is hydrogen, R6 is methyl and R7 is 2-pyrazinylthio.
148. A process according to claim 142, wherein R?
is formamido, R? is hydrogen, R6 is methyl and R7 is 1-allyl-1H-tetrazol-5-ylthio.
149. A process according to claim 142, wherein R?
is formamido, R? is hydrogen, R6 is methyl and R7 is 5-(4-chlorophenyl)-1,3,4-oxadiazol-2-ylthio.
150. A process according to claim 142, wherein R?
is amino, R? is chloro, R6 is methyl and R7 is 1,3,4-thiadiazol-2-ylthio.
151. A process according to claim 142, wherein R?
is amino, R? is hydrogen, R6 is ethyl and R7 is 1,3,4-thiadiazol-2-ylthio.
152. A process according to claim 142, wherein R?
is amino, R? is hydrogen, R6 is propyl and R7 is 1,3,4-thiadiazol-2-ylthio.
153. A process according to claim 142, wherein R?
is amino, R? is hydrogen, R6 is allyl and R7 is 1,3,4-thiadiazol-2-ylthio.
154. A process according to claim 142, wherein R?
is amino, R? is hydrogen, R6 is benzyl and R7 is 1,3,4-thiadiazol-2-ylthio.
155. A process according to claim 142, wherein R?
is amino, R? is hydrogen, R6 is methyl and R7 is tetra-zolo[1,5-b]pyridazin-6-ylthio.
156. A process according to claim 142, wherein R?
is amino, R? is methoxy, R6 is methyl and R7 is 1,3,4-thiadiazol-2-ylthio.
157. A process according to claim 142, wherein R?
is amino, R? is phenylthio, R6 is methyl and R7 is 1,3,4-thiadiazol-2-ylthio.
158. A process according to claim 140, wherein R1 is a group of the formula:

in which R? is hydrogen or halogen, R2 and R3 are hydrogen, R5 is carboxy, R7 is tetrazolylthio substituted by lower alkyl, X is a group of the formula:

such that the compound of formula (Ih) is in the syn form, in which R6 is lower alkyl and Y is lower alkanoyl-oxy .
159. A process according to claim 158, wherein R?
is hydrogen, R6 is methyl, R7 is 1-methyl-1H-tetrazol-5-ylthio and Y is acetoxy.
160. A process according to claim 158, wherein R?
is chloro, R6 is methyl, R7 is 1-methyl-1H-tetrazol-5-ylthio and Y is acetoxy.
161. A process according to claim 140, wherein R1 is a group of the formula:

in which R? is amino or lower alkanoylamino, R? and R?
axe hydrogen or halogen, R3 is hydrogen, R7 is thiadiazolyl-thio which is unsubstituted or substituted by amino(lower)-alkyl, or tetrazolylthio suhstituted by lower alkyl, carboxy(lower)alkyl or lower alkenyl, X is a group of the formula:

such that the compound of formula (Ih) is in the syn form, in which R6 is hydrogen, lower alkyl, trihalo(lower)-alkyl, lower alkenyl or lower alkynyl, and Y is lower alkanoyloxy.
162. A process according to claim 161, wherein R?
is amino, R? and R? are hydrogen or chloro, R2 is hydrogen or methoxy, R6 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, 2,2,2-trifluoro-ethyl, allyl or propargyl, R7 is 1,3,4-thiadiazol-2-ylthio, 5-methyl-1,3,4-thiadiazol-2-ylthio, l-methyl-1H-tetrazol-5-ylthio, 1-hexyl-1H-tetrazol-5-ylthio, 1-carboxymethyl-1H-tetrazol-5-ylthio or 1-allyl-1H-tetrazol-5-ylthio and Y is acetoxy.
163. A process according to claim 161, wherein R?
is formamido, R?, R? and R2 are hydrogen, R6 is methyl, and R7 is 1-carboxymethyl-1H-tetrazol-5-ylthio.
164. A process according to claim 140, wherein R1 is a group of the formula:

R2 and R3 are hydrogen, R5 is carboxy, R7 is tetrazolyl-thio having lower alkyl, X is a group of the formula:

such that the compound of formula (Ih) is in the syn form in which R6 is lower alkyl and Y is lower alkanoyl-oxy .
165. A process according to claim 164, wherein R6 is methyl, R7 is 1-methyl-1H-tetrazol-5-ylthio and Y is acetoxy.
166. A process according to claim 140, wherein R1 is a group of the formula:

R2 and R3 are hydrogen, R5 is carboxy, R7 is tetrazolyl-thio substituted by lower alkyl, X is a group of the formula:
such that the compound of formula (Ih) is in the syn form, in which R6 is lower alkyl and Y is lower alkanoyl-oxy.
167. A process according to claim 166, wherein R6 is methyl, R7 is 1-methyl-1H-tetrazol-5-ylthio and Y is acetoxy.
168. A process according to claim 140, wherein R1 is a group of the formula:

R2 and R3 are hydrogen, R5 is carboxy, R7 is tetra-zolylthio substituted by lower alkyl, X is a group of the formula:
such that the compound of formula (Ih) is in the syn form, in which R6 is lower alkyl and Y is lower alkanoyl-oxy.
169. A process according to claim 168 wherein R6 is methyl, R7 is 1-methyl-1H-tetrazol-5-ylthio and Y is acetoxy.
170. A process according to claim 140, wherein R1 is a group of the formula:

R2 and R3 are hydrogen, R5 is carboxy, R7 is tetrazolyl-thio substituted by lower alkyl, X is a group of the formula:
such that said compound of formula (Ih) is in the anti form, in which R6 is lower alkyl and Y is lower alkanoyl-oxy .
171. A process according to claim 170, wherein R6 is methyl, R7 is 1-methyl-1H-tetrazol-5-ylthio and Y is acetoxy.
172. A process according to claim 140, wherein R1 is a group of the formula:

R2 and R3 are hydrogen, R5 is carboxy, R7 is tetrazolyl-thio substituted by lower alkyl, X is lower alkylene and Y is lower alkanoyloxy.
173. A process according to claim 172, wherein R7 is 1-methyl-1H-tetrazol-5-ylthio, X is methylene and Y is acetoxy.
174. A compound of the formula:

(I) wherein R1, R2, R3, R4, R5 and X are each as defined in claim 1, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 1, or by an obvious chemical equivalent.
175. A compound of the formula:

( I ) wherein R1,R2,R3,R4,R5 and X are each as defined in claim 2, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 2, or by an obvious chemical equivalent.
176. A compound of the formula (I), as defined in claim 2, wherein R1,R2,R3,R4,R5 and X are each as defined in claim 3, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 3, or by an obvious chemical equivalent.
177. A compound of the formula (I), as defined in claim 2, wherein R1,R2,R3,R4,R5 and X are each as defined in claim 4, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 4, or by an obvious chemical equivalent.
178. A compound of the formula (I), as defined in claim 2, wherein R1, R2, R3, R4, R5 and X are each as defined in claim 5, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 5, or by an obvious chemical equivalent.
179. The compound of the formula (I), as defined in claim 2, wherein R1,R2,R3,R4,R5 and X are each as defined in claim 6, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 6, or by an obvious chemical equivalent.
180. A compound of the formula (I), as defined in claim 2, wherein R1,R2,R3,R4,R5 and X are each as defined in claim 7, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 7, or by an obvious chemical equivalent.
181. A compound of the formula (I), as defined in claim 2, wherein R1,R2,R3,R4,R5 and X are each as defined in claim 8, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 8, or by an obvious chemical equivalent.
182. 7-[2-(4-Aminopyrimidin-2-yl)-2-methoxyimino-acetamido]-3-cephem-4-carboxylic acid, syn isomer, or a pharmaceutically acceptable salt thereof, whenever pre-pared by the process of claim 9, or by an obvious chemical equivalent.
183. 7-[2-(4-Aminopyrimidin-2-yl)-2-methoxyimino-acetamido]-2-methyl-3-cephem-4-carboxylic acid, syn isomer, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 10, or by an obvious chemical equivalent.
184. 7-[2-(2-Aminopyrimidin-2-yl)-2-methoxyimino-acetamido]cephalosporanic acid, syn isomer, or a pharma-ceutically acceptable salt thereof, whenever prepared by the process of claim 11, or by an obvious chemical equivalent.
185. 7-[2-(4-Aminopyrimidin 2-yl)-2-methoxyimino-acetamido]-3-carbomoyloxymethyl-3-cephem-4-carboxylic acid, syn isomer, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 12, or by an obvious chemical equivalent.
186. 7-[2-(4-Aminopyrimidin-2-yl)-2-methoxyimino-acetamido]-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid, syn isomer, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 13 or by an obvious chemical equivalent.
187. 7-[2-(4-Aminopyrimidin-2-yl)-2-ethoxyimino-acetamido]-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cepham-4-carboxylic acid, syn isomer, or a pharma-ceutically acceptable salt thereof, whenever prepared by the process of claim 14, or by an obvious chemical equivalent.
188. 7-[2-(4-Aminopyrimidin-2-yl)-2-propoxyimino-acetamido]-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid, syn isomer, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 15, or by an obvious chemical equivalent.
189. 7-[2-Allyloxyimino-2-(4-aminopyrimidin-2-yl) acetamido]-3-(1,3,4-thiadiazol-2-yltniomethyl)-3-cephem-4-carboxylic acid, syn isomer, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 16, or by an obvious chemical equivalent.
190. 7-[2-(4-Aminopyrimidin-2-yl)-2-methoxyimino-acetamido]-3-(5-methyl-1,3,4-thiadaizol-2-ylthiomethyl)-3-cephem-4-carboxylic acid, syn isomer, or a pharma-ceutically acceptable salt thereof, whenever prepared by the process of claim 17, or by an obvious chemical equivalent.
191. 7-[2-(4-Aminopyrimidin-2-yl)-2-methoxyimino-acetamido]-3-(1-methyl-1H-tetrazol-5-ylthio-methyl)-3-cephem 4-carboxylic acid, syn isomer, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 18, or by an obvious chemical equivalent.
192. 7-[2-(4-Aminopyrimidin-2-yl)-2-methoxyimino-acetamido]-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid, syn isomer, or a pharma-ceutically acceptable salt thereof, whenever prepared by the process of claim 19, or by an obvious chemical equivalent.
193. 7-[2-(4-Aminopyrimidin-2-yl)-2-methoxyimino-acetamido]-3-(tetrazolo[1,5-b]pyridazin-6-ylthiomethyl)-3-cephem-4-carboxylic acid, syn isomer, or a pharma-ceutically acceptable salt thereof, whenever prepared by the process of claim 20, or by an obvious chemical equiva-lent.
194. 7-[2-(4-Aminopyrimidin-2-yl)-2-methoxyimino-acetamido]-3-methyl-3-cephem-4-carboxylic acid, syn isomer, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 21, or by an obvious chemical equivalent.
195. 7-[2-(4-Aminopyrimidin-2-yl)-2-methoxyimino-acetamido]-3-acetylthiomethyl-3-cephem-4-carboxylic acid, syn isomer, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 22, or by an obvious chemical equivalent.
196. 7-[2-(4-Aminopyrimidin-2-yl)-2-methoxyimino-acetamido]-3-chloro-3-cephem-4-carboxylic acid, syn isomer, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 23, or by an obvious chemical equivalent.
197. 7 [2-(4-Aminopyrimidin-2-yl)-2-methoxy-iminoacetamido]-3-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-ylthiomethyl]-3-cephem-4-carboxylic acid, syn isomer, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 24, or by an obvious chemical equivalent.
198. 7-[2-(4-Amino-6-chloropyrimidin-2-yl)-2-methoxyiminoacetamido]-3-(1,3,4-thiadiazol-2-yl.thio-methyl)-3-cephem-4-carboxylic acid, syn isomer, or a pharmaceutically acceptable salt thereof, whenever pre-pared by the process of claim 25, or by an obvious chemical equivalent.
199. 7-[2-(4-Aminopyrimidin-2-yl)-2-benzyloxyimino-acetamido]-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid, syn isomer, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 26, or by an obvious chemical equivalent.
200. 7-[2-(4-Aminopyrimidin-2-yl)-2-methoxyimino-acetamido]-3-(pyrazin-2-ylthiomethyl)-3-cephem-4-carboxylic acid, syn isomer, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 27, or by an obvious chemical equivalent.
201. 7-[2-(4-Amino-6-methoxypryimidin-2-yl)-2-methoxyiminoacetamido]-3-(1,3,4-thiadiazol-2-yl)thio-methyl-3-cephem-4-carboxylic acid, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 28, or by an obvious chemical equivalent.
202. 7-[2-(4-Amino-6-phenylthiopyrimidin-2-yl)-2-methoxyiminoacetamido]-3-(1,3,4-thiadiazol-2-yl)-thiomethyl-3-cephem-4-carboxylic acid, or a pharma-ceutically acceptable salt thereof, whenever prepared by the process of claim 29, or by an obvious chemical equivalent.
203. 7-[2-(4-Aminopyrimidin-2-yl)-2-methoxyimino-acetamido]-3-[1-(2-tert-butoxycarbonylaminoethyl)-1H-tetrazol-5-yl]-thiomethyl-3-cephem-4-carboxylic acid syn isomer, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 30, or by an obvious chemical equivalent.
204. A compound of the formula (I), as defined in claim 2, wherein R1,R2,R3,R4,R5 and X are each as defined in claim 31, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 31, or by an obvious chemical equivalent.
205. A compound of the formula (I), as defined in claim 2, wherein R1,R2,R3,R4,R5 and X are each as defined in claim 32, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 32, or by an obvious chemical equivalent.
206. 7-[2-(2-Aminopyrimidin-4-yl)-2-methoxyimino-acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid, or a pharmaceutically accept-able salt thereof, whenever prepared by the process of claim 33, or by an obvious chemical equivalent.
207. 7-[2-(2-Amino-6-chloropyrimidin-4-yl)-2-methoxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-ylthio methyl)-3-cephem-4-carboxylic acid, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 34, or by an obvious chemical equivalent.
208. A compound of the formula (I), as defined in claim 2, wherein Rl,R2,R3,R4,R5 and X are each as defined in claim 35, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 35, or by an obvious chemical equivalent.
209. A compound of the formula (I), as defined in claim 2, wherein R1,R2,R3,R4,R5 and X are each as defined in claim 36, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 36, or by an obvious chemical equivalent.
210. A compound of the formula (I), as defined in claim 2, wherein Rl,R2,R3,R4,R5 and X are each as defined in claim 37, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 37, or by an obvious chemical equivalent.
211. A compound of the formula (I), as defined in claim 2, wherein R1,R2,R3,R4,R5 and X are each as defined in claim 38, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 38, or by an obvious chemical equivalent.
212. 7-[2-(4-Aminopyridin-2-yl)-2-methoxyimino-acetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid, syn isomer, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 39, or by an obvious chemical equivalent.
213. A compound of the formula (I), as defined in claim 2, wherein R1,R2,R3, R4,R5 and X are each as defined in claim 40, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 40, or by an obvious chemical equivalent.
214. 7-[2-(6-Aminopyridin-3-yl)-2-methoxyimino-acetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid, syn isomer, or a pharma-ceutically acceptable salt thereof, whenever prepared by the process of claim 41, or by an obvious chemical equiva-lent.
215. A compound of the formula (I), as defined in claim 2, wherein R1,R2,R3,R4,R5 and X are each as defined in claim 42, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 42, or by an obvious chemical equivalent.
216. 7-[2-(2-Aminopyridin-4-yl)-2-methoxyimino-acetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid, syn isomer, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 43, or by an obvious chemical equivalent.
217. A compound of the formula (I), as defined in claim 2, wherein R1,R2,R3,R4,R5 and X are each as defined in claim 44, or a pharmaceutically acceptable.
salt thereof, whenever prepared by the process of claim 44, or by an obvious chemical equivalent.
218. A compound of the formula (I), as defined in claim 2, wherein R1,R2,R3,R4,R5 and X are each as defined in claim 45, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 45, or by an obvious chemical equivalent.
219. A compound of the formula (I), as defined in claim 2, wherein R1, R2, R3, R4, R5 and X are each as defined in claim 46, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 46, or by an obvious chemical equivalent.
220. A compound of the formula (I), as defined in claim 2, wherein R1,R2,R3,R4,R5 and X are each as defined in claim 47, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 47, or by an obvious chemical equivalent.
221. A compound of the formula (I), as defined in claim 2, wherein R1,R2,R3,R4,R5 and X are each as defined in claim 48, or by a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 48, or by an obvious chemical equivalent.
222. 7-[2-(2-Formamidopyridin-4-yl)-2-methoxy-iminoacetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid, syn isomer, or a pharma-ceutically acceptable salt thereof, whenever prepared by the process of claim 49, or by an obvious chemical equivalent.
223. 7-[2-(4-Formamidopyridin-2-yl)-2-methoxy-iminoacetamido]-3-(1-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid, syn isomer, or a pharma-ceutically acceptable salt thereof, whenever prepared by the process of claim 50, or by an obvious chemical equivalent.
224. 7-[2-(6-Formamidopyridin-3-yl)-2-methoxyimino-acetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid, syn isomer, or a pharma-ceutically acceptable salt thereof, whenever prepared by the process of claim 51, or by an obvious chemical equivalent.
225. A compound of the formula (I), as defined in claim 2, wherein R1,R2,R3,R4,R5 and X are each as defined in claim 52, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 52, or by an obvious chemical equivalent.
226. A compound of the formula (I), as defined in claim 2, wherein R1,R2,R3,R4,R5 and X are each as defined in claim 53, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 53, or by an obvious chemical equivalent.
227. A compound of the formula (I), as defined in claim 2, wherein R1,R2,R3,R4,R5 and X are each as defined in claim 54, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 54, or by an obvious chemical equivalent.
228. A compound of the formula (Ib) wherein R1,R2,R3,R4,R5 and X are each as defined in claim 55, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 55, or by an obvious chemical equivalent.
229. A compound of the formula (Ib), as defined in claim 55, wherein R1,R2,R3,R4,R5 and X are each as defined in claim 56, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 56, or by an obvious chemical equivalent.
230. A compound of the formula (Ib), as defined in claim 55, wherein R1,R2,R3,R4,R5 and X are each as defined in claim 57, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 57, or by an obvious chemical equivalent.
231. 7-[2-(4-Aminopyrimidin-2-yl)-2-methoxyimino-acetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 58, or by an obvious chemical equivalent.
232. 7-[2-(4-Aminopyrimidin-2-yl)-2-methoxyimino-acetamido]-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid, syn isomer, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 59, or by an obvious chemical equivalent.
233. 7-[2-(4-Aminopyrimidin-2-yl)-2-methoxyiminoacet-amido]-3-(5-methyl-1,3,4-thiadiazol-2 ylthiomethyl)-3-cephem-4-carboxylic acid, syn isomer, or a pharma-ceutically acceptable salt thereof, whenever prepared by the process of claim 60, or by an obvious chemical equivalent.
234. 7-[2-(4-Aminopyrimidin-2-yl)-2-methoxyimino-acetamido]-cephalosporanic acid, syn isomer, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 61, or by an obvious chemical equivalent.
235. 7-[2-(4-Aminopyrimidin-2-yl)-2-ethoxyimino-acetamido]-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid, syn isomer, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 62, or by an obvious chemical equivalent.
236. 7-[2-(4-Aminopyrimidin-2-yl)-2-propoxyimino-acetamido]-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid, syn isomer, or a pharma-ceutically acceptable salt thereof, whenever prepared by the process of claim 63, or by an obvious chemical equivalent.
237. 7-[2-Allyloxyimino-2-(4-aminopyrimidin-2-yl)-acetamido]-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid, syn isomer, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 64, or by an obvious chemical equivalent.
238. 7-[2-(4 Aminopyrimidin-2-yl)-2-benzyloxyimino-acetamido]-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid, syn isomer, or a pharma-ceutically acceptable salt thereof, whenever prepared by the process of claim 65, or by an obvious chemical equivalent.
239. 7-[2-(4-Aminopyrimidin 2-yl)-2-methoxyimino-acetamido]-3-[(1-allyl-1H-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid, syn isomer, or a pharma-ceutically acceptable salt thereof, whenever prepared by the process of claim 66, or by an obvious chemical equivalent.
240. 7-[2-(4-Aminopyrimidin-2-yl)-2-methoxyimino-acetamido]-3-cephem-4-carboxylic acid, syn isomer, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 67, or by an obvious chemical equivalent.
241. 7-[2-(4-Aminopyrimidin-2-yl)-2-methoxyimino-acetamido]-2-methyl-3-cephem-4-carboxylic acid, syn isomer, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 68, or by an obvious chemical equivalent.
242. 7-[2-(4-Aminopyrimidin-2-yl)-2-methoxyimino-acetamido]-3-methyl-3-cephem-4-carboxylic acid, syn isomer, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 69, or by an obvious chemical equivalent.
243. 7-[2-(4-Aminopyrimidin-2-yl)-2-methoxyimino-acetamido]-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid, syn isomer, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 70, or by an obvious chemical equivalent.
244. 7-[2-(4-Aminopyrimidin-2-yl)-2-methoxyimino-acetamido]-3-acetylthiomethyl-3-cephem-4-carboxylic acid, syn isomer, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 71, or by an obvious chemical equivalent.
245. 7-[2-(4-Aminopyrimidin-2-yl)-2-methoxyimino-acetamido]-3-chloro-3-cephem-4-carboxylic acid, syn isomer, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 72, or by an obvious chemical equivalent.
246. 7-[2-(4-Aminopyrimidin-2-yl)-2-methoxyimino-acetamido]-3-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-ylthiomethyl]-3-cephem-4-carboxylate, syn isomer, or a pharmaceutically acceptable salt thereof, whenever pre-pared by the process of claim 73, or by an obvious chemical equivalent.
247. 7-[2-(4-Amino-6-chloropyrimidin-2-yl)-2-methoxyiminoacetamido]-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid, syn isomer, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 74, or by an obvious chemical equivalent.
248 7-[2-(4-Aminopyrimidin-2-yl)-2-methoxyimino-acetamido]-3-(pyrazin-2-ylthiomethyl)-3-cephem-4-carboxylic acid, syn isomer, or a pharmaceutically accept-able salt thereof, whenever prepared by the process of claim 75, or by an obvious chemical equivalent.
249. 7-[2-(4-Aminopyrimidin-2-yl)-2-methoxyimino-acetamido]-3-(tetrazolo[1,5-b]pyridazin-6-ylthiomethyl)-3-cephem-4-carboxylic acid, syn isomer, or a pharma-ceutically acceptable salt thereof, whenever prepared by the process of claim 76, or by an obvious chemical equivalent.
250. 7-[2-(4-Amino-6-methoxypyrimidin-2-yl)-2-methoxyiminoacetamido]-3-(1,3,4-thiadiazol-2-yl)thio-methyl-3-cephem-4-carboxylic acid, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 77, or by an obvious chemical equivalent.
251. 7-[2-(4-Amino-6-phenylthiopyrimidin 2 yl)-2-methoxyiminoacetamido]-3-(1,3,4-thiadiazol-2-yl)-thio-methyl-3-cephem-4-carboxylic acid, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 78, or by an obvious chemical equivalent.
252. A compound of the formula (Ib), as defined in claim 55, wherein R1",R2,R3,R4,R5 and X are each as defined in claim 79, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 79, or by an obvious chemical equivalent.
253. 7-[2-(2-Aminopyrimidin-4-yl)-2-methoxyimino acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid, or a pharmaceutically accept-able salt thereof, whenever prepared by the process of claim 80, or by an obvious chemical equivalent.
254. 7-[2-(2-amino-6-chloropyrimidin-4-yl)-2-methoxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-yl-thiomethyl)-3-cephem-4-carboxylic acid, or a pharma-ceutically acceptable salt thereof, whenever prepared by the process of claim 81, or by an obvious chemical equivalent.
255. A compound of the formula (Ib), as defined in claim 55, wherein R1",R2,R3,R4,R5 and X are each as defined in claim 82, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 82, or by an obvious chemical equivalent.
256. A compound of the formula (Ib), as defined in claim 55, wherein R1",R2,R3,R4,R5 and X are each as defined in claim 83, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 83, or by an obvious chemical equivalent.
257. A compound of the formula (Ib), as defined in claim 55, wherein R1",R2,R3,R4,R5 and X are each as defined in claim 84, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 84, or by an obvious chemical equivalent.
258. 7-[2-(4-Aminopyridin-2-yl)-2-methoxyimino-acetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid, syn isomer, or a pharmaceutic-ally acceptable salt thereof, whenever prepared by the process of claim 85, or by an obvious chemical equiva-lent.
259. A compound of the formula (Ib), as defined in claim 55, wherein R1,R2,R3,R4,R5 and X are each as defined in claim 86, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 86, or by an obvious chemical equivalent.
260. 7-C2-(2-Aminopyridin-4-yl)-2-methoxyimino-acetamido]-3-(1-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid, syn isomer, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 87, or hy an obvious chemical equivalent.
261. A compound of the formula (Ib), as defined in claim 55, wherein R1",R2,R3,R4,R5 and X are each as defined in claim 88, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 88, or by an obvious chemical equivalent.
262. 7 [2-(6-Aminopyridin-3-yl)-2-methoxyimino-acetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid, syn isomer, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 89, or by an obvious chemical equivalent.
263. A compound of the formula (Ib), as defined in claim 55, wherein R1",R2,R3,R4,R5 and X are each as defined in claim 90, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 90, or by an obvious chemical equivalent.
264. 7-[2-(6-Aminopyridin-3-yl)-2-methoxyimino-acetamido]-3-(1-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid, anti isomer, or a pharma-ceutically acceptable salt thereof, whenever prepared by the process of claim 91, or by an obvious chemical equivalent.
265. A compound of the formula (Ib), as defined in claim 55, wherein R1",R2,R3,R4,R5 and X are each as defined in claim 92, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 92, or by an obvious chemical equivalent.
266. 7-[2-(6-Aminopyridin-2-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid, syn isomer, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 93, or by an obvious chemical equivalent.
267. A compound of the formula:

(Id) wherein R1,R2,R3,R?,R5 and X are each as defined in claim 94, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 94, or by an obvious chemical equivalent.
268. A compound of the formula (Id), as defined in claim 94, wherein R1,R2,R3,R?,R5 and X are each as defined in claim 95, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 95, or by an obvious chemical equivalent.
269. 7-[2-Allyloxyimino-2-(6-aminopyridin-2-yl-acetamido]-3-(5-aminomethyl-1,3,4-thiadiazol-2-ylthio-methyl)-3-cephem-4-carboxylic acid, syn isomer, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 96, or by an obvious chemical equivalent.
270. 7-[2-(4-Aminopyrimidin-2-yl)-2-methoxyimino-acetamido]-3-[1-(2-aminoethyl)-1H-tetrazol-5-yl]hio-methyl-3-cephem-4-carboxylic acid, syn isomer, or a pharmaceutically acceptable salt thereof, whenever pre-pared by the process of claim 97, or by an obvious chemical equivalent.
271. A compound of the formula (Id), as defined in claim 94, wherein R1,R2,R3,R?, R5 and X are each as defined in claim 98, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 98, or by an obvious chemical equivalent.
272. 7-[2-(6-Aminopyridin-2-yl)-2-methoxyimino-acetamido]-3-(5-aminomethyl-1,3,4-thiadiazol-2-yl)-thiomethyl-3-cephem-4-carboxylic acid, syn isomer, or a pharmaceutically acceptable salt thereof, whenever pre-pared by the process of claim 99, or by an obvious chemical equivalent.
273. A compound of the formula:

( If) wherein R1,R2,R3,R4 and X are each as defined in claim 100, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 100, or by an obvious chemical equivalent.
274. A compound of the formula (If), as defined in claim 100, wherein R1, R2, R3, R4 and X are each as defined in claim 101, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 101, or by an obvious chemical equivalent.
275. A compound of the formula (If), as defined in claim 100, wherein R1,R2,R3,R4 and X are each as defined in claim 102, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 102, or by an obvious chemical equivalent.
276. 7-[2-(4-Aminopyrimidin-2-yl)-2-methoxyimino-acetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid, or a pharmaceutically accept-able salt thereof, whenever prepared by the process of claim 103, or by an obvious chemical equivalent.
277. 7-[2-(4-Aminopyrimidin-2-yl)-2-methoxyimino-acetamido]-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid, syn isomer, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 104, or by an obvious chemical equivalent.
278. 7-[2-4-Aminopyrimidin-2-yl)-2-methoxyimino-acetamido]-3-(5-methyl-1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid, syn isomer, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 105, or by an obvious chemical equivalent.
279. 7-[2-(4-Aminopyrimidin-2-yl)-2-methoxyimino-acetamido]-cephalosporanic acid, syn isomer, or a pharma-ceutically acceptable salt thereof, whenever prepared by the process of claim 106, or by an obvious chemical equivalent.
280. 7-[2-(4-Aminopyrimidin-2-yl)-2-methoxyimino-acetamido]-3-cephem-4-carboxylic acid, syn isomer, or a pharmaceutically acceptable salt thereof, whenever pre-pared by the process of claim 107, or by an obvious chemical equivalent.
281. 7-[2-(4-Aminopyrimidin-2-yl)-2-methoxyimino-acetamido]-3-chloro-3-cephem-4-carboxylic acid, syn isomer, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 108, or by an obvious chemical equivalent.
282. 7-[2-(4-Aminopyrimidin-2-yl)-2-methoxyimino-acetamido]-3-[1-allyl-lH-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid, syn isomer, or a pharma ceutically acceptable salt thereof, whenever prepared by the process of claim 109, or by an obvious chemical equivalent.
283. 7-[2-(4-Aminopyrimidin-2-yl)-2-methoxyimino-acetamido]-2-methyl-3-cephem-4-carboxylic acid, syn isomer, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 110, or by an obvious chemical equivalent.
284. 7-[2-(4-Aminopyrimidin-2-yl)-2-methoxyimino-acetamido]-3-methyl-3-cephem-4-carboxylic acid, syn isomer, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 111, or by an obvious chemical equivalent.
285. 7-[2-(4-Aminopyrimidin-2-yl)-2-methoxyimino-acetamido]-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid, syn isomer, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 112, or by an obvious chemical equivalent.
286. 7-[2-(4-Aminopyrimidin-2-yl)-2-methoxyimino-acetamido]-3-acetylthiomethyl-3-cephem-4-carboxylic acid, syn isomer, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 113, or by an obvious chemical equivalent.
287. 7-[2-(4-Aminopyrimidin-2-yl)-2-methoxy-iminoacetamido]-3-[5-(4-chlorophenyl)-13,4-oxadiazol-2-ylthiomethyl]-3-cephem-4-carboxylic acid, syn isomer, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 114, or by an obvious chemical equivalent.
288. 7-[2-(4-Amino-6-chloropyrimidin-2-yl)-2-methoxyiminoacetamido]-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid, syn isomer, or a pharmaceuti-cally acceptable salt thereof, whenever prepared by the process of claim 115, or by an obvious chemical equivalent.
289. 7-[2-(4-Aminopyrimidin-2-yl)-2-ethoxyimino-acetamido]-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid, syn isomer, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 116, or by an obvious chemical equivalent.
290. 7-[2-(4-Aminopyrimidin-2-yl)-2-propoxyimino-acetamido]-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid, syn isomer, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 117, or by an obvious chemical equivalent.
291. 7-[2-Allyloxyimino-2-(4-aminopyrimidin-2-yl)-acetamido]-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid, syn isomer, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 118, or by an obvious chemical equivalent.
292. 7-[2-(4-Aminopyrimidin-2-yl)-2-benzyloxyimino-acetamido]-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid, syn isomer, or a pharma-ceutically acceptable salt thereof, whenever prepared by the process of claim 119, or by an obvious chemical equivalent.
293. 7-[2-(4-Aminopyrlmidin-2-yl)-2 methoxyimino-acetamido]-3-(pyrazin-2-ylthiomethyl)-3-cephem-4-carboxylic acid, syn isomer, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 120, or by an obvious chemical equivalent.
294. 7-[2-4-Aminopyrimidin-2-yl)-2-methoxyimino-acetamido]-3-(tetrazolo[1,5-b]pyridazin-6-ylthlomethyl)-3-cephem-4-carboxylic acid, syn isomer, or a pharma-ceutically acceptable salt thereof, whenever prepared by the process of claim 121, or by an obvious chemical equivalent.
295. 7-[2-(4-Amino-6-methoxypyrimidin-2-yl)-2-methoxyiminoacetamido]-3-[1,3,4-thiadiazol-2-yl)-thio-methyl-3-cephem-4-carboxylic acid, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 122, or by an obvious chemical equivalent.
296. 7-[2-(4-Amino-6-phenylthiopyrimidin-2-yl)-2-methoxyiminoacetamido]-3-(1,3,4-thiadiazol-2-yl)-thio-methyl-3-cephem-4-carboxylic acid, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 123, or by an obvious chemical equivalent.
297. A compound of the formula (If), as defined in claim 100, wherein R1,R2,R3,R? and X are each as defined in claim 124, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 124, or by an obvious chemical equivalent.
298. 7-[2-(2-Aminopyrimidin-4-yl)-2-methoxyimino-acetamido]-3 (1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 125, or by an obvious chemical equivalent.
299. 7-[2-(2-Amino-6-chloropyrimidin-4-yl)-2-methoxy-iminoacetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid, or a pharmaceutically accept-able salt thereof, whenever prepared by the process of claim 126, or by an obvious chemical equivalent.
300. A compound of the formula (If), as defined in claim 100, wherein R1,R2,R3,R? and X are each as defined in claim 127, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 127, or by an obvious chemical equivalent.
301. A compound of the formula (If), as defined in claim 100, wherein R1,R2,R3,R? and X are each as defined in claim 128, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 128, or by an obvious chemical equivalent.
302. A compound of the formula (If), as defined in claim 100, wherein R1,R2,R3,R? and X are each as defined in claim 129, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 129, or by an obvious chemcial equivalent.
303. A compound of the formula (If), as defined in claim 100, wherein R1,R2,R3,R? and X are each as defined in claim 130, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 130, or by an obvious chemical equivalent.
304. 7 [2 (4-Aminopyridin-2-yl)-2-methoxyimino-acetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid, syn isomer, or a pharmaceutic-ally acceptahle salt thereof, whenever prepared by the process of claim 131, or by an obvious chemical equivalent.
305. A compound of the formula (If), as defined in claim 100, wherein R1,R2,R3,R? and X are each as defined in claim 132, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 132, or by an obvious chemical equivalent.
306. 7-[2-(2-Aminopyridin-4-yl)-2-methoxyimino-acetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid, syn isomer, or a pharma-ceutically acceptable salt thereof, whenever prepared by the process of claim 133, or by an obvious chemical equivalent.
307. A compound of the formula (If), as defined in claim 100, wherein R1,R2,R3,R? and X are each as defined in claim 134, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 134, or by an obvious chemical equivalent.
308. 7-[2-(6-Aminopyridin-3-yl)-2-methoxyimino-acetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid, syn isomer, or a pharma ceutically acceptable salt thereof, whenever prepared by the process of claim 135, or by an obvious chemical equivalent.
309. A compound of the formula (If), as defined in claim 100, wherein R1,R2,R3,R? and X are each as defined in claim 36, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 136, or by an obvious chemical equivalent.
310. 7-[2-(6-Aminopyridin-3-yl)-2-methoxyimino-acetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid, anti isomer, or a pharma-ceutically acceptable salt thereof, whenever prepared by the process of claim 137, or by an obvious chemical equivalent.
311. A compound of the formula (If), as defined in claim 100, wherein R1, R2, R3, R? and X are each as de-fined in claim 138, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 138, or by an obvious chemical equivalent.
312. 7-[2-(6-Aminopyridin-2-yl)acetamido]-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid, syn isomer, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 139, or by an obvious chemical equivalent.
313. A compound of the formula:

(Ih) wherein R1, R2, R3, R5, R7 and X are each as defined in claim 140, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 140, or by an obvious chemical equivalent.
314. A compound of the formula (Ih), as defined in claim 140, wherein R1, R2, R3, R5, R7 and X are each as defined in claim 141, or by a pharmaceutically accept-able salt thereof, whenever prepared by the process of claim 141, or by an obvious chemical equivalent.
315. A compound of the formula (Ih), as defined in claim 140, wherein R1, R2, R3, R5, R7 and X are each as defined in claim 142, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 142, or by an obvious chemical equivalent.
316. 7-[2-(4-Aminopyrimidin-2-yl)-2-methoxyimino-acetamido]-3-(1-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid, or a pharmaceutically accept-able salt thereof, whenever prepared by the process of claim 143, or by an obvious chemical equivalent.
317. 7-[2-(4-Aminopyrimidin-2-yl)-2-methoxyimino-acetamido]-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid, syn isomer, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 144, or by an obvious chemical equivalent.
318. 7-[2-(4-Aminopyrimidin-2-yl)-2-methoxyimino-acetamido]-3-(5-methyl-1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid, syn isomer, or a pharma-ceutically acceptable salt thereof, whenever prepared by the process of claim 145, or by an obvious chemical equivalent.
319. 7-[2-(4-Formamidopyrimidin-2-yl)-2-methoxyimino-acetamido]-3-(tetrazolo[1,5-b]pyridazin-6-ylthiomethyl)-3-cephem-4-carboxylic acid, syn isomer, or a pharma-ceutically acceptable salt thereof, whenever prepared by the process of claim 146, or by an obvious chemical equivalent.
320. 7-[2-(4-Aminopyrimidin-2-yl)-2-methoxyimino-acetamido]-3-(pyrazin-2-yl-thiomethyl)-3-cephem-4-carboxylic acid, syn isomer, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 147, or by an obvious chemical equivalent.
321. 7-[2-(4-Aminopyrimidin-2-yl)-2-methoxyimino-acetamido]-3-[(l-allyl-lH-tetrazol-5-yl)thiomethyl]-3-cephem,4-carboxylic acid, syn isomer, or a pharma-ceutically acceptable salt thereof, whenever prepared by the process of claim 148, or by an obvious chemical equivalent.
322. 7-[2-(4-Aminopyrimidin-2-yl)-2-methoxyimino-acetamido]-3-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-ylthiomethyl]-3-cephem-4-carboxylic acid, syn isomer, or a pharmaceutically acceptable salt thereof, wllenever prepared by the process of claim 149, or by an obvious chemical equivalent.
323. 7-[2-(4-Amino-6-chloropyrimidin-2-yl)-2-methoxyiminoacetamido]-3-(1,3,4-thiadiazol-2-ylthio-methyl)-3-cephem-4-carboxylic acid, syn isomer, or a pharmaceutically acceptable salt thereof, whenever pre-pared by the process of claim 150, or by an obvious chemical equivalent.
324. 7-[2-(4-Aminopyrimidin-2-yl)-2-ethoxyimino-acetamido]-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid, syn isomer, or a pharma-ceutically acceptable salt thereof, whenever prepared by the process of claim 151, or by an obvious chemical equivalent.
325. 7-[2-(4-Aminopyrimidin-2-yl)-2-propoxyimino-acetamido]-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid, syn isomer, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 152, or by an obvious chemical equivalent.
326. 7-[2-Allyloxyimino-2-(4-aminopyrimidin-2-yl)-acetamido]-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid, syn isomer, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 153, or by an obvious chemical equivalent.
327. 7-[2-(4-Aminopyrimidin-2-yl)-2-benzyloxyimino-acetamido]-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid, syn isomer, or a pharmaceutically acceptable salt thereof, whenever prepared by the pro-cess of claim 154, or by an obvious chemical equivalent.
328. 7-[2-(4-Aminopyrimidin-2-yl)-2-methoxyimino-acetamido]-3-(tetrazolo[1,5-b]pyridazin-6-ylthiomethyl)-3-cephem-4-carboxylic acid, syn isomer, or a pharma-ceutically acceptable salt thereof, whenever prepared by the process of claim 155, or by an obvious chemical equivalent.
329. 7-[2-(4-Amino-6-methoxypyrimidin-2-yl)-2-methoxyiminoacetamido]-3-(1,3,4-thiadiazol-2-yl)thio-methyl-3-cephem-4-carboxylic acid, or a pharmaceutically acceptable salt thereof, whenever prepared by the pro-cess of claim 156, or by an obvious chemical equivalent.
330. 7-[2-(4-Amino-6-phenylthiopyrimidin-2-yl)-2-methoxyiminoacetamido]-3-(1,3,4-thiadiazol-2-yl)-thio-methyl-3-cephem-4-carboxylic acid, or a pharmaceutically acceptable salt thereof, whenever prepared by the pro-cess of claim 157, or by an obvious chemical equivalent.
331. A compound of the formula (Ih), as defined in claim 140, wherein R1, R2, R3, R5, R7 and X are each as defined in claim 158, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 158, or by an obvious chemical equivalent.
332. 7-[2-(2-Aminopyrimidin-4-yl)-2-methoxyimino-acetamido]-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid, or a pharmaceutically accept-able salt thereof, whenever prepared by the process of claim 159, or by an obvious chemical equivalent.
333. 7-[2-(2-Amino-6-chloropyrimidin-4-yl)-2-methoxyiminoacetamido]-3-(1-methyl-lH-tetrazol-5-ylthio-methyl)-3-cephem-4-carboxylic acid, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 160, or by an obvious chemical equivalent.
334. A compound of the formula (Ih), as defined in claim 140, wherein R1, R2, R3, R5, R7 and X are each as defined in claim 161, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 161, or by an obvious chemical equivalent.
335. A compound of the formula (Ih), as defined in claim 140, wherein R1, R2, R3, R5, R7 and X are each as defined in claim 162, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 162, or by an obvious chemical equivalent.
336. A compound of the formula (Ih), as defined in claim 140, wherein R1, R2, R3, R5, R7 and X are each as defined in claim 163, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 163, or by an obvious chemical equivalent.
337. A compound of the formula (Ih), as defined in claim 140, wherein R1, R2, R3, R5, R7 and X are each as defined in claim 164, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 164, or by an obvious chemical equivalent.
338. 7-[2-(4-Aminopyridin-2-yl)-2-methoxyimino-acetamido]-3-(1-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid, syn isomer, or a pharmaceutically acceptable salt thereof whenever prepared by the process of claim 165, or by an obvious chemical equivalent.
339. A compound of the formula (Ih), as defined in claim 140, wherein R1, R2, R3, R5, R7 and X are each as defined in claim 166, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 166, or by an obvious chemical equivalent.
340. 7-[2-(2-Aminopyridin-4-yl)-2-methoxyimino-acetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid, syn isomer, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 167, or by an obvious chemical equivalent.
341. The compound of the formula (Ih), as defined in claim 140, wherein R1, R2, R3, R5, R7 and X are each as defined in claim 168, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 168, or by an obvious chemical equivalent.
342. 7-[2-(6-Aminopyridin-3-yl)-2-methoxyimino-acetamido]-3-(1-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid, syn isomer, or a pharma-ceutically acceptable salt thereof, whenever prepared by the process of claim 169, or by an obvious chemical equivalent.
343. The compound of the formula (Ih), as defined in claim 140, wherein R1, R2, R3, R5, R7 and X are each as defined in claim 170, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 170, or by an obvious chemical equivalent.
344. 7-[2-(6-Aminopyridin-3-yl)-2-methoxyimino-acetamido]-3-(1-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid, anti isomer, or a pharma-ceutically acceptable salt thereof, whenever prepared by the process of claim 171, or by an obvious chemical equivalent.
345. A compound of the formula (Ih), as defined in claim 140, wherein R1, R2, R3, R5, R7 and X are each as defined in claim 172, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 172, or by an obvious chemical equivalent.
346. 7-[2-(6-Aminopyridin-2-yl)acetamido]-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid, syn isomer, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 173, or by an obvious chemical equivalent.

CLAIMS SUPPORTED BY THE SUPPLEMENTARY DISCLOSURE
347. The process of claim 44, wherein R? is formamido, R3, is hydrogen, R4 is 1,3,4-thiadiazol-2-ylthiomethyl, R5 is carboxy and R6 is phenyl.
348. The process of claim 44, wherein R? is formamido, R3 is hydrogen, R4 is 1-(2-tert-butoxy-carbonylaminoethyl)-lH-tetrazol-5-ylthiomethyl, R5 is carboxy and R6 is phenyl.
349. The process of claim 55, wherein R1' is a group of the formula:

in which R?' is formamido, R1" is a group of the formula:

R2 and R3 are each hydrogen, R4 is 1,3,4-thiadiazol-2-ylthiomethyl, R5 is carboxy, and X is a group of the formula:

such that said compound of formula (Ib) is in the syn form.
350. The process of claim 55, wherein R1' is a group of the formula:

in which R?' is formamido, R1" is a group of the formula:

R2 and R3 are hydrogen, R4 is 1-(2-aminoethyl)-lH-tetra-zol-5-ylthiomethyl, R5 is carboxy and X is a group of the formula:

such that the compound of formula (Ib) is in the syn form.
351. The process of claim 94, wherein R1 is a group of the formula:

in which R? is formamido, R2 and R3 are hydrogen, R? is 1-(2-tert-butoxycarbonylaminoethyl)-lH-tetrazol-5-ylthio-methyl, R? is 1-(2-aminoethyl)-lH-tetrazol-5-ylthiomethyl, R5 is carboxy, and X is a group of the formula:

such that the compound of formula (Id) is in the syn form.
352. 7-[2-(4-Formamidopyrimidin-2-yl)-2-phenoxy-iminoacetamido]-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid, syn isomer, or a pharma-ceutically acceptable salt thereof, whenever prepared by the process of claim 347, or by an obvious chemical equivalent.
353. 7-[2-(4-Formamidopyrimidin-2-yl)-2-phenoxy-iminoacetamido]-3-[1-(2-tert-butoxycarbonylaminoethyl)-lH-tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid, syn isomer, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 348, or by an obvious chemical equivalent.
354. 7-[2-(4-Aminopyrimldin-2-yl)-2-phenoxyimino-acetamido]-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid, syn isomer, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 349, or by an obvious chemical equivalent.
355. 7-[2-(4-Aminopyrimidin-2-yl)-2-phenoxyimino-acetamido]-3-[1-(2-aminoethyl)-lH-tetrazol-5-ylthio-methyl]-3-cephem-4-carboxylic acid, syn isomer, or a pharmaceutically acceptable salt thereof, whenever pre-pared by the process of claim 350, or by an obvious chemical equivalent.
356. 7-[2-(4-Formamidopyrimidin-2-yl)-2-phenoxy-iminoacetamido]-3-[1-(2-aminoethyl)-lH-tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid, syn isomer, or a pharmaceitucally acceptable salt thereof, whenever prepared by the process of claim 351, or by an obvious chemical equivalent.
CA000316120A 1977-11-14 1978-11-10 Cephalosporanic acid derivatives and processes for the preparation thereof Expired CA1120923A (en)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
GB4735277 1977-11-14
GB47352/77 1977-11-14
GB16810/78 1978-04-27
GB1681078 1978-04-27
GB35436/78 1978-09-04
GB7835436 1978-09-04

Publications (1)

Publication Number Publication Date
CA1120923A true CA1120923A (en) 1982-03-30

Family

ID=27257420

Family Applications (1)

Application Number Title Priority Date Filing Date
CA000316120A Expired CA1120923A (en) 1977-11-14 1978-11-10 Cephalosporanic acid derivatives and processes for the preparation thereof

Country Status (15)

Country Link
US (3) US4267176A (en)
JP (1) JPS5492987A (en)
AT (1) AT369005B (en)
AU (1) AU523346B2 (en)
CA (1) CA1120923A (en)
CH (1) CH645904A5 (en)
DE (1) DE2848912A1 (en)
DK (1) DK502078A (en)
ES (5) ES475035A1 (en)
FR (2) FR2411839B1 (en)
GB (1) GB2010840B (en)
HU (2) HU183008B (en)
IT (1) IT1192287B (en)
NL (1) NL7811220A (en)
SE (2) SE7811637L (en)

Families Citing this family (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IT1192287B (en) * 1977-11-14 1988-03-31 Fujisawa Pharmaceutical Co PHARMACEUTICAL ACTION DERIVATIVES OF CEPHALOSPORANIC ACID AND RELATED PREPARATION PROCEDURE
DE2818263A1 (en) * 1978-04-26 1979-11-08 Bayer Ag BETA LACTAMANTIBIOTICS
US4409214A (en) * 1979-11-19 1983-10-11 Fujisawa Pharmaceutical, Co., Ltd. 7-Acylamino-3-vinylcephalosporanic acid derivatives and processes for the preparation thereof
JPS5716886A (en) * 1980-07-04 1982-01-28 Fujisawa Pharmaceut Co Ltd Azetidinone bearing oxo group or its salt or hydrate and their preparation
EP0046964B1 (en) * 1980-08-29 1986-08-20 Fujisawa Pharmaceutical Co., Ltd. New cephem compounds and processes for preparation thereof
US4577014A (en) * 1981-09-08 1986-03-18 Eli Lilly And Company Thieno and furopyridinium-substituted cephalosporins
US4379787A (en) * 1981-10-02 1983-04-12 Eli Lilly And Company Oximino-substituted cephalosporin compounds
US4402955A (en) * 1981-10-02 1983-09-06 Eli Lilly And Company Dioximino cephalosporin antibiotics
US4450270A (en) * 1981-10-02 1984-05-22 Eli Lilly And Company Dioximino cephalosporin antibiotics
US4501739A (en) * 1982-01-19 1985-02-26 Eli Lilly And Company Thieno and furopyridinium-substituted cephalosporins
US4683227A (en) * 1985-07-09 1987-07-28 Eli Lilly And Company Antibiotic derivatives of 7β-[2-(thiazol-4-yl)acetamide]-3-chloro-3-cephem-4-carboxylic acids and compositions and method of use thereof
AU2006322564B2 (en) 2005-12-07 2010-09-09 Basilea Pharmaceutica Ag Useful combinations of monobactam antibiotics with beta-lactamase inhibitors
EP2862569A1 (en) 2011-09-09 2015-04-22 Cubist Pharmaceuticals, Inc. Methods for treating intrapulmonary infections
US8809314B1 (en) 2012-09-07 2014-08-19 Cubist Pharmacueticals, Inc. Cephalosporin compound
US8476425B1 (en) 2012-09-27 2013-07-02 Cubist Pharmaceuticals, Inc. Tazobactam arginine compositions
US20140274993A1 (en) 2013-03-15 2014-09-18 Cubist Pharmaceuticals, Inc. Ceftolozane-tazobactam pharmaceutical compositions
KR102329764B1 (en) 2013-03-15 2021-11-23 머크 샤프 앤드 돔 코포레이션 Ceftolozane antibiotic compositions
US9872906B2 (en) 2013-03-15 2018-01-23 Merck Sharp & Dohme Corp. Ceftolozane antibiotic compositions
EP3043797B1 (en) 2013-09-09 2020-04-08 Merck Sharp & Dohme Corp. Treating infections with ceftolozane/tazobactam in subjects having impaired renal function
US8906898B1 (en) 2013-09-27 2014-12-09 Calixa Therapeutics, Inc. Solid forms of ceftolozane

Family Cites Families (28)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3459746A (en) * 1965-10-04 1969-08-05 Lilly Co Eli 7 - heteromonocyclic-substituted acylamido derivatives of desacetyl cephalosporanic acid
GB1195203A (en) * 1966-06-24 1970-06-17 Glaxo Lab Ltd Cephalosporins
CH557381A (en) * 1967-04-15 1974-12-31 Fujisawa Pharmaceutical Co PROCESS FOR PRODUCING (DELTA) 3-CEPHEM COMPOUNDS.
CH522677A (en) * 1969-10-10 1972-06-30 Ciba Geigy Ag Process for the preparation of new derivatives of 7-aminocephalosporanic acid
FR2068419A1 (en) * 1969-10-27 1971-08-27 Fujisawa Pharmaceutical Co Antibacterial cephalosporin compsns
IL39094A (en) * 1971-04-21 1976-05-31 Ciba Geigy Ag 7-(aminopyridiniumacetyl)-3-heterocyclylthiomethyl-cephalosporanic acid derivatives,their manufacture and pharmaceutical compositions containing them
US4017515A (en) * 1971-05-14 1977-04-12 Glaxo Laboratories Limited α-(Etherified oximino) carboxylic acids and acid chlorides
GB1399086A (en) * 1971-05-14 1975-06-25 Glaxo Lab Ltd Cephalosporin compounds
US3966717A (en) * 1971-05-14 1976-06-29 Glaxo Laboratories Limited 7-β-Acylamido-3-carbamoyloxymethylceph-3-em-4-carboxylic acids and salts thereof
US4033950A (en) * 1971-05-14 1977-07-05 Glaxo Laboratories Limited 3-Hydroxymethyl-7β-(2-alkoxy-or benzyloxyimino-2-arylacetamido)ceph-3-em-4-carboxylic acids and salts thereof
DE2222791A1 (en) * 1971-05-19 1972-12-07 Ciba Geigy Ag New pyridine acid derivatives and processes for their preparation
BE790287A (en) * 1971-10-28 1973-04-19 Delalande Sa PYRIMIDIN-6YL ACETHYDROXAMIC ACIDS, THEIR PREPARATION PROCESS AND THEIR THERAPEUTIC APPLICATION
BE793724A (en) * 1972-01-12 1973-07-05 Smith Kline French Lab PROCESS FOR THE PREPARATION OF CEPHALOSPHORINS NOT SUBSTITUTED IN POSITION 3, NEW CEPHALOSPORINS OBTAINED AND THEIR USE
AR208171A1 (en) * 1972-09-29 1976-12-09 Ciba Geigy Ag PROCEDURE FOR OBTAINING NEW DERIVATIVES OF CEF-3-EM-4-CARBOXYL ACID
GB1390141A (en) * 1973-01-08 1975-04-09 Ici Ltd Pyrimidine derivatives and processes for their production
JPS5932472B2 (en) * 1973-03-15 1984-08-09 藤沢薬品工業株式会社 Method for producing 2-alkyl-7-acylamino-2 (or 3)-cephem-4-carboxylic acids
JPS4970990A (en) * 1973-09-29 1974-07-09
US3968109A (en) * 1973-11-23 1976-07-06 E. R. Squibb & Sons, Inc. Production of 2-(thio substituted)cephalosporin sulfoxides and 2-(thio substituted)cephalosporins
FR2262965A1 (en) * 1974-03-05 1975-10-03 Delalande Sa Beta-(4-amino-6-methylpyrimidin-5-yl)propionic acid derivs - with antiulcer, bronchodilator, anticholinergic, hypotensive, diuretic and vasodilator activity
US4122259A (en) * 1974-08-23 1978-10-24 Glaxo Laboratories Limited 7β-[2-Aryl-2-(etherified oximino)acetamido]-3-N-substituted carbamoyloxymethylceph-3-em-4-carboxylic acids
JPS604171B2 (en) * 1974-12-05 1985-02-01 久光製薬株式会社 Method for producing a novel 2-anilinopyridine-3-acetic acid derivative
DK154939C (en) * 1974-12-19 1989-06-12 Takeda Chemical Industries Ltd METHOD OF ANALOGUE FOR THE PREPARATION OF THIAZOLYLACETAMIDO-CEPHEM COMPOUNDS OR PHARMACEUTICAL ACCEPTABLE SALTS OR ESTERS THEREOF
CA1088049A (en) * 1975-06-03 1980-10-21 Takashi Masugi 3-substituted-7-substituted alkanamido-3-cephem-4- carboxylic acid compounds and processes for preparation thereof
US4152433A (en) * 1976-03-12 1979-05-01 Fujisawa Pharmaceutical Co., Ltd. 2-Lower alkyl-7-substituted-2 or 3-cephem-4-carboxylic acid compounds and pharmaceutical compositions
US4166115A (en) * 1976-04-12 1979-08-28 Fujisawa Pharmaceutical Co., Ltd. Syn 7-oxoimino substituted derivatives of cephalosporanic acid
US4104469A (en) * 1977-04-15 1978-08-01 Bristol-Myers Company 7-(Syn-α-alkoxy-iminofuryl)acetamido-3-(2-methyl-2,3-dihydro-s-triazolo[4,3-b]pyridazin-3-on-6-ylthiomethyl)-3-cephem-4-carboxylic acids
NL7714319A (en) * 1976-12-27 1978-06-29 Fujisawa Pharmaceutical Co CEPHALOSPORIN COMPOUNDS AND METHODS FOR PREPARING THEM.
IT1192287B (en) * 1977-11-14 1988-03-31 Fujisawa Pharmaceutical Co PHARMACEUTICAL ACTION DERIVATIVES OF CEPHALOSPORANIC ACID AND RELATED PREPARATION PROCEDURE

Also Published As

Publication number Publication date
FR2411839A1 (en) 1979-07-13
NL7811220A (en) 1979-05-16
ES485065A1 (en) 1980-06-16
AU4154678A (en) 1979-05-24
DK502078A (en) 1979-05-15
ATA807178A (en) 1982-04-15
GB2010840B (en) 1982-12-22
ES475035A1 (en) 1980-01-01
SE8400332D0 (en) 1984-01-23
US4267176A (en) 1981-05-12
US4395411A (en) 1983-07-26
AU523346B2 (en) 1982-07-22
IT1192287B (en) 1988-03-31
CH645904A5 (en) 1984-10-31
GB2010840A (en) 1979-07-04
SE7811637L (en) 1979-05-15
ES485068A1 (en) 1980-06-16
HU182098B (en) 1983-12-28
JPS6320832B2 (en) 1988-04-30
DE2848912A1 (en) 1979-05-17
IT7829653A0 (en) 1978-11-09
ES485066A1 (en) 1980-06-16
JPS5492987A (en) 1979-07-23
ES485067A1 (en) 1980-06-16
AT369005B (en) 1982-11-25
HU183008B (en) 1984-04-28
FR2411839B1 (en) 1985-09-27
DE2848912C2 (en) 1990-10-04
FR2413369A1 (en) 1979-07-27
US4596869A (en) 1986-06-24
SE8400332L (en) 1984-01-23
FR2413369B1 (en) 1984-04-06

Similar Documents

Publication Publication Date Title
CA1120923A (en) Cephalosporanic acid derivatives and processes for the preparation thereof
CA1235414A (en) 7-acylamino-3-vinylcephalosporanic acid derivatives and processes for the preparation thereof
CA1321580C (en) Cephem and cepham compounds and processes for preparation thereof
EP0013762B1 (en) Cephem and cepham compounds, processes for their preparation, pharmaceutical compositions containing them
US5026695A (en) 7-acylamino-3-substituted cephalosporanic acid derivatives
US4447429A (en) 7-[2-Alkoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-cephems
US4639448A (en) 7-amino-3-[substituted vinyl]-3-cephem-4-carboxylates having antimicrobial activity
EP0055465B1 (en) 7-acylaminocephalosporanic acid derivatives and processes for the preparation thereof
JPS61267583A (en) Novel beta-lactam antibiotic
CA1152062A (en) 3,7-disubstituted-3-cephem-4-carboxylic acid compounds and processes for the preparation thereof
US4366153A (en) Cephem compounds
EP0184227A1 (en) 2-Oxymino 2-aminothiazolyl acetic acid derivatives and processes for preparation thereof
EP0009548B1 (en) Cephalosporin derivatives, process for their preparation and pharmaceutical compositions containing them
CA1161032A (en) Cephalosporin derivatives, their production and use as antimicrobial agents
US4077965A (en) Aminoalkyl- or hydroxyalkyl-substituted thiadiazole derivatives
CA1146553A (en) Intermediates for cephalosporanic acid derivatives and processes for their preparation
US4172198A (en) 7-(N-substituted-2-phenylglycinamido)-3-substituted-3-cephem-4-carboxylic acid compounds and preparation thereof
CA1110624A (en) Cephalosporin analogues and processes for the preparation thereof
GB2033377A (en) New Cephem Compounds and Processes for Preparation Thereof
KR820001324B1 (en) Process for preparing cephalosporanic acid
EP0214462A2 (en) 3,7-Disubstituted-3-cephem compounds and processes for production of the same
GB2039890A (en) New cephem compounds
CA1182453A (en) Intermediates for cephalosporin analogues and processes for the preparation thereof
JPS6053028B2 (en) Tetrazole derivative
CA1112237A (en) Cephem compounds and processes for preparation thereof

Legal Events

Date Code Title Description
MKEX Expiry