CA1253146A - Azetidinones - Google Patents

Abstract

ABSTRACT
AZETIDINONES
Antibacterial activity is exhibited by 2-azetidinones having a 3-acylamino substituent and a 1-substituent of the formula

Description

-l- GC213a AZETIDINONES
Compounds having the formula Rl-NH - _R3 S \~ C
¦ 5~ 6 ~ C -N-~ - ~-C-COOH

and esters and salts thereof, have antibacterial activity. In formula I, and throughout the specification, the symbols are as defined below.
Zl is oxygen or sulfur;
~1 is acyl;
R2 is hydrogen or methoxy;
R3 and R4 are the same or different and each is hydrogen, alkyl, alkenyl, alkynyl, cyclo-alkyl, phenyl, substituted phenyl or a 4, 5, 6 or 7-membered heterocycle (referred to hereinafter as Rx) or one of R3 and R4 is hydrogen and the other is azido, halomethyl, dihalomethyl, trihalo-methyl, alkoxycarbonyl, 2-phenylethenyl,

2-phenylethynyl, carboxy, -CH2Xl [wherein X
is azido, amino (-NH2), hydroxy, carboxy, alkoxycarbonyl, alkanoylamino, phenylcarbonylamino, (substituted phenyl)carbonylamino, alkylsulfonyl-oxy, phenylsulfonyloxy, (substituted phenyl)-sulfonyloxy, phenyl, substituted phenyl, cyano, -S-X2, or -O-X2 (wherein X2, is as hereinafter defined)], -S-X2 or -O-X2 [wherein X2 is alkyl,

3~

GC213a phenyl, or substituted phenyl], -O-IC-X4 or -S-l-X4 [wherein one of X3 and X4 is hydrogen and the other is hydrogen or alkyl, or X3 and X4 when taken together with the carbon atom to which they are attached form a cycloalkyl group; and X5 is formyl, alkanoyl, phenylcarbonyl, (substituted phenyl)carbonyl, phenylalkylcarbonyl, (substituted phenyl)alkylcarbonyl, carboxy, alkoxycarbonyl, amino-o carbonyl (NH2-C-), (substituted amino)carbonyl, or cyano (-C--N)], or -A-C-NX6X7, (wherein A is -CH=CH-, ( 2)n ' 2 ~ CH2 NH , CH2 S CH2 , or -CH2-O-CH2-, n is 0, 1 or 2, and X6 and X7 are the same or different and each is hydrogen, alkyl, phenyl or substituted phenyl, or X6 is hydrogen and X7 is amino, substituted amino, alkanoylamino or alkoxy, or X6 and X7 when taken together with the nitrogen atom to which they are attached form a 4, 5, or 5- membered nitrogen containing heterocycle);
R5 and R6 are the same or different and each is hydrogen, alkyl, alkenyl, alkynyl, phenyl, substituted phenyl, cycloalkyl or Rx, or R5 and R6 together with the carbon atom to which they are attached are cycloalkyl, _3_ GC213a or one of R5 and R6 is hydrogen and the other is halomethyl, dihalomethyl, trihalomethyl, alkoxycarbonyl, alkenyl, alkynyl, 2-phenylethenyl, o 2-phenylethynyl, carboxy, -CH2-Xl, or -A-C-NX6X7, or R6 is hydrogen and R5 together with R7 and the atoms to which they are attached form a 4, 5, or 6-membered nitrogen containing heterocycle; and R7 is hydrogen, alkyl, phenyl, substituted o z phenyl, cycloalkyl, Rx, -CH2-C-N ~
-CH2-~-N ~ N-Z5, -CH2-C- ~ Z6 l O O
2 7' (CH2)n Z3 wherein n is 2, 3 or 4 and Z3 is azido, -NZ5Z6, halogen, O O
hydroxy, -C-OZ7, cyano, -C-NZ5Z6, -I-N ~ N-Z5, -~- O

alkanoyloxy, alkoxy, phenyloxy, (substituted phenyl)oxy, Rx-oxy, mercapto, alkylthio, phenylthio, (substituted phenyl)thio, alkyl-O
sulfinyl, alkylsulfonyl, -Z4-C-Z5, N

4 C NZ5Z6, _ N-Z5 , or -N N-Z5, wherein Z4 is oxygen, sulfur 0~0 _4_ GC213a or -N-, Z5 is hydrogen, alkyl, phenyl, substituted phenyl, phenylalkyl or (substitu-ted phenyl)alkyl, Z6 is hydrogen, alkyl, phenyl, substituted phenyl, phenylalkyl, ~substituted phenyl)alkyl, alkanoyl, phenylcarbonyl, or (substituted phenyl)carbonyl, and Z7 is hydrogen, alkyl, phenyl or substituted phenyl.
Listed below are definitions of various terms used to describe the ~-lactams of this invention.
These definitions apply to the terms as they are used throughout the specification (unless they are otherwise limited in specific instances) either individually or as part of a larger group.
The terms "alkyl" and "alkoxy" refer to both straight and branched chain groups. Those groups having 1 to 10 carbon atoms are preferred.
The terms "cycloalkyl" and "cycloalkenyl"
refer to cycloalkyl and cycloalkenyl groups having 20 3,4,5,6 or 7 carbon atoms.
The term "substituted alkyl" refers to alkyl groups substituted with one or more (preferably l, 2 or 3) azido, amino (-NH2), halogen, hydroxy, carboxy, cyano, alkoxycarbonyl, aminocarbonyl, alkanoyloxy, alkoxy, phenyloxy, (substituted phenyl)oxy, Rx-oxy, mercapto, alkylthio, phenyl-thio, (substituted phenyl)thio, alkylsulfinyl, or alkylsulfonyl groups.
The terms "alkanoyl", "alkenyl", and "alkynyl" refer to both straight and branched chain groups. Those groups having 2 to 10 carbon atoms are preferred.
The terms "halogen" and "halo" refer to fluorine, chlorine, bromine and iodine GC213a The term "protected carboxy" refers to a carboxy group which has been esterified with a conventional acid protecting group. These groups are well known in the art; see, for example, United States patent 4,144,333, issued March 13, 1979.
The preferred protected carboxy groups are benzyl, benzhydryl, t-butyl, and p-nitrobenzyl esters.
The term "substituted phenyl" refers to a phenyl group substituted with 1, 2 or 3 amino (-NH2j, halogen, hydroxyl, trifluoromethyl, alkyl (of 1 to 4 carbon atoms), alkoxy (of 1 to 4 carbon atoms), alkanoyloxy, aminocarbonyl, or carboxy groups.
The expression "a 4,5,6 or 7-membered heterocycle" (re~erred to as ''Rx'') refers to substituted and unsubstituted, aromatic and non-aromatic groups containing one or more (preferably 1, 2 or 3~ nitro~en, oxygen or sulfur atoms. Exemplary substituents are oxo (=O), halogen, hydroxy, nitro, amino, cyano, trifluoro-methyl, alkyl of 1 to 4 carbons, alkoxy of l to 4~arbons, alkylsulfonyl, phenyl, substituted phenyl, O CH=N-2-furfurylideneamino ( ~ ), benzylideneamino and substituted alkyl groups (wherein the alkyl group has l to 4 carbons). One type of "4,5,6 or 7-membered heterocycle" is the "heteroaryl" group.
The term "heteroaryl" refers to those 4,5,6 or 7-membered heterocycles which are aromatic.
Exemplary heteroaryl groups are substituted and unsubstituted pyridinyl, furanyl, pyrrolyl, thienyl, 1,2,3,-triazolyl, 1,2,4-triazolyl, imidazolyl, thiazoly:L, thiadiazolyl, pyrimidinyl, oxazolyl, tria~inyl, and tetrazolyl. Exemplary nonaromatic heterocycles (l e., fully or partially saturated GC213a heterocyclic groups) are substituted and unsubstituted azetidinyl, oxetanyl, thietanyl, piperidinyl, piperazinyl, imidazolidinyl, oxazolidinyl, pyrrolidinyl, tetrahydropyrimidinyl, dihyrothiazolyl and hexahydroazepinyl. Exemplary of the substituted 4,5,6 or 7-membered heterocycles are 1-alkyl-3-azetidinyl, 2-oxo-1-imidazolidinyl, 3-alkylsulfonyl-2-oxo-1-imidazolidinyl, 3-benzylideneamino-2-oxo-1-imidazolidinyl, 3-alkyl-2-oxo-1 imidazolidinyl, 3-phenyl (or substituted phenyl~-2-oxo-l-imidazolidinyl, 3-benzyl-2-oxo-1-imidazolidinyl, 3-(2-aminoethyl3-2-oxo-1-imidazolidinyl, 3-amino-2-oxo-l-imidazolidinyl, 3-[(alkoxycarbonyl)amino]-2-oxo-1-imidazolidinyl, 3-[2-[(alkoxycarbonyl)-amino]ethyl]-~-oxo-l-imidazolidinyl, 2-oxo-1-pyrrolidinyl, 2-oxo-3-oxazolidinyl, 4-hydroxy-6-methyl-2-pyrimidinyl, 2-oxo-1-he~ahydroazepinyl, 2-oxo-3-pyrrolidinyl, 2-oxo-3-tetrahydro~uranyl, 20 2,3-dioxo-1-piperazinyl, 2,5-dioxo-1-piperazinyl, 4-alkyl-2,3-dioxo-1--pip2razinyl, and 4-phenyl-2,3-dioxo-1-piperazinyl.
The term "substituted amino" r~fers to a group having the ~ormula -NZ8Zg wherein Z8 is hydrogen, alkyl, phenyl, substituted phenyl, phenylalkyl or (substituted phenyl)alkyl, and Zg is alkyl, phenyl, s~bstituted phenyl, phenylalkyl, (substituted phenyl)alkyl, hydroxy, cyano, alkoxy, phenylalkoxy, or amino (-NH2).
The expression "a 4, 5, or 6-membered nitroge~ containing heterocycle" re~ers to l-pyrrolidinyl, Q3-pyrrolin-1-yl, 1-azetidinyl, l-piperidinyl, ~3-piperidein-1-yl, ~-piperidein-1-yl, 3-oxazolidinyl, 3-thiazolidinyl, l-imidazolidinyl, 4-thiomorpholinyl, 4-morpholinyl, 1-piperazinyl, l-hexa-~5i3~

GC213a hydropyrimidinyl, ~etrahydro-2H-1,3-thiazin-3-yl, - tetrahydro-2H-1,3-oxazin-3-yl, 3-thiazolidinyl, 1-oxide, 3-thiazolidinyl,1,1-dioxide, 4-thiomor-pholinyl,1-oxide, 4-thiomorpholinyl,l,1-dioxide, tetrahydro-2H-1,3-thiazin-3-yl,1-oxide, tetra-hydro-2H-1,3-thiazin-3-yl,1,1-dioxide, or one of the above groups substituted with one or more (preferably 1, 2 or 3) oxo, halogen, hydroxy, amino, cyano, trifluoromethyl, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkylsulfonyl, phenyl, substitu-ted phenyl, azido, carboxy, aminocarbonyl~ ZlO~ NZ1o, or SzlO where ZlO is alkanoyl, aminocaxbonyl, aminosulfonyl, phenylcarbonyl, (substituted phenyl)carbonyl, alkyl, substituted alkyl, phenyl or substituted phenyl.

: ~ ~53~a6 -8- GC213a The term "acyl" refers to all organic radicals derived from an organic a~id (i.e., a carboxylic acid) by removal of the hydroxyl group. Certain acyl groups are, of course, preferred but this preference should not be viewed as a limitation of the scope of this invention.
Exemplary acyl groups are those acyl groups which have been used in the past to acylate ~-lactam antibiotics including 6-aminopenicillanic acid and derivatives and 7-aminocephalosporanic acid and derivatives; see, for example, Cephalos~orins and Penicillins, edited by Flynn, Academic Press ~1972), German Vffenlegungsschrift 2,716,677, published October 10, 1978, Belgian patent 867,994, published December 11, 1978, United States patent 4,152,432, issued May 1, 1979, U~ited States patent 3,971,77B, issued July 27, 1976, United States patent ~,172,199, issued October 23, 1979, British patent 1,348,894, published March 27, 1974, and European patent application 75,805, published April 6, 1983.

The following list of acyl groups is presented to further exemplify the term "acyl"; it sh~uld not be regarded as limiting that term. Exemplary acyl groups are:
(a) Aliphatic groups having the formula Ra C
wherein Ra is alkyl; cycloalkyl; alkoxy; alkenyl;

,, ~
, ` I . .

9 1253~46 GC213a -cycloalkenyl; cyclohexadienyl; or alkyl or alkenyl substituted with one or moLe halogen, cyano, nitro, amino, mercapto, alkylthio, or cyanon~thyl-tiliO groups.
~b) Carbocyclic aromatic groups havillg the formula b ~ (CH2) b ~ CH-C-Re Rb ~ CH2-O-C-, b ~ O-CH2-C- , -10- 1253146 GC213a Rb ~S--S-CH2-C- or 10b ~H -S -C -wherein n is 0, 1, 2 or 3; Rb, Rc, and Rd each is independently hydrogen, halogen, hydroxyl, nitro, amino, cyano, trifluoromethyl, a].kyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms or aminornethyl; and Re is amino, hydroxyl, a carboxyl salt, protected carboxyl, foLrilyloxy, a sulfo salt, a sulfoamino salt, azido, halo~cn, hydrazino, alkylhydrazino, phenylhydrazino, or [(alkylthio)thioxomethyl]thio.
20Preferred carbocyclic aromatic acyl groups include those having the formula HO ~ CH -C-, ~ -CH -Cl-, ~253~
~ C213a .

HO ~ I~-C- (Re is preferably a carboxyl salt or sulfo salt) and ~ CI~-C- (Re is preferably a carboxyl salt or sulfo salt).
(c~ Heteroaromatic groups having the formula O
~I
R
e Rf-O--CH2--C--O
Rf-S-CH2-C- , O O

Rf-C -C-wherein n is 0, 1, 2 or 3; Re is as defined above; and Rf is a substituted or unsubsti~uted

5-, 6- or 7-membered lleterocyclic ring containing 1,2,3 or 4 (preferably 1 or 2) nitlogeIl~ o~ygen and sulfur atoms. Exemplary heterocyclic . ~S3~4~ GC213a -12- _ rings are thienyl, furyl, pyrrolyl, pyridinyl, pyrazolyl, pyrazinyl, thiazolyl, pyrimidinyl, thiadiazolyl and tetrazolyl. Excmplary sub~tituents are halogen, hydroxyl, nitro, ami.no, protectcd ~mino, cyano, trifluoromethyl, alkyl of 1 to 4 carhon at~,~s, alkoxy of 1 to 4 carbon atoms, or R

~OOC-CH-CH2-0-C-NH- .

Prcfcrred heteroaromatic acyl groups include those groups of the above formulas whercin Rf is 2-amino-4-thiazolyl, 2-amino-5-halo-4-thiazolyl, 4-aminopyrimidin-2-yl, 5-amino-1,2,4-thiadiazol-3-yl, 2-thicnyl, 2-furanyl, or 6-aminopyridin-2-yl.
(d) [~(4-Substituted-2,3-dioxo-1-piper-azinyl)carbonyl]amino]arylacetyl groups having the formula O 01 ~_~
-C-CH-NH-C-N N-R~h g O o whcreln Rg is an aromatic group (including carbocyclic aromatics such as those of the formula Rc Rb`~5~ Rd and heteroaromatics as included within the definition of Rf); and Rh is alkyl, substitutcd ~53~6 GC213a alkyl (wherein the alkyl group is substituted with one or more halogen, cyano, nitro, amino or mercapto groups), arylmethyleneamino (l.e., ~N=CH~Rg wherein Rg is as defined above), O
arylcarbonylamino (i.e., ~NH~C~Rg wherein Rg ls as defined above~ or alkylcarbonylamino.
Preferred [[(4-substituted-2,3-dioxo-1-piperazinyl)carbonyl]amino]arylacetyl groups include those wherein Rh is ethyl, phenylmethylene-amino or 2-furylmethyleneamino.
(e) (Substituted oxyimino)arylacetyl groups having the formula R
-C-C=N-O-Ri wherein Rg is as defined above and Ri is hydrogen, alkyl, cycloalkyl, alkylaminccarbonyl, arylamino-carbonyl (i.e., ~C-NH~Rg wherein Rg is as de~ined above) or substituted alkyl (wherein the alkyl group is substituted with one or more halogen, cyano, nitro, amino, mercapto, alkylthio, aromatic group ~as defined by Rg), carboxyl (including salts thereof), amido, alkoxycarbonyl, phenyl-methoxycarbonyl, diphenylmethoxycarbonyl, hydroxy-alkoxyphosphinyl, dihydroxyphosphinyl, hydroxy-(phenylmethoxy)phosphinyl, dialkoxyphosphinyl sub-stltuents, l-piperazinylcarbonyl, or 4-methyl-1-piperazinylcarbonyl).

~ 6 ~C213~ -Preferred tsubstituted oxyimino)arylacetylgroups include those wherein Rg is 2-amino-4-thiazolyl. ~lso preferred are those groups wherein Ri is methyl, ethyl, carboxyme-thyl, l-carboxy-l-methylethyl, 2,2,2-trifluoroethyl or l-carboxycyclopropyl.
(f) (Acylamino)arylacetyl groups having the formula O O
-C-CII-NII-C-R
Rg wherein Rg is as defined abo~e and Rj is R

b ~ ~ d ~ (CH2)n-O-, amino, alkylamino, (cyanoalkyl)-amino, amido, alkylamido, (cyanoalkyl)amido, -CH2-NH-C ~ N -CH-CH2-C-NH-CH3, ~ SO2-N(CH2-CH2-OH)2 ~ rCH3, OH
OH OH

~ /

HO ~ C-O O

~ 3~ C213a Preferrcd (acylamino)arylacetyl groups of the above formula include those groups wherein Rj is amino or a!nido. Also preferred are those groups wherein R is phenyl or 2-thienyl.
(g) [[[3-Substitutcd-2-oxo-l~imidazoli-dinyl]carbonyl]amino]arylacetyl groups having the formula O O C
Il 11 ~ ~
-C-CH-NII-C-N N-Rk Rg CH2 -CH2 wherein Rg is as defined above and Rk is hydrogen, alkylsulfonyl, arylmethylencamino (i.e., ~N=CH~Rg wherein Rg is as defined above), -C-Rm (wherein Rm is hydrogen, alkyl or halogen substituted alkyl), aromatic group (as defined by Rg above), alkyl or substituted alkyl (wherein the alkyl group is substituted with one or more halogen, cyano, nitro, amino or mercapto groups).
Preferred [[3-substituted-2-oxo-1-imidazoli-dinyl]carbonyl]amino]arylacetyl groups of the above formula include those wherein Rg is phenyl or 2-thienyl. Also preferred are those groups wherein Rk is hydrogen, methylsulfonyl, phenyl-methyleneamino or 2-furylmethyleneamino.

125 ~ C213a ~ he terms "salt" and "salts" re~er ~o basic salts fo~med with inorganic and organic bases.
Such salts include ammonium salts, alkali metal salts like sodium and potassium salts (which a~e preferred), alkaline earth metal salts like the calciu~ and magnesium salts, salts with organic -bases, e q., dicyclohexylamine salt, benzathine, N-methyl-D-glucamine, hydrabamine salts, salts with amino acids like arginine, lysine and the like.
The nontoxic, pharmaceutically acceptable salts are preferred, although other salts are also useful, ., in isolating or purifying the product.
The salts are formed in conventional manner by reacting the f~ee acid foLm of the product with one o~ more equivalents of the appropriate base providing the desired cation in a solvent or medium in which the salt is insoluble, or in water and removing the water by freeze drying. ~y neutralizing the sal~ with an insoluble acid like a cation exchange resin in the hydrogen ~orm (e.q., polystyrene sulfonic acid resin like Dowex 50) or with an aqueous acid and extraction with an o~ganic solvent, e.a., ethyl acetate, dichloromethane or the like, the free acid form can be obtained, and, if desired, another salt formed.
~ s set forth throughout the specification, ~-lactams having in the l-posltion an ester of the R5~ 6 g~oup -C~ C-COOH are contemplated as an integral ~1 R7 part of this invention. Exemplary esters include a~kyl, alkenyl, alkynyl, cycloalkyl, tcycloalkyl)-*Trademark ,, ~
. ~, .
.~

~L~253~ GC213a ~

alkyl, Rx-alkyl, trialkylsilylalkyl, mono-, di-or trihaloalkyl, hydroxyal~yl, alkoxyalkyl, carboxyalkyl, alkoxycaLbonylalkyl, diphcnylmethoxy-carbonylalkyl, carbamoylalkyl, alkylcarbamoylalkyl, dialkylcarbamoylalkyl, indanyl, phenyl, substitl~ted phenyl, phenylalkyl, (substituted phenyl)alkyl, Rx-carbonylalkyl, -~ --~-Y2 ~wherein Yl is hyd~ogen, alkyl or phenyl and Y2 is hydLogen, alkyl, cycloalkyl, (cycloalkyl)oxy, phenyl, or alkoxy, or toyether Yl and Y2 are -(CH2)2-, lS -(CH2)3-, -CH=CH-, or ~ ], and -IC~ ~ Yl esters. Yl Hydrolyzable esters are those esters that can be hydrolyzed in vivo to give the parent carboxylic acid product; they exhibit the antibiotic activity of the parent carboxylic acid. Non-hydrolyzable esters (esters that do not hydrolze in vivo to the parent carboxylic acid) are contemplated for use in this invention as intermediates; some of them are also active as antibiotics.
R~ R~
~-Lactams having a -ICl - N~-C-COOH substituent (or an ester or salt thereof) in the l-position and an amino or acylamino substituent in the 3-position contain at least one chiral center -- the carbon atom (in the 3-position of the B-lactam nucleus) to which the amino or acylamino substituent is GC213a attached. This invention is directed to those B-lactams which have been described above, wherein the stereochemistry at the chiral center in the 3-position of the ~-lactam nucleus is the same.as the configuration at the carbon atom in the

6-position of naturally occurring penicillins (e.q., pcnicillin G) and as the configuration at the carbon atom in the 7-position of naturally occurring cephamycins, le.q.. cephamycin C).
'~Jith rospect to the preferred B-lactams of fo~mula I. the structural formulas have been d~awn to show the stereochemistry at the chiral center in the 3-position.
Also included within the scope of this invention are racemic mixtures which contain the above-described B-lactams.

The ~-lactams of formula I, and esters and sal~s thereof, have activity against a range of gram-negative and gram-positive organisms. The compounds of this invention can be used as agents to combat bacterial ineections (including urinary tract infections and respiratory infections) in mammalian species, such as domesticated animals (e.q., dogs, cats, cows, horses, and the like) and humans.
For combating bacterial infections in mammals a compound of this invention can be administered to GCZ13a a mammal in nced thereof in an amount of about 1.4 mg/~g/day to about 350 mg/kg/day, preferably about L4 mg/kg/Aay to about L00 mg/kg/day. All modes of administration which have been used in the past to deliver penieillins and eephalospocins to the site of the infection are also contemplated foc use with the novel amily of ~-lactalns of this invention.
Such methods of administeation include oral, intravenous, intramuscular, and as a suppository.
The products of formula I can be prepared from a 3-protected amino-2-azetidinone having the f o rmul a ~ 1H

wherein the symbol "~l" represents an amino protecting group (~g~, t-butoxycarbonyl, benzyloxycarbonyl, o-nitrophenylsulfenyl, ete.).
Those products of formula I wherein R7 is hydrogen can be prepared by reacting a compound of formula II with an isocyanate, or thioisocyanate, having the fosmula III 5~ ~ 6 Zl=C=N-C-COOA2 wherein the symbol "A2" represents a carboxyl protecting group. The reaction proceeds by the soquelltial addition of a strong base (e.q., an alkyl lithium) to a compound of formula II followed by the addition of a compound of formula III, and after aqueous workup yields a compound having the formula 4~
GC213a A~

0~ ¦J C NH5~C/CooA
Alternatively, if Zl is oxygen, the reaction proceeds in the absence of base at elevated temperatures.
Those products of formula I wherein R7 is as defined above, but not hydrogen (this subgenus is referred to hereinafter as R7 ) can be prepared by reacting a compound of formula II with a compound having the formula ~5 ~ 6 L-ICl~ C-COOA2 Zl R7 wherein L is a leaving group such as a halogen or imidazole. The reaction proceeds in the presence of a base (such as triethylamine), and a catalytic amount of 4-dimethylaminopyridine, and yields a compound having the formula A1-N~
\C C-R3 C/

C~c . . N_ lCI I -, COOA2 Compounds of formula V can be prepared by reacting a compound having the formula H - N ~ COOA
with phosgene or thiophosgene in the presence of base (such as triethylamine or pyridine).

~2$3~46 GC213a Alternatively, an intermediate of formula VIcan be prepared by reacting a compound of foLmula II with phosgene or thiophosgene in the presence of a base (such as triethylamine) followed by the S addition of a compound of ~ormula VII in the presence of a base lsuch as triethylamine).
A comeound of formula I can be prepared from a corresponding compound of formula IV or VI by (i) Removing the Al and A2 protecting groups simultaneou~ly to obtain a compound having the formula N 2 - _ R~
C C
¦ ¦ ~5 /6 C N-~-N-C-COOH

or a salt thereof. and then acylating the compound of formula VIII.
(ii) Removing the A2 protec~ing, then removing the Al protecting group. to ob~ain a compound of formula VIII, or a salt thereof, and then acylating the compound of formula VIII.
(iii) Removing the Al protecting group to obtain a compound having the formula ~L~25~

IX R2 _4 NH - - R
2 = _ ~ 3 ~C C
¦ I R5 R6 ~ ~ N~ C-COOA2, acylating the intecmediate of formula IX, and ~hen removing the A2 protecting gcoup.
The deprotection reactions can be run using art-recogni2ed techniques. If, for example, the protecting group is t-butoxycarbonyl, trifll~oro-acetic acid can be used to deprotect the amino group. If the protecting group is benzyloxy-carbonyl, catalytic (e.q., palladium on charcoal) hydrogenation can be used. If the protecting group is o-nitrophenylsulfenyl, p-toluenesulfonic acid can be used in combination with ~-thiocresol.
Alternatively, a compound of ~ormula IV or VI can be reacted with N-methyl-N-trimethylsilyl-tri-fluoeoacetamide (MSTFA) and a silane such as iodo-trimethylsilane to cleave the "Al" and "A~"
groups (e.q., when Al is t-butoxycarbonyl or benzyloxycarbonyl and A2 is alkyl or cycloalkyl) and yield the corresponding 3-trimethylsilylatnino compound which can then be acylated.
The acylation reactions can also be run using art-recognized techniques. Exemplary techniques include reaction with a carboxylic acid (Rl-OH) or corresponding carboxylic acid halide or carboxylic acid anhydride. The reactions with a carboxylic acid proceed most readily in the ~253~L46 (7'C213a presence of a carbodiimide such as dicyclo-hexylcarbodiimide and a substance capable of forming a reaction intermediate ln situ such as N-hydroxybenzotriazole or N-hydroxysuccinimide. In those instances wherein the acyl group (Rl) contains reactive functionality (such as am;no or carboxyl groups) it may be necessary to first protect these funct;onal groups, then car~y out the acylation reaction. and finally deprotect the resulting product.
When prepacing an ester of a compound of formula I, it is also possible to choose the "A2"
group to correspond to the desired ester group.
This avoids the need for deprotecting and ~hen re-esterifying the carboxyl group.
Methodology for the preparation of the starting 2-azetidinones of formula II is described in United Kingdom patent application 2,071,6S0, published September 23. 1981. These azetidinones are obtainable using any one of numerous procedures.
Reacting an olefin having the focmula CH2=C-R3 with a halosulfonylisocyanate (peeferably c~loro-sulfonylisocyanate) having the formula XI
O=C=N-S02-halogen, yields an azetidinone having the formula 33La~6 GC213 a a ~ C - W-S02-halogen.
s Reductive hydrolysis of an azetidinone of focmula XII yields an N-unsubstituted B-lactam having the ~ormula CH2 l R3 C ~H.
0~
For a more detailed description of the above-descLibed reaction sequence, refeLence can be made to the literature; see, for example, Chem.
Soc. Rev., 5, 181 (1976) and J. Orq. Chem., 35, 2043 (1970).
An azido group can be introduced in the 3-position of an azetidinone of formula XIII by reaction o~ the compound with an arylsulfonyl azide (such as toluenesulfonyl azide) to obtain an azetidinone having the formula XIV R~
N3 = / 3 H- C

~1 1H.

The reaction proceeds best by first protecting the azetidinone nitrogen with a silyl residue (e.~., t-butyldimethylsilyl, or t-butyldiphenylsilyl), ~253~6 GC213a then generating the anion at the 3-position of the nucleus with a strong organic base (e.q.. lithium diisopropylamine) at a low temperature, and then treating the anion with toluenesulfonyl a%ide. The reslllting intermediate is quenched with trimethyl-silyl chloLide, and subsequent acid hydrolysis or fluoride solvolysis of the N-protecting group yields the compound of formula XIV.
A 3-azido-2-azetidinone of formula XIV
~herein R4 is hydrogen can also be prepared by first reacting a primary amine having the formula XV H2N-CH2- ~ 0-alkyl 0-alkyl or XVI H2N- ~ 0-alkyl with an aldehyde having the formula XVII
R3-~H

(or a hemiacetal) to yield the coLresponding Schi~f base. A t2+2~ cycloaddition reaction of the Schiff base with an activated ~orm of ~-azidoacetic acid yields a 3-azido-2-azetidinone having the formula ~CH Ç''' ~ N-Q

GC213a wherein Q i5 -CH2 ~ -O-alkyl or ~ -alkyl.

O-alkyl Oxidative cemoval of the l-substituent yields ihe corresponding compound having the formula H l_~3 I -~H
A 3-azido-2-azetidinone of formula XIV oc XVIII can be reduced to the corresponding 3-amino-2-azetidinone having the formula XX WH2 _4 3 - CH- - C
I
~ NH .

The reduction can be accomplished by catalytic te-q ~ palladium on charcoal, or platinum oxide) hydrogenation or with reducing agents such as zinc or triphenylphosphine. A 3-amino-2-azenidinone can be converted to a corresponding 3-protected amino-2-azetidinone of formula II using art-recognized techniques.
A compound of formula II wherein R3 is hydrogen can also be obtained using a procedure analogous to that described above ~or the preparation of a 3-azido-2-azelidinone whcrein R3 i6 hydrogen. In place of an activated form of ~-azidoacetic acid, an activated form of ~-phthalimidoacetic acid is used, yielding a compound having the formula 53~a6 GC21~a XXI

~ /N \ ~ R3 T
~ C N-Q .

Trea~men~ of a compound of formula XXI with base yields the corrcsponding 4~ compound having the formula XXII
~ C\ R4 ~ ~ CH

Reaction of a compound of formula XXI or XXII with a reagent such as methyl hydrazine (to cleave the phthaloyl group), followed by the introduction of a protecting group on the 3-nitrogen substituent, and oxidative removal of the l-protecting group will yield a compound of formula II wherein R2 and R4 are hydrogen.
The starting 2-azetidinones of formula II
wherein R2 is methoxy can be prepared by me~hoxylating the corresponding non-methoxylated compound of formula II. Chlorination of a non-methyoxylated compound of formula II yields a compound having the formula ~253~46 GC213a XXIII ll R4 Al -N
fH - C-R3 /~ ~-Cl, ~ .
and can be accomplished by reaction of a compound of formula II with a ceagent such as t-butyl hypochlorite, sodium hypochlorite, chlorine or othec ceayent useful for N-chlorinating amides.
The rcaction can be run in an organic solvent (r.~g~, a lower al~anol such as methanol) or in a two phase solvent system (e.~l , water/methylene chloride) in the presence of a base such as sodium borate decahydrate. The reaction is prefeLably run at a reduced temperature.
Reaction of a compound of formula XXIII wi~h a methoxylating agent, e.q., an alkali metal methoxide, and subsequently adding a reducing agent such as trimethylphosphite, yields a compound having the formula XXI~ OCH3 R4 A -NH
C -- -C-R

/~
O~
in combination with its enantiomers.

~253~
GC213a Additional methodology for the preparation ofthe starting 2-azetidinones of formula II is described in United Kingdom patent application 2,071,650, eublished September Z3. 1981. The cyclization of amino acids to yield 2-aze~idinones is described as is the degradation of 6-amino-penicillanie acids and 7-aminopenicillanic acids to yield 2-azetidinones.
Compounds of formula III can be prepared by the general methods descLibed in Ann. Chem., 575:217 (1951). Anqew. Chem. Int. ~d. Eng., 18:~74 ~1979), and Coll. Czech. Chem. Comm., 40:2845 (19~5).
The following examples are specifie embodiments of this invention.

~53~6 GC213a Example 1l 3s- ~ 3~( z~, 4~ N- r r 3-~ r (2-~mino-4- hiaæolyl~_ (methoxvimino~acetyllamlno-~-methYl-2 o:
azetidinYllcarbonyl1qlvcine, potass_um salt A) ~3S-trans)-N- r r 3-[[(t-ButYloxYlcarbo_yll-aminol-4-methyl--2-oxo-1-azetidinyl~carbonyl]-glycine, t-butYl ester To a suspension of potassium cyanate (186 mg, 2.3 mmol) in Zml of dimethylformamide was added t-butyl bromoacetate t0.356ml, 2.2 mmol). The mixture was heated to 100C for 1 hour and cooled to room temperature. (3S-trans)-3-[[(t-Butyloxy)-carbonyl]amino3-~-methyl-2-azetidinone (400 mg, 2.0 mmol) was then added, and the mixture was heated to 140C for 1 hour. Upon cooling to room temperature, the crude product was extracted from ice cold 5t HCl with three portions of ethyl ace~ate. The combined organic layers were extracted twice with water, once with aqucous potassium bicarbonate, and dried over sodium sulfate. The volatiles were removed, and the residue was subjected to chromatography on silica gel (eluting with 40% ethyl acetate-hexane) yielding 149 mg of the title compound.
E3) ~3s-l3~(z~ ,q~ll-N-r r3-r r (2-Amino-4-thiazolYl)(methoxvimino~acctyll_mino-4-methYl-2-oxo-l-azetidinyllcaLbonyl~glyc~ne, potassi m salt l-EIydroxybenzotriazole hydrate (55 mg, 0.407 mmol) and 8Z mg (0.~07 mmol) of (Z)-2-amino--(methoxyimino)-4-tlliazoleacetic acid were disGolved in l.lml of ~imethylfoLmamide and cooled to obc.
N,N-Dicyclohexylcarbodiimide (84 mg, 0.~07 mmol) ~L2~ii3~
GC213a was added and the mixture was warmed to room temperature. The reaction mixture was sti~red for 30 minutes to yield the hydroxybenzotria~ole ester of the starting acid which was then cooled to 0C.
(3S-trans)-N-[t~-[t(t-Butyloxy)carbonyi]-amino~-4-methyl-2-oxo-1-azeti-]inyl]carbonyl~-glycine, t-butyl ester (121 mg, 0.339 mmol) was dissolved in 0.15ml of anisole and cooled to O~C.
Tri~luoroacetic acid (1.5ml) was added and the resulting mixture was stirred at 0C foe 4 hours.
The volatiles were evaporated and the rcsidue ~Jas triturated with hexane and anhydrous ether. The residue was cooled to 0C and dissolved in l.lml of water. The pH was adjusted to 6.5 with solid K~IC03 and this solution was immediately added to ~he above hydroxybenzot~iazole ester at 0C. The resulting mixtuce was stirred at 0C for 3 hours while maintaining the pH a~ 6.5-7.Q with agueous HCl and KHC03. The reaction mixture was stirred at 5C overnight.
The reaction mixture was filtered to remove the dicyclohexylurea precipitate. and the volatiles were evaporated. The residue was purified by column ch~omatography with water on Do~Jex 50X2-400*~ resin (~ form) followed by chromatography on HP-20* (eluting with wate~ and 5%
acetone-water) to yield 54 mg of ~he title compound, melting point 190-195~C, dec.
_______________ *~IP-20 is a macroporous styrene-divinylbenzene copolymer manufactured by Mitsubishi Chemical Industries.
~Dowex 50X2 is a strongly acidic cation exchange resin made by the nuclear sulfonation of styrene-divinylbenzene beads containing 2% divinylbenzene and 98% styrene and other monovinyl monomers.

,~ .
~ *Trademark i253~4~ GC213a F.xam~le 2 f3StZ)l-N [ r~ -r r (2-Amino 4-thiazolyl)~ln~thQxy-imino~acetY~ minol-2-oxo-l-azetidi.n-yl]c-a qlYcine,_~ot_ssium salt A) (S~-N~ - r [ 1 t--ButYlox Y~carbonyll~m-n~l=2-oxo-l-a?,etidiny-llcArbon-yl]qlycine~ t_butyl ester To a suspension of potassium cyanate (la6 mg, Z.3 mmol) in 2ml o~ dimethylformamide was added 10 t-butyl bromoacetate (0.356ml, 2.2 mlnol). The mixture was heated to 100C for 1 hour and cooled to room tcmperature. (3S)-3-[t(t-~utyloxy)-carbonyl]amino]-2-azetidinone (372 mg, 2.0 mmol) was then added, and the mixture was heated from 15 65C to 140C over a period of 3.5 hours, finally maintaining the temperature at 140C for 0.5 hours. Upon cooling to room temperature, the crllde product was extracted from ice cold 5~ HCl with three portions of ethyl acetate. The combined organic layers were extracted twice with water and once with aqueous potassium bicarbonate. The organic layers were then dried over sodium sulfate and filtered through a pad of silica gel. The volatiles were removed. and the residue was subjected to chromatography on silica gel (eluting with 40~ ethyl acetate-hexane) yielding 180 mg of the title compound.

B) [3S(Z)l-N-rf3-r[(2-Amino-4-thia7olyl~l_ethoxY-imino~acetyllaminol-2-oxo-1-azetidinyllcarbonYl-qlycine, potassium salt l-Hydroxybenzotriazole hydrate (33 mg, 0.61 mmol) and 123 mg (0.61 mmol) of (Z)-2-amino-~-~3~ GC2l3a (methoxyimino)-4-thiazoleacetic acid were dissolved in 1.5ml of dimethylformamide and cooled to 0C.
N,N-Dicyclohexylcacbodiimide (126 mg, 0.61 mmol) was added, and the mixture was warmed to room temperature. The reaction mixture was stirred for 30 minutes to yield the hydroxyben~.otriazole ester of the startir.g acid which was then cooled to 0C.
(S)-N-[~3-[~(t-Butyloxy)carbonyl~amino]-Z-oxo-l-azetidinyl~carbonyl]glycine, t-butyl e3ter (175 mg, 0.51 mmol) was dissolved in 0.23ml of anisole and cooled to 0C. Trifluoroacetic acid (2.3ml) was added and the resulting mixture was stirred at 0C for 4 hours. The volatiles were evaporated and the residue was triturated ~ith hexane and anhydrous ether. The residue was coolcd to 0C and dissolved in 1.5ml of water. The pEI was adjusted to 6.5, with solid K~IC03, and this solution was immediately added to the above hydroxyben70triazole ester at 0C. The resulting mixture was stirred at 0C for 2-1~2 hours while maintaining the pH at 6.5-7.0 with aqueous ~ICl and KHC03. The reaction mixture was then stirred at 5C overnight.
The reaction mixture was filtered to reInove the dicyclohexyl urea precipitate, and the volatiles were evaporated. The residue was purified by column chromatography with water on ~owex 50X2-400 cesin (K form) ~ollowed by chromatogcaphy on HP-20 (eluting with water) to yield 74 mg of the title compound, melting point 162-172C, dec.

~ 46 GC213a Example 3 r 3s-t3~-~z~4~ N-~ r 3- r ~ ( 2-Amino-4-thiazolyl) (methoxYiminolacetyllaminol--q-methyl-2-c,xo-1-azetidinYllcarbonyll~lycine~ potassium salt A) (3S-cis)-N-~3-~ r (t-~utvloxY)carbOnYll-aminol-4-methYl-2-oxo-l-azetidinyllcarbo-n glycine, t-butYl ester To a suspension of potassium cyanate (55a mg, 6.9 mmol) in 6ml of dimethyl~ormamide was added t-butyl bromoacetate (l.lml, 6.6 mmol). The mixture was heated to 100C for 1 hour and cooled to room temperature. (3S-cis)-3-[ttt-butyloxy)-carbonyl]amino]-4-methyl-2-azetidinone tl.2g, 6.0 mmol) was then added, and the mixture was hcated to 65C. After being stirred at 65C for 1 hour, the mixture was heated to 100C and stirred for an additional hour. Additional isocyanate was prepared tusing 5sa mg potassium cyanate and l.lml of t-butyl bromoacetate as described above) and added to the reaction mixture at room temperature.
After being heated at 65C for 1 hour and 100C for 1 hour, the reaction mixture was stirred at room temperature overnight.
The crude product was extracted from ice cold 5~ HC1 with three portions of ethyl acetate. The combined organic layers were extracted twice with water and once with aqueous potassium bicarbonate.
The organic layers were then dried over sodium sulfate, filtered, and the volatiles were removed.
The residue was subjected to flash chromatography on silica gel (eluting with ~0~ ethyl acetate-hexane) yielding 993 mg o~ the title compound.

lZ5~46 GC213a B) r 3S-[3~(%~ 11-N-LL3-r[(2-Amino-4-thiazolyl)(methoxyimino~_cetvllaminoJ-4-methyl_ 2-oxo-1-azetidinYllcarbonyllqlycine, potassium salt l-EIydcoxybenzotriazole hydrate (81 mg, 0.6 mmol) and 121 mg (0.6 mmol) of (Z)-2--amino-~-(methoxyimino)-4-thiazoleacetic acid were dissolved in l.Sml of dimethylformamide and cooled to 0C.
N,W--Dicyclohexylcarbodiimide (124 mg, 0.6 mmol) was added, and the mixture was warmed to room temperature. The reaction mixture was stirred for 30 minutes to yield the hydroxybenzotriazole estec of the starting acid which was then cooled to 0C.
(3S-cis~-N--t[3-tt~t-Butyloxy)carbonyl]
amino]-4-methyl-2-oxo-1-azetidinyl]carbonyl]-glycine, t-butyl estec (179 mg, a.s mmol) was dissolved in 0.23ml of anisole and cooled to ooc.
Trifluoroacetic acid (2.3ml) was added and the resulting mixture was stirred at oC for 2 hours.
The volatiles were evaporated and the residue was triturated with hexane and anhydrous ether. The residue was cooled to 0C and dissolved in 1.5ml of water. The pH was adjusted to 6.5 with solid K~IC03, and this solution was immediately added to the above hydroxybenzotriazole ester at 0C. The resulting mixture was stirred at 0C for 2 hours while maintaining the p~ at 6.5-7.0 with aqueous ~ICl and KHC03. The reaction mixture was then stirred at 5C overnight.
The reaction mixture was ~iltered to remove the dicyclohexylurea precipitate, and the volatiles were evaporated. The residue was purified by column chromatography with water on Dowex 50X2-~00 resin (K form) followed by chromatography on ii3~6 GC213a HP-20 (eluting with water) to yield 73 mg of the title compound, melting point 190-200C, dec.

Flxample 4 r 3S(Z)l-2-~ r r 1- (2-~nino-~-thiazolyl3-2- r ~ 1-~E(carboxYmethyl)aminolcaLbonyll-2-oxo-3-a~etidinyllaminol-2-oxoethYlidenelaminoloxyl-_methylpropanoic acid A) ts~--N-[r3-~ r (t-ButYloxy~carbonyllaminol-2-oxo-l-azetidinyl]carbonyllqlYcine, t-butyl ester To a suspension of potassium cyanate (933 mg, 11.5 mmol) in lOml of dimethylformamide was added t-butyl bromoacetate (1.8ml, ll mmol). The mixture was heated to 100C for 1 hour and cooled to room tempe~atULe. (S)-3-I[(t-Butyloxy~carbonyllamino]-2-azetidinone (1.860g, lO mmol) was then added, and the mixture was heated to 65C. After being stirred at 65C for l hour, the mixture was heated to 100C and stirred for an additional hour.
Additional isocyanate was prepared (using 933 mg of potassium cyanate and 1.8ml of t-butyl bromoacetate as described above) and added to the reaction mixture at room temperature. After being heated at 25 65C for 1 hour and 100C for 1 hour, the reaction mixture was stirred at room temperature overnight.
The crude product was extracted from ice cold 5% EICl with three portions of ethyl acetate. The combined organic layers were extracted twice with water and once with aqueous potassium bicarbonate.
The organic layers were then dried over sodium sulfate, filtered, and the volatiles removed. The residue was subjected to flash chromatography on silica gel (eluting with 40~ ethyl acetate--hexane) 35 yielding 1.1369 of the title compound.

~;~53~
GC213a B) [3S(Z)1-2-rr~1-(2-Amino-4-thiazolyl)-2-rll-r r tcarboxYmethYllam nolcarbonYl1-2-OxO-3-a etidinYllaminol-2-oxoethylidenelamin 2-methylpropanoic acid, diPhenYlmethyl ester Diisopropylethylamine (0.165ml, o.a6 mmol) was added to 342 mg (0.78 mmol) of (Z)-Z-amino--t~2-(diphenylmethoxy)-1,1-dimethyl-2-oxoethoxy]-imino]-4-thiazoleacetic acid in 2.5ml of dimethylformamide at room temperature. The mixture was cooled to -20C, diphenyl chlorophosphate (0.162ml, 0.7a mrnol) was added, and the resulting mix~ure was stirred for 30 minutes to yield a m;xed anhydride.
(S)-N-~3-~t(t-Butyloxy)carbonyl]amino]-2-oxo-l-azetidinyl]carbonyl]glycine, t-butyl ester (224 mg, 0.65 mmol) was suspended in 0.3ml of anisole and cooled to 0C. Trifluoroacetic acid (3ml) was added, and the resulting mixture was stirred at 0C for 3.5 hours. The volatiles were evaporated, and the residue was triturated with hexane and anhydrous ether to yield at yellow-white solid. The residue was dissolved in 2.2ml of dimethylformamide at 0C and 0.55ml of diisopropyl-ethylamine was added. The mixed anhydride prepared above was then added immediately, and the reaction was stirred a~ 5C overnight.
The volatiles were removed under vacuum. The residue was purified by column chromatography with 20% acetone-water on Dowex 50X2-400 resin ~K
form) followed by chromatography on ~IP-20 (el~lting with water, 5% acetone-water, 10% acetone-water and 20~o acetone-water) to give 125 mg of the title compound .

~25~6 GC213a C) ~S(Z)~-2-LL[1-(2-Amino-4-thiazolyl)-2-[11-LL(carboxYmethyl)alninolcarbonv~ oxo-3-_etidinYllaminol-2-oxoethylidenelalninolox~-l_ 2-;nethvlpropanoic acid t3S(Z)]-2-[~tl-(2-~lnino-4-thiazolyl)-2-~tl-[[(carboxymethyl)amino]carbonyl] 2-oxo-3-azetidinyl]amino]-2-oxoethylidene]amino]oxy]-2-methylpropanoic acid, diphenylmethyl ester (125 mg) was dissolved in 1.5ml of anisole and cooled to 0C. Trifluoroacetic acid ~3ml) was added, and the resulting mixture was stirred at 0C for 1 ilour.
The volatiles were evaporated and the residue was triturated with hexane and anhydrous ether to yield a white solid. The cesidue was dissolved in 2ml of water at 0C and the pH was adjusted to 2.55 with aqueous KHC03. This solution was subjected to chromatography on ~IP-20 (eluting with water, 10%
acetone-water, and 20% acetone-water) to yield 24 mg of the title compound, melting point 160-165C, dec -Example 5 r3s(z)l-rrr3-[r(2-Amino-4-thiazolyl)r(cyano-methYoxY)iminolacetvllaminol-2-oxo-1-azetidinYll-carbonYllamino~acetic acid, monopotassium salt l-EIydroxybenzotriazole hydrate (97 mg, 0,72 mmol) and 163 mg (0.72 mmol) of (Z)-2--amino-~-(cyanomethoxyimino)-~-thiazoleacetic acid were dissolved in 2ml of dimethylformamide and cooled to 30 0C. N,N-Dicyclohexylcarbodiimide (199 mg, 0.72 mmol) was added and the mixture was warmed to room temperature. The reaction mixture was stirred for 30 minutes to yield a hydroxybenzotriazole ester.

i3~4~
GC21~a (S)-N-~t3-[~t--~utyloxy)ca~bonyl]amino]-2-oxo-l-azetidinyl]carbonyl]glycine, t-butyl ester (206 mg, 0.6 mmol: see example 4A) was dissolved in 6ml of dry acetonitrile cooled to 0C. N-Methyl-N-trimethylsilyl trifluoroacetamide (0.2~4ml, 1.32 mmol) was addèd and the mixture was warmed to room temperature. After stirring for 45 minutes at room temperature, trimethylsilyliodide ~0.188ml, 1.32 mmol) was added dropwise and the reac~ion mixture was stir~ed for 15 minutes at room tempeLature.
The volatiles were e~aporated without external heating, the residue was dissol~ed in ~ml of dimethyl~ormamide and this solution was immcdiately added to the hydroxybenzotriazole ester. The reaction mixture was stirred at room temperature overnight.
The reaction mixture was filtered to remove the dicyclohexyl urea precipitate and then cooled to 0C. After adding lml of water and stirring at 0C for 30 minutes, the ~olatiles were evaporated.
The residue was suspended in water at 0C and the pH was adiusted to 6.5 with agueous KHCO3.
Purification by column chromatography on ~IP-20 (eluting with water) yielded ~6 mg of the title 25 compound, melting poin~ 160-165C, dec.

Ex~
[3S(Z)l-N-[~3-~[(2-~mino-4-thiazolyl)(ethoxy-imino2acetyllaminol-2-oxo-l-azetidinYllcarbonY
qlYcine, potass um salt L-~Iydroxybenzotriazole hydrate (97 mg, 0.72 mmol) and 155 mg (0.72 mmol) of (Z)-2-amino-~-(ethoxyimino)-4-thiazoleacetic acid were dissolved in 2ml of dimethylformamide and cooled to 0C.

~53~
GC213a N,N-Dicyclohexylcarbodiimide (149 mg, 0.72 mmol) was added, and the mixture was warmed to coom temperature. The reaction mixture was stirred for 30 minutes to yield a hydroxybenzotriazole este~.
(S)-N-t~3-~t(t-Butyloxy)carbonyl]amino]-2-oxo-l-azetidinyl]carbonyl]glycine, t-butyl ester (206 mg, 0.6 mmol; see example ~A) was dissolved in 6ml of dry acetonitrile and cooled to 0C.
N-Methyl-N-(trimethylsilyl)trifluoroacetamide (0.244ml, 1.32 mmol) was added and the mixture was warmed to room temperature. After stirring for ~5 minutes at room temperature, trimethylsilyliodide (0.188ml, 1.32 mmol) was added dropwise, and the reaction mixture was stirred for 15 minutes at room ~5 temperature. The volatiles were evaporated withou~
external heating, the residue was dissolved in 4ml of dimethylformamide, and this solution was then immediately added to the hydroxybenzotriazole ester. The reaction mixture was stirred at room tempera~ure overnight.
The reaction mixture was filtered to remove the dicyclohexylurea precipitate and was then cooled to 0C. ~fter adding lml of water and stirring at oC for 30 minutes, the volatiles were evaporated. The residue was suspended in water at 0C and the p~l was adjusted to 6.5 with aqueous KHC03. Purification by column chromatography on HP-20 (eluting with water) yielded 60 mg of the title compound, melting point 175-130C, dec.

~53~46 GC213a Example 7 [3S(Z)l-N-[E3-[~(2-Amino-4-thiazolYl~(methoxy-imino)acetYllaminol-2-oxo- _azetidinYllcarbon DL-alanine A) rl-t(PhenYlmethoxY)carbonYllethYl]isocy~nate Benzyl alaninate hydrochloride (9.3g, 43 minol) was suspended in 150ml of dry toluene under a positive pressure of argon. The ~eaction mixture was heated to re~lux and phosgene was bubbled through for 2 hours. Nitrogen was then bubbled th~ough while the reaction mixture continued to reflux for 15 minutes. The reaction mixture was cooled to ~oom temperature while nitrogen was bubbled through for an additional hour to remove any phosgene present. ~`he toluene was evaporated, and the residue was distilled (97-107C, 0.3 mm of ~Ig) to yield the title compound.

B) (S~-N-i' r 3- r r (PhenvlmethoxY)carbonYllaminol-2-oxo-l-azetidinyllcarbonyll-DL-alanine, Phenylmethyl ester ~ solution of (S)-3-[l(phenylmechoxy)-carbonyl]amino~-2-azetidinone (416 mg, 2.0 mmol) in 12ml of dry tetrahydrofuran at -75C was treated with 1.2fiml (2.2 mmol) of 1.72 N n-butyl lithium.
~fter 30 minutes, a solution of tl-t(phenyl-methoxy)carbonyl]ethyl]isocyanate (0.54~iml, ~2.2 mmol--corrected for -73% purity by weight) in 2ml of dry tetrahydrofuran was added to the reaction mixture.
After stirring at -75C for 45 minutes, the reaction mixture was pou~ed into aqueous Ki---i2PO4 and extracted with 3 portions of ethyl acetate.

GC213a -~2-The combined organic layecs were extracted oncewith water, dried over Na2S04, and filtcred.
The ~olatiles were removed, and the residue was subjected to chromatography on silica gel (eluting with ~0% ethyl acetate-hexane) yielding 524 mg of the title compound.

C) ~3S(Z~l-N- r ~ 3-~(2-Amino-4-thiazolyl)(meth_xy-imino)acetYllaminol-2-oxo-l-azetidinyllcarbon D.-alanine Diisopropylethylamine (0.283ml. L.62 mmol) was added to 296 mg (1.47 mmol) of (Z)-2-amino-Q-(methoxyimino)-4-thiazoleacetic acid in 4.5ml of dimethylformamide at 23C. The mixture was cooled 15 to -20C and diphenylchlorophosphate (0.305ml, 1.47 mmol) was added. The resulting mixture was stirred for 30 minutes to yield a mixed anhydride.
(S)-N-~3-~(Phenylmethoxy)carbonyl]amino]-~-oxo-l-azetidinyl]carbonyl]-~L-alanine, phenylmethyl 20 ester (518 mg, l.Z2 mmol) was dissolved i-n 4.5ml of dimethylformamide and 232 mg (1.22 mmol) of p-toluenesulfonic acid monohydrate was added.
Hydrogenolysis of the protecting groups at room temperature over 252 mg of 10% palladium on charcoal was complete after l-1/2 hours. The reaction mixture was placed under nitrogen and cooled to 0C. Diisopropylethylamine (0.7ml, 4.02 mmol) was then added to the a~etidinone, followed by the mixed anhydride ~repared above. ~fter stirring at 0C for l hour, the reaction mixture was stirred at 5C overnight.
The volatiles were removed under vacuum. The residue was purified by column chromatography with ~253~6 GC213a water on Dowex 50X2-400 resin (K focm) followed by chromatography on MP-20 resin (eluting with water) to yield ~he title compound contaminated with potassium tosylate. This material was cooled to 0C and acidified to pH 2.5 by addition of lN
HCl. Ch~omatogLaphy on HP-20 resin (eluting with water, 5% acetone-water, and lO~o acetone-water) followed by lyophilization yielded 1~0 mg of the title compound, melting point 140-150C.
Example B
~35(Z)l-[N-[[3-[~(2-~mino-4-thiazolyl)(methoxy-~ ~)acetyllaminol-2-oxo-l-azetidirlYllcacbon m thylamino~acetic acid A) (5)-~N-~3-~ r (PhenylmethoxY~carbonYllaminol~2-oxo-l-a~etidinYllcarbonyllmcthylaminolacetic acid phenYlmethyl ester Potassium carbonate (553 mg, 4 mmol) was added to a rapidly stirring solution of ben~yl sarcosine hydrochloride (43~ mg, 2.0 mmol) in 5ml of dichloromethane at 0C (pH ~8). The mixtu~e was extracted 3 times with dichloromethane and the combined organic layers were dried over Na2SO4 and filtered. The volume of solvent was Leduced to ~2ml by evacuation and dried with 4A molecular sieves to yield the free amine of the starting sarcosine.
The solution containing the free amine was 30 cooled to 0C and 0.32ml (2.3 mmol) of triethylamine was added~ The resulting mixture was immediately added dropwise to a solution of L2.5 phosgene in toluene (2.9mL, 3.4 mmol) at --25C.

~253~
GC213a After stir~ing at -25C ~or 1 hour, the volatilcs were evaporated without extecnal heating to yield crude N-(chlorocarbonyl)-N-methylglycine, phenyl-methyl ester. The compound was not characterized but was used as a crude intermediate.
The crude N-(chlorocarbonyl)-N-me~hylglycine, phenylmethyl ester was redissolved in 4ml of dichloromethane and cooled to 0C. (S)-3-[~Phenylmetho~y)carbonyllamino-2-azetidinone (440 mg, 2.0 mmol) and 24 mg of dimethylaminopyridine were added to the stirring solution. Triethylamine (0.307ml, Z.2 mmol) was added dropwise, and the reaction mixture was warmed to room temperature.
~fter stirring for 45 hours at room temperature, the crude reaction mixture was poured into a~ueous K~l2P04 and extracted 4 times with ethyl acetate. The combined organic layers were dried over Na2S04 and filtered. The volatiles were removed, and the residue was subjected to chromatography on silica gel (eluting with 50~
ethyl acetate-hexane) yielding 231 mg of the title compound.

B) ~ Z)l-lN-[13 1[(2-Amino-4-thiazolYl)(methoxY-imino~acetY11aminol-2-oxo-1-azetidinYllCarbOnYll-mcthYlamino1acetic acid Diisopropylethylamine (0.204ml, 1.17 mmol) was added to 213 mg (1.06 mmol) of (Z)-2-amino-~-(methoxyimino)-~-thiazoleacetic acid in 3.3ml of dimethylformamide at 23C. The mixture of cooled to -20C and diphenylchlorophosphate (0.220ml, 1.06 mmol) was added, and the resulting mixture was stirred for 30 minutes to yield a mixed anllydride.

~:253~
GC213a (S)-~N-[t3-t[(Phenylmethoxy3cacbonyl]alnino~
oxo-l-azetidinyl]carbonyl]methylamino]acetic acid, phenylmethyl ester (372 mg, 0.88 mmol) was dissolved in 3.3ml of dimethylformamide and 167 mg (0.88 mmol) of p-toluenesulfonic acid monohydLate was added. Hydrogenolysis of the phenylmethyl and (phenylmethoxy)carbonyl protecting groups at Loom temperature over 182 mg of lO~o palladium on charcoal was complete after L-1/2 hours. ~rhe reaction miXtULe was placed under nitrogerI and cooled to 0C. Diisopropylethylamine (0.506ml, 2.90 mmol) was then added to the a~etidinone followed by the mixed anhydride in the presence of 3A molecular sieves. ~fter stirring at 0C for 2 hours, the reaction mix~ure was stirred at 5C
overnight.
The volatiles wcre removed under vacuum. The residue was purified by column chromatography with water on Dowex 50X2-400 rcsin (K form) followed by chromatography on E~P-20 resin (eluting with water) to yield 165 mg of crude product. The product was cooled to 0C and acidified to a pH of 2.5 with the addition of lN HCl. Chromatoyraphy on EIP-20 resin (eluting with water, 5% acetone-wdter, and 10% acetone-water) followed by lyophilization yielded 139 mg of the title compound, melting point 145-150C, dec.

~t~253~
GC213a Fxample 9 13S(Z~l-N-~3~LL~2 _mino-4-thiazoly~(me~hoxy_ imino~acetyllaminol-2-oxo-1-azetidinylltilioxo-methyllqlycine, Potassium salt ~) (s~-N-r ~3-r r (t-Bu~yloxY~carbonyllaminol-2-_xo-l-azetidinYllthioxomethYllnlycine~ t-bu~yl ester A solution of (S)-3-~(t-butyloxy)caLbonyl~-amino~-2-azetidinone (186 mg, 1 mlnol) in 6ml of dry 10 tetrahydroEuran at -75C was treated with 0.65ml (1.1 mmol~ of 1.68 N n-butyl lithium. Aftee 30 minutes, a solution of t-butyl isothiocyanato-acetate (0.17ml, 1.1 mmol) in lml of dry tetra-hydrofuran was added to the rcaction mixture.
After stirring at -75C for 2 hours, the reaction mixture was placed at -70C overnight.
The crude product was extracted from aqueous KH2P04 with three portions of ethyl acetate.
The combined organic layers were extracted once with water, dried over Na2S04 and filtered.
The volatiles were ~emoved, and the residue was subjected to chromatography on silica gel teluting with 20% ethyl acetate-hexane) yielding 168 mg of the title compound.
B) ~3S(Z)l-N-~3-[~(2-Amino-4-thiazolyl)tmethox~-imino~acet~llaminol-2-oxo-1-azetidinyllthioxo-methyllq~ycine, potassium salt l-Hydroxybenzotriazole hydrate (74 mg, 0.55 30 mmol) and 111 mg ~0.55 mmol) of (Z)-2-amino-~-(methoxyimino)-4-thia~oleacetic acid were dissolved in 2ml of dimethylfo~mamide and cooled to 0C.
N,N-Dicyclohexylcarbodiimide (114 mg, 0.55 mmol) ~2~ 6 GC213a was added, and the mlxture was warmed to roomtemperature. The reaction mixture was stirred for 30 minutes to yield a hydroxybenzotria~ole ester.
~S)-N-I~3-tt(t-Butyloxy)carbonyl]a~ino]-2-oxo-l-azetidinyl]thioxomethyl]glycine, t-butyl ester (164 mg, 0.46 mmol) was dissolved in 5ml of dry acetonitrile and cooled to 0C. N-Methyl-N-(trimethylsilyl)trifluoroacetamide (0.187ml, 1.01 mmol) was added and the mixture was warmed to room temperature. ~fter stirring for 45 minutes at room temperature, trimethylsilyl iodide (O.l~ml, 1.01 mmol) was added dropwise, and the reaction mixture was stirred for 15 minutes at room temperature.
The volatiles were evaporated without exteLnal heating, the residue was dissolved in 3ml of dimethylformamide, and this solution was then immediately added to the ester. The reaction mixture was stirred at room temperature overnight.
The reaction mixture was filtered to remove the dicyclohexylurea precipitate and cooled to 0C. After adding lml of water and stirring at 0C
for 30 minutes, the volatiles were evaporated. The residue was suspended in water at 0C and the pH
was adjusted to 6.5 with aqueous K~IC03.
Purification by column chromatography on HP-20 (eluting with water) yielded 66 mg of the title compound, melting point 180-190C, dec.

~L~253~46 GC213a Fxample 10~3S(Z)l-N-r~3-~[(2-~mino--4-thia%olvl)(eth xyim no) acetyllaminol-2-oxo-1-azet-dinYllca~bonyll-N-met.hyl-_ ~lyci _, PotaGsium salt S ' A) (S)-L(3-Amino-2-oxo-1-aZetidinYl~carbonYll-N_ methYlqlycine~ p-toluenesulfonate To a solution of (S)-[N-tt3-t~tphenyl-methoxy)carbonyl]amino]-2-oxo-1-azetidinyl]carbonyl]-methylamino]acetic acid, phenylmethyl ester (581mg, 1.37 mmol: see example ~A) in dimethylformamide (4ml) was added 10~ palladium on charcoal (284 mg) and ~-toluene- sulfonic acid (260 mg, 1.37 mmol).
The nitrogen atmosphere was replaced with hydro~Jen and the slurry was stirred for 1.5 hours to yield the title compound.

B) ~3S(Z)l-N-~ r 3- r [(2-Amlno-4-thiazolYl)(ethoxy-imino~acetYllaminol-2-oxo-1-azetidinVllcarbonyll-N-methylqlYcine, potassium salt To a slurry of N-hydroxybenzotriazole (185 mg. 1.37 mmol) and IZ)-2-amino-~-(ethoxyimino)-4-thiazoleacetic acid (294 mg, 1.37 mmol) in dimethylformamide (7ml) at OoC was added dicyclo-25 hexylcarbodiimide (310 mg, 1.5 mmol). After stirring for 30 minutes, ethyldiisopropylamine (lml, 5.48 mmol) and the azetidinone from above were added without filtering. This was stirred at room temperature for 20 hours. The slurry was filtered and washed with dimethylformamide. The filtrate was concentrated in vacuo. The residue was suspended in acetone (7ml) and a small amount of precipitate filtered. To the filtrate was then ~ GC213a added perfluorobutanesulfonic acid, potassium saltt463 mg, 1.36 mmol). After agitating for 10 minutes, ether (12ml) was added and the slurry was cooled to 5C and filteced. The pLecipitate was washed with ether ~two 5ml portions) and dried to give 800 mg o~ material, which was dissolved in water, a~plied to a column o~ ~IP20 (2.5x20 cm) and eluted with a gradient of 0-30% acetone. The product was eluted with 30~ acetone. The product ~as still impure by TLC and was rechcomatographed on EIP20 at pH 7 (K2C03~ and was eluted with 15%
acetone. This was concentrated to give 45 mg of product, melting point 180-190C, dec.
~nalYSiS calc'd ~or C14H17N606SK ~I20:
C, 37.00; H, 4.21, N, 18.49: S, 7.05 Found: C, 37.10; ~, 4.29; N, 18.05: S, 6.20 Examele 11 ~s(z)l-2-[ r rl-~2-AminO-4-thiazOlYl)-2-r rl-t[(carboxYmethYl)methylaminolcarbonyll-2-oxo-3-azetidinyllaminol-2-oxoethYlidenelaminoloxyl-2-methylpropanoic acid A) r3S(%)1-2-r[rl-(2-~mino-4-thiazolyl~-2-r ~ (carboxymethyl)methYlaminOlca~bOnyl1-2-oxo--azetidinYllaminol-2-oxoethylidenelaminoloxY
2-methvlpropanoic acid, diphenYlmethyl ester, ~2~a~
Diisopropylethylamine (0.185ml, 1.05 mmol) was added to 376 mg of (Z)-2-amino--~-t[2-tdiphenylmethoxy)-l,l-dimethyl-2-oxoethoxy]imino]-4-thiazoleacetic acid in 3ml of dimethylforInamide at room tempe~ature. The mixture was cooled to ~'~S3~
GC213a -20C, diphenyl chloroS?hosphate was added and the resulting mixture was stirred for 30 minutes to yield a mixed anhydride.
(S)-[N-tt3-t[(Phenylmethoxy)carbonyl]amino]-2-oxo-l-azetidinyl~carbonyllmethylamino]acetic acid, phenylmb~hyl ester (340 mg, 0.8 mmol; see exa)nple 8A) was dissolved in 3ml of dimethylformamide and 152 mg (0.8 mmol) of ~-toluenesulfonic acid monohydrate was added. ~IYdrogenolysis of the protecting groups at room tcmperature over 165 mg of lO~o palladium on charcoal was complete after ~lO
minutes. The reaction mixture was placed under nitLogen and cooled to 0C. Diisopropylethylamine (0.46~ml, 2.66 mmol) was then added to the azetidinone immediately followed by the above prepared mixed anhydride. After stirring at 0C
for 1 hour, the reaction mixture was stirred at 5C
overnight.
The reaction mixture was filtered to remove the ~alladium on charcoal and the volatiles were removed under vacuum. The residue was purified by column chromatography with 20% acetone-water on Dowex 50X2-400 resin (K form) followed by chromatography on HP-20 (eluting with water, 10%
acetone-water, and 20~ acetone-water) to give -200 mg of the title compound.
B) ~3s~z)1-2-r r [l-~2-AminO-~-thiazOlYll-2-r [1-r s (carboxYmethyl)methYlaminolcarbonyll-2-oxo-3-azetidinYllaminol-2-oxoethylidenelamin _methylpcopanoic acid t3S(Z)l-2-tttl-(2-~mino-4-thiazolyl)-2-[t [[(carboxymethyl)methylamino]carbonyl]-2-oxo-~2S3~46 GC213a 3-a2etidinyl~amino~-2-oxoethylidene]amino~oxy)-2-methylpropanoic acid (~190 mg) was cooled to -20C and a solution containing 4ml of trifluoro-acetic acid, 4ml of dichlocomethane, and 2ml of anisole at 0C was added. After stirLing at -20C
for 30 minutes, the volatiles were evaporated and the residue was triturated with hexane and anhydrous ether to yield a white solid. The residue was dissolved in ~2ml of water at 0C and the pH was adjusted to 2.5 with aqueous KI~C03.
This solution was subjected to chromatography on EIP-20 ~eluting with water, lO~o acetone-water, and Z0% ~acetone-water) to yield 35 mg of the title compound, melting point 150-160C, dec.
~5 Fxample 12 ~3S(Z~l-N-t[3-r~(2-~mino-4-thiazolyl)tmethoxyimino~-_ acetYlLaminol-2-oxo-1-azetidinvllcarbonvl]-N-methyl-DL-alanine, Potassium salt A) N-MethYl-DL-alanine Pyruvic acid (2.5ml, 0.036 mol) and ben~yl-methylamine (2.9ml, 0.022 mol) were added to ethanol (50ml) containing Pearlman's catalyst (Pd(0~)2, 0.5g). The mixture was vigorously stirred under one atmosphere of hydrogen at ambient temperature until an eqIlivalent amount of hydrogen had ~eacted. The mixture was filtered through Celite and ethanol was removed -in vacuo. The filter cake was extracted with hot ethanol and the combined filtrates crystallized upon standing in the freezer. Upon filtration, the desired product was collected and dried yielding a solid (725 ~g).

~S3~
GC213a B) N-Methyl-DL-alanine, benzyl ester A mixture of N-methyl-DL-alanine (2.5g, 0.024 mol), benzyl alcohol (12.5g, 0.116 mol) and ~-toluenesulfonic acid monohydrate (5.04g, O.OZ6 mol) were heated at reflux for 48 hours in benzene (75ml) under a Dean-Stark trap to remove water.
~fter cooling to room tcmperature, the mixture was diluted with ether (lOOml) and allowed to stand in the freezer. The toluenesulfonate salt of the desired product was collected by filtration, washed with ether, and then dried in vacuo, yielding crystals (7.46g).
The free amine was obtained by dissolving the salt (5.48g, 0.015 mol) in water (15ml) and adjusting to pH 8 with dilute potassium carbonate solution. After extracting three times with ethyl acetate, the extracts were combined, washed with saturated NaCl solution, dried (Na2S04~, and solvent was removed in acuo yielding the desired product as an oil (2.Bg).
c) (s)-N-r r3-r r (Phenylmethoxy~carbonYllaminol-2-oxo-l-azetidinvllcarbonyll-N-methYl-~L-alanine~
PhenYlmethvl ester A solution of phosgene in toluene (4.7ml of a 20% solution, 9.36 mmol) was cooled to -25C under argon. While stirring, a solution (pre-cooled to 0C) of N-methyl-DL-alanine, benzyl ester (l.Og, 5.2 mmol) and triethylamine (870 ~1, 6.25 mmol) in dichloromethane (Sml) was added over 5 minutes maintaining the temperature at -20 to -25C.
After stirring at -25C for 1 hour, solvent and excess phosgene were removed in vacuo. The residue ., ~25311~
GC213a was dissolved in dichloromethane (12ml), coolcd to0C and then (S)-3-[[(phenylmethoxy)carbonyl]-amino]-2-azetidinone (1.15g, 5.2 mmol), dimethylaminopyridine (63 mg, 0.52 mmol), and s triethylamine (a~0 ~1, 6.2 mmol) were added scqucntially. Sticring was continued for 10 minutes at 0C and then overnight at room temperature. After re~luxing for an additional 7 hours, the mixture ~?as again stirred overnight at room tempcrature. 'rhe mixture was washed t~ith water, dried (Na25O4) and solvent was removed in vacuo. The resulting oil ~as chLomatographed on silica gel eluting with a 4:6 ethyl acetate:hexane mixture. The desired product was obtained as an 15 oil (580 mg).
.
D) (S)- r ( 3-Amino-2-oxo-1-azetidinYl)carbonY11-N-m_thYl-DL-alanine, phenylmethYl ester, P-toluene-sulfonate (S)-N-~t3-tt(Phenylmethoxy)carbonyl]amino]-2-oxo-l-azetidinyl]carbonyl]-N-methyl-DL-alanine, phenylmethyl ester (105 mg, 0.24 mmol) was dissolved in dimethylformamide (3ml), and p-toluenesulfonic acid monohydrate (46 mg, 0.24 mmol) and lO~o palladium on charcoal (50 mg) vere added. Stirring under a hydrogen atmosphere for 2.5 hours at room temperature cleaved both protecting yroups.

E) ~3S(Zll-N-[ r3-r~(2-Amino-4-thiazolyl)(methoxy-_mino)acetYllaminol-2-oxo-1-azetidinyllcarbonyll-N-mcthyl-DL-alanine, potassium salt (Z)-2-Amino-~-(methoxyimino)-4-thiazoleacetic acid (58 mg, 0.288 mmol) was dissolved in ~`s~
GC213a dimethylformamide (2ml), cooled to -25c, and - diphenyl chlorophosphate (6ml! 0.288 mmol) followed by diisopropylethylamine (56 ~1, 0.32 mmol) was added. After stirring the mixture at -20 to -15C
for 30 minutes, this solution was added to the hydrogenation mixture which had been cooled to 0C
and treated with diisopropylethylamine (138 IJl, 0.7g mmol). The reaction was maintained under argon at 0 to 5C for 18 hours. Solvent was removed ln vacuo, the residue was taken up in water, and the pH was adjusted to 6.5 with dilute KHCO3 solution. The mixture was chromatographed on an ion-exchange column (34ml, Dowex 50X2-400, K form) eluting with water. The partially purified product was then chromatographed on an HP-20 resin column eluting with water. After lyophilization, the desired product was obtained as a powder (32 mg).

Example 13 [3S-[3~(Z),4~1]-N-[[3-[[~2-Amino-4-thiazolyl)-(methoxvimino)acetyl]amino]-4-methyl-2-oxo-1-azetidinYl]carbonyll-N-methylglycine, potassium salt A) (3S-trans) N- [ [3- ~ [t-Butoxycarbonyllamino]-4-methyl-2 oxo-l-azetidinyl]carbonyl]-N-methylglycine, t-butyl ester A solution of phosgene in toluene (1.35ml of a 20% solution, 2.698 mmol) was cooled to -25C
under an argon atmosphere. A solution of N-methyl-glycine, t-butyl ester (218 mg, 1.498 mmol) and triethylamine (251 ~1, 1.798 mmol) in dichlorome-thane (2ml) was added dropwise over 5 ~ 25~
GC213a -~5-minutes. The reaction was stirred for 1 hour at - -25C (after 15 minutes an additional 0.2ml of dichloromethane was added to facilitate stirring).
The volatiles were removed starting at -25C and slowly by warming to room temperature. The residue was dissolved in methylene chloride ~5ml), cooIed - to 0C and treated with (3S-trans)-3-[[t-butoxy-carbonyl]amino]-4-methyl-2-azetidinone (300 mg, 1.498 mmol; pre-dried over P2O5 at 25C under 10 high vacuum), 4-dimethylaminopyridine (18 mg, 0.149 mmol), and triethylamine (251 ~1, 1.798 mmol). The resulting mixture was warmed to room temperature, stirred for 36 hours, treated with additional triethylamine (502 ~1), and re~luxed for 5 hours.
The reaction was cooled, diluted with ethyl acetate, washed with pH 4.5 KH2P04, and with brine, and then dried over sodium sulfate.
Filtration and concentration in vacuo produced 525 mg of an oil which was chromatographed on 21g of 20 silica gel (230-400 mesh). Elution with 40% ethyl acetate-hexane gave 356 mg of the title compound as a white solid.

B3 (3S-trans)-N-[(3-amino-2-methyl-4-oxo-1-azetidinyl)carbonvl]-N-methylqlycine, trifluoroacetic acid salt A solution of (3S-trans)-N-[[3-[[t-butoxycarbonyl]amino]-4-methyl-2-oxo-1-azetidinyl]-carbonyl]-N-methylglycine, t-butyl ester (140 mg, 30 0.377 mmol) in anisole (0.68ml) was cooled to -30C
under an argon atmosphere. Trifluoroacetic acid (1.4ml) was added dropwise and the reaction was warmed to 0C and stirred for 1 hour, at 10C for ~.~53~l~6 GC213a 30 minutes, and at room temperature for 2.5 hours.
The reaction was cooled to -15C, treated sequentially with ether (9.5ml) and hexane (4.8ml), and stirred for 10 minutes. The cooling bath was removed and the mixture was stirred for 30 minutes. The precipitated white solid was isolated by centrifugation, washed with ether and hexane, and dried ln vacuo. The yield of the title compound was 110 mg.

C) r3s-~3[(z)~4~ll-N-[[3-[[(2-Amino-4-thiazolyl)(methoxYimino)acetyl]amino]-4-methyl-2-oxo-l-a2etidinvl]carbonyll-N-methylglycine, potassium salt A solution of (Z)-2-amino-~-(methoxyimino)-4-thiazoleacetic acid (58 mg, 0.288 mmol) in dimethylformamide ~1.3ml) was treated with triethylamine S40 ~1, 0.288 mmol) and stirred at room temperature for lO minutes under an argon atmosphere. The mixture was cooled to -30C and diphenyl chlorophosphate (60 ~1, 0.288 mmol) was added. The reaction mixture was stirred for 35 minutes at -25C to -30C, cooled to -45C, and treated with (3S-trans)-N-[(3-amino-2-methyl-4-oxo-1-azetidinyl)carbonyl]-N-methylglycine, trifluoroacetic acid salt (95 mg, 0.288 mmol) followed by N,N-diisopropylethylamine (251 ~1, 1.44 mmol) and dimethylfoxmamide (0.2ml). The reaction was warmed to -25C, stirred for 30 minutes, warmed to 5C and stirred overn.ight. The volatiles were removed under high vacuum, the residue was dissolved in water, and passed through a Dowex K
ion-exchange resin (32ml). Fractions GC213a 1-16 (3ml fractions) were combined and lyophili~ed producing 100 mg of an orange solid. The crude product was chromatogLphed on 120ml of ~IP-20.
Fractions 1-20 (5ml fractions) were eluted with water, fractions 21-40 with 5% acetone-water, and fractions 41-80 with 10% acetone-water. Fractions 60-62 were combined and lyophilized to afford 43 mg of the ~itle compound as a white solid.
Analysls calc'd for C14H17N66SK 3 1~T20 C,34.LS: H,4.75 N,17.07 Found: C,34.13; H, 5.00; N, 16.90 Example 14 r3s(R)l-~N-rr3-r[rrt~-Ethyl-~3-dioxo-l-piperazinyl)-carbonYllaminolphenYlacetYllaminol-2-oxo-1-azetidinyllcarbonyllmethYlaminolacetic acid, tassium salt A) (S)-[ r ~3-Amino-2-oxo-l-azetidinvl~carbonyll-methYlamino~acetic acid, p-toluenesulfonate To a solution of ~S)-t[[3-[[(phenylmethoxy)-carbonyl~amino~-2-oxo-1-azetidinyl~carbonyl]methyl-amino]acetic acid, phenylmethyl ester (800 m~, 1.88 mmol~ in dimethylformamide (5ml) was added ~-toluenesul~onic acid (357 mg, 1.8~ mmol) and 10 palladium on charcoal (388 mg). The nitrogen atmosphere was replaced with hydrogen and the slurry was stirred for 1 hour at room temperatu~e to yield the title compound.

~253~
GC213a B) ~3S(R)l-~rr3-~N-[r~(4-EthYl-2,3-dioxo-1-Piperazinyl)carbonYllam n~ phenYlacetyllaminol 2-oxo-l-azetidinyllcarbony~lmethvlaminolacetic acid.
potassium salt Dicyclohexylcarbodiimide (~26 mg, 2 mmol) was added to a slurry of N-hydroxyben~otriazole (254 mg, 1.88 mmol) and ~-~[(4-ethyl-2,3--dioxo-1-piperazinyl)caLbonyl3amino]benzencacetic acid (600 mg, l.a3 mmol) at 0C. After 30 minutes, ethyldiisopropylamine (1.3ml, 7.96 mmol) was ad(led to (S)-[N-[(3-amino-2-oxo-1-azetidinyl)carbonyl]-methylaminolacetic acid, p-tolucncsulfonate, and this mixture was then added to the benzeneacetic acid derivative containing mixture. This was stirred at room temperature for 20 hours, filte~ed, and the solvents removed in vacuo. The residue was t~iturated with acetone and dicyclohcxylurea was filtered off. The acetone was evaporated in vacuo and the residue was dissolved in water and the pH
raised to 7 with KHC03. Purification on Dowex 50WX2 (200-400 mesh, K~ form) gave 400 mg of product which was further purified by chromatographing it twice on HP20, eluting with a 0-30% gradient of acetone, and yielding 33 mg of the title compound, melting point 155C, dec.

i3~
GC213a Fxample 15[3S(Z)l-N-[~3-[~(2-~mino-4-thiazoly~llmethoxY-imino)acetYllaminol-2-oxo-1-azetidinvll-carbonYll-N-ethylqlycine, potassium salt A) (S~-~N-[~-t~(PhenYlmethoxv~carbonyllaminol-2-oxo-l-azetidinyllcarbonyllethYlaminolacetic ACid phenvlmethYl ester (S)-3-~(Phenylmethoxy)carbonyl]amino]-2-azetidinone was suspended in 5ml of dichlorome~haneand cooled to -10C. A solution of 12.5% phosgene in toluene (2.9ml, 3.~ mmol) was added dropwise to the rapidly stirring mixture. After stirring at -10C for Z hours, the volatiles were evaporated without external heating. The residue was cooled to -10C and dissolved in 5ml of dichloromethane to give (S)-l-chlorocarbonyl-3-t[(phenyl]nethoxy)-carbonyl~amino~-2-azetidinone. The compound was not characterized, but was used as a crude intermediate.
Potassium carbonate t608 m~, 4.4 mmol) was added to a rapidly stirring solution of N-ethyl-glycine benzyl ester hydrochloride (505 mg, 2.2 mmol) in Sml of water and 5ml of dichloromethane at 0C (pH-8). The mixture was extracted three times with dichloromethane and the combined organic layers were dried over Na2SO4 and filtered.
The volume of solvent was reduced to ~2ml by evacuation and dried with ~ molecular sieves to yield the free amine of the benzyl ester.
Triethylamine (0.307ml, 2.2 mmol) was added to the solution containing the free amine and the resulting mixture was immediately added to the solution containing (S)-1-chlorocarbonyl-3-1253~46 GC213a [(phenylmethoxy)carbonyl]amino]-Z-azetidinone at -10C. After stirring at -10C for 0.5 hour, the reaction mixture was poured into aqueous KH2P0 and extracted three times with dichloromethane.
5- The combined organic layers were dried over Na2SO~ and filtered. The volatiles were removed-and the residue was subjected to chromatography on silica gel (eluting with 40~O
ethyl acetate-hexane) yielding 296 mg of the title compound.

B) [3S(Z)l-N-tr3-r~(2-~mino-~-thiazolyll~methoxY-imino~acetYllaminol-2-oxo-1-azetidinyl]carbonyll-N-ethYlqlvcine, potassium salt Diisopropylethylamine ~0.155ml, o.ag mmol) was added to 163 mg (0.31 mmol) of tZ)-2-amino-~-(methoxyimino)-4-thiazoleacetic acid in 2.7ml of dimethylformamide at 23C. The mixture was cooled to -20C and diphenylchlorophosphate 20 (0.168ml, 0.81 mmol) was added and the resulting mixture was stirred for 30 minutes to yield a mixed anhydride.
(S)-[N-[t3-~t(Phenylmethoxy)carbonyl]amino]-2-oxo-l-azetidinyl]carbonyl]e~hylamino]acetic acid, 25 phenylmethyl ester (296 mg, 0.67 mmol) was dissolved in 2.7ml of dimethylformamide and 123 mg (0.67 mmol~ of p-toluenesulfonic acid monohydrate was added. Hydrogenolysis of the protecting groups at room temperature over 139 mg of lO~o palladium on charcoal was complete after 1 hour and 30 minutes.
The reaction mixture was placed under nitrogen and cooled to 0C. Diisopropylethylamine (o.3a7m ~2~46 .-- GC213a 2.21 mmol) was then added to the azetidinoneimmcdiately followed by the mixed anhydride, and the resulting mixture was stirred at 5C overniyht.
The reaction mixtuLe was filtered to remove `
the palladium on charcoal and the volatiles were removed under vacuum. The residue was purified by column chromatography with water on Dowex 50x2-~00 resin (K form) followed by chromatography on EIP-20 (eluting with water) to yield, after lyophilization, 109 mg of the title compound, melting point la7-195C, dec.

Example 16 [3S(Z)l-~N-[~3-~ r (2-~mino-4-thiazolYl)(methoxy-imino~ace~yllaminol-2-oxo-1-azetidinYllcarbonYll-methYlaminolacetic acid, methyl ester A) [35~Z)l-rN-r[3-~[(2-Amino-4-thiazolyl)(methoxy-nyll-methYlaminolacetic acid, potassium salt [35(Z)~-t[~3-t[(2-Amino-4-thiazolyl)(methoxy-imino)acetyllamino]-2-oxo-1-azetidinyl]carbonyl]-methylamino]acetic acid (-ag of crude) was dissolved in lOml of O.lm KHCO3. The pH was adjusted to 6.5 with a concentrated solution of K2C03 in water, and the material was purified on Dowex 50~X2 (K~ orm). The fractions containing the desired material were combined and purified on HP20 (Sx30cm) eluting with water.
Fractions 37-40 contained the title compound plus p-toluenesulfonic acid, potassium salt in the molar ratio of 6.5/10.

3~
GC213a B) ~3S(Z)l-~N- r ~ 3-[~(2-Amino-4-thiazolyl~(methoxY-imino~acetYllaminol-2-oxo-l-azetidiny~Jca bonyll-methylaminolacetic ac;d, me~-hYl ester ~3S(~)]-ttt3-tt(2-Alnino-4-thiazolyl)(meth imino~acetyl]amino]-2-oxo-1-azetidinyl]carbonyl]-methylamino]acetic acid, potassium salt (318 mg of a mixture containing 150 mg of the potassium salt) was dissolved in dimethyl~oLmamide (5ml) and the volume ~educed to lml. Methyl iodide (22 ~1) was added, and after 1 hour an additional 22 ~1 of methyl iodide was added. After another hour, the solvents were removed, the product was extracted in acetone, and the sol~ent was removed.
The residue was chromatographed on silica gel lS in 2~o acetonitrile/ethyl acetate and fractions 7-18 were concentrated to gi~e 110 mg of the title compound. This was combined with other smaller reactions for a total of 180 mg of an oil which was triturated with ethyl acetate and ether to give 99 20 mg of a solid, melting point 132-136C.
~nal~sis calc'd for C14H18N606S H20' C,39.95; H, 4.91; N, 17~76 Found: C, 39.95; H, 4.54; N, 18.55 ~53~4~ GC213a Example 17 ~3S(Z) l-rN~[ r rr3-~L~2-Amino-~-thiazolyl)(methoxv-imino)ac_tYllaminol-2-oxo-1-azetidinYllca bonyll-methylamino]acetylloxylacetic acid, l,l-dimethYl-ethYl ester ~3S(Z)]-~tt3-[t(2-~mino-4-thiazolyl)(methoxy-imino)acetyl~amino]-2-oxo-1-azetidinyl]carbonyl]-methylamino]acetic acid, potassium salt (544 mg of a mixture containing 200 mg of the potassium salt) as dissolved in dimethylforinamide (5ml) and the volume ~Jas reduced to lml. t-Butyl bromoacetate (lQ2 ~1. 0.708 mmol) was added and the reaction was stirred for 1.5 hours at room temperature. The solvents were removed. the product was extrac~ed into acetone and the acetone was evaporated.
The residue was chromatographed on silica gel (l.lx30cm) in hexane/ethyl acetate (3:1).
Fractions 11-23 were concentrated and trituLated with ether to give 130 mg of the title compound, melting point 100-104C.
Analys1s calc d 19 26 6 a 5.22; N,lÇ.87 Found: C, 45.61; H, 5.50; N. 15.60 ~53~

GC213a Example la ~3S(%)1-2,2' -r r r3-r ~ (2-Amino-4-_hiazolYl)(meth i~ no)acetYllaminol-2-oxo=-l-azctitlinyllcarbon imin~l_ s_ etic acid, dipotassium salt A) (Sl-2,2'-r[~3-~l(t-ButoxY)carbonYlla~nino~-2-oxo-1-azetidinYllcarbonYl~min~_isacetic aci~
dibenzyl ester Dibenzyl irninodiacetate hydrochloride (699 mg) and 3A sieves were suspended in 6ml of dry toluene and cooled to -20C. A phosgene solution (2.9ml of 12.5% in toluene) was added to the reaction mixture followed by the dropwise addition of pyridine (0.3~8ml) with rapid stirring. The reaction was stirred at -20C for 1 hour and then allowed to warm to room temperature. The precipi-tate of pyridinium hydrochloride was filtered under argon, and the volatiles were removed from the filtrate, which was dissolved in 4ml of te~ra-hydrofuran and cooled to 0C. To this solution wasadded the (S)-3-[~(t-butoxy~carbonyl]amino]-2-azetidinone (372 mg) and dimethylaminopyridine (36 mg). Triethylamine (0.307ml) was then added dropwise and the reaction was allowed to warm to room temperature and stir for 5 hours. The product wa~ extracCed from dilute aqueous hydrochloric acid with ethyl acetate. The combined organic extracts were dried with sodium sulfate and the volatiles removed. The residue was purified by flash chroma-30 tography on silica gel (eluting with 35% ethylacetate/hexane) to yield 566 mg of the title compound as a white solid.

~5i3~a~6 GC213a -~5-. B) [3S(Z~1-2,2'-r~3-~ r (2-AInino-~-thiazolYl~-(methoxYimino)ace ~ aminol-2-oxo-1-azetidinYll-carbonYl]iminolbisacetic acid, dipotassiu~n salt (S~--2,2'-[[~3-[t~t-Butoxy)cacbonyl~amino]-2-oxo-1-azetidinyl]carbonyl]imino]bisacetic acid, dibenzyl ester (566 mg, 1.08 mmol) was dissolved in 6ml of dry tetrahydrouran. Hydrogenolysis of the benzyl protecting groups at room temperature over 2~3 mg of 10% palladium on charcoal was complete after 50 minutes. The reaction mixture was filtered to remove the palladium on charcoal catalyst and the volatiles were evaporated to yield (S)-2,2~-~[[3-[[St-butoxy)carbonyl]amino~-2-oxo-1-azetidinyl~carbonyl]imino]bisacetic acid.
Diisopropylethylamine (0.25ml, 1.~4 mmol) was added to 254 mg (1:~1 mmol) of ~Z)-2-amino-~-(methoxyimino)-4-thiazoleacetic acid in 3.5ml of dimethylformamide at 23C. The mixture was cooled to -20C and diphenyl chlorophospate (0.272ml, 1.31 mmol) was added and ~he-resulting mixture was stirred for 30 minutes to yield a mixed anhydride.
(S)-2,2'-~[3-~(t-Butoxy)ca~bonyl]amino]-2-oxo-l-azetidinyl]carbonyl]imino]biacetic acid was cooled to -20C and a solution containing 5ml of trifluoroacetic acid, Sml of dichloromethane, and lml of anisole at 0C was added. ~fter stirring at -20C for 1 hour, the reaction mixturè was warmed to 0C for 2 hours. Toluene (~2ml) was added, and the volatiles were evaporated. Ths residue was triturated with hexane and anhydrous ether to yield a white solid. The residue was then dissolved in 5.3ml of dimethylformamide and upon cooling to 0C, i3~
GC213a O.91ml (5.2 mmol) oE diisopropylethylamine wa-s added. the reaction mixture containing the mixed anhydride was then immediately addcd, and the resulting mixture was stirred at 5C overnight.
The volatiles were removed undec vacuum, and the residue was 6ubjected to column chromatography with water on Dowex 50X2-400 resin (~ form).
The pH of the crude product ~7as adjusted to 2.5 with lN EICl, and this was then subjected to chromatography on HP-20 (eluting with water, 5%
acetone-water, 10% acetone-water, and 20~o ace~one-water) ~o give the impure diacid of title compound at 0C and the pH was adjusted to 6 with agueous KHCO3. Purification of this solution by column chromatography on HP-20 (eluting with t~ater) yielded, upon lyophili2ation, 112 mg of the title compound, melting point 155-165C, dec.

F.xam~le 19 r3s(z)~ tr3-rr ~2-Amino-4-thiazolyl)(methoxy-iminolacetyllamino]-2-oxo-l-azetidinYllcarbon DL-proline, potassium salt A) ~Sl-l-tr3-rt~PhenYlmethoxY)carbonylJamlnoL-2 oxo-l-azetidinvllcarbonvll-DL-Proline, phenylmethY
este~
A solution of d,1-proline, benzyl ester (1.13 grams, 5.5 mmol) in 6ml of dichloromethane was cooled to O~C and 1.2 equivalents (0.92ml) of 1~253~
GC213a triethylamine (668 mg, 6.6 mmol) was added. Theresulting mixture was immediately added dropwise to a solution of 20% pho~gene in toluene (6ml, 9.9 mmol) at -25C. After stirring at -25C for 1 hour, the volatiles were evaporated without external heating. and the residue was redissolvod in lOml of dichloromethane and cooled to 0C.
(S)-3-[ L (Phenylmethoxy)carbonyl~amino]-2-azetidinone (1.21 grams, 5.5 mmol) and dimethylaminopyridine (67 mg, 0,55 mmol) were added to the stirring solution. Triethylamine (0.92ml, 6.6 mmol) was added and the reaction mixture was warmed to room temperature and stirred for 24 hours. The reaction mixture was washed with water, dried over anhydrous Na2S0~, filtered and the dichloromethane removed in vacuo. The residue was purified by flash chromatography on silica gel 230-400 mesh (eluting with ~0~ ethyl acetate in hexane) yielding 1.2 g~ams of the title compound as a colorless oil.
B) L3S(Z)l~l- r r 3- r ~ ( 2-Amino-4-thiazolyl~(methoxy-imino)acetY~ aminol-2-oxo-1-azetidinYllcarbonYll-DL-proline, potassium salt l-~ydroxybenzotLiazole hydrate (54 mg, o.~0 mmol) and (Z)-2-amino-~-(methoxyimino)-4-thiazole-acetic acid (80.5 mg, 0.40 mmol) were dissolved in 3ml of dimethylformamide and cooled to ooc. N,N-Dicyclohexylcarbodiimide (83 mg, 0.40 mmol) was added, and the mixture was warmed to ~oom temperature. The rcaction mixture was stirred for 30 minutes to yield the N-hydroxybenzotriazole ester of the acid.

~53 L~
GC213a (S)-1-[[3-[[(Phenylmethoxy)carbonyl]amino]-2-oxo-1-azetidinyl]carbonyl]-DL-proline, phenylmethyl ester (155 mg,-0.364 mmol) was dissolved in 3ml of dimethylformamide and p-toluenesulfonic acid monohydrate (69 mg, 0.364 mmol) was added.
Hydrogenolysis of the protecting groups at room temperature over 75 mg of 10% palladium on charcoal was complete after 2.5 hours. The reaction mixture was pl~ced under argon and cooled to 0C. Diiso-propylethylamine (47 mg, 0.364 mmol) was then added to the azetidinone followed by the above-prepared ester. After stirring at 0C for 2 hours, the reaction mixture was stirred at 5C overnight.
The volatiles were removed under vacuum. The residue was dissolved in water (5ml), the p~
adjusted to pH 6.5 with KHC03 and the insoluble dicyclohexylurea wa~ removed by filtration. The residue was purified by column chromatography with water on Dowex 50X2-400 resin (K form) followed by chromatography on HP-20 resin (eluting with water). Lyophilization yielded 32 mg of the title compound as a colorless solid, melting point 180C, dec.

Example 20 L3S(Z)~-N-[[3-[[(2-Amino-4-thiazolyl)-(methoxyimino)acetYllaminol-2-oxo-1-azetidinyl~-carbonYll-N-phenylglycine A) Benzyl N-phenYlqlycine To a solution of benzyl bromoacetate (4.Oml) and aniline (2.28ml) in 25ml of dry dimethyl-~25~*fi GC213a formamide was added sodium acetate (2.05g). Thereaction was stirred at room temperature oveLnight and extracted from water with three portions of ethyl acetate. The combined organic layers were washed with water and dried over sodium sulfate.
The volatiles were removed, and the residue was purified by flash column chromatography on silica gel (eluting with 10% ethyl aceta~e/hexane) to yield 4.54g of benzyl N-phenylglycinate.
8) (S)-N-r~3-[t(PhenYlmethoxY~carbonYl]aminol-2-oxo-l-a7,etidinYl~carbonyll-N-phenylqlycine~ benzYl ester Benzyl N-phenylglycine (482 my) was dis~olved in 6ml of dry toluene and cooled to -20C. A
phosgene solution (2.9ml of 12.5% in toluene) was added to the reaction mixture followed by the dropwise addition of pyridine (0.3~8ml) with rapid stirring. The reaction was stirred for 1 hour at -20C and then allowed to warm to room tempera-ture. The precipitate of pyridinium hydrochloride was filtered under argon, and the volatiles were removed from the filtrate. which was dissolved in ~ml of tetrahydrofuran and cooled to 0C. To this solution was added the (S)-3-~t(phenylmethoxy)-carbonyl~amino~-2-azetidinone (~40 mg) and dimethylaminopyridine (36 mg). Triethylamine (0.307ml) was then added dropwise and the reaction was allowed to warm to room temperature and stir overnight. The product was extracted with ethyl acetate from dilute agueous hydrochloric acid. The combined organic extracts wcre dried with sodium ~25 3~46 GC213a sulfate and the volat;les removed. The residue waspurified by flash chromatogLaphy on silica gel teluting with ~5% ethyl acetate/hexane) to yield 381 mg of the title compound.

C) 13S(Z)l-N-[r3-~(2-Am no-4-thiazolvl)(methoxy-iminolacetyl1aminol-2-oxo-1-azetidinyllcarbonyll--N-phenylqlYcine Diisopropylethylamine (0.249ml) was added to 202 mg of (Z)-2-amino-~-(methoxyimino)-4-thiazolcacetic acid (containing 0.38 molar equivalents of HCl) in 3.lml of dimethylforinamide at 23C. The mixture was cooled to -15C and diphenylchlorophosphate (0.195ml) was added, and the resulting mixture was stirred for 30 minutes to yield a mixed anhydride.
(S)-N-[t3-~[(Phenylmethoxy)carbonyl]amino]-2-oxo-l-azetidinyl]carbonyl~-N-phenylglycine, phenyl-methyl ester (37a mg) was dissolved in i.lml of dimethyl~ormamide and 148 mg of p-toluenesulfonic acid monohydrate was added. Hydrogenolysis of the protecting groups at room temperature over 189 mg of 10~ palladium on charcoal was complete within 1 hour. The reaction mixture was placed under inert atmosphere and cooled to 0C.
Diisopropylethylamine (0.451ml) was then added to the azetidinone immediately followed by the mixed anhydride, and the resulting mixture was stirred at 0C for 3 hours.
The reaction mixture was filtered to remove the palladium on chaccoal, and the volatiles WeLe removed unde~ vacuum. The residue was subjected to column chromatography with water on Dowex 50X2-400 ~L~5~
GC213a resin (K~ fo~m) followed by chromatography on~IP-20 (eluting with water and 5% acetone-water) to yield iInpure product upon lyophilization. This material was dissolved in water, the pH adjustcd to 3.0 with dilute hydrochloric acid, and purified by column chLomatography on ~IP-20 (eluting with water, s% acetone water, 10% acetone-water and 20%
acetone-water) to yield 143 mg of the title compound upon lyophilization, melting point 10 155-160C, dec.

F.xample 21 [3S(Z~l~rN-~[3- U(2-Amino-4-thiazol~l~(methoxyimino)-acetYllamlnol-2-oxo-l-azetidinyllcarbony ~ th aminolacetic acid, Pivaloyloxymethyl ester t3S(Z)]-tN-[t3-~(2-Amino-~-thiazolyl)(methoxy-imino)acetyllamino]-2-oxo-1-azetidinyl]carbonyl]-methylamino]acetic acid, potassium salt (647 mg of a mixture containing Z38 mg or 0.564 mmol of the ZO potassium salt) was dissolved in dimethylformamide (lOml) and the volume was reduced to lml. Chloro-methyl pivalate (122 ~1, 0.846 mmol) was added and the reaction was stirred for 8 hours at room tempeLature. Additional chloromethyl pivalate (366 ~1) was added and the reaction was run overnight.
Solvent was removed, and the residue was dissolved in water and extracted with ethyl acetate (three 20ml portions). The organic layers were dried (Na~SOg), filtered and concentrated.
The residue was chromatographed on silica gel (1.5 x 20cm) in hexane: ethyl acetate (3:1) and ethyl acetate. The title compound was eluted with ethyl acetate, and ater removal of the solvent, weighed 1~0 mg. Trituration with ether gave 100 mg 35 o a solid, melting point 108-113C.

~253~
GC213a Example 22 - [3S(Z)]-1-[[3-[[(2-Amino-4-thiaozlyl)(methoxyimino)-acetyl]amino]-2-oxo-1-azetidinyl]carbonyl]-D-proline, potassium salt A) 1-(t-Butyloxycarbonyl~-D-proline A solution of D-proline (0.8 g, 6.94 rnmole) in 50 ml of 1:1 ace-tone:water was treated with triethylamine (1.05 g, 10.4 mmole) and then 1,1-dimethylethoxycarboxylic anhydride (1.77 g, 8.1 mmole). After stirring at 25C overnight, most of the acetone was removed in vacuo, 1 g of solid sodium bicarbonate was added and the mixture was extracted two times with ethyl acetate. The aqueous layer was acidified with 10% potassium bisulfate and extracted with ethyl acetate, the organics were dried (sodium sulfate) and evaporated to give 1.6 g o~ a thick oil which solidified on standing.
B) D-proline, phenylmethyl ester 1-(t-Butyloxycarbonyl)-D-proline (6.94 mmole) in 15 ml of dry dimethylformamide was treated with 1.2 g (15 mmole) of powdered sodlum bicarbonate followed by 6g (35 mmole) of benzyl bromide at 25C. Stirring for 15 hours resulted in complete esterification as judged by TLC (Rf =
0.5, silica, hexane:ethyl acetate 4:1). Solvent was removed ln vacuo, and the resi.due was partitioned between water and ethyl acetate, the oryanics were dried (sodium sulfate) and diluted with hexane. Washing through a tall pad of 60-200 mesh silica removed benzyl bromide. Subsequent washing with ethyl acetate gave 2.0 g of ~;253~
~ GC213a (_-butyloxycarbonyl)-D-proline, phenylmethyl ester as a thick oil. This was dissolved in 50 ml of ethyl acetate at -10C and treated with hydrogen chloride gas for 5 minutes. The mixture was warmed to 25C over 45 minutes and evaporated to an oil. A second addition and evaporation of ethyl acetate gave a white solid. Trituration with ethyl acetate gave 1.44 g of D-proline, benzyl ester, hydrochloride, [~]D = ~45.6 (H20), as a white solid.

C) (S)-1-[[3-[[(Phenylmethoxy)carbonyl]amino]-2-oxo~1-azetidinyl]carbonyl]-D-proline, phenylmethyl ester To a slurry of dried (S)-3-[[(phenyl-methoxy)carbonyl]amino]-2-azetidinone (0.44 g, 2 mmoles) in 10 ml of dry dichloromethane under argon at -10C was added triethylamine (0.3 g, 3 mmoles) followed by 4 ml of 12.5% phosgene in toluene (5 mmoles). After stirring for 1.5 hours at -10C, the solvent was evaporated, and the residue taken up in dichloromethane (10 ml) and chilled to -10C. To this was added 0.48 g (2 mmoles) of D-proline, phenylme~hyl ester, hydrochloride followed by 0.4 g (4 mmoles) of triethylamine. The mixture was stirred at -10C
for 30 minutes, then quenched and washed with 10%
monobasic potassium phosphate. The organics were washed with brine, dried (sodium sulfate), and chromatographed on silica (LPS-1) in 1:1 hexane:
ethyl acetate. The pure product fractions (Rf =
0.23 on silica, same system) were evaporated to give 0.42 g of a thick oil.

~5~6 GC213a D) [35(Z)]-l-[[3-~[(2-Amino-4-thiaozlyl)(methoxy-imino)acetyl]amino~-2-oxo-l-azetidinyl]carbonyl]-D-proline,potassium salt (S)-l-[[3-[[(Phenylmethoxy)caxbonyl]amino]-2-oxo-1-azetidinyl]carbonyl]-D-proline, phenylmethyl ester was dissolved in 8 ml of dimethylformamide in the presence of 0.18 g (1 mmole) of toluene-sulfonic acid, hydrate and 0.18 g of 10% palladium on charcoal and hydrogenated at 1 atmosphere and 25C for 3 hours. A solution of (Z)-2-amino-~-(methoxyimino~-4-thiazoleacetic acid (0.19 g, 1 mmole) and N-hydroxybenzotriazole (0.13 g, 1 mmole) in 8 ml of dimethylformamide was chilled to 0C and treated with 0.19 g (1 mmole) of dicyclohexylcarbodiimide, and then stirred for 1.5 hours at 25C. The hydrogenation mixture was chilled to 0C and the N-hydroxybenzotriazole ester mixture was added along with 0.18 g (1.4 mmole) of diisopropylethylamine, and the mixture was stirred at 5~C overnight. The solvent was evaporated at 15C ln vacuo and the residue taken up in water and filtered through Celite, pH = 3.45. The pH was adjusted to 6.9 with potassium bicarbonate, and the solution passed through 30 ml of Dowex AG-50 (K form). The eluent was concentrated in vacuo at 15C and chromatographed on HP-20 in water. Product (Rf = 0.45, Q-1) was lyophilized to give 219 mg of a slightly yellow powder, melting point 190-215C
(dec.) which analyzed correctly for the presence of 3.0 moles of water.

*Trademark :, :
.. j, , , ~ .

:~.2~ii33~
_75_ GC213a Example 23 [3S(Z)] 1-[[3-[[(2-Amino-4-thiazolyl)(methoxy-imino)acetyl]amino]-2-oxo-1-azetidinyl]carbonyll-L-proline, potassium salt Following the procedure of example 22, but substituting L-proline for D-proline and utilizing 0.36 g (instead of 0.18 g) of diisopropylethyl amine, yielded the title compound, melting point 190-220C (dec.).
Anal. Calc'd. for C15H17N6O65K-2.34H2O: C, 3~.72;
H, 4.45; N, 17.13; S, 6.54.
Found: C, 36.29; H, 4.03; N, 17.16; S, 6.45.

Example 24 [3S(Z)]-1-[[3-[[(2-Amino-4-thiazolyl)[~l-carboxy-1-methylethoxy)imino]acetyl]amino]-2-oxo l-azetidinyllcarbonyl]-L-proline (S)-1-[[3-[[(Phenylmethoxy)carbonyl]amino]-2 oxo-1-azetidinyl]carbonyl]-L-proline, phenyl-methyl ester (0.45 g, 1 mmole; prepared as described in examples 22 and 23) was hydrogenated at 1 atmosphere of hydrogen and 25C over 0.2 g of 10% palladium on charcoal in the presence of 0.19 g (1 mmole) of ~-toluenesulfonic acid for 3 hours. (Z)-2 Amino-~-[[2-(diphenylmethoxy)-1,1-dimethyl-2-oxoethoxy]imino]-4-thiazoleacetic acid (0.47 g, 1 mmole) and N-hydroxybenzotriazole (0.15 g, 1 mmole) in 4 ml of dimethylformamide at 0C was treated with 0.21 g (1 mmole) of dicyclo-hexylcarbodiimide and the mixture warmed to 20Cfor 2 hours. The hydrogenolysis mixture was chilled to 0C and treated with the solution of N-hydroxybenzotriazole ester, along with 0.14 g (1.1 mmole) of diisopropylethylamine. After 14 GC213a hours at 5C, the mixture was evaporated at 15C
ln vacuo and diluted with water. The grey slurry was filtered on Celite and the pad washed w~th acetone which was added to the aqueous filtrate.
The pH of the mixture (3.45) was adjusted to 6.75 with potassium bicarbonate, and the mixture was washed through a Dowex AG-50 (K ) column in 20%
acetone-water. The product fractions (Rf = 0.81) were combined and chromatographed on HP-20 in a water-acetone gradient. Those fractions containing mostly pure product were combined, evaporated and lyophilized to yield 0.28 g of the ester, potassium salt of the title compound.
The ester (0.28 g, 0.39 mmole) was slurried in 6 ml of anisole at 0C and 10 ml of cold tri-fluoroacetic acid was added and stirred for 1.5 hours. The mixture was evaporated in the cold (5C) and water and hexane were added, the organics being discarded. The aqueous layer was chromatographed on HP-20 with a water, acetone:water (1:1) gradient. Lyophilization gave 54 mg of white powder analyzing low in nitrogen.
Rechromatography on HP-20 gave 24 mg of the title compound which analyzed for the presence of 25 0.82 moles of water, melting point 200-220C
(dec.).
Anal. Calc'd. for C12H22N6O85 82H2 H, 4.79; N, 16.90; S, 6.45.
Found: C, 43.48; H, 4.60; N, 16.21; S, 6.27.

~L~253~L~6 GC213a Example 25 (trans)-1-[[3S(Z)]-[3-[[(2-Amino-4-thiazolyl)-(methoxyimino~acetyl]amino]-2-oxo-1-azetidinyl]-carbonyl]-4-hydroxy-L-proline, po-tassium salt A) (trans)-1-[[3S [[IPhenylmethoxy)carbonyl]-amino]-2-oxo-1-azetidinyl]carbonyl]-4-hydroxy-L-proline, phenylmethyl ester A slurry of (S)-3-[[(phenylmethoxy)-carbonyl]amino]-2-azetidinone (0.44 g, 2 mmole) in 10 ml of dichloromethane was chilled to -10C
under argon and treated with 0.3 g (3 mmoles) of triethylamine followed by 3.0 ml (3.75 mmoles) of 12.5% phosgene in toluene. After 2 hours at -10C, the mixture was evaporated ln vacuo at 10C, the residue taken up in 15 ml of dichloro-methane at 0C, and 0.51 g (2 mmole) of 4(R)-hydroxy-L-proline, phenylmethyl ester, hydrochloride added, followed by 0.4 g (4 mmole) of triethylamine. After 30 minutes, 10 ml of 10%
monobasic potassium phosphate was added, and the organics were separated and washed with brine.
Chromatography on silica (LPS-l) in ethyl acetate gave the title compound (0.3 g, Rf = 0.57 (ethyl acetate)) as a thick oil.

B) (trans)-l-[[3S(Z)]-[3-[[(2-Amino-4-thiazolyl)-___ (rnethoxyimino)acetyl]amino]-2-oxo-1-azetidinyl]-carbonyll-4-hydroxy-L-proline, potassium salt (trans3-1-[[3S-[[(Phenylmethoxy)carbonyl]-amino]-2-oxo-l-azetidinyl]carbonyl]-4-hydroxy-L-proline, phenylmethyl ester (0.3 g, 0.64 mmole) in 6 ml of dimethylformamide with 0.13 g (0.68 mmole) of ~-toluenesulfonic acid and 0.2 g ~3~46 GC213a of 10% palladium on charcoal was hydrogenated at 1 - atmosphere and 25C for 3 hours. 0.13 g (0.64 mmole) of (Z)-2-amino-a-(methoxyimino)-4-thiazoleacetic acid in 4 ml of dimethylformamide at 0C was treated with 0.1 g (0.64 mmole) of N-hydroxy-benzotriazole and 0.13 g (O.64 mmole) o dicyclohexylcarbodiimide. After 2 hours at 25C, the N-hydroxybenzotria~ole ester mixture was chilled to 0C and added to the hydrogenation mixture at 0C. After the resulting mixture was stirred at 5C for 14 hours, it was evaporated ln vacuo at 15C. The residue was taken up in water, filtered (pH = 3.45), and adjusted to pH = 6.75 with potassium bicarbonate. This solution was passed through a Dowex AG-50 (K ) column in water and lyophilized to a powder. This was chromato-graphed on HP-20, and the partially purified product lyophilized, taken up in a small a~ount of water and adjusted to pH ~ 2.5. -Two HP-2G chromato-graphies using a water~50% acetone/water gradientga~e still impure product. Conversion back to the potassium salt (pH = 6.9) with potassium blcarbonate and HP-70 chromatography gave 70 mg of nearly pure product. Chromatography on a 7 g Sephadex (LH-20) column in water gave product which was >80% pure by Hl, and whose microanalysis was consistent with the presence of 2.16 moles of water and up to 19% of the dipotassium salt of the product of ~-lactam ring opening. The yield was 35 mg., melting point 30 200-220C, dec.
Anal- Calc'd- for C15Hl7N67SK~2 16H2 C~ 35-04;
H, 4.22; N, 16.35; S, 6.23.
Found: C, 35.04; ~, 3.82; N, 16.07; S, 6.06.

*Trademark ~2~i3~

GC213a Exam~le 26 [3S(Z)]-1-[[3-[[(2-Amino-4-thiazolyl)[(1-carboxy-l-methylethoxy)imino]acetyl]amino]-2-oxo-1-azetidinyllcarbonYll-D-proline Following the procedure of example 24, but substituting (S)-1-[[3-[[(phenylmethoxy)carbonyl]-amino]-2-oxo-1-azetidinyl]carbonyl]-D-proline, phenylmethyl ester for the corresponding L-proline derivative, yielded the title compound, melting point 180-210C, which analyzed for the presence of 1.07 moles of water.
Anal. Calc'd. for C18H2~N6O8S-1.07~2O: C, 43.09;
H, 4.85; N, 16.75; S, 6.39.
Found: C, 43.09; H, 4.57; N, 16.05; S, 5.98.
Example 27 1-[[(3S)-3-(Benzoylamino)-2-oxo-1-azetidinyl]-carbonyll-L-prollne A solution of (S)-1-[[3-[[tphenylmethoxy)-carbonyl]amino]-2-oxo-1-azetidinyl]carbonyl]-L-proline, phenylmethyl ester (0.35 g, 0.78 mmole;
prepared as described in examples 22 and 23) in 4.5 ml of dimethylformamide with 0.15 g (0.8 mmole) of ~-toluenesulfonic acid and 0.2 g of 10% palladium on charcoal was hydrogenated at 1 atmosphere and 25C for 3 hours. The solution was chilled to 0C and treated with 0.3 g (2.3 mmoles) of diisopropylethylamine followed by 0.16 g (1.1 mmole) of benzoyl chloride, and stirred at 30 5C for 31-2 days. Water (10 ml) was added to the dimethylformamide solution and the slurry filtered on Celite. The pH was 3.35, and this was adjusted to 2.0 with dilute hydrochloric acid. The solution was extracted with ethyl acetate, ;3~
GC213a saturated with solid sodium chloride and extracted again. The organics were dried (sodium sulfate) and evaporated to a yellow oil which showed one major component by TLC (Rf = 0.56) with some less polar impurities. The oil was dissolved in dichloromethane and diluted to cloud with hexane.
Scratching gave 70 mg of a white solid, melting point 148-151C.
A 20 mg sample of this solid was dissolved in 0.5 ml of acetone and diluted with 0.5 ml of water. Standing in an open vial at 25C overnight gave large, well-formed needles, 10 mg, suitable for x-ray analysis, which were found to be mono-hydrated.
15 Anal Calc'd. for C16H17N3O5 0-4H2 5.29; N, 12.43.
Found: C, 56.83; H, 5.07; N, 12.43.

Example 28 20 (cis)-1-[[3S(Z)]-[3-[[~2-Amino-4-thiazolyl~-(methoxyimino)acetyl]amino]-2-oxo-1-azetidinyl]-carbonYl~-4-hydroxy-L-~roline, potassium salt A) (cis)-1-[[3S-[[(Phenylmethoxy)carbonyl]amino]-2-oxo-1-azetidinyl]carbonyl]-4-hydroxy-L-proline, phenylmethyl ester A slurry of 3S-[[(phenylmethoxy)carbonyl]-amino]-2-azetidinone (0.44 g, 2.0 mmole) and 0.3 g (3 mmoles) of triethylamine in 15 ml dichloro-methane at -10C under argon was treated with 3.0 ml (3.75 mmoles) of 12.5% phosgene in toluene and the resultant mixture stirred at -10C for 2 hours. Solvents were removed ln vacuo at 10C and the residue taken up in 20 ml of dichloromethane 53~6 GC213a (Rf = 0.37) were partially evaporated at 10C then chromatographed on HP-20 in water. Lyophilization of early, middle, and late pure product fractions gave a total of 0.21 g of final product. The more intense middle cut, 0.135 g, melting point 230-240C (dec.) was submitted for analysis, and was found to contain 2.09 moles of water. 400MHz NMR showed this sample to contain 5-10% of ~-toluenesulfonic acid potassium salt, accounting for the low analysis.
Anal. Calc'd. for C15H17N6O7SK-2 O9H2O C, 35.87;
H, 4.25; N, 16.73; S, 6.38; K, 7.78.
Found: C, 35.87; H~ 3.85; N, 15.94; S, 6.33; K, 8.25.
Example 29 (S)-4-[(Aminocarbonyl)oxy]-1-[~(S)-3-[[(2-amino-4-thiazolyl)~methoxyimino)acetyl]amino]-2-oxo-1-azetidinyllcarbonyl~-L-proline~ potassium salt A) (cis)-1-[[3S-[t~Phenylmethoxy)carbonyl]amino]-2-oxo-1-azetidinyl]carbonyl]-4-[(aminocarbonyl)oxy]-L-proline, Phenylmethyl ester A solution of ~cis)-1-[[3S-[[(phenyl-methoxy)carbonyl]amino]-2-oxo-1-azetidinyl]-carbonyl]-4-hydroxy-L-proline, phenylmethyl ester (0.26 g, 0.56 mmole; see example 28A) in 8 ml of dry dichloromethane under argon at -10C was treated with 0.07 ml of chlorosulfonyl isocyanate (d = 1.626, 0.11 g, 0.81 mmole) and stirred at this temperature for 20 minutes~ A
solution of 0.1 g of sodium sulfite in l ml of water was added to give a milky suspension.
Stirring for 1 hour at 25C and adding more water ~3~4~
5C213a and sodium sulfite did not change the TLC. water and a larye volume of ethyl acetate (200 ml) was added with vigorous shaking to dissolve a heavy oil. The organic phase contained material (Rf = 0.49) virtually identical by TLC to the starting alcohol. Drying (sodium sulfate) and evaporation gave 0.32 g of a white solid.
A solution of the above solid (0.32 g, 0.56 mmole) in 8 ml of dimethylformamide with 0.12 g (0.62 mmole) of ~-toluenesulfonic acid and 0.2 g of 10% palladium on charcoal was hydrogenated at 25C for 4 hours. A solution of 0.13 g (0.64 mmole) of (Z)-2-amino-~-(methoxy-imino)-4-thiazoleacetic acid and 1-hydroxybenzo-triazole (0.1 g, 0.67 mmole~ in 4 ml of dimethyl-formamide at 0C was treated with 0.13 g (0.63 mmole) of dicyclohexylcarbodiimide and warmed to 25C for 2 hours. The two solutions were chilled to 0C, combined and treated wi~h 0.1 g (0.78 mmole) of diisopropylethylamine.
After 15 hours at 5C, the mixture was evaporated ln vacuo, taken up in water, filtered, and the pH
of 3.05 adjusted to 6.90 with potassium bicarbonate. This solution was passed through Dowex AG-50 (K ), the product fractions (Rf ~ 0.49) combined and partially evaporated, and the resultant mixture chromatographed on HP 20 in water. Product fractions were combined and lyophilized to give 0.14 g of the final product, melting point 225-240C (dec.), which analyzed for 2.45 moles of water. NMR indicates the presence of 4-5% of ~-toluenesulfonic acid.
~nal Calc'd. for C16H18N7O8SK 2.45H2O:
H, 4.18; N! 17.77; S, 5.81; K, 7.09.
Found: C, 34.83; EI, 3.75; N, 17.22; S, 5.69; K, 7.17.

~;3~

~C213a 83 !

Example 0 (S)-1-[[(S)-3-[(Z)-[(2-Amino-4-thiazolyl)-[(carboxymethoxy)imino]acetyl]amino~-2-oxo-1-azetidinyl3carbonyl]-2-azetidinecarboxylic acid A~ (S)-l-[[(S)-3-[[(Phenylmethoxy)carbonyl~-amino]-2-oxo-1-azetidinyl]carbonyl]-2-azetidine-carboxYli.c acid, phenylmethyl ester A slurry OI ( S ) -3- [ [ (phenylmethoxy)-carbonyl]amino]-2-azetidinone (0.78 g, 3.54 mmole) in dry dichloromethane was warmed briefly to 50C and then cooled to -5C. Triethylamine (0.35~ g, 3.54 mmole) and phosgene ~5.7 ml of 12.5% phosgene/toluene) were added and the reaction was stirred at -5C for 2 hours. The reaction was concentrated to a residue and fresh dichloromethane was added. After the solution was cooled to -50C, triethylamine (0.714 g,

7.08 mmole) and azetidine-2-carboxylic acid, benzyl ester hydrochloride (0.8 g, 3.54 mmole) were added. The reaction was stirred at -5C for 45 minutes. The reaction mixture was poured into lO~ monobasic potassium phosphate and the dichloro-methane layer was separated and washed with water and brine. After drying over sodium sulfate the solvent evaporated. The crude oil was flash chromatographed on silica (LPS-1) eluting with ethyl/acetate:hexane (1:1). Fractions containing pure compound were concentrated to give 0.622 g of the title compound.

~3~

GC213a at 0C and treated with 0.51 g (2 mmole) o~ 4~S)-hydroxy-L-proline, phenylmethyl ester followed by 0.4 g (4 mmole) of triethylamine. After 1.5 hours at 0C, the mixture was washed with monobasic potassium phosphate, water and brine, dried (sodium sulfate), and chromatographed on silica (LPS-l) in ethyl acetate:dichloromethane, 6:1. Product fractions (Rf = 0.46, ethyl acetate) were evaporated to give the title compound as a colorless oil, 0.36 g.

B) (cis)-1-[[3S(Z)]-[3-[[(2-Amino-4-thiazolyl)-(methoxyimino)acetyl]amino]-2-oxo-1-azetidinyl]-carbonyl]-4-hydroxy-L-proline, potassium salt (cis)-1-[[3S-[[(Phenylmethoxy)carbonyl]amino~-2-oxo-1-azetidinyl]carbonyl]-4-hydroxy-L-proline, phenylmethyl ester (0.36 g, 0.76 mmole) in 8 ml of dimethylformamide with 0.15 g (O.79 mmole) of ~-toluenesulfonic acid and 0.25 g of 10% palladium on charcoal was hydrogenated at 1 atmosphere and 25C for 2.5 hours. 0.16 g (0.79 mmole) of (Z)-2-amino-~-(methoxyimino)-4-thiazoleacetic acid and 0.12 g (0.7~3 mmole) of N-hydroxybenzotriazole in 5 ml of dimethylformamide at 0C was treated with 0.16 g (0.79 mmole) of dicyclohexylcarbodiimide, and the temperature allowed to come to 25C over 2 hours. The solutions were chilled to 0C, combined, and treated with 0.09 g (0.7 mmole) of diisopropylethylamine. After 14 hours at 5C, the 3Q solvent was removed ln vacuo at 10C and the residue was slurried in water and filtered. The pH of the filtrate (pH = 3.30) was adjusted to 6.75 with potassium bicarbonate and passed through a Dowex AG-50 (K ) column. The product fractions ~2533~

GC213a B) (S~ [[(S)-3-[(Z)-[(2-Amino-4-thiazolyl)-[(carboxymethoxy)imino]acetyl]amino]-2-oxo-1-azetidinyllcarbonyl]-2-azetidinecarboxylic acid A mixture of (S)-l-[[(S)-3-[[(phenyl-methoxy)carbonyl]amino]-2-oxo-1-azetidinyl]-carbonyl]-2-azetidinecarboxylic acid, phenyl methyl ester (0.31 g, 0.71 mmole), ~-toluene-sulfonic acid (0.13 g, 0.71 mmole) and 10%
palladium on charcoal (0.15 g) in dimethyl-formamide were stirred at room temperature undera stream of hydrogen for three hours. To a mi~ture of (Z)-2-amino-~-[[2-(diphenylmethoxy)-2-oxo-ethoxy]imino]-~-thiazoleacetic acid (290 mg, 0.71 mmole) and N-hydroxybenzotriazole (96 mg, 0.71 mmole) in dimethylformamide at 0C was added dicyclohexylcarbodiimide (146 mg, 0.71 mmole).
This was stirred at room temperature for 2 hours to form the N-hydroxybenzotriazole ester. The hydrogenated reaction mixture was cooled to O~C
and diisopropylethylamine (0.12 ml, 0.71 mmole) was added followed immediately by the addition of the N-hydroxybenzotriazole ester mixture. This reaction mixture was stirred at 0C to 5C for 16 hours. The dimethylformamide was then removed under vacuum at room temperature. The residue was diluted with acetone and filtered through Celi-te.
An equal volume of water was added and the solution was loaded onto an AG-50 (K ) column and eluted with acetone:water (1:1). Fractions containing product were adjusted to pH 6.7 and then concentrated to a slurry. The slurry was added to an HP-20 column and eluted with water until the N-hydroxybenzotriazole was removed and then eluted with an acetone/water gradient to GC213a remove the product from the column. The product fractions were lyophilized to a residue.
The lyophilate was added to a chilled solution of anisole/trifluoroacetic acid (6 ml/10 ml) and stirred at 0C for 1 hour. The solution was concentrated under vacuum. Wat~r and hexane were added and the phases were separated.
The aqueous layer was adjusted from pH 1.5 to 2.5 with lN potassium bicarbonate and then chromatographed on an HP-20 column eluting first with water and then with an acetone/water gradient. Fractions containing pure product were lyophilized to a white solid (49.1 mg), melting point >200C, dec.
Anal. Calc'd- for C15H16N68S 1 3~2 C~ 38-82; H~
4.04; N, 18.11; S, 6.91.
Found: C, 38.82; H, 3.70; N, 17.79; S, 6.59.

Example 31 (S)-l-[[(S)-3-[[(Z)-(2-Amino-4-thiaæolyl)[(l-carboxy-l-methylethoxy)imino]acetyl]amino]-2-oxo-1-azetidinyl]carbonyl]-2-azetidinecarboxyllc acid _ _ _ _ A mixture of (S)-l-[[(S)-3-[[(phenyl-methoxy)carbonyl]amino]-2-oxo-1-azetidinyl]-carbonyl]-2-azetidinecarboxylic acid, phenyl-methyl ester (0.31 g, 0.71 mmole; see example 30A), ~-toluenesulfonic acid (0.13 g, 0.71 mmole) and 10% palladium on charcoal (0.15 g) in dimethyl-formamide were stirred at room temperature under a stream of hydrogen for three hours. To a mixture of (Z)-2-amino-~-[[2-(diphenylmethoxy)-1,1-dimethyl-2-oxoethoxy]imino]-4-thiazoleacetic acid (330 mg, 0.71 mmole) and N-hydroxybenzotriazole (96 mg, 0.71 mmole) in dimethylformamide at 0C

~253~

GC213a was added dicyclohexylcarbodiimide (146 mg, 0.71 mmole). This was stirred at room temperature for 2 hours to form the N-hydro~ybenzotriazole ester. The hydrogenation reaction mixture was cooled to OGC and diisopropylethylamine (0.12 ml, 0.71 mmole) was added followed immediately by the addition of the N-hydroxybenzotriazole ester mixture. This reaction mixture was stirred at 0C
to 5C for 16 hours. The dimethylformamide was then removed under vacuum at room temperature.
The residue was diluted with acetone and filtered through Celite. An equal volume of water was added and the solution was loaded onto an AG-50 (K~) column and eluted with acetone:water (1:1).
Fractions containing product were adjusted to pH
6.7 and then concentrated to a slurry. The slurry was added to an HP-20 column and eluted with water until the N-hydroxybenzotriazole was removed and then eluted with an acetone/water gradient to - 20 remove the product from the column. The product fractions were lyophilized to a residue.
The lyophilate was added to a chilled solution of anisole/trifluoroacetic acid (6 ml/10 ml) and stirred at 0C for 1 hour. The solution was concentrated under vacuum. Water and hexane were added and the phases were separated.
The aqueous layer was adjusted from pH l.9 to 2.5 with lN potassium bicarbonate and then chromatographed on an HP-20 column eluting first with water and then with an acekone/water gradient. Fractions containing pure product were lyophilized to a white solid (94 mg), melting point >230C, dec.
Anal- CalC'd- for C17H20N68S 1 6H2 4.90; N, 16.87; S, 6.41.
Found: C, 40.98; H, 4.11; N, 16.74; S, 6.31.

~53~

GC213a Example 32 (S)-1-[[3S(Z)]-~3-[[(2-Amino-4~thiazolyl)(methoxy-imino)acetyl]amino]-2-oxo-1-azetidinyl]carbonyl]-2-azetidinecarboxylic acid s A) L-Azetidine-2-carboxylic acid, phenylmethyl ester L-Azetidine-2-carboxylic acid (0.88 g,

8.7 mmole) in 30 ml of 1:1 acetone:water was treated with 1.32 g (13.1 mmole) of triethylamine followed by 2.22 g (10.1 mmole) of 1,1-dimethyl-ethoxycarbo~ylic anhydride. After 24 hours at 25C, acetone was evaporated ln vacuo, 1.0 g of sodium bicarbonate and S0 ml water were added, and the mixture was extracted with ethyl acetate. The aqueous layer was acidified (10% potassium bisulfate) and extracted with ethyl acetate.
Drying ~sodium sulfate) and evaporation gave 1.8 g of a low melting solid. This was dissolved in 6 ml of dimethylformamide and treated with 1.5 g of sodium bicarbonate and 6 g of benzyl bromide.
Stirring at 25C for 14 hours caused complete reaction. Water and ethyl acetate were added, layers separated, the organics washed (water), dried ~sodium sulfate) and evaporated to an oil.
Chromatography on silica in hexane:ethyl acetate (1:1) gave 1-[(1,1-dimethylethoxy)carbonyl]-L-azetidine-2-carboxylic acid, phenylmethyl ester (1.8 g) as a colorless oil. This oil was treated with hydrogen chloride gas at 0C in 50 ml of ethyl acetate for 5 minutes, and warmed to 25C
for 1 hour. Evaporation gave an oil whic~
solidified with the addition of ether. The solid was washed with ether and ethyl acetate, and dried ln vacuo to give 1.28 g of the title compound.

;3~

GC213a B) (S)-l-[[(S)-3-[[(Phenylmethoxy)carbonyl]amino]-2-oxo-1-azetidinyl]carbonyl]-2-azetidinecarboxylic acid, phenylmeth~l ester A slurry of (S)-3-[[(phenylmethoxy)-carbonyl]amino]-2-azetidinone (0.44 g, 2 mmole) in 10 ml of dichloromethane was chilled to -10C
under argon and treated with 0.3 g (3 mmoles) of triethylamine, followed by 3 ml (3.75 mmoles) of 12.5% phosgene in toluene. After 2 hours a-t -10C, the mixture was evaporated ln vacuo a-t 10C, the residue taken up in 15 ml of dichloro-methane at -10C, and 0.4 g (4 mmole) of triethyl-amine was added followed by 0.45 g (2 mmole) of L-aze-tidine-2-carboxylic acid, phenylmethyl ester. After 30 minutes at 0C, the reaction was extracted with 10% monobasic potassium phosphate and ~?ater, dried (sodium sulfate) and chromatographed on silica (LPS-1) (hexane:ethyl acetate, l:1), to give the title compound (R~ = 0.71 in ethyl acetate), 0.34 g.

C) (S)-1-[[3S(Z)]-[3-[[(2-Amino-4 thiazolyl)-(methoxyimino)acetyl]amino]-2-oxo-l-azetidinyl]-carbonyl]-2-azetidinecarboxylic acid (S)-1-[[(S)-3-[[(Phenylmethoxy)carbonyl]-amino]-2-oxo-l-aæetidinyl]carbonyl]-2-azetidine-carboxylic acid, phenylmethyl ester (0.34 g, 0.78 mmole) in 0.5 ml of dimethylformamide with 0.15 g (0.79 mmole) of ~-toluenesulfonic acid hydrate and 0.2 g of 10% palladium on charcoal was hydrogenated at l atmosphere and 25C for 3 hours. (Z)-2-Amino-~-(methoxyimino)-4-thiazole-acetic acid (0.14 g, 0.7 mmoles) and 0.11 y (0.72 mmoles) of N-hydroxybenzotriazole in 4 ml of ii33L~;

GC213a dimethylformamide at 0C was treated with 0.14 g (0.7 mmoles) of dicyclohexylcarbodiimide and warmed to 25C for 30 minutes. Both reactions were chilled to 0C and combined with 0.11 g (0.85 mmole) of dilsopropylethylamine, and the mixture stirred for 14 hours at 5C. Evaporation ln vacuo at 15C, slurrying in water, and filtering through a Celite pad gave a solution (pH 3.45).
The pH was adjusted to 6.9 with potassium bicarbonate and this solution was passed through a Dowex AG-50 (K ) column. The eluate was concentrated ln vacuo at 15C and chromatographed on HP-20 in water. T~e product (Rf = O.4) fractions were lyophilized to give 146 mg of the potassium salt of the title compound which was shown by microanalysis and NMR to contain l mole of the potassium salt of ~-toluenesulfonic acid.
A solution of the salt in water was adjusted to pH 2.45 with dilute hydrochloric acid and chromatographed on HP-20 with a water-20~
acetone/water gradient. Product fractions were partially evaporated, then lyophilized to give 60 mg of final product, melting point 170-200C
(dec.), which analyzed for the presence of 0.93 mmoles of water.
Anal. CalC'd- for C14H16N66S 0 93H2 H, 4.35; N, 20.34; S, 7.76.
Found: C, 40.70; H, 4.57; N, 19.90; S, 7.65.

GC213a Example 33 [3S(Z)]-1-[[3-[[(2-Amino-4-thiazolyl)~methoxy-imino)acetyl]amino]-2-oxo-l~azetidinyl]carbonyl]-2-piperidirlecarboxylic acid, potassium salt A) 1-[(1,1-Dimethylethoxy)carbonyl]-D,L-pipe-colinic acid D,L-Pipecolinic acid (2.6 g, 0.02 mole) in 40 ml of 50% a~ueous acetone was treated with 2.6 g (0.026 mole) of triethylamine followed by 4.8 g (0.022 mole) of l,l-dimethylethoxycarboxylic anhydride at 20C. After 24 hours, acetone was evaporated and water, ethyl acetate and 2 g of sodium bicarbonate were added. The organic layer was discarded and the aqueous layer was acidified (sodium sulfate), extracted (ethyl acetate) and evaporated to give 4.2 g of a white solid.

~) D,L-Pipecolinic acid, phenylmethyl ester, hydrochloride l-[(1,1-Dimethylethoxy)carbonyl]-D,L-pipe-colinic acid (2 g, 8.7 mmole) in 6 ml of dimethyl-formamide and 1.5 g of sodium bicarbonate was treated with 6.0 g of benzyl bromide for 2l-2 days at 25C. Evaporation and partitioning between ethyl acetate and water gave a crude product which was separated by silica (LPS-l) chromatography in hexane/ethyl acetate, 6:1. The colorless oil thus obtained (Rf = .51, ethyl acetate) was treated at 0C in 50 ml of ethyl acetate with hydrogen chloride gas. Evaporation gave a solid which was triturated with ethyl acetate, filtered, and dried in vacuo to give 2.06 g of the title compound.

~2~ 6 -92- GC213a C) (3S)-1 [[3-[[(Phenylmethoxy)carbonyl]amino~-2-oxo-1-azetidinyl]carbonyl]-2-piperidinecarboxylic acid, phenylmethYl ester A slurry of (S)-3-[[(phenylmetho~y)-carbonyl]amino]-2-azetidinone (1.32 g, 6 mmoles) in 50 ml of dichloromethane was treated with 0.9 g (9 mmoles) of triethylamine and chilled to -10C.
Phosgene (9.O ml of 12.5% in tolunee, 11.3 mmoles) was added and after 2 hours at -10C, the mixture was evaporated at 10C ln vacuo. The residue was dissolved in 50 ml of dry dichloromethane at -5C
and treated with 1.2 g (12 mmoles) of triethyl-amine and 1.53 g (6 mmoles) of D,L-pipecolinic acid, phenylmethyl ester, hydrochloride. This mi~ture was allowed to warm to 25C over 3 hours, washed with 10% monobasic potassium phosphate and water, dried (sodium sulfate) and chromatographed on silica (LPS-l) in hexane:ethyl acetate 1:1, to give 1.1 g of the title compound as a colorless oil.

D) [3S(Z)]-1-[[3-[[(2-Amino-4-thiazolyl)(methoxy-imino)acetyl]amino]-2-oxo-1-azetidinyl]carbonyl]-2-piperidinecarboxylic acid, potassium salt ~3S)-1-[[3-[[(Phenylmethoxy)carbonyl]amino]-2-oxo-1-azetidinyl]carbonyl]-2-piperidinecarboxylic acid, phenylmethyl ester (1.1 g, 2.4 mmoles) was hydrogenated at 25C in 20 ml of dimethylformamide in the presence of 0.46 g (2.4 mmole) of _-toluene-sulfonic acid and 0.8 g of 10% palladium on charcoal for 4 hours. (Z)-2-Amino-~-(methoxy-imino) 4-thiazoleacetic acid (0.48 g, 2.4 mmoles) and 0.40 g (2.4 mmoles) of N-hydroxybenzotriazole in 7 ml of dimethylformamide at O~C and treated ~53~l~6 GC213a with 0.49 g (2.4 mmoles) of dicyclohexylcarbo-diimide and allowed to come to 25C o~er 2 hours.
Both solutions were chilled to 0C, combined, and treated with 0.31 g (2.4 mmoles) of diisopropyl-ethylamine. After 15 hours at 5C, the solventswere evaporated at 10C in vacuo to a gum. This was taken up in water, filtered (Celite pad), and the pH of 3.5 adjusted to p~l 6.5 with potassium bicarbonate. Filtering through Dowex AG-50 (K ) and lyophilization gave 2.7 g of a beige solid.
Chromatography on HP-20 in water and combination of the most intense product spots (Rf = 0.69) gave, on lyophilization, 0.275 g of final product, melting point 205-225C (dec.~, which analyzed for the presence of 2.28 moles of water.
Anal- Calc'd. for C16H19N665K 2 28H20 H, 4.72; N, 16.68; S, 6.37; K, 7.78.
Found: C, 38.15; H, 4.10; N, 16.68; s, 6.12; K, 8.38.
Example 34 [3SIZ)]-[(2-Amino-2-oxoethyl)[[3-[[(2-amino-4-thiazolyl)(methoxyimino)acetyl]amino]-2-oxo-1-azetidinyl]carbonyl]amino]acetic acid, potassium salt A) (35)-[(2-Amino-2-oxoethyl)[[3-[[(t-butyloxy)-carbonyl]amino]-2-oxo-1-azetidinyl]carbonyl]amino]-acetic acid (S)-2,2'-[[[3-[[(t-Butyloxy)carbonyl~amino]-2-oxo-1-azetidinyl]carbonyl]imino]bisacetic acid, diphenyl ester (1.575 g, 3 mmol; see example 18A) was dissolved in 18 ml of dry tetrahydrofuran.
Hydrogenolysis of the benzyl protecting groups at ~C213a room temperature over 788 mg of 10% palladium on charcoal was complete after 50 minutes. The reaction mixture was filtered to remove the palladium on charcoal catalyst, toluene (~3 ml) was added, and the volatiles were evaporated to yield the presumed diacid of the azetidinone startlng material.
The diacid was dissolved in 45 ml of dry tetrahydrofuran and a solution of dicyclohexyl-carbodiimide (681 mg, 3.3 mmol) in 12 ml of dry tetrahydrofuran was added dropwise to the stirring reaction mixture at room temperature. The reaction mixture was stirred for 70 minutes at room temperature. The solvent volume was reduced to ~24 ml by evacuation and the reaction mixturewas cooled to 0C An a~ueous 15% diammonium phosphate solution (30 ml) was added, and the mixture was stirred vigorously for 2 hours. The tetrahydrofuran was evaporated, the reaction mixture was cooled to 0C, and the pH was adjusted to 2.5 with lN hydrochloric acid. Purification of this crude product by column chromatograph on HP-20 (eluting with water, 5% acetone-water, and 10% acetone-water) yielded upon lyophilization, 588 mg of the title compound.

B) [3S(Z)]~[(2-Amino 2-oxoethyl)[[3~[[(2-amino-4-thiazolyl)(methoxyimino)acetyl]amino]-2-oxo-1-azetidinyl]carbonyl]amino~acetic acid, potassium salt Diisopropylethylamine (0.270 ml, 1.55 mmol) was added to 219 mg (1.02 mmol) of (Z)-2-amino-4-(methoxyimino)-4-thiazoleacetic acid (containing 0.38 ~:~533L~

GC213a molar equivalents of hydrochloric acid) in 3.4 ml of dimethylformamide at 23C. The mixture was - cooled to -20C, diphenylchlorophosphate (0.211 ml, 1.02 ~nol) ~as added, and the resulting mixture was stirred for 30 minutes to yield a mixed anhydride.
(3S)-[(2-Amino-2-oxoethyl)[[3-[[(t-butyloxy)-carbonyl]amino]-2-oxo-1-azetidinyl]carbonyl]amino]-acetic acid (294 mg, 0.85 mmol) was cooled to 0C
and a solution containing 4 ml of trifluoroacetic acid, 4 ml of dichloromethane and 0.8 ml of anisole at 0C was added. After stirring at 0C for 2 hours, toluene (~2 ml) was added, and the volatiles were evaporated. The residue was triturated with hexane and anhydrous ether to yield a white solid.
The residue was then dissolved in 3.4 ml of dimethylformamide and upon cooling to 0C, 0.491 ml (2.82 mmol) of diisopropylethylamine was added.
The reaction mixture containing the mixed anhydride was immediately added, and the resulting mixture was stirred at 0C for 3 hours.
The volatiles were removed under vacuum, and the residue was subjected to column chromatography with water on Dowex SOX2-400 resin +

~K form). The pH of the crude product was adjusted to 2.5 with lN hydrochloric acid, and this was subjected to chromatography on HP-20 (eluting with water, 5% acetone-water, and 10%
acetone-water) to give the impure acid of the title compound. The crude product was dissolved in ~4 ml of water at 0C and the pH was adjusted to 6.5 with aqueous potassium bicarbonate.
Purification of this solution by column ~;25~

GC213a chromatography on HP-20 (eluting with water) yielded, upon lyophilization, 215 mg of the title compound, melting point 187-195C, dec.
Anal. Calc'd. for C14H16N7O7SK: C, 36.12; H, 3.46;
~, 21.06.
Found: C, 31.92; H, 3.58; N, 17.94.

Example 35 [3S(Z)]-[[[3-[[(2-Amino-4-thiazolyl)(methoxy-imino)acetyl]amino]-2-oxo-1-azetidinyl]carbonyl]-(2,2-dimethoxYethyl)amino]acetic acid, potassium salt A) (2,2-Dimethoxyethyl)(2-phenylmethoxy-2-oxo-ethyl ? amine A solution of aminoacetaldehyde dimethyl acetal (2.2 ml, 0.04 mole) in ether (10 ml) was cooled to 0C. Benzyl bromoacetate (1.6 ml, O.02 mole) was added. After stirring at ambient temperature overnight, the solid aminoacetaldehyde dimethyl acetal hydrobromide was filtered and the solution was concentrated to an oil. Flash chromatography on silica (LPS-l) (40:60 ethyl acetate:hexane eluant) gave 2.2 gms of the purified title compound.

B) (3S)-[[[3-[[(Phenylmethoxy)carbonyl]amino]-2-oxo-1-azetidinyl]carbonyl](2,2-dimethyoxyethyl)-amino]acetic acid, phenylmethYl ester To a slurry of (S)-3-[[(phenylmethoxy)-carbonyl]amino]-2-azetidinone (0.88 g, 4 mmole) in 10 ml o dichloromethane at -10C under argon was added 12.5% phosgene/toluene (5.8 ml, 6.8 mmole) followed by triethylamine (0.465 g, ~L253~L~6 GC213a 4.6 mmole~. The reaction mixture was stirred at -10C for 2 hours. The reaction mixture was concentrated with no external heating and then redissolved in dichloromethane and cooled to -10C. (2,2-Dimethoxyethyl)(2-phenylmethoxy-2-oxo-ethyl)amine (1.06 g, 4.2 mmole) was added followed by the addition of triethylamine. The reaction mixture was stirred at -10C for 45 minutes.
The reaction was worked up by pouring into 10% mo~obasic potassium phosphate and extracting with dichloromethane. After washing with brine and drying over anhydrous sodium sulfate, the solvent was evaporated leaving an oil. The crude material was flash chromatographed on silica (LPS-1) eluting with 3:7 ethyl acetate:hexane.
The fractions containing pure material were combined and conc~ntrated to give 0.454 gm of material which crystallized on cooling.

C) [3S(Z)]-[[[3-~[(2-Amino-4-thiazolyl)(methoxy-imino)acetyl]amino]-2-oxo-1-azetidinyl]carbonyl]-(2,2-dime~hoxyethyl)amino]acetic acid, potassium salt To a solution of (3S)-[[[3-[[(phenyl-methoxy)carbonyl]aminol-2-oxo-1-azetidinyl]-carbonyl](2,2-dimethoxyethyl)amino]acetic acid, phenylmethyl ester (0.20 gm, 0.4 mmole) in 3 ml of dimethylformamide was added to 100 mg of 10% palladium on charcoal and 76 mg (0.4 mmole) of ~-toluenesulfonic acid. The protecting groups were removed by atmospheric hydrogenation at 0C
for 3.5 hours.
To a solution of (Z)-2-amino-a-(methoxy-imino)-4 thiazoleacetic acid (90.64 mg, ;i3~

-98- GC213a 0.44 mmole) and N-hydroxybenzotriazole (59.S mg, 0.44 mmole) in dimethylformamide (3 ml) under argon at 0C was ~dded N,N-dicyclohexylcarbo-diimide (90.7 mg, 0.44 mmole). The reaction mixture was stirred at room temperature for 1.5 hours. The side chain ester was filtered away from the solid dicyclohexylurea formed.
Af-ter the hydrogenation was completed, diisopropylethylamine (51.6 m~, 0.4 rnmole) was added at 0C followed by the addition of the solution of side chain ester. The reaction mixture was stirred at 5C overnight.
The reaction mixture was concentrated as rapidly as possihle using a vacuum pump (throughout the subsequent isolation and purification, the solutions were kept at 0-5C at all times). The residue was dissolved in cold doubly distilled water and filtered through Celite. The pH of the filtrate was adjusted to 6.5 with lN potassium bicarbonate. This solution was sent through a column of Dowex AG-50 K form and then purified on an HP 20 column eluting with water. After lyophilization, 146 mg (57.7%) of the title compound was obtained, melting point 25 163-175C, dec. 400 MHz NMR and microanalysis established the presence of 0.5 moles of potassium tolylsulfonate.
Anal. Calc'd. for C16H21N6O8SK: C, 36.01; H, 4.35;
N, 12.92; S, 7.39; K, 9.02.
30 Found: C, 35.60; H, 4.07; N, 12.92; S, 7.02; K,

9.29.

- ~2~3~

GC213a _99_ Example 36 [3S(Z)]-~[[3-[[t2-Amino-4-thiazolyl)(methoxy-imino)acetyl]amino]-2-oxo-1-azetidinyl]carbonyl)- -[2-(dimethylamino)-2-oxoeth~l]amino]acetic acid, ~otassium salt A) (3S)-[[[3 [[(t-Butyloxy)carbonyl]amino]-2-oxo-1-azetidinyl]carbonyl](2,2-dimethoxyethyl)-aminolacetic acid

10(S)-2,2'-[[[3-[[(t-Butyloxy)carbonyl]-amino]-2-oxo-1-azetidinyl]carbonyl]imino~bisacetic acid, dibenzyl ester (1.05 g, 2 mmol; see example l~A) was dissolved in 12 ml of dry tetrahydro-furan. Hydrogenolysis of the benzyl protecting 15groups at room temperature over 525 mg of 10%
palladium on charcoal was complete after 1 hour.
The reaction mixture was filtered to remove the palladium on charcoal catalyst, toluene (~4 ml) was added, and the volatiles were e~aporated to yield the diacid of the azetidinone starting material.
The diacid was dissolved in 30 ml of dry tetrahydrofuran and a solution of dicyclohexyl-carbodiimide (454 mg, 2.2 mmol) in 8 ml of dry tetrahydrofuran was added dropwise to the stirred reaction mixture at room temperature. The reaction mixture was stirred for 1.5 hours at room temperature. The reaction mixture was cooled to -78C and a solution of lN dimethylamine in tetra-hydrofuran (4 ml) at 0C was added dropwise. Therea~tion mixture was warmed to 0C and was stirred for 45 minutes. The mixture was then cooled to -73C, and 4 ml of 0.5 N hydrochloric acid was added. As the reaction mixture was warmed to 0C, GC2i3a 4 ml of water was added, and the pH was adjusted to 2.5 with 0.5 N hydrochloric acid. The tetra-hydrofuran was evaporated, and the crude product was purified by column chromatography on HP-20 (eluting with water, 5% acetone-water, 10%
acetone-water, and 20% acetone water) to yield upon lyophilization 509 mg of the title compound.

B) [3S(Z)]-[[[3-[[(2-Amino-4-thiazolyl)(methoxy-imino)acetyl]amino]-2-oxo-1-azetidinyl]carbonyl)-[2-(dimethylamino)-2-oxoethyl]amino]acetic acid, potassium salt Diisopropylethylamine (0.323 ml, 1.86 mmol) was added to 258 mg (1.2 mmol) o (Z)-2-amino-~-(methoxyimino)-4-thiazoleacetic acid (containiIlg 0.38 molar equivalents of hydrochloric acid in 4 ml of dimethylformamide at 23C. The mixture was cooled to -20C, diphenyl chlorophosphate (0.249 ml, 1.2 mmol) was added, and the resulting mixture was stirred for 30 minutes to yield a mixed anhydride.
~ 3S)-[[[3-[[(t-Butyloxy)carbonyl]amino]-2-oxo-1-azetidinyl]carbonyl](2,2-dimethoxyethyl)-amino]acetic acid (372 mg, 1 mmol) was cooled to 0C and a solution containing 5 ml of trifluoro-acetic acid, 5 ml of dichloromethane, and 1 ml of anisole at 0C was added. After stirring at 0C for 2 hours, toluene (~3 ml) was added, and the volatiles were evaporated. The residue was triturated with hexane and anhydrous ether to yield a white solid. The residue was then dissolved in 4 ml of dimethylformamide and upon cooling to 0C, 0.587 ml (3.32 mmol) of diiso-propylethylamine was added. The reaction mixture 3~

GC213a containing the mixed anhydride was then immediately added, and the resulting mixture was stirred at 0C for 2 hours The volatiles were removed under vacuum, and the residue was subjected to column chromatography with water on Dowex 50X2-400 resin (K form). After lyophilization, the pH of the crude product (in ~4 ml H20~ was adjusted to 2.5 with lN hydrochloric acid, and this was then subject0d to chromatography on HP-20 (eluting with water, 5% acetone-water, 10% acetone-water, and 20% acetone-water) to give the impure acid of the title compound. After lyophilization, the crude product was dissolved in ~4 ml of water at 0C and the pH was adjusted to 6.5 with aqueous potassium bicarbonate. Purification of this solution by column chromatography on HP-20 (eluting with water yielded, upon lyophilization, 240 mg of the title compound, melting point 162-171C, dec.
20 Anal. Calc'd. for C16H2oN7O7SK-2H20: C, 36.27; H, 4.57; N, 18.51.
Found: C, 36.41; H, 4.75; N, 18.37.

Example 37 [3S(Z)]-[[[3-[[(2-Amino-4-thiazolyl)(methoxy-imino)acetyl]amino]-2-oxo-1-azetidinyl]carbonyl]-(1 methylethyl)amino]acetic acid A) Isopropyl[2-(phenylmethoxy)-2-oxoethyl]amine N-isopropyl ethyl glycinate (22.9 g, 0.158 mole) and 33.1 g of ~-toluenesulfonic acid monohydrate (0.174 mole) were placed in a reaction vessel filtered with a reflux condenser and a Dean-Stark apparatus. Benzyl alcohol ~158 ml, ~L~53~a~6 GC213a 1.53 mole) and 158 ml of benzene (1.77 mole) were added, and the reaction mixture was refluxed for 24 hours. The reaction mixture was cooled to room temperature, and ~800 ml of ether was added.
After sitting at -30C overnight, the reaction mixture was fil~ered and the precipitate collected. The precipitate was washed with cold ether to yield 60.97 g of the impure ~-toluene sulfonate salt of the title compound.
The ~-toluenesulfonate salt was suspended in ~400 ml of ice-cold water and 26.22 g of potassium carbonate was added (pH 8-9). The aqueous mixture wa~s extracted 3 times with ether and the combined organic layers were dried over sodium sulfate and filtered. The volume of the ether solution was reduced to ~400 ml and was cooled to 0C. Water (~400 ml) was added, and the pH was adjusted to 1.5 with lN hydrochloric acid while rapidly stirring. The ether was evaporated, and the remaining aqueous solution was lyophilized to yield 28.63 g of the title compound.

B) (3S)-[[[3-[[(Phenylmethoxy)carbonyl]amlno]-2-oxo-l-azetidinyl]carbonyl](l-methylethyl)amino]-acetic acid, Phenylmethyl ester (S)-3-[[(Phenylmetho~y)carbonyl]amino]-2-azetidinone (660 mg, 3.0 mmol) was suspended in 7.5 ml of dichloromethane and cooled to -10C.
A solution of 12.5% phosgene in toluene (4.4 ml, 5.1 mmol) was added, and then triethylamine (0.481 ml, 3.45 mmol) was added dropwise to the rapidly stirring mixture. After stirring at -10C
for 2 hours, the volatiles were evaporated without ~L~53~
GC213a external heating. The residue was cooled to -10C, and dissolved in 7.5 ml of dichloromethane.
Potassium carbonate (911 mg, 6.6 mmol) was added to a rapidly stirring solution of N-iso-propylglycine benzyl ester hydrochloride (804 mg, 3.3 mmol) in 7.5 ml of water and 5 ml of dichloro-methane at 0C (pH 8). The mixture was extracted 3 times with dichloromethane, and the combined organic layers were dried over sodium sulfate and filtered. The volume of solvent was reduced to ~3 ml by evacuation and dried with 4A molecular sieves to yield the free amine of the benzyl ester Triethylamine (0.460 ml, 3.3 mmol) was added to the solution containing the free amine, and the resulting mixture was immediately added to the solution containing the azetidinone reagent at -10C. After stirring at -10C for 3 hours, the reaction mixture was poured into aqueous monobasic potassium phosphate and extracted 3 times with dichloromethane. The combined organic layers were dried over sodium sulfate and filtered. The volatiles were removed, and the residue was subjected to chromatography on silica (LPS-1) (eluting with 35% ethyl acetate-hexane) yielding 342 mg of the title compound.

C) [3S(Z)]-[[[3-[[(2-Amino-4-thiazolyl)(methoxy-imino)acetyl]amino]-2-oxo-1-azetidinyl]carbonyl]-(l-methylethyl)amino]acetic acid _ _ Diisopropylethylamine (0.240 ml, 1.38 mmol) was added to 191 mg (0.8g mmole) of (Z)-2-amino-~-(methoxyimino)-4-thiazoleacetic acid (containing 0.38 molar equivalents of hydrochloric acid) in 4 ml of dimethylformamide at 23c. The mixture ~53~
GC213a was cooled to -20C, diphenylchlorophosphate (0.184 ml, 0.89 mmol) was added, and the resulting mixture was stirred for 30 minutes to yield a mixed anhydride.
(3S)-[[[3-[[(Phenylmethoxy)carbonyl]amino]-2-oxo-1-azetidinyl]carbonyl](l-methylethyl)amino]-acetic acid, phenylmethyl ester (335 mg, 0.74 mmol) was dissolved in 3 ml of dimethyl-formamide and 141 mg (0.74 mmol) of ~-toluene-sulfonic acid monohydrate was added. Hydrogen-olysis of the protecting groups at room temperature over 167 mg of 10% palladium on charcoal was complete after 75 minutes. The reaction mixture was placed under nitrogen and 15 cooled to 0C. Diisopropylethylamine (0.425 ml, 2.44 mmol) was then added to the azetidinone, immediately followed by the mixed anhydride, and the resultin~ mixture was stirred at 0C for 2 hours.
The reaction mixture was filtered to remove the palladium on charcoal and the volatiles were removed under vacuum. The residue was subjected to column chromatography with water on Dowex 50X2-400 resin (K form) followed by chroma-tography on HP-20 (eluting with water, and 5%
acetone-water) to give the impure potassium salt of the title compound. The crude product was dissolved in ~5 ml of water at 0C and the pH was adjusted to 2.5 with lN hydrochloric acid.
Purification of this solution by column chromatography on HP-20 (eluting with water, 5%
acetone-water, 10% acetone-water, 20%
acetone-water, an 25% acetone water) yielded upon lyophilization 185 mg of the title compound, ~53~4~
GC213a melting point 150C, dec.
Anal- Calc'd- for C15H20N66S C~ 43-69; H~ 4-85;
N, 20.39.
Found: C, 44.75; H, 5.15; N, 15.82.
Exam~le 38 [3S(Z~]-[[2-(Acetylamino)ethyl][[3-[[(2-amino-4-thiazolyl)(methoxyimino)acetyl]amino]-2-oxo-1-azetidinyl]carbonyl]amino]acetic acid, potassium salt A) N-Acetyl-N'-[2-(phenylmethoxy)-2-oxoethyl]-ethylenediamine Benzyl glyoxylate (3.28 g, 20.0 mmol) in dry tetrahydrofuran (15 ml) was added dropwise in monoacetylethylenediamine (1.53 g, 15 mmol) in dry tetrahydrofuran (60 ml) at room temperature.
After 2 hours, the tetrahydrofuran was removed under vacuum, and the residue was dissolved in dry 20 methanol (100 ml). Upon cooling to 0C, 1.55 g of sodium cyanoborohydride was added, immediately followed by dropwise addition of 1.54 ml of acetic acid. The reaction was allowed to warm to room temperature and stirred for 40 minutes. The volatiles were removed under vacuum, and the residue was extracted from aqueous sodium bicar-bonate with ethyl acetate. The combined organic layers were dried with sodium sulfate, and the volatiles were removed. The residue was purified by column chromatography on silica (LPS-l) (loading with 2~ methanol/dichloromethane and eluting with 5% methanol/dichloromethane to yield 1.46 g of the title compound.

~3~ GC213a B) (3S~-[[2-(Acetylamino)ethyl][[3-[[(phenyl-methoxy)carbonyl]amino]-2-oxo-l-azetidinyl]-carbonyllaminolacetic acid, phenylmethYl ester (S)-3-[[(Phenylmethoxy)carbonyl]amino]-2-azetidinone (440 mg, 2.0 mmol) was suspended in 5 ml of dry dichloromethane and cooled to -10C.
A solution of 12.5% phosgene in toluene (2.9 ml, 3.4 mmol) was added and then triethylamine (0.307 ml, 2.2 mmol) was added dropwise to the rapidly stirring mixture. After stirring at -10C
for 1.5 hours, the volatiles were evaporated without external heating. The residue was cooled to -10C and dissolved in 5 ml of dichloromethane.
Triethylamine (O.307 ml, 2.2 mmol) was added to a solution of N-acetyl-N'-[2-(phenylmethoxy)-2-oxoethyl]ethylenediamine (500 mg, 2.0 mmol) in dichloromethane (2.0 ml), and the resulting mixture was immediately added to the above-prepared solution at -10C. After stirring at 20 -10C for 15 minutes and 0C for 3 hours, the reaction mixture was poured into agueous monobasic potassium phosphate and extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate and filtered. The volatiles were removed, and the residue was subjected to chromatography on silica (LPS-l) (eluting with 10% acetonitrile/ethyl acetate) yielding 325 mg of the title compound.

~2~ 6 GC213a C) [3S(Z)]-[[2-(Acetylamino)ethyl][[3-[[~2-amino-4-thiazolyl)(methoxyimino)acetyl]amino]-2-oxo-1-azetidinyl]carbonyl]amino]acetic acid, potassium _alt Diisopropylethylamine (0.204 ml, 1.17 mmol) was added to 165 mg (0.77 mmol) of (Z)-2-amino-~-(methoxyimino)-4-thiazoleacetic acid (containing 38 mole % hydrochloric acid) in 2.5 ml of dimethyl-formamide at 23C. The mixture was cooled to -10C and diphenylchlorophosphate (0.160 ml, 0.77 mmol) was added, and the resulting mixture was stirred for 30 minutes to yield a mixed anhydride.
(3S)-[[2-(Acetylamino)ethyl][[3-[[(phenyl-methoxy)carbonyl]amino]-2-oxo-1-azetidinyl]-carbonyl~amino]acetic acid, phenylmethyl ester (319 mg, 0.64 mmol) was dissolved in 2.5 ml of dimethylformamide and 121 mg (0.64 mmol) of ~-toluenesulfonic acid monohydrate was added.
Hydrogenolysis of the protecting groups at room temperature over 160 mg of 10% palladium on charcoal was complete after 1 hour. The reaction mixture was placed under an inert atmosphere and cooled to 0C. Diisopropylethylamine (0.369 ml, 2.11 mmol) was then added to the azetidinone, immediately followed by the mixed anhydride, and the resulting mixture was stirred at 0C for 2 hours.
The reaction mixture was filtered to remove the palladium on charcoal and the volatiles were removed under vacuum. The residue was purified by column chromatography with water on Dowex 50X2-400 resin (K form). Upon lyophilization, the pH of the residue (in ~4 ml of water at 0C) was ii3~

GC213a adjusted to 2.5 with lN hydrochloric acid, and this was then subjected to chromatography on HP-20 (eluting with water, 5% acetone-water, 10% acetone-water, and 15% acetone-water) to give the impure acid of the title compound. After lyophilization, the crude product was dissolved in ~4 ml of water at 0C, and the pH was adjusted to 7.5 with aqueous potassium bicarbonate. Purification of this solution by column chromatography on HP-20 (eluting with water) yielded, upon lyophilization, 114 mg of the title compound, melting point 170-180C, dec.
Anal. CalC'd- for Cl6H2oN7o7sK-3-oH2o C~ 35-09;
~, 4.79; N, 17.91.
Found: C, 35.15; H, 4.52; N, 17.48.

Example 39 [3S(Z)]-N-[[2-~[(2-Amino-4-thiazolyl)-(methoxyimino)acetyl]amino]-2-oxo-1-azetidinyl]-carbon~l]-N-(3-hydroxyphenyl~glycine A) Benzyl N-(3-benzyloxv)phenYlglYcinate To a solution of benzyl bromoacetate (4.0 ml, 25 mmole) and 3-benzyloxyaniline (4.98 g, 25 mmole) in 25 ml of dry dimethylformamide was added sodium acetate (2.05 g, 25 mmole). The reaction mixture was stirred at room temperature overnight and extracted from water with three portions of ethyl acetate. The combined organic layers were washed with water and dried over sodium sulfate. The volatiles were removed, and the residue was purified by flash chromatography on silica (LPS-1) (eluting with 10% ethyl acetate/hexane) to yield 6.0 g of moderately pure benzyl N-(3-benzyloxy)phenylglycinate.

~253~6 GC213a B) (3S)-N-[[3 [[(Phenylmethoxy)carbonyl]amino~-2-oxo-1-azetidinyl]carbonyl]-N-[3-(phenylmethoxy)-phenyl)~lycine, phenylmethyl ester Benzyl ~-(3-benzyloxy)phenylglycinate (780 mg) was dissolved in 6 ml of dry toluene and cooled to -15C. A phosgene solution (2.9 ml of 12.5% in toluene, 3.4 mmole) was added to the reaction mixture followed by the dropwise addition of pyridine (0.348 ml, 4.3 mmol) with rapid stirring. The reaction mixture was stirred for 1.5 hours at -15C and then allowed to warm to room temperature.
The precipitate of pyridinium hydrochloride was filtered under argon, and the volatiles were removed from the filtrate. This was dissolved in 4 ml of dry tetrahydrofuran and cooled to O~C. To this solution was added (S)-3-[[(phenylmethoxy)-carbonyl]amino]-2-azetidinone (440 mg, 2.0 mmol) and dimethylaminopyridine (36 mg, 0.3 mmol).
Triethylamine (0.307 ml, 2.2 mmol) was added dropwise and the reaction was allowed to warm to room temperature and stir overnight. The product was extracted from dilute aqueous hydrochloric acid with three portions of e-thyl acetate. The combined organic extracts were dried with sodium sulfate, filtered, and the volatiles removed. The residue was purified by flash chromatography on silica (LPS-l) (eluting with 50% ethyl acetate/hexane) to yield 559 mg of impure title compound.

~2~ii3~

GC213a C ) [3S ( Z ) ] -N- 1 [2-[[~2-Amino-4-thiazolyl)-(methoxyimino)acetyl]amino]-2-oxo-l~azetidinyl]-carbony~l-N~3-hydroxyphenyl)glycine Diisopropylethylamine (0.305 ml, 1.75 mmol) was added to 243 mg (1.13 mmol) of (Z)-2-amino-~-(methoxyimino)-4-thiazoleacetic acid (containing 0.38 molar equivalents of hydrochloric acid in 4 ml of dimethylformamide at 23C. The mixture was cooled to -15C, diphenylchlorophosphate (0.234 ml, 1.13 mmol) was added, and the resulting mixture was stirred for 30 minutes to yield a mixed anhydride.
(3S)-N-[C3-[[(Phenylmethoxy)carbonyl]amino~-2-oxo-1-azetidinyl]carbonyl]-N-[3-(phenylmethoxy)-phenyl)glycine, phenylmethyl ester (555 mg, ~0.94 mmol) was dissolved in 4 ml of dimethylformamide and 179 mg (0.94 mmol) of ~-toluenesulfonic acid monohydrate was added.
~ydrogenolysis of the protecting groups at room 20 temperature over 278 mg o~ 10% palladium on charcoal was complete after 50 mlnutes. The reaction mixture was placed under nitrogen and cooled to 0C.
Diisopropylethylamine (0.540 ml, 3.10 nlmol) was then added to the azetidinone, immediately followed by the mixed anhydride, and the resulting mixture was stirred at 0C for 3 hours.
The reaction mixture was filtered to remove the palladium on charcoal and the volatiles were removed under vacuum. The residue was suspended in 3 ml of water at 0C, the pH was adjusted to 6.5 with aqueous potassium bicarbonate, and the resulting mixture was subjected to column chromatography with water on Dowex 50X2-400 resin ~S3~
GC213a (K form). The crude product was dissolved in ~5 ml of water at 0C and the pH was adjusted to 3.0 with lN hydrochloric acid. Purification of this suspension by column chromatography on ~P-20 (eluting with water, 5% acetone/water, 10%
acetone/water, 15% acetone/water, and 20%
acetone/water) yielded, upon lyophilization, 183 mg of the title compound, melting point 163-171C, dec.
Anal- Calc'd- for C18H18N67S C~ 46-75; H~ 3-90;
N, 18.18.
Found: C, 47.46; H, 4.07; N, 15.12.

Example 40 [3S(Z)]-N-[[3-[[(2-Amino-4-thiazolyl~-(methoxyimino)acetyl~amino]-2-oxo-1-azetidinyl]-carbonyl]-N-(4-hydroxyphenyl)glycine, potassium salt A) N-[2-(Phenylmethoxy)-2-oxoethyl]-4-benzyloxy-aniline ~ ~. __ _ 4-Benzyloxyaniline hydrochloride (5.893 g, 25 mmol) was added to a solution of benzyl bromoacetate (4.0 ml, 25 mmoll in 25 ml of dry dimethylformamide. Sodium acetate (2.051 g, 25 mmole) and 13.82 g (0.1 mole) of potassium carbonate were added, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was extracted from water wi-th three portions of ethyl acetate. The combined organic layers were washed with water and dried over sodium sulfate. The volatiles were removed, and the residue was purified by flash column chromatography on silica (LPS-1) (eluting with 15%
ethyl acetate/hexane) to yield 5.64 g of the title compound.

~Z53~6 GC213a B) (3S)-N-[[3-[[(Phenylmethoxy)carbonyl]amino]-2-oxo-1-azetidinyl]carbonyl]-N-[4-(phenylmethoxy)-phenyl~glycine, phenylmethyl ester Benzyl-N-(4-benzyloxyphenyl)glycinate (694 mg, 2.0 mmole) was dissolved in 6 ml of dry toluene and cooled to 0C. A phosgene solution (2.9 ml, 12.5% in toluene) was added to the reaction mixture followed by the dropwise solution of pyridine (0.348 ml, 4.3 mmol) with rapid stirring. The reaction was stirred for 1.5 hours at 0C and then allowed to warm to room temperature. The precipitate of pyridinium hydrochloride was filtered under argon, and the volatiles were removed from the filtrate. This was dissolved in 4 ml of dry tetrahydrofuran and cooled to 0C. To this solution was added (S)-3-[[~phenylmethoxy)carbonyl]amino]-2-azetidinone (440 mg, 2.0 mmole) and 36 mg (0.3 mmole) o~
dimethylaminopyridine. Triethylamine (0.307 ml, 2.2 mmol) was then added dropwise, and the reaction mixture was allowed to warm to room temperature and stir overnight. The product was extracted with ethyl acetate from dllute aqueous hydrochloric acid. The combined organic extracts were dried with sodium sulfate and the volatiles removed. The residue was purified by flash chromatography on silica (LPS-l) (eluting with 1:1 ethyl acetate/hexane) to yield 465 mg of the title compound.

~-2539L~6 GC213a C) [3S(Z)]-N-[[3-[[(2-Amino-4~thiazolyl)-(methoxyimino)acetyl]amino]-2-oxo~l-azetidinylJ-carbonyl]-N-(4-hydroxyphenyl)glycine, potassium salt -N-Hydroxybenzotriazole hydrate (125 mg, 0.924 mmol) and 191 mg tO.924 mmol) of (Z)-2-amino-~-(methoxyimino)-4-thiazoleacetic acid (containing 0.15 molar equivalents of methanol were dissolved in 3.3 ml of dimethylformamide and cooled to 0C. N,N'-Dicyclohexylcarbodiimide (191 mg, 0.924 mmol) was added, and the mixture was warmed to room temperature. The reaction mixture was stirred for 30 minutes to yield the N-hydroxybenzotriazole ester.
(3S)-N-[[3-[[(Phenylmethoxy)carbonyl]amino]-2-oxo-1-azetidinyl]carbonyl]-N-[4-(phenylmethoxy)-phenyl]glycine, phenylmethyl ester (457 mg, 0.77 mmol) was dissolved in 3.3 ml of dimethyl-~ormamide and 147 mg (0.77 mmol) of p-toluene-sulfonic acid monohydrate was added. Hydrogen-olysis of the groups at room temperature over 229 mg of 10% palladium on charcoal was complete after 45 minutes. The reac-tion mixture was placed under nitrogen and cooled to 0C. Diisopropyl 25 ethylamine (0.442 ml, 2.54 mmol) was then added to the azetidinone immediately followed by the N-hydroxybenzotriazole ester, and the resulting mixture was stirred at 5C overnight.
The reaction mixture was filtered to remove the palladium on charcoal and the dicyclohexylurea precipitate, and the volatiles were removed under vacuum. The residue W2S dissolved in ~3 ml of water at 0C, and the pH was adjusted to 6.5 with ~253~

GC213a aqueous potassium bicarbonate. This solution was subjected to column chromatography with water on Dowex 50X2-400 resin (K form) to yield impure title compound. The crude product was dissolved in ~3 ml of water at 0C and the pH was readjusted to 6.5 with lN hydrochloric acid. Purification of this solution by column chromatography on HP-20 (eluting with water, and 5% acetone/water) yielded, upon lyophilization, 108 mg of the title compound, melting point 162-168C, dec.
Anal- Calc'd- for Cl8~l7N6o7sK-2-44~I2o C, 39-75;
H, 4.05; N, 15.45.
Found: C, 39.75; H, 4.05; N, 15.59.

Example 41 (R)-4-[(Aminocarbonyl)oxy]-1-[[(S)-3-[[(2-amino-4-thiazolyl)(methoxyimino)acetyl]amino]-2-oxo-1-azetidinYllcarbonyl]-L-proline __ A~ (trans)-1-[[3S-[[(Phenylmethoxy)carbonyl]-amino]-2-oxo-1-azetidinyl]carbonyl]-4-[(amino-carbonyl ~oxy]-L-proline, phenvlmethyl ester (trans)-1-[[3S-[[(Phenylmethoxy)carbonyl]-amino]-2-oxo-1-azetidinyl]carbonyl]-4-hydroxy-L-proline, phenylmethyl ester (1.32 g, 2.83 mmole;
see example 25A) in 25 ml of dry dichloromethane a-t -5C was added dropwise chlorosulfonyliso-cyanate (0.4 g, 2.83 mmole). The reaction mixture was stirred at -5C for 20 minutes at which point it became turbid white. Sodium sulfite (0.36 g, 2.86 mmole) in 2 ml water was added and the reaction was stirred and allowed -to warm to 15C
over a period of 1 hour. Ethyl acetate and water were added and the layers were separated. The ~5~
GC213a -115~

organic layer was washed with water and brine and dried over anhydrous sodium sulfate. After concen-trating to a residue, the crude product was purified on a silica (LPS-l) column eluting with ethyl acetate:hexane (1:1) to give 1 gm of pure compound.

B) (R)-4-[(Aminocarbonyl)oxy]-l-[[(S)-3-[[(2-amino-4-thiazolyl)(methoxyimino)acetyl]amino]-2-oxo-1-azetidinvl]carbonyl]-L-proline A mixture of (trans)-1-[[3S-[[(phenyl-methoxy)carbonyl]amino]-2-oxo-1-azetidinyl]-carbonyl]-~-[(aminocar~onyl)oxy]-L-proline, phenylmethyl ester (0.5 gms, 0.98 mmole), ~-toluenesulfonic acid monohydra~e (0.19 gms, 1 mmole) and 10% palladium on charcoal (0.25 gms) in 5 ml dimethylformamide was stirred at room temperature under a stream of hydrogen for 3 hours at which time tlc con~irmed that the deprotection was completed. To (Z)-2-amino-~-(methoxyimino)-4-thiazoleacetic acid (0.206 gms,~l mmole) and N-hydroxybenzotriazole (0.135 gms, 1 mmole) in 3 ml of dimethylformamide at 0C was added dicyclo-hexylcarbodiimide (0.206 gms, 1 mmole). This was stirred at ambient temperature for 1 hour. The deprotected ~-lactam was cooled to 0C and diiso-propylethylamine (0.12~ gms, 1 mmole) was added, . followed by the N-hydroxybenzotriazole ester. The reaction mixture was stirred at 5C overnight and the dimethylformamide was removed at room temperature. The reaction mixture was diluted with water, filtered through Celite and adjusted to pH 6.8 with lN potassium bicarbonate. This aqueous solution was applied to an AG-50 (K ) 3~46 GC213a column and eluted with water until all of the fluorescent material was collected. The aqueous solution was concentrated to a small volume and chromatographed twice on an HP-20 column eluting with water to achieve complete separation from N-hydroxybenzotriazole. However, the potassium s~lt of the title compound was contaminated wlth a large amount of the potassium salt of ~-toluene-sulfonic acid. The sample was then taken up in water and adjusted to pH 2.55 with 1% hydrochloric acid. This solution was then applied to an HP-20 column and eluted first with water until all the ~-toluenesulfonic acid was removed and then eluted with an acetone/water gradient to recover the product. The fractions containing pure product were lyophilized to a whlte solid (61 mg), melting point >190C, dec.

Exam~le 42 [3S(Z~]-[[[3-[[(2-Amino-4-thiazolyl)[[1,1-dimethyl-2-oxo-2-(1-piperazinyl)ethoxy]imino]-acetyl]amino]-2-oxo-1-azetidinyl]carbonyl]-methylaminolacetic acid A) N-Tritylpi~erazine To a solution of piperazine (25.9 g, 0.30 mol) in tetrahydrofuran (300 ml) at 0C was added triphenylmethyl chloride (27.9 g, 0.10 mol). The reaction was stirred for 48 hours at room temperature. The product was extracted from aqueous sodium carbonate with three portions of ether. The combined organic layers were washed with three portions of water, dried with sodium sulfate, and the volatiles were then evaporated.

~53~

-117- GC213a The residue was subjected to chromatography on silica (LPS-1) (eluting with 90:10:4 ether~acetoni-trile/triethylamine) to yield 7.62 g of N-trityl-piperazine.
S
- B) 5Z~-2-Amino-a-[[1,1-dimethyl-2-oxo-2-(N-tri-tylpiperazinyl)ethoxy]imino]-4-thiazoleacetic acid, methYl ester To a solution of (Z)-2-amino-~-[(1-carboxy-1-methylethoxy)imino]-4-thiazoleacetic acid, methyl ester (3.16 g, 11.0 mmol) in dimethylformamide (44 ml) and N,N-diisopropyl-ethylamine (2.11 ml, 12.1 mmol) at -10C was added diphenylchlorophosphate (2.51 ml, 12.1 mmol).
After one hour at -10C, a solution of N-trityl-piperazine (3.87 g, 11.0 mmol correcting for 7% by weight triethylamine) in tetrahydrofuran (20 ml) and triethylamine (1.54 ml, 11.0 mmol) was added over 15 minutes. The reaction was stirred for an additional 15 minutes at -lO~C and for 2 hours at OC
The product was extracted from agueous sodium bicarbonate with three portions of ethyl acetate, and the combined organic layers were washed with two portions of water. After drying with sodium sulfate, the volatiles were removed.
The residue was subjected to column chromatography *
on Mallinckrodt CC-7 silica (eluting with 1:1 ethyl acetate/hexane) to yield 4.02 g of the title compound.

*Trademark ~s~

-118- G~213a C) (2)-2-Amino-~-[[1,1-dimethyl-2-oxo-2-(N-tri-tylpiperazinyl)ethoxy~imino]-4-thiazoleacetic acid (Z)-2-Amino-~-[[l,l-dimethyl-2-oxo-2-(N-tri-tylpiperazinyl)ethoxy~imino]-4-thiazoleacetic acid, methyl ester (4.03 g, 6.75 mmol) was suspended in a s~lution of 0.90 g of potassium hydroxide in ethanol (22.5 ml) and water (1.8 ml), and stirred overnight at room temperature. The reaction was then heated to 60C for 30 minutes.
Upon cooling to room temperature, water (22.5 ml) was added, and the reaction mixture was filtered through Celite. The filtrate was then acidified to pH 3 with lN hydrochloric acid while cooling in ice, and the precipitate that formed was isolated by filtration. The precipitate was washed with water, ether and acetonitrile to yield 1.71 g of the title compound.

D) [3S(Z)]-[[[3-[[(2-Amino-4-thiazolyl)[[1,1-dimethyl-2-oxo-2-(N-trityl-1-piperazinyl)ethoxy]-imino3acetyl]amino]-2-oxo-1-azetdinyl]carbonyl]-methylamino]acetic acid, potassium salt Diisopropylethylamine (0.148 ml, 0,85 mmol) was added to 455 mg (0.78 mmol) of (Z)-2-amino-~-[[1,1-dimethyl-2-oxo~2-(N-tritylpiperazinyl)-ethoxy]imino]-4-thiazoleacetic acid in 3 ml of dimethylformamide a-t 23C. The mixture was cooled to -15C, diphenylchlorophosphate (0.1~2 ml, 0.78 mmol) was added, and the resulting mixture was stirred for 30 minutes to yield a mixed anhydride.
(S)-[N-[[3-[[(Phenylmethoxy)carbonyl]amino]-2-oxo-1-aze-tidinyl]carbonyl]methylamino]acetic acid, A C
GC213a phenylmethyl ester (333 mg, 0.78 mmol, see example - 8A) was dissolved in 5 ml of dimethylformamide and 148 mg (0.78 mmol) of ~-toluenesulfonic acid mono-hydrate was added. Hydrogenolysis of the protecting groups at room temperature over 166 mg of 10% palladium on charcoal was complete after 1 hour. The reaction mixture was placed in an inert atmosphere and cooled to 0C. Diisopropylethyl-amine (0.448 ml, 2.57 mmol) was then added to the azetidinone, immediately followed by the mixed anhydride, and the resulting mixture was stirred at 5C overnight.
The reaction mixture was filtered to remove the palladium on charcoal, and the volatiles were removed under vacuum. The residue was subjected to column chromatography with 20% acetone-water on Dowex 50X2-400 resin (K form). Upon lyophiliza-tion, the crude produc-t was dissolved in wa~er and purified by column chromatography on HP-20 (eluting with water, 10% acetone-water, 20%
acetone-water, and 40% acetone-water) to yield upon lyophilization 266 mg o~ the title compound.

E) [3S(Z)]-[[[3-[[(2-Amino-4-thiazolyl)[[1,1-dimethyl-2-oxo-2-(1-piperazinyl)ethoxy]imino]-acetyl]amino]-2~oxo-1-azetidinyl]carbonyl]-methylamino]acetic acid [3S(Z)]-[[[3-[[(2-Amino-4-thiaæolyl)[[l,1-dimethyl-2 oxo-2-(N-trityl-1-piperazinyl)etkloxy]-imino]acetyl]amino]-2-oxo-1-azetdinyl]carbonyl]-methylamino]acetic acid, potassium salt (60 mg, 0. 075 mmol) was dissolved in 1 ml of g8% formic acid at room temperature. After 2 hours, the volatiles were removed under vacuum (without ~5314G
GC213a external heating). The residue was purified by column chromatography on HP-20 (eluting with water, 5% acetone-water, and 10% acetone-water) to yield, upon lyophilization, 18 mg of the title compound, melting point 220-225C, dec.
Anal- Calc'd- for C2oH28N8O7S-2-27~2O C, 44.02 H, 5.60; N, 20.54.
Found: C, 44.02; H, 5.57; N, 19.82.

Example 43 [3S(Z)]-N-[[3-[[(2~Amino-4-thiazolyl)-(methoxyimino)acetyl]amino]-2-oxo-l-azetidinyl]-carbonyl]-N-(3,4-dihydroxyphenyl)glycine, potassium salt A) Benzyl N-~,4-dibenæyloxy)Phenylqlycinate To a solution of benzyl bromoacetate (2.39 ml, 15 mmole) and 3,4-dibenzyloxyaniline (4.575 g, 15 mmole) in 15 ml of dry dimethyl-formamide was added sodium acetate (1.231 g, 15 mmole). The reaction was stirred at room temperature overnight and extracted from water with three portions of ethyl acetate. The combined organic layers were washed with water, dried over sodium sulfate, and filtered. The volatiles were removed, and the residue was purified by flash chromatography on silica (LPS-l) (eluting with 15% ethyl acetate/hexane) to yleld 3.86 g of the title compound.

~253~6 GC213a B) (3S)-N-[[3-[[(Phenylmethoxy)carbonyl]amino]-2-oxo-1-azetidinyl]carbonyl]-N-[3,4-(diphenyl-methoxy)phenvl]qlycine, phenylmethyl ester Benzyl N-(3,4-dibenzyloxy)phenylglycinate (902 mg, 2.0 mmole) was dissolved in 6 ml of dry toluene and cooled to 0C. A phosgene solution (2.9 ml of 12.5% in toluene, 3.4 mmole) was added to the reaction mixture followed by the dropwise addition of pyridine ~0.348 ml, 4.3 mmole) wlth rapid stirring. The reaction mixture was stirred for 1.5 hours at 0C and then allowed to warm to room temperature. The precipitate of pyridinium hydrochloride was filtered under argon, and the volatiles were removed from the filtrate. This was dissolved in 4 ml of dry tetrahydrofuran and cooled to 0C. To this solution was added the (S)-3-[[(phenylmethoxy)carbonyl]amino]-2-azetidinone (440 mg, 2.0 mmole) and dimethylamino-pyridine (36 mg, 0.3 mmol). Triethylamine 20 (O.307 ml, 2.2 mmole) was then added dropwise, and the reaction mixture was allowed to warm to room temperature and stir overnight. Tha product was extracted from dilute aqueous hydrochloric acid with three portions of ethyl acetate. The combined organic extracts were dried with sodium sulfate, filtered, and the volatiles removed. The residue was purified by flash chromatography on silica (LPS-1) (eluting with 55% ethyl acetate/hexane) to yield 500 mg of the title compound.

~2S3~
GC213a -l?2-C) [3S-[3~(Z),4~]]-N-[[3-[[(2-Amino-4-thiazolyl)-- (methoxyimino)acetyl]amino]-2-oxo-1-azetidinyl]-carbonyl]-N-(3,4-dihydroxyphenyl)glycine, potassium salt N-Hydroxybenzotriazole hydrate (127 mg, 0.936 mmole) and 193 mg (0.936 mmole) of (Z)-2-amino-a-(methoxyimino)-4-thiazoleacetic acid (containing 0.15 molar equivalents of methanol were dissolved in 3.4 ml of dimethylformamide and cooled to 0C. N,N-Dicyclohexylcarbodiimide (193 mg, 0.936 mmole) was added, and the mixture was warmed to room temperature. The reaction mixture was stirred for 30 minutes to yield the N-hydroxybenzotriazole ester.
Benzyl N-(3,4-dibenzyloxy)phenylglycinate (543 mg, 0.78 mmole) was dissolved in 3.4 ml of dimethylformamide and 148 mg (0.78 mmole) of p-toluenesulfonic acid monohydrate was added.
Hydrogenolysis of the protecting groups at room 20 temperature over 272 mg of 10% palladium on charcoal was complete after 45 minutes. The reaction mixture was placed under nitrogen and cooled to 0C. Diisopropylethylamine (0.447 ml, 2.57 mmole) was then added to the azetidinone immediately followed by the N-hydroxybenzotriazole ester, and the resulting mixture was stirred at 5C overnight.
The reaction mixture was filtered to remove the palladium on charcoal and the dicyclohexylurea precipitate, and the volatiles were removed under vacuum. The residue was suspended in ~3 ml of water at 0C, and the pH was adjusted to 6.5 with aqueous potassium bicarbonate. ~cetone (~2 ml) ~33~46 -123- GC213a was added, and the resulting solution was subjected to column chromatography with water on Dowex 50X2-400 resin (K form) to yield impure title compound. The crude product was dissolved in ~3 ml of water at 0C and the pH was readjusted to 6.5 with lN hydrochloric acid. Purification of this solution by column chromatography on ~7P-20 ~eluting with water, and 5% acetone/water) yielded, upon lyophilization, 66 mg of the -title compound, melting point 165-170C, dec.
Anal- Calc'd- for C18H17N68SK-1 8H2 C~ 39-39;
H, 3.76; N, 15.32; K, 7.11.
Found: C, 39.39; H, 3.96; N, 14.84; K, 7.11.

Claims (68)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A compound having the formula or a pharmaceutically acceptable ester or salt thereof, wherein Z1 is oxygen or sulfur;
R1 is hydrogen or an acyl group derived from a carboxylic acid;
R2 is hydrogen or methoxy;
R3 and R4 are the same or different and each is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, substituted phenyl or a 4, 5, 6 or 7-membered heterocycle, or one of R3 and R4 is hydrogen and the other is azido, halomethyl, dihalomethyl, trihalomethyl, alkoxycarbonyl, 2-phenylethenyl, 2-phenylethynyl, carboxy, -CH2X1, wherein X1 is azido,amino, hydroxy, carboxy, alkoxycarbonyl, alkanoylamino, phenylcarbonylamino, (substituted phenyl)carbonylamino, alkylsulfonyl-oxy, phenylsulfonyloxy, (substituted phenyl)-sulfonyloxy, phenyl, substituted phenyl, cyano, -S-X2 or -O-X2; X2 is alkyl, phenyl, or substituted phenyl;
one of X3 and X4 is hydrogen and the other is hydrogen or alkyl, or X3 and X4 when taken together with the carbon atom to which they are attached form a cycloalkyl group; X5 is formyl, alkanoyl, phenylcarbonyl, (substituted phenyl)carbonyl, phenylalkylcarbonyl, (substituted phenyl)alkyl-carbonyl, carboxy, alkoxycarbonyl, aminocarbonyl, (substituted amino)carbonyl, or cyano; A is -CH=CH-, -(CH2)n-, -CH2-O-, -CH2-NH- -CH2-S-CH2- or -CH2-O-CH2-; n is 0, 1 or 2; and X6 and X7 are the same or different and each is hydrogen, alkyl, phenyl or substituted phenyl, or X6 is hydrogen and X7 is amino, substituted amino, alkanoylamino or alkoxy, or X6 and X7 when taken together with the nitrogen atom to which they are attached form a 4, 5, or 6- membered nitrogen containing heterocycle;
R5 and R6 are the same or different and each is hydrogen, alkyl, alkenyl, alkynyl, phenyl, substituted phenyl, cycloalkyl or a 4, 5, 6 or 7-membered heterocycle, or R5 and R6 together with the carbon atom to which they are attached are cycloalkyl, or one of R5 and R6 is hydrogen and the other is halomethyl, dihalomethyl, trihalomethyl, alkoxycarbonyl, alkenyl, alkynyl, 2-phenylethenyl, 2-phenylethynyl, carboxy, -CH2-X1, or or R6 is hydrogen and R5 together with R7 and the atoms to which they are attached form a 4, 5, or 6-membered nitrogen containing heterocycle; and R7 is hydrogen, alkyl, phenyl, substituted phenyl, cycloalkyl, a 4, 5, 6 or 7-membered heterocycle, or -(CH2)n-Z3 wherein n is 2, 3 or 4 and Z3 is azido, -NZ5Z6, halogen, hydroxy,, cyano, , alkanoyloxy, alkoxy, phenyloxy, (substituted phenyl)oxy, (a 4, 5, 6 or 7-membered hetero-cycle)-O-, mercapto, alkylthio, phenylthio, (substituted phenyl)thio, alkylsulfinyl, alkylsulfonyl, , or , wherein Z4 is oxygen, sulfur or Z5 is hydrogen, alkyl, phenyl, substituted phenyl, phenylalkyl or (sub-stituted phenyl)alkyl, Z6 is hydrogen, alkyl, phenyl, substituted phenyl, phenylalkyl, (sub-stituted phenyl)alkyl, alkanoyl, phenylcarbonyl, or (substituted phenyl)carbonyl, and Z7 is hydrogen, alkyl, phenyl or substituted phenyl;
wherein the terms "alkyl" and "alkoxy" refer to groups having 1 to 10 carbon atoms;
the term "cycloalkyl" refers to groups having 3, 4, 5, 6 or 7 carbon atoms;
the term "substituted alkyl" refers to alkyl groups substituted with one, or more, azido, amino, halogen, hydroxy, carboxy, cyano, alkoxycarbonyl, aminocarbonyl, alkanoyloxy, alkoxy, phenyloxy, (substituted phenyl)oxy, (4, 5, 6 or 7-membered heterocycle)oxy, mercapto, alkylthio, phenylthio, (substituted phenyl)thio, alkylsulfinyl or alkyl-sulfonyl groups;
the terms "alkanoyl", "alkenyl", and "alkynyl"
refer to groups having 2 to 10 carbon atoms;

the term "substituted phenyl" refers to a phenyl group substituted with 1, 2 or 3 amino, halogen, hydroxyl, trifluoromethyl, alkyl (of 1 to 4 carbon atoms), alkoxy (of 1 to 4 carbon atoms), alkanoyloxy, aminocarbonyl or carboxy groups;
the term "a 4, 5, 6 or 7-membered hetero-cycle" refers to pyridinyl, furanyl, pyrrolyl, thienyl, 1,2,3-triazolyl, 1,2,4-triazolyl, imidazolyl, thiazolyl, thiadiazolyl, pyrimidinyl, oxazolyl, triazinyl, tetrazolyl, azetidinyl, oxetanyl, thietanyl, piperidinyl, piperazinyl, imidazolidinyl, oxazolidinyl, pyrrolidinyl, tetra-hydropyrimidinyl, dihydrothiazolyl, hexahydroaze-pinyl, or one of the above groups substituted with one, or more, oxo, halogen, hydroxy, nitro, amino, cyano, trifluoromethyl, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkylsul-fonyl, phenyl, substituted phenyl, 2-furfurylidene-amino, benzylideneamino, or substituted alkyl, wherein the alkyl group has 1 to 4 carbon atoms, groups;
the term "heteroaryl" refers to pyridinyl, furanyl, pyrrolyl, thienyl, 1,2,3-triazolyl, 1,2,4-triazolyl, imidazolyl, thiazolyl, thia-diazolyl, pyrimidinyl, oxazolyl, triazinyl, tetrazolyl or one of the above groups substituted with one, or more, oxo, halogen, hydroxy, nitro, amino, cyano, trifluoromethyl, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkyl-sulfonyl, phenyl, substituted phenyl, 2-fur-furylideneamino, benzylideneamino, or substituted alkyl, wherein the alkyl group has 1 to 4 carbon atoms, groups;
the term "substituted amino" refers to a group having the formula -NZ8Z9 wherein Z8 is hydrogen, alkyl, phenyl, substituted phenyl, phenylalkyl or (substituted phenyl)alkyl and Z9 is alkyl, phenyl, substituted phenyl, phenylalkyl, (substituted phenyl)alkyl, hydroxy, cyano, alkoxy, phenylalkoxy, or amino;
the expression "a 4, 5, or 6- membered nitrogen containing heterocycle" refers to 1-pyrroli-dinyl, .DELTA.3-pyrrolin-1-yl, 1-azetidinyl, 1-piperi-dinyl, .DELTA.3-piperidein-1-yl, .DELTA.4-piperidein-1-yl, 3-oxazolidinyl, 3-thiazolidinyl, 1-imidazolidinyl, 4-thiomorpholinyl, 4-morpholinyl, 1-piperazinyl, 1-hexahydropyrimidinyl, tetrahydro-2H-1,3-thiazin-3-yl, tetrahydro-2H-1,3-oxazin-3-yl, 3-thiazolidinyl,-1-oxide, 3-thiazolidinyl,1,1-dioxide, 4-thio-morpholinyl,1-oxide, 4-thiomorpholinyl,1,1-dioxide, tetrahydro-2H-1,3-thiazin-3-yl,1-oxide, tetrahydro-2H-1,3-thiazin-3-yl,1,1-dioxide, or one of the above groups substituted with one, or more, oxo, halogen, hydroxy, amino, cyano, trifluoro-methyl, alky1 of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkylsulfonyl, phenyl, sub-stituted phenyl, azido, carboxy, aminocarbonyl, OZ10, NZ10, or SZ10 groups where Z10 is alkanoyl, aminocarbonyl, aminosulfonyl, phenylcarbonyl, (substituted phenyl)carbonyl, alkyl, substituted alkyl, phenyl or substituted phenyl.

2. A compound in accordance with claim 1 wherein Z1 is oxygen and R2 is hydrogen.

3. A compound in accordance with claim 2 wherein R7 is hydrogen.

4. A compound in accordance with claim 2 wherein R7 is alkyl.

5. A compound in accordance with claim 2 wherein R7 is phenyl or substituted phenyl.

6. A compound in accordance with claim 2 wherein R7 is -(CH2)n-Z3

7. A compound in accordance with claim 2 wherein R3, R4, R5 and R6 are each independently hydrogen or methyl.

8. A compound in accordance with claim 2 wherein R3, R4, R5 and R6 are each hydrogen.

9. A compound in accordance with claim 1 wherein R1 is and Ri is methyl, ethyl, carboxymethyl, 1-carboxy-1-methylethyl, 2,2,2-trifluoroethyl or 1-carboxycyclopropyl.

10. A compound in accordance with claim 2 wherein R1 is and Ri is methyl, ethyl, carboxymethyl, 1-carboxy-1-methylethyl, 2,2,2-trifluoroethyl or 1-carboxycyclopropyl.

11. A compound in accordance with claim 1 having the formula.
or a pharmaceutically acceptable ester or salt thereof, wherein R1 is an acyl group derived from a carboxylic acid and R7 is methyl or ethyl.

12. A compound in accordance with claim 11 wherein R1 is and Ri is methyl, ethyl, carboxymethyl, 1-carboxy-1-methylethyl, 2,2,2-trifluoroethyl or 1-carboxy-cyclopropyl.

13. A compound in accordance with claim 1 having the formula or a pharmaceutically acceptable ester or salt thereof, wherein R1 is an acyl group derived from a carboxylic acid and R7 is phenyl or substituted phenyl.

14. A compound in accordance with claim 13 wherein R1 is and Ri is methyl, ethyl, carboxymethyl, 1-carboxy-1-methylethyl, 2,2,2-trifluoroethyl or 1-carboxy-cyclopropyl.

15. A compound in accordance with claim 1 having the formula or a pharmaceutically acceptable ester or salt thereof, wherein R1 is an acyl group derived from a carboxylic acid and R5 together with R7 and the atoms to which they are attached form a 4, 5, or 6-membered nitrogen containing heterocycle.

16. A compound in accordance with claim 15 wherein R5 together with R7 and the atoms to which they are attached are pyrrolidinyl or pyrrolidinyl substituted in the 4-position with halogen, hydroxy, aminocarbonyloxy, aminocarbonylamino, or aminosulfonylamino.

17. A compound in accordance with claim 15 wherein R5 together with R7 and the atoms to which they are attached are azetidinyl or azetidinyl substituted in the 3-position with halogen, hydroxy, aminocarbonyloxy, aminocarbonylamino, or aminosulfonylamino.

18. A compound in accordance with claim 15 wherein R1 is and Ri is methyl, ethyl, carboxymethyl, 1-carboxy-1-methylethyl, 2,2,2-trifluoroethyl or 1-carboxy-cyclopropyl.

19. A compound in accordance with claim 16 wherein R1 is and Ri is methyl, ethyl, carboxymethyl, 1-carboxy-1-methylethyl, 2,2,2-trifluoroethyl or 1-carboxy-cyclopropyl.

20. A compound in accordance with claim 17 wherein Ri is and Ri is methyl, ethyl, carboxymethyl, 1-carboxy-1-methylethyl, 2,2,2-trifluoroethyl or 1-carboxy-cyclopropyl.

21. The compound in accordance with claim 1, [3S(Z)]-1-[[3-[[(2-amino-4-thiazolyl)(methoxy-imino)acetyl]amino] 2-oxo-1-azetidinyl]carbonyl]-L-proline, or a pharmaceutically acceptable salt thereof.

22. The compound in accordance with claim 1, [3S(Z)]-1-[[3-[[(2-amino-4-thiazolyl)[(1-carboxy-1-methylethoxy)imino]acetyl]amino]-2-oxo-1-azetidinyl]carbonyl]-L-proline, or a pharmaceutically acceptable salt thereof.

23. The compound in accordance with claim 1, (trans)-1-[[3S(Z)]-[3-[[(2-amino-4-thiazolyl)-(methoxyimino)acetyl]amino]-2-oxo-1-azetidinyl]-carbonyl]-4-hydroxy-L-proline, or a pharmaceutically acceptable salt thereof.

24. The compound in accordance with claim 1, (S)-1-[[3S(Z)]-[3-[[(2-amino-4-thiazolyl)(methoxy-imino)acetyl]amino]-2-oxo-1-azetidinyl]carbonyl]-2-azetidinecarboxylic acid, or a pharmaceutically acceptable salt thereof.

25. The compound in accordance with claim 1, (S)-1-[[(S)-3-[(Z)-[(2-amino-4-thiazolyl)-[(carboxymethoxy)imino]acetyl]amino]-2-oxo-1-azetidinyl]carbonyl]-2-azetidinecarboxylic acid, or a pharmaceutically acceptable salt thereof.

26. The compound in accordance with claim 1, (S)-1-[[(S)-3-[[(Z)-(2-amino-4-thiazolyl)[(1-carboxy-1-methylethoxy)imino]acetyl]amino]-2-oxo-1-azetidinyl]carbonyl]-2-azetidinecarboxylic acid, or a pharmaceutically acceptable salt thereof.

27. The compound in accordance with claim 1, [3S(Z)]-N-[[3-[[(2-amino-4-thiazolyl)-(methoxyimino)acetyl]amino]-2-oxo-1-azetidinyl]-carbonyl]-N-(4-hydroxyphenyl)glycine, or a pharmaceutically acceptable salt thereof.

28. The compound in accordance with claim 1, (R)-4-[(aminocarbonyl)oxy]-1-[[(S)-3-[[(2-amino-4-thiazolyl)(methoxyimino)acetyl]amino]-2-oxo-1-azetidinyl]carbonyl]-L-proline, or a pharmaceutically acceptable salt thereof.

29. The compound in accordance with claim 1, [3S(Z)]-2-[[[1-(2-amino-4-thiazolyl)-2-[[1-[[(carboxymethyl)methylamino]carbonyl]-2-oxo-3-azetidinyl]amino]-2-oxoethylidene]amino]oxy]-2-methylpropanoic acid, or a pharmaceutically acceptable salt thereof.

30. The compound in accordance with claim 1, [3S(Z)]-[N-[[3-[[(2-amino-4-thiazolyl)(methoxy-imino)acetyl]amino]-2-oxo-1-azetidinyl]carbonyl]-methylamino]acetic acid, or a pharmaceutically acceptable salt thereof.

31. The compound in accordance with claim 1, [3S(Z)]-N-[[3-[[(2-amino-4-thiazolyl)(methoxy-imino)acetyl]amino]-2-oxo-1-azetidinyl]carbonyl]-N-ethylglycine, or a pharmaceutically acceptable salt thereof.

32. A process for preparing a compound having the formula or a pharmaceutically acceptable ester or salt thereof, wherein Z1 is oxygen or sulfur;
R1 is an acyl group derived from a carboxylic acid;
R2 is hydrogen or methoxy;
R3 and R4 are the same or different and each is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, substituted phenyl or a 4, 5, 6 or 7-membered heterocycle, or one of R3 and R4 is hydrogen and the other is azido, halomethyl, dihalomethyl, trihalomethyl, alkoxycarbonyl, 2-phenylethenyl, 2-phenylethynyl, carboxy, -CH2X1, wherein X1 is azido, amino, hydroxy, carboxy, alkoxy-carbonyl, alkanoylamino, phenylcarbonylamino, (substituted phenyl)carbonylamino, alkylsulfonyloxy, phenylsulfonyloxy, (substituted phenyl)sulfonyloxy, phenyl, substituted phenyl, cyano, -S-X2 or -O-X2; X2 is alkyl, phenyl, or substituted phenyl; one of X3 and X4 is hydrogen and the other is hydrogen or alkyl, or X3 and X4 when taken together with the carbon atom to which they are attached form a cycloalkyl group;
X5 is formyl, alkanoyl, phenylcarbonyl, (substituted phenyl)-carbonyl, phenylalkylcarbonyl, (substituted phenyl)alkylcar-bonyl, carboxy, alkoxycarbonyl, aminocarbonyl, (substituted amino)carbonyl, or cyano; A is -CH=CH-, -(CH2)n-, -CH2-O-, -CH2-NH-, -CH2-S-CH2- or -CH2-O-CH2-; n is 0, 1 or 2; and X6 and X7 are the same or different and each is hydrogen, alkyl, phenyl or substituted phenyl, or X6 is hydrogen and X7 is amino, substituted amino, alkanoylamino or alkoxy or X6 and X7 when taken together with the nitrogen atom to which they are attached form a 4, 5, or 6-membered nitrogen contain-ing heterocycle;
R5 and R6 are the same or different and each is hydrogen, alkyl, alkenyl, alkynyl, phenyl, substituted phenyl, cycloalkyl or a 4, 5, 6 or 7-membered heterocycle, or R5 and R6 together with the carbon atom to which they are attached are cycloalkyl, or one of R5 and R6 is hydrogen and the other is halomethyl, dihalomethyl, trihalomethyl, alkoxycarbonyl, alkenyl, alkynyl, 2-phenylethenyl, 2-phenylethynyl, carboxy, -CH2-Xl, or , or R6 is hydrogen and R5 together with R7 and the atoms to which they are attached form a 4, 5, or 6-membered nitrogen contain-ing heterocycle; and R7 is hydrogen, alkyl, phenyl, substituted phenyl, cycloalkyl, a 4, 5, 6 or 7-membered heterocycle, , or -(CH2)n-Z3 wherein n is 2, 3 or 4 and Z3 is azido, -NZ5Z6, halogen hydroxy, , alkanoyloxy, alkoxy, phenyloxy, (substituted phenyl)oxy, (a 4, 5, 6 or 7-membered heterocycle)-O-, mercapto, alkythio, phenyl-thio, (substituted phenyl)thio, alkylsulfinyl, alkylsulfonyl, , or wherein Z4 is oxygen, sulfur or Z5 is hydrogen, alkyl, phenyl, substituted phenyl, phenylalkyl or (substituted phenyl)alkyl, Z6 is hydrogen, alkyl, phenyl, substituted phenyl, phenylalkyl, (substituted phenyl)alkyl, alkanoyl, phenylcarbonyl, or (sub-stituted phenyl)carbonyl, and Z7 is hydrogen, alkyl, phenyl or substituted phenyl, wherein the terms "alkyl"and "alkoxy" refer to groups having 1 to 10 carbon atoms;
the term "cycloalkyl" refers to groups having 3, 4, 5 6 or 7 carbon atoms;
the term "substituted alkyl" refers to alkyl groups substituted with one, or more, azido, amino, halogen, hydroxy, carboxy, cyano, alkoxycarbonyl, aminocarbonyl, alkanoyloxy, alkoxy, phenyloxy, (substituted phenyl)oxy, (4, 5, 6 or 7-membered heterocycle)oxy, mercapto, alkylthio, phenylthio, (substituted phenyl)thio, alkylsulfinyl or alkylsulfonyl groups;
the term "alkanoyl", "alkenyl", and "alkynyl" refer to groups having 2 to 10 carbon atoms;

the term "substituted phenyl" refers to a phenyl group substituted with 1, 2 or 3 amino, halogen, hydroxyl, trifluoro-methyl, alkyl (of 1 to 4 carbon atoms), alkoxy (of 1 to 4 car-bon atoms), alkanoyloxy, aminocarbonyl or carboxy groups;
the term "a 4, 5, 6 or 7-membered heterocycle" refers to a pyridinyl, furanyl, pyrrolyl, thienyl, 1,2,3-trizolyl, 1,2,4-triazolyl, imidazoyl, thiazoyl, thiadiazolyl, pyrimid-inyl, oxazolyl, triazinyl , tetrazolyl, azetidinyl, oxetanyl, thietanyl, piperidinyl, piperazinyl, imidazolidinyl, oxasoli-dinyl, pyrrolidinyl, tetrahydropyrimidinyl, dihydrothiazolyl, hexahydroazepinyl, or one of the above groups substituted with one, or more, oxo, halogen, hydroxy, nitro, amino, cycano, tri-fluoromethyl, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkylsulfonyl, phenyl, substituted phenyl, 2-fur-furylideneamino, benzylideneamino, or substituted alkyl, where-in the alkyl group has 1 to 4 carbon atoms, groups;
the term "heteroaryl" refers to pyridinyl, furanyl, pyrrolyl, thienyl, 1,2,3-triazolyl, 1,2,4-triazolyl, imidazoyl, thiazolyl, thiadiazolyl, pyrimidinyl, oxazolyl, triazinyl, tetrazolyl or one of the above groups substituted with one, or more, oxo, halogen, hydroxy, nitro, amino, cyano, trifluoro-methyl, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkylsulfonyl, phenyl, substituted phenyl, 2-furfuryli-deneamino, benzylideneamino, or substituted alkyl, wherein the alkyl group has 1 to 4 carbon atoms, groups;
the term "substituted amino" refers to a group having the formula -NZ8Z9 wherein Z8 is hydrogen, alkyl, phenyl, substituted phenyl, phenylalkyl or (substituted phenyl)alkyl, and Z9 is alkyl, phenyl, substituted phenyl, phenylalkyl, (sub-situted phenyl)alkyl, hydroxy, cyano, alkoxy, phenylalkoxy, or amino;
the expression "a 4, 5, or 6-membered nitrogen containing heterocycle" refers to 1-pyrrolidinyl, .DELTA.3-pyrrolin-1-yl, 1-azetidinyl, 1-piperidinyl, .DELTA.3-piperidein-1-yl, .DELTA.4-piperidein-1-yl, 3-oxazolidinyl, 3-thiazolidinyl, 1-imidazoli-dinyl,4-thiomorpholinyl, 4-morpholinyl, 1-piperazinyl, 1-hexa-hydropyrimidinyl, tetrahydro-2H-1,3-thiazin-3-yl, tetrahydro-2H-1,3-oxazin-3-yl, 3-thiazolidinyl,1-oxide, 3-thiazolidinyl,-1,1-dioxide, 4-thiomorpholinyl,1-oxide, 4-thiomorphoinyl,1,1-dioxide, tetrahydro-2H-1,3-thiazin 3-yl,1-oxide, tetrahydro-2H-1,3-thiazin-3-yl,1,1-dioxide, or one of the above groups substituted with one, or more, oxo, halogen, hydroxy, amino, cyano, trifluoromethyl, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkylsulfonyl, phenyl, substituted phenyl, azido, carboxy, aminocarbonyl, OZ10, NZ10, or SZ10 groups where Z10 is alkanoyl, aminocarbonyl, aminosulfonyl, phenylcarbonyl, (substituted phenyl)carbonyl, alkyl, substituted alkyl, phenyl or substituted phenyl, characterized by acyl-ating a compound of the formula with an R1-acyl group according to conventional procedures.

33. A compound having the formula or a pharmaceutically acceptable ester or salt thereof wherein Z1 is oxygen or sulfur;
R1 is an acyl group derived from a carboxylic acid;
R2 is hydrogen or methoxy;
R3 and R4 are the same or different and each is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, substituted phenyl or a 4, 5, 6 or 7-membered heterocycle, or one of R3 and R4 is hydrogen and the other is azido, halomethyl, dihalomethyl, trihalomethyl, alkoxycarbonyl, 2-phenylethenyl, 2-phenylethynyl, carboxy,-CH2X1, -S-X2, -O-X2, or wherein X1 is azido, amino, hydroxy, carboxy, alkoxycarbonyl, alkanoylamino, phenylcarbonylamino, (substituted phenyl)carbonyl-amino, alkylsufonyloxy, phenylsulfonyloxy, (substituted phenyl)-sulfonyloxy, phenyl, substituted phenyl, cyano, -S-X2 or -O-X2; X2 is alkyl, phenyl or substituted phenyl; one of X3 and X4 is hydrogen and the other is hydrogen or alkyl, or X3 and X4 when taken together with the carbon atom to which they are attached form a cycloalkyl group; X5 is formyl, alkanoyl, phenylcarbonyl, (substituted phenyl)carbonyl, phenylalkyl-carbonyl, (substituted phenyl)alkylcarbonyl, carboxy, alkoxy-carbonyl, aminocarbonyl, (substituted amino)carbonyl, or cyano;
A is -CH=CH-, -(CH2)n-, -CH2-O-, -CH2-NH-, -CH2-S-CH2- or -CH2-O-CH2-;n is 0, 1 or 2; and X6 and X7 are the same or different and each is hydrogen, alkyl, phenyl or substituted phenyl, or X6 is hydrogen and X7 is amino, substituted amino, alkanoylamino or alkoxy, or X6 and X7 when taken together with the nitrogen atom to which they are attached form a 4, 5, or 6-membered nitrogen containing heterocycle;

R5 and R6 are the same or different and each is hydrogen, alkyl, alkenyl, alkynyl, phenyl, substituted phenyl, cycloalkyl or a 4, 5, 6 or 7-membered heterocycle, or R5 and R6 together with the carbon atom to which they are attached are cycloalkyl, or one of R5 and R6 is hydrogen and the other is halomethyl, dihalomethyl, trihalomethyl, alkoxycarbonyl, alkenyl, alkynyl, 2-phenylethenyl, 2-phenylethynyl, carboxy, -CH2-X1, or , or R6 is hydrogen and R5 together with R7 and the atoms to which they are attached form a 4, 5 or 6-membered nitrogen containing heterocycle; and R7 is hydrogen, alkyl, phenyl, substituted phenyl, cycloalkyl, a 4, 5, 6 or 7-membered heterocycle, , or -(CH2)n-Z3 wherein n is 2, 3 or 4 and Z3 is azido, -NZ5Z6, halogen, hydroxy, , cyano, alkanoyloxy, alkoxy, phenyl-oxy, (substituted phenyl)oxy, (a 4, 5, 6 or 7-membered hetero-cycle)-O-, mercapto, alkylthio, phenylthio, (substituted phenyl)thio, alkylsulfinyl, alkylsulfonyl, or wherein Z4 is oxygen, sulfur, or , Z5 is hydrogen, alkyl, phenyl, substituted phenyl, phenylalkyl, or (substituted phenyl)alkyl, Z6 is hydrogen, alkyl, phenyl, substituted phenyl, phenylalkyl, (substituted phenyl)alkyl, alkanoyl, phenylcarbonyl, or (substituted phenyl)carbonyl, and Z7 is hydrogen, alkyl, phenyl or substituted phenyl;
wherein the terms "alkyl" and "alkoxy" refer to groups having 1 to 10 carbon atoms;
the term "cycloalkyl" refers to groups having 3, 4, 5, 6 or 7 carbon atoms;
the term "substituted alkyl" refers to alkyl groups substituted with one, or more, azido, amino, halogen, hydroxy, carboxy, cyano, alkoxycarbonyl, aminocarbonyl, alkanoyloxy, alkoxy, phenyloxy, (substituted phenyl)oxy, (4, 5, 6 or 7-membered heterocycle)oxy, mercapto, alkylthio, phenylthio, (substituted phenyl)thio, alkylsulfinyl or alkylsulfonyl groups;
the terms "alkanoyl", "alkenyl", and "alkynyl" refer to groups having 2 to 10 carbon atoms;
the term "substituted phenyl" refers to a phenyl group substituted with 1, 2 or 3 amino, halogen, hydroxyl, trifluoromethyl, alkyl (of 1 to 4 carbon atoms), alkoxy (of 1 to 4 carbon atoms), alkanoyloxy, aminocarbonyl or carboxy groups;
the term "a 4, 5, 6 or 7-membered heterocycle"
refers to pyridinyl, furanyl, pyrrolyl, thienyl, 1,2,3-tria-zolyl, 1,2,4-triazolyl, imidazolyl, thiazolyl, thiadiazolyl, pyrimidinyl, oxazolyl, triazinyl, tetrazolyl, azetidinyl, oxetanyl, thetanyl, piperidinyl, piperazinyl, imidazolidinyl, oxazolidinyl, pyrrolidinyl, tetrahydropyrimidinyl, dihydro-thiazolyl, hexahydroazepinyl, or one of the above groups substituted with one, or more, oxo, halogen, hydroxy, nitro, amino, cyano, trifluoromethyl, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkylsulfonyl, phenyl, sub-stituted phenyl, 2-furfurylideneamino, benzylideneamino, or substituted alkyl, wherein the alkyl group has 1 to 4 carbon atoms, groups;
the term "heteroaryl" refers to pyridinyl, furanyl, pyrrolyl, thienyl, 1,2,3-triazolyl, 1,2,4-triazolyl, imida-zolyl, thiazolyl, thiadiazolyl, pyrimidinyl, oxazolyl, tri-azinyl, tetrazolyl or one of the above groups substituted with one, or more, oxo, halogen, hydroxy, nitro, amino, cyano, trifluoromethyl, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkylsulfonyl, phenyl, substituted phenyl, 2-furfurylideneamino, benzylideneamino, or substituted alkyl, wherein the alkyl group has 1 to 4 carbon atoms, groups;
the term "substituted amino" refers to a group having the formula -NZ8Z9 wherein Z8 is hydrogen, alkyl, phenyl, substituted phenyl, phenylalkyl or (substituted phenyl)alkyl and Z9 is alkyl, phenyl, substituted phenyl, phenylalkyl, (substituted phenyl)alkyl, hydroxy, cyano, alkoxy, phenyl-alkoxy or amino;
the expression "a 4, 5 or 6-membered nitrogen contain-ing heterocycle" refers to 1-pyrrolidinyl, .DELTA.3-pyrrolin-1-yl, 1-azetidinyl, 1-piperidinyl, .DELTA.3 -piperidein-1-yl, .DELTA.4 -piperidein-1-yl, 3-oxazolidinyl, 3-thiazolidinyl, 1-imidazolidinyl, 4 thiomorpholinyl, 4-morpholinyl, 1-piperazinyl, 1-hexa-hydropyrimidinyl, tetrahydro-2H-1,3-thiazin-3-yl, tetrahydro-2H-1,3-oxazin-3-yl, 3-thiazolidinyl,1-oxide, 3-thiazolidinyl,-1,1-dioxide, 4-thiomorpholinyl,1-oxide, 4-thiomorpholinyl,1,1-dioxide, tetrahydro-2H-1,3-thiazin-3-yl,1-oxide, tetrahydro-2H-1,3-thiazin-3-yl,1,1-dioxide, or one of the above groups substituted with one, or more, oxo, halogen, hydroxy, amino, cyano, trifluoromethyl, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkylsulfonyl, phenyl, substituted phenyl, azido, carboxyl aminocarbonyl, OZ10, NZ10, or SZ10 groups where Z10 is alkanoyl, aminocarbonyl, aminosulfonyl, phenylcarbonyl, (substituted phenyl)carbonyl, alkyl, sub-stituted alkyl, phenyl or substituted phenyl, whenever pre-pared by the process of claim 33.

34. A pharmaceutical composition comprising a com-pound having the formula or a pharmaceutically acceptable ester or salt thereof, in admixture with a pharmaceutically acceptable carrier there-for, wherein Z1 is oxygen or sulfur;
R1 is an acyl group derived from a carboxylic acid;
R2 is hydrogen or methoxy;
R3 and R4 are the same or different and each is hydro-gen, alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, substituted phenyl or a 4, 5, 6 or 7-membered heterocycle, or one of R3 and R4 is hydrogen and the other is azido, halomethyl, dihalo-methyl, trihalomethyl, alkoxycarbonyl, 2-phenylethenyl, 2-phenylethynyl, carboxy, -CH2Xl, -S-X2, -O-X2, or wherein X1 is azido, amino, hydroxy, car-boxy, alkoxycarbonyl, alkanoylamino, phenylcarbonylamino, (substituted phenyl)carbonylamino, alkylsulfonyloxy, phenyl-sulfonyloxy, (substituted phenyl)sulfonyloxy, phenyl, substi-tuted phenyl, cyano, -S-X2 or -O-X2; X2 is alkyl, phenyl, or substituted phenyl; one of X3 and X4 is hydrogen and the other is hydrogen or alkyl, or X3 and X4 when taken together with the carbon atom to which they are attached form a cycloalkyl group; X5 is formyl, alkanoyl, phenylcarbonyl, (substituted phenyl)carbonyl, phenylalkylcarbonyl, (substituted phenyl)alkyl-carbonyl, carboxy, alkoxycarbonyl, aminocarbonyl, (substituted amino)carbonyl, or cyano; A is -CH=CH-, -(CH2)n-, -CH2-O-, -CH2-NH- -CH2-S-CH2- or -CH2-O-CH2-; n is 0, 1 or 2; and X6 and X7 are the same or different and each is hydrogen, alkyl, phenyl or substituted phenyl, or X6 is hydrogen and X7 is amino, substituted amino, alkanoylamino or alkoxy, or X6 and X7 when taken together with the nitrogen atom to which they are attached form a 4, 5, or 6- membered nitrogen containing heterocycle;
R5 and R6 are the same or different and each is hydrogen, alkyl, alkenyl, alkynyl, phenyl, substituted phenyl, cycloalkyl or a 4, 5, 6 or 7-membered heterocycle, or R5 and R6 together with the carbon atom to which they are attached are cycloalkyl, or one of R5 and R6 is hydrogen and the other is halomethyl, dihalomethyl, trihalomethyl, alkoxycarbonyl, alkenyl, alkynyl, 2-phenylethenyl, 2-phenylethynyl, carboxy, -CH2 Xl, or or R6 is hydrogen and R5 together with R7 and the atoms to which they are attached form a 4, 5, or 6-membered nitrogen containing heterocycle; and R7 is hydrogen, alkyl, phenyl, substituted phenyl, cycloalkyl, a 4, 5, 6 or 7-membered heterocycle, , , or -(CH2)n-Z3 wherein n is 2, 3 or 4 and Z3 is azido, -NZ5Z6, halogen, hydroxy, , cyano, , alkanoyloxy, alkoxy, phenyloxy, (substituted phenyl)oxy, (a 4, 5, 6 or 7-membered hetero-cycle)-O-, mercapto, alkylthio, phenylthio, (substituted phenyl)thio, alkylsulfinyl, alkylsulfonyl, , or , wherein Z4 is oxygen, sulfur or , Z5 is hydrogen, alkyl, phenyl, substituted phenyl, phenylalkyl or (sub-stituted phenyl)alkyl, Z6 is hydrogen, alkyl, phenyl, substituted phenyl, phenylalkyl, (sub-stituted phenyl)alkyl, alkanoyl, phenylcarbonyl, or (substituted phenyl)carbonyl, and Z7 is hydrogen, alkyl, phenyl or substituted phenyl;
wherein the terms "alkyl" and "alkoxy" refer to groups having 1 to 10 carbon atoms;
the term "cycloalkyl" refers to groups having 3, 4, 5, 6 or 7 carbon atoms;
the term "substituted alkyl" refers to alkyl groups substituted with one, or more, azido, amino, halogen, hydroxy, carboxy, cyano, alkoxycarbonyl, aminocarbonyl, alkanoyloxy, alkoxy, phenyloxy, (substituted phenyl)oxy, (4, 5, 6 or 7-membered heterocycle)oxy, mercapto, alkylthio, phenylthio, (substituted phenyl)thio, alkylsulfinyl or alkyl-sulfonyl groups;
the terms "alkanoyl", "alkenyl", and "alkynyl"
refer to groups having 2 to 10 carbon atoms;

the term "substituted phenyl" refers to a phenyl group substituted with 1, 2 or 3 amino, halogen, hydroxyl, trifluoromethyl, alkyl (of 1 to 4 carbon atoms), alkoxy (of 1 to 4 carbon atoms), alkanoyloxy, aminocarbonyl or carboxy groups;
the term "a 4, 5, 6 or 7-membered hetero-cycle" refers to pyridinyl, furanyl, pyrrolyl, thienyl, 1,2,3-triazolyl, 1,2,4-triazolyl, imidazolyl, thiazolyl, thiadiazolyl, pyrimidinyl, oxazolyl, triazinyl, tetrazolyl, azetidinyl, oxetanyl, thietanyl, piperidinyl, piperazinyl, imidazolidinyl, oxazolidinyl, pyrrolidinyl, tetra-hydropyrimidinyl, dihydrothiazolyl, hexahydroaze-pinyl, or one of the above groups substituted with one, or more, oxo, halogen, hydroxy, nitro, amino, cyano, trifluoromethyl, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkylsul-fonyl, phenyl, substituted phenyl, 2-furfurylidene-amino, benzylideneamino, or substituted alkyl, wherein the alkyl group has 1 to 4 carbon atoms, groups;
the term "heteroaryl" refers to pyridinyl, furanyl, pyrrolyl, thienyl, 1,2,3-triazolyl, 1,2,4-triazolyl, imidazolyl, thiazolyl, thia-diazolyl, pyrimidinyl, oxazolyl, triazinyl, tetrazolyl or one of the above groups substituted with one, or more, oxo, halogen, hydroxy, nitro, amino, cyano, trifluoromethyl, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkyl-sulfonyl, phenyl, substituted phenyl, 2-fur-furylideneamino, benzylideneamino, or substituted alkyl, wherein the alkyl group has 1 to 4 carbon atoms, groups;
the term "substituted amino" refers to a group having the formula -NZ8Z9 wherein Z8 is hydrogen, alkyl, phenyl, substituted phenyl, phenylalkyl or (substituted phenyl)alkyl and Z9 is alkyl, phenyl, substituted phenyl, phenylalkyl, (substituted phenyl)alkyl, hydroxy, cyano, alkoxy, phenylalkoxy, or amino;
the expression "a 4, 5, or 6- membered nitrogen containing heterocycle" refers to 1-pyrroli-dinyl, .DELTA.3-pyxrolin-1-yl, 1-azetidinyl, 1-piperi-dinyl, .DELTA.3-piperidein-1-yl, .DELTA.4-piperidein-1-yl, 3-oxazolidinyl, 3-thiazolidinyl, 1-imidazolidinyl, 4-thiomorpholinyl, 4-morpholinyl, 1-piperazinyl, 1-hexahydropyrimidinyl, tetrahydro-2H-1,3-thiazin-3-yl, tetrahydro-2H-1,3-oxazin-3-yl, 3-thiazolidinyl,-1-oxide, 3-thiazolidinyl,1,1-dioxide, 4-thio-morpholinyl,1-oxide, 4-thiomorpholinyl,1,1-dioxide, tetrahydro-2H-1,3-thiazin-3-yl,1-oxide, tetrahydro-2H-1,3-thiazin-3-yl,1,1-dioxide, or one of the above groups substituted with one, or more, oxo, halogen, hydroxy, amino, cyano, trifluoro-methyl, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms. alkylsulfonyl, phenyl, sub-stituted phenyl, azido, carboxy, aminocarbonyl, OZ10, NZ10, or SZ10 groups where Z10 is alkanoyl, aminocarbonyl, aminosulfonyl, phenylcarbonyl, (substituted phenyl)carbonyl, alkyl, substituted alkyl, phenyl or substituted phenyl.

35. A composition, as defined in claim 34, wherein Z1 is oxygen and R2 is hydrogen.

36. A composition, as defined in claim 35, wherein R7 is hydrogen.

37. A composition, as defined in claim 35, wherein R7 is alkyl.

3B. A composition, as defined in claim 35, wherein R7 is phenyl or substituted phenyl.

39. A composition, as defined in claim 35, wherein R7 is -(CH2)n-Z3.

40. A composition, as defined in claim 35, wherein R3, R4, R5 and R6 are each independently hydrogen or methyl.

41. A composition, as defined in claim 35, wherein R3, R4, R5 and R6 are each hydrogen.

42 A composition, as defined in claim 34, wherein R1 is and Ri is methyl, ethyl, carboxymethyl, 1-carboxy-1-methylethyl, 2,2,2-trifluoroethyl or 1-carboxycyclopropyl.

43. A composition, as defined in claim 35, wherein R1 is and Ri is methyl, ethyl, carboxymethyl, 1-carboxy-1-methylethyl, 2,2,2-trifluoroethyl or 1-carboxycyclopropyl.

44. A composition, as defined in claim 34, having the formula or a pharmaceutically acceptable ester or salt thereof, wherein R1 is an acyl group derived from a carboxylic acid and R7 is methyl or ethyl.

45. A composition, as defined in claim 44, wherein R1 is and Ri is methyl, ethyl, carboxymethyl, 1-carboxy-1-methylethyl, 2,2,2-trifluoroethyl or 1-carboxy cyclopropyl.

46. A composition, as defined in claim 34, having the fonmula or a pharmaceutically acceptable ester or salt thereof, wharein R1 is an acyl group derived from a carboxylic acid and R7 is phenyl or substituted phenyl.

47. A composition, as defined in claim 46, wherein R1 is and Ri is methyl, ethyl, carboxymethyl, 1-carboxy-1-methylethyl, 2,2,2-trifluoroethyl or 1-carboxy-cyclopropyl.

48. A composition, as defined in claim 34, having the formula or a pharmaceutically acceptable ester or salt thereof, wherein R1 is an acyl group derived from a carboxylic acid and R5 together with R7 and the atoms to which they are attached form a 4, 5, or 6-membered nitrogen containing heterocycle.

49. A composition, as defined in claim 48 wherein R5 together with R7 and the atoms to which they are attached are pyrrolidinyl or pyrrolidinyl substituted in the 4-position with halogen, hydroxy, aminocarbonyloxy, aminocarbonylamino, or aminosulfonylamino.

50. A composition, as defined in claim 48, wherein R5 together with R7 and the atoms to which they are attached are azetidinyl or azetidinyl substituted in the 3-position with halogen, hydroxy, aminocarbonyloxy, aminocarbonylamino, or aminosulfonylamino.

51. A composition, as defined in claim 48, wherein R1 is and Ri is methyl, ethyl, carboxymethyl, 1-carboxy-1-methylethyl, 2,2,2-trifluoroethyl or 1-carboxy-cyclopropyl.

52. A composition, as defined in claim 49, wherein R1 is and Ri is methyl, ethyl, carboxymethyl, 1-carboxy-1-methyl-ethyl, 2,2,2-trifluoroethyl or 1-carboxycyclopropyl.

53. A composition, as defined in claim 50, wherein Ri is and Ri is methyl, ethyl, carboxymethyl, 1-carboxy-1-methyl-ethyl, 2,2,2-trifluoroethyl or 1-carboxycyclopropyl.

54. A composition, as defined in claim 34, wherein the compound is [3S(Z)]-1-[[3-[[(2-amino-4-thiazolyl)(methoxy-imino)acetyl]amino]-2-oxo-1-azetidinyl]carbonyl]-L-proline, or a pharmaceutically acceptable salt thereof.

55. A composition, as defined in claim 34, wherein the compound is [3S(Z)]-1-[[3-[[(2-amino-4-thiazolyl)[(1-car-boxy-1-methylethoxy)imino]acetyl]amino]-2-oxo-1-azetidinyl]-carbonyl]-L-proline, or a pharmaceutically acceptable salt thereof.

56. A composition, as defined in claim 34, wherein the compound is (trans)-1-[[3S(Z)]-[3-[[(2-amino-4-thiazolyl)-(methoxyimino)acetyl]amino]-2-oxo-1-azetidinyl]carbonyl]-4-hydroxy-L-proline, or a pharmaceutically acceptable salt thereof.

57. A composition, as defined in claim 34, wherein the compound is (S)-1-[[3S(Z)]-[3-[[(2-amino-4-thiazolyl)-(methoxyimino)acetyl]amino]-2-oxo-1-azetidinyl]carbonyl]-2-azetidinecarboxylic acid, or a pharmaceutically acceptable salt thereof.

58. A composition, as defined in claim 34, wherein the compound is (S)-1-[[(S)-3-[(Z)-[(2-amino-4-thiazolyl)-[(carboxymethoxy)imino]acetyl]amino]-2-oxo-1-azetidinyl]car-bony?]-2-azetidinecarboxylic acid, or a pharmaceutically ac-ceptable salt thereof.

59. A composition, as defined in claim 34, wherein the compound is (S)-1-[[(S)-3-[[(Z)-(2-amino-4-thiazolyl)[(1-carboxy-1-methylethoxy)imino]acetyl]amino]-2-oxo-1-azetidi-nyl]carbonyl]-2-azetidinecarboxylic acid, or a pharmaceuti-cally acceptable salt thereof.

60. A composition, as defined in claim 34, wherein the compound is [3S(Z)]-N-[[3-[[(2-amino-4-thiazolyl)(meth-oxyimino)acetyl]amino]-2-oxo-1-azetidinyl]carbonyl]-N-(4-hydroxyphenyl)glycine, or a pharmaceutically acceptable salt thereof.

61. A composition, as defined in claim 34, wherein the compound is (R)-4-[(aminocarbonyl)oxy]-1-[[(S)-3-[[(2-amino-4-thiazolyl)(methoxyimino)acetyl]amino]-2-oxo-1-azeti-dinyl]carbonyl]-L-proline, or a pharmaceutically acceptable salt thereof.

62. A composition, as defined in claim 34, wherein the compound is [3S(Z)]-2-[[[1-(2-amino-4-thiazolyl) 2[[[1-[[(carboxymethyl)methylamino]carbonyl]-2-oxo-3-azetidinyl]-amino]-2-oxoethylidene]amino]oxy]-2-methylpropanoic acid, or a pharmaceutically acceptable salt thereof.

63. A composition, as defined in claim 34, wherein the compound is [3S(Z)]-[N-[[3-[[(2-amino-4-thiazolyl)(meth-oxyimino)acetyl]amino]-2-oxo-1-azetidinyl]carbonyl]methylam-ino]acetic acid, or a pharmaceutically acceptable salt there-of.

64. A composition, as defined in claim 34, wherein the compound is [3S(Z)]-N-[[3-[[(2-amino-4-thiazolyl)(meth-oxyimino)acetyl]amino]-2-oxo-1-azetidinyl]carbonyl]-N-eth-ylglycine, or a pharmaceutically acceptable salt thereof.

65. A composition, as defined in claim 34, which is in an oral dosage form for administration.

66. A composition, as defined in claim 34, which is in a form suitable for parenteral administration.

67. A composition, as defined in claim 34, which is in a form suitable for intravenous or intramuscular adminis-tration.

68. A composition, as defined in claim 34, which is in the form of a suppository.