CA1308708C - Cephalosporins - Google Patents

Abstract

NEW CEPHALOSPORINS

Abstract of the disclosure .

A 7-(2-(2-aminothiazol-4-yl)-2-(syn)-methoxyimino-acetamido)cephalosporin derivative of the formula;

Description

1 30S7Q~

New Cephalcsporins This invention relates to novel cephalosporin derivatives having a novel 7-acyl group and processes for the production thereof, More particularly, this invention relates to 7-(2-(2-aminothiazol-4-yl)-2-(syn)-methoxyimino-acetamido)cephalosporin derivatives of the formula (I);

R2NH~ S~
N C-CONH ~ S~
N O ~ N ~ CH2 ~ COOH
wherein R3 is hydrogen or a residue of a nucleophilic compound; R2NH is an amino group which may optionally be protected, a pha~maceutically acceptable salt or ester thereof and also relates to processes for the production of the same, Heretofore, studies on synthetic cephalosporin derivatives have been directed to the conversion of 7-aminocephalosporanic acid to various acyl derivatives at the 7-position or to derivatives at the 3-position in order to synthesize compounds having a broad anti-bacterial spectrum or a specific anti-bacterial spectrum, Xowever, known cephalosporin derivatives are not satisfactory in anti-bacterial activity against a wide variety of micro-organisms, Under these circumstances, the present inventors et al, h~ foundcephalosporin derivatives represented by the following .ormula;

1 3n37~

xl ~ S R8 R3 N ~ ~HCONH ~ ~
R2 O N ~ CH2R
(OOH
wherein Rl represents amino or hydroxyl group which may be protected, R2 represents amino or hydroxyl group or a group convertible into these groups, R3 represents hydrogen or methoxy group or a group convertible into methoxy group, R4 represents hydrogen or a residue of a nucleophilic compound and R8 represents hydrogen or a halogen, or a pharmaceutically acceptable salt or ester thereof (West German ~atent Application Laid Open ~o 2556736~, Among these compounds the present inventors further found that the compounds of the formula (I) were highly active against a broad spectrum of gram-positive and gram-negative bacteria including Serratia marcescens, Proteus mor~anii, and further, that the compounds (I) were effective against ~-lactamase producing bacteria. ~ihis invention have accomplished on the ground of these finding~.
Referring to compound of the formula (I), R3 is hydrogen or a residue of a nucleophilic compound. As examples of said residue of a nucleophilic compound which is represented by R3 may be mentioned hydroxy; mercapto;
acyloxy derived from lower aliphatic carboxylic acid having 2 to 4 carbon atoms, which may optionally be substituted by oxo, carboxy or ethoxycarbamoyl (e g, acetyloxy, propionyloxy, 3-oxobutyryloxy, 3-carboxypropionyloxy, 3-ethoxycarbamoylpropionyloxy, 4-carboxybutyryloxy);

i !

1 3r~70~

acyloxy derived from aromatic carboxylic acid, which may optionally be substituted by hydroxy, carboxy, carbo-ethoxycarbamoyl or carboethoxysulfamoyl, (e.g. mandelyloxy, 2-carboxybenzoyloxy, 2-(carboethoxycarbamoyl)benzoyloxy, 2-(carboethoxysulfamoyl)benzoyloxy); carbamoyloxy; cyano; azido, amino, carbamoylthio; thiocarbamoyloxy; carbamoyloxy whose amino group is protected by a conventional protecting group for amino function (e.g., N-mono-, di- and trihalogenoacetylcarbamoyloxy groups such as N-chloroacetylcarbamoyloxy, N-dichloroacetylcarba-moyloxy, N-trichloroacetylcarbamoyloxy, N-chlorosulfonylcarbamoy-loxy, N-trimethylsilylcarbamoyloxy, etc.); phenylglycyloxy; and so forth. These residues of nucleophilic compounds (such as hydroxyl, mercapto and amino) may be substituted, the number of sub6tituents being normally from 1 to 2. Thus, the substituents on the residues which have been mentloned above may for example be ~lkyls (such as lowe~ alkyl~ of 1 to 3 carbon atoms, e.g. methyl, ethyl, propyl, etc.) and acyl groups (such as acyls derived from lower aliphatic carboxylic acid having ~ to 4 carbon atoms, e.g.
acetyl, propionyl, butyryl, etc.; acyls derived from aromatic carboxylic acid, e.g. benzoyl, p-chlorobenzoyl, p-methylbenzoyl, mandeloyl, etc.). The residue of a nucleophilic compound represented by R3 may alternatively be a quaternary ammonium group. The residue represented by R3 may further be a heterocyclic ring attached through S (sulphur atom), i.e.
heterocyclicthio group represented by the formula -S-heterocyclic ring. The heterocyclic ring mentioned above is a five- or six-, ~ 3C~ 70~

membered ring including l to 4 hetero-atoms selected from the group consisting of oxygen, sulphur and nitrogen atoms, and the nitrogen atom or atoms may be in oxide form. It follows, therefore, that said heterocyclic group (i.e., group derived from the heterocyclic compound corresponding to the heterocyclic ring) may usually be one of the follow-ing and other groups: pyridyl; N-oxidopyridyl~ pyrimidyl;
pyridazinyl, N-oxidopyridazinyl; pyrazolyl; diazolyl such as pyrazolyl, imidazolyl, thiazolyl such as 1,2-thiazolyl, 1,3-thiazolyl; thiadiazolyl such as 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl;
oxadiazolyl such as 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl; triazolyl such as 1,2,3-triazolyl, 1,2,4-triazolyl; tetrazolyl such as lH-tetrazolyl, 2H-tetrazolyl, etc. Such hetero group may each carry substituents such as lower alkyls of 1 to 3 carbon atoms (e.g. methyl, ethyl, i-propyl, allyl), lower alkoxy groups of 1 to 3 carbon atoms (e.g. methoxy, ethoxy, propoxy), halogens (e.g. chlorine, bromine), trihalogeno-lower alkyls (e.g. trifluoromethyl, trichloroethyl), hydro-xyl, mercapto, amino, carboxyl, carbamoyl, di-lower alkyl (having 1 to 3 carbon atoms) amino lower alkyl of 1 to 3 carbon atoms (e.g. dimethylaminoethyl, dimethylaminomethyl) carboxymethyl, carbamoylmethyl, carboxymethylthio, sul~o-methyl, methoxycarbonylamino.
The number of such substituents that may occur on the heterocyclic group is normally in the range of 1 to 2.
The quaternary ammonium group represented by R3 may ~ I !

1 3r~370~

for example be pyridinium which may optionally be substituted by one me~mber of methyl, halogen, carbamoyl, N-hydroxymethylcarbamo-yl, carbomethoxycarbamoyl, cyanocarbamoyl, carboxymethyl, hydroxymethyl or trifluoromethyl such as pyridinium, 3-methylpyridinum, 4-methylpyridinium, 3-chloropyridinium, 3-bromopyridinium, 3-iodopyridinium, 4-carbamoylpyridinium, 4-(N-hydroxymethylcarbamoyl)pyridinium, 4-(N-carbomethoxycarbamoyl) pyridinium, 4-(N-cyanocarbamoyl~pyridinium, 4-(carboxymethyl) pyridinium, 4-(hydroxymethyl)pyridinium, 4-(~rifluoromethyl) pyridinium; quinolinium; picolinium; lutidinium.
When R3 is hydrogen; hydroxyl; acetoxy; carbamoyloxy;
1,3,4-thiadiazol-2-ylthio; 5-amino-1,3,4-thiadiazoyl-2-ylthio;
1,3,4-triazol-2-ylthio; 1,5-dimethyl-1,3,4-triazol-2-ylthlo; 1-methylimidazol-2-ylthio; 5-methyl-1,3,4-oxadiazol-2-ylthio; 5-methyl-1,3,4-thiadiazoyl-2-ylthio; or 1-methyltriazol-5-ylthio, then the derivative (I) is in the form of a pharmaceutically acceptable ester.
Referring to compounds of the formula (I), the group represented by R3 is preferably hydrogen, carbamoyloxy, acyloxy derived from lower aliphatic carboxylic acid having 2 to 4 carbon atoms such as acetoxy, or the heterocyclic-thio group whose heterocyclic group is unsubstituted or substituted.
The preferred substituents of heterocyclic group of heterocyclic-thio group are one or two members of lower alkyl (Cl 4), di-lower alkyl (Cl 4) amino-substituted lower alkyl (Cl 4), carboxymethyl, amino, methoxycarbonylamino, carbamoylmethyl, carboxymethylthio or sulfomethyl. Among them, 1 3rj~,70~

preferred R3 is carbamoyloxy, 1-methyl-lH-tetrazol-5-ylthio, 2-methyl-1,3,4-thiadiazol-5-ylthio, 1,2-dimethyl-1,3,4-triazol-5-ylthio group and so on.
Where R3 is a carbamoyloxy group whose amino group has been protected, e.g. N-chloroacetylcarbamoyloxy, N-5a 'I

I, ~ . ~

~ 30~70~
:~.
dichloroace~ylcar~amoyloxy or N-trichloroacetylcarbamoyloxy, such protecting group for the amino group may be removed by a proce~ure similar to that used for removing the prot;ecting group from the protected amino group repre-sented by R2NH-, which is described hereinafter. Generally, the compound (I) is employed with its amino and carbamoyloxy group (where Rl is carbamoyloxymethyl) being free and unprotected, as an active compound. Indicated by R2NH
is an amino group which may optionally be protected.
Therefore, R2 means hydrogen or a protecting group for amino function, the latter being any of the ~ se known protective groups generally used for the protection of ami~o, i.e, conventional protecting group for amino function, Thus, such protective groups include, among others, aromatic acyl groups such as phthaloyl, benzoyl, benzoyl substituted by halogen, nitro or a lower alkyl of 1 to 4 carbon atoms (e.g. chlorobenzoyl, p-nitrobenzoyl, p-tert-butylbenzoyl, toluoyl)~ naphthoyl; phenylacetyl;
phenoxyacetyl; benzenesulfonyl; benzenesulfonyl substituted by a lower alkyl of 1 to 4 carbon atoms (e.g. p-tert-butylbenzenesulfonyl, toluenesulfonyl); acyl derived from aliphatic or halogenated aliphatic carboxylic acid such as acetyl, valeryl, caprylyl, n-decanoyl, acryloyl, pivaloyl, halogenoacetyl (e.g. monochloroacetyl, mono-bromoacetyl, dichloroacetyl, trichloroacetyl); camphor-sulfonyl; methanesulfonyl; esterified carboxyl groups such as ethoxycarbonyl, tert-butyloxycarbo~yl J isobornyloxy-carbonyl, phenyloxycarbonyl, trichloroethoxycarbonyl, .

1 3r~J?~

benzyloxycarbonyl, etc.; carbamoyl groups such as methyl-carbamoyl, phenylcarbamoyl, naphthylcarbamoyl, etc.; and the corresponding thiocarbamoyl groups.
The cephalosporin derivative of the form~
(I) is thought to take a tautomeric form, i.e. a 2-aminothiazole compound and a 2-iminothiazoline compound as shown below, although it is described as the thiazole compound throughout this specification.
R2HN ,r ~ ~
N C-CONH T~
N ~-- N ~ CH2R3 `OC~ COOH
R N
2 ~,S~

`OC~ ~ 2 ~

While the carboxyl group in 4-position of the compound of the formula (I) may be free, it may form a salt, for example with a nontoxic cation such as an alkali metal, e g sodium or potassium; a basic amino acid, e.g. arginine, ornithine, lysine or histidine; or a polyhydroxyalkylamine, e.g. N-methylglucamine, diethanolamine, triethanolamine or trishydroxymethylaminomethane, The compound ~I) may form acid salt with an inorganic acid such as hydrogen chloride, sulfuric acid, etc. or with an organic acid such as toluenesulfonic acid, benzenesulfonic acid, etc.
~he 4-carboxyl group may also be one of those biologically active ester forms which conduce, for example, to increase ~, ~ I ~

1 3~'~'10~

of blood levels and prolonged efficacy. Such ester residues inclu~e lower alkoxymethyl groups, e.g. methoxymethyl, ethoxymethyl, isopropoxymethyl, a-methoxyethyl, a-ethoxyethyl, etc.; a-lower al~oxy-~-substltuted methyl groups such as a-lower alkoxy(Cl 4) ethyl (e.g. methoxyethyl, ethoxyethyl, propoxyethyl, i-propoxyethyl), etc.; lower alkylthiomethyl groups of 1 to 3 carbon atoms, e.g. methylthiomethyl, ethylthiomethyl, isopropylthiomethyl, etc.; acyloxymethyl groups, e.g. pivaloyloxy methyl, a-acetoxymethyl, etc.; ethoxycarbonyloxy-l-methylmethyl;
or a-acyloxy-a-substituted methyl groups (e.g. a-acetoxy-a-methylmethyl). These salts and esters of compound (I) also fall within the scope of the present invention.
As the known cephalosporins or penicillins, the compounds (I) according to thls lnvention may be administered usually in such pharmaceutical composition forms as injections, capsules, tablets and granules, which contain pharmaceutically acceptable carriers as well. Thus, compounds (I) are novel compounds which show excellent activity against a broad spectrum of bacteria inclusive of gram-negative bacteria, such as Escherichia coli, Serratia marcescens, Proteus rettqeri, Enterobacter cloacae and Citrobacter freundii, and are resistant to ~-lactamase. The compound (I) may be used, for example as a disinfectant for removing the aforesaid microorganisms from surgical instruments or as an antiinfective agent. Where the compound ~I) is employed as an antiinfective agent, for example for the treatment of intraperitoneal infections, respiratory organ infections, urinary tract infections and other infectious deseases I

I ! ` ,, .

1 3""'?0~

caused by the aforementioned microorganisms, it may be safely administered to mammals including humans, mice and rats at a daily dose level of 0 5 to 80 mg per kilogram body weight, preferably 1 to 20 mg on the same basis, in 3 to 4 installments daily The compounds (1) may be administered orally or parenterally in varied dosage forms such as injections, capsules, powders, granules and tablets which may be manufactured by established or known arts. Where the compound (I) is used as an injection, the carrier may for example be distilled water or physio-logical saline In the case the compound (I) is used as a capsule, powder, granule or tablet, the compound (I) is employed, fox example in admiæture with pha~macologically acceptable, per se known excipients (e ~ starch, lactose, sucrose, calcium carbonate, calcium phosphate), binders (starch, gum arabic, carbo~ymethyl-cellulose, hydroxy-propylcellulose, crystalline cellulose, etc,), lubricants (e.g magnesium stearate, talc, etc.), and disintegrating agents (e.g carboxgmethyl calcium, talc, etc~).
The compound (I) of this invention may be produced by a technique known ~ se (1) Th~s, the cephalosporin derivative of the formula (I) is produced by acylating the 7-amino group of a 7-aminocephalosporin compound of the fo~lul :
(II):
H2N ~ S~
CH~R3 (II) COOH

- g _ I ,!

l -S~''70~

wherein R~ is as previously defined with a 2-(2- ~in thiaz~l 4-y~-2-(s~n)-methoxyimino acetic acid of formula (III):

R2NH~
N C-~OOH
" (III) N~

wherein R2NH is as previously defined, if necessary followed by removing the pretective group for the amino group (Process I), In this process, the compound (III) is employed, either as a free compound or in the form of a reactive derivative, as an acylating agent for the acylation of the amino group in 7-position on compound (II) Thus, the free acid (III~, an alkali or alkaline earth metal salt of the free acid (III) (e g sodium, potassium or calcium salt), an organic amine salt of the free acid (III) (e.g trimethylamine salt or pyridine salt), or a reactive derivative thereof (such as an acid halide (e g. acid chloride or acid bromide), acid anhydride, mixed acid anhydride, active amide, active ester or the like) is subiected to the aforementioned acylation reaction. As examples of said active ester may be mentioned p-nitro-phenyl ester, 2,4-dinitrophenyl ester, pentachlorophenyl ester, N-hydroxysuccinimide ester and N-hydroxyphthalimide ester. As examples of said mixed acid anhydride may be menticned mixed acid anhydride with a carbonic acid monoester (e.g carbonic acid monometh~l ester or carbonic acid monoisobutyl ester) and a mixed acid anhydride with ~' 1 3",~70~

. . . * .
a lower alkanoic acid which may be substituted by halogen (e.g.

pivalic acid or trichloroacetic acid). Where the carboxylic ,, ~, .
acid (III) is e~ployed as the free acid or in the form of a salt, there is employed a suitable condensing agent. As examples of said condensing agent may be mentioned N,N'-di-substituted carbodiimides, e.g. N,N'-dicyclohexylcarbodiimide; azolides, e.g.
N,N'-carbonylimidazole and N,N'-thionyldiimidazole; dehydrating agents, e.g. N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, phosphorus oxychloride and aIkoxyacetylene; 2-halogenopyridinium salts (e.g. 2-chloropyridiniummethyl iodide, 2-fluoropyridinium-methyl iodide) and the like. Where such a condensing agent is employed, it is supposed that the reaction proceeds via the reac-tive derivative of the carboxylic acid (III). The reaction is generally conducted in a suitable inert solvent. As examples of such solvent may be mentioned halogenated hydrocarbons, e.g.
chloroformf methylene dichloride, etc.; ethers, e.g. tetrahydro-furan, dioxane, etc.; dimethylformamide; dimethylacetamide;
acetone; water and mixtures of such solvents. The proportion of said acylating agent is normally within the range of about 1 to S, preferably 1 to 2 molar equivalents based on the compound (II).
This reaction is generally carried out at a temperature in the range of -50 to ~40 C. The reaction time is selected from the range of 1 to 10 hours~ preferably 1 to 3 hours. Following the acylation reaction, the protective group for amino function may be removed, if necessary. The removal of the protective group for amino function may be generally accomplished by procedures kno~n per se (e.g., by the 13"~7~

procedure described in Japanese Patent Application Laid Open No.
52083/197S and Pure and Applied Chemistry, 7, 335(1963)] or a procedure analogous thereto. It should be understood that where R2 in the formula (I) is monohalogenoacetyl (e.g. monochloroacetyl and R3 is carbamoyloxy group whose amino group has been protected, such as N-monohalogenoacetylcarbamoyloxy (e.g. N-monochloroacetyl-carbamoyloxy), these two monohalogenoacetyl groups (e.g.
monochloroacetyl) may be simultaneously removed. In this sense, the protecting group for amino represented by R2 is preferably a monohalogenoacetyl group. The reaction for removing the monohalogenoacetyl group from the amino group is performed by reacting a compound of formula (I) whose amino group or groups have been protected by monohalogeno acetyl with thiourea and a basic substance. Normally this reaction is conducted in a solvent at a temperature near room temperature and, in many instances, goes to completion in a time varying from 1 to 10 and odd hours.
The solvent may be any solvent that will not interfere with the present reaction. Thus, there may be mentioned ethers, e.g. ethyl ether, tetrahydrofuran, dioxane, etc.; lower alcohols, e.g.
methanol, ethanol, etc.; halogenated hydrocarbons, e.g. chloroform methylene dichloride, etc.; esters, e.g. ethyl acetate, butyl acetate, ketones, e.g. acetone, methyl ethyl ketone, etc.; water and various mixtures of such solvents.

I

~ 3~ ~7~1~

This reaction for the removal of the N-halogenoacetyl group from the N-monohalogenoacetylcarbamoyloxymethyl group in ~-position of the compound (I) does not proceed in any substantial extent when thiourea alone is permitted to act upon the compound (I). However, if the compound (I) is reacted with thiourea and a basic substance, the desired reaction for removing the monohalogenoacetyl group takes place selectively and smoothly to give the ~-carbamoyloxy-methyl compound (I) As the basic substance used for the purposes of this reaction, there may be mentioned an alkali or alkaline earth metal salt of a lower aliphatic carboxylic acid or an inorganic or organic base having a pK value of not less than 9,5~ preferably within the range of pKa 9 8 to 12 0. As e~amples of said salt of lower aliphatic carboxylic acid may be mentioned the salts of lower aliphatic carboxylic acids of 1 to 6 carbon atoms, such as sodium acetate, potassium acetate, calcium acetate, barium acetate, sodium formate, sodium propionate, potassium hexanoate, etc. As examples of said inorganic base may be mentioned the alkali metal salts of carbonic acid such as sodium carbonate, potassium carbonate, etc.
~he organic base may for example be one of the mono-, di-or tri-lower alkyl substituted amines whose lo~er alkyl is that of 1 to 4 carbon atoms, e.g trimethylamine, triethylamine, ethylamine, methylamine, diethylamine, dimethylamine, tributylamine, dibutylamine, butylamine, etc.; and 5- to 6-membered cyclic amines substituted in ~-position by lower alkyls of 1 to 2 carbon atoms such as 1 3'`,~,7~

N-methylpyrrolidine, N-ethylpyrrolidine, N-methylpiperazine, N-ethylpiperazine, etc. While, as aforesaid, thiourea is employed in this reaction, the reaction may also be successfully conducted with N- or N,N-substituted thiourea, such as methylthiourea, N,N-diethylthiourea or N~N-hexamethylenethiourea.
(2) The 7~(2-(2-aminothiazol-4-yl)-2-(s~n)-methoxyimino-acetamido)ce~halcsporirn derivative of the formula (V):

R2NH~f 11 S
C-CONH ~ ~
N G/~ N ~ ~H ~5 (V) OCH~ COOH
wher~in R2NH is as previously defined; R5 is a residue of a nucleophilic compound, i8 produced by reacting a compound of the formula (IV):

R2~I ~f N C-CONH , I,S~
N ~ N ~ CH2R4 (IV) wherein R2NH is as previously defined; R4 is acyloxy, carbamoyloxy or halogen, with a nucleophilic compound, if necessary followed by removal of the protective group for the amino group (Process 2).
As the acyloxy group represented by R4 in the formula (I~), there may for instance be mentioned acyloxy derived from lower aliphatic carboxylic acid having 2 to 4 carbon atoms, which may optionally be substituted by 1 -~" 3 I (~

oxo, carboxy or ethoxycarbamoyl, e.g. acetyloxy, propionyloxy, 3-oxobut:yryloxy, 3-carboxypropionyloxy, 3-ethoxy-carbamoylpropiony-loxy, 4-carboxybutyryloxy, etc.; and acyloxy derived from aromatic carboxylic acid, which may optionally be substituted by hydroxy, carboxy, carboethoxycarbamoyl or carboethoxysulfamoyl, e.g.
mandelyloxy, 2-carboxybenzoyloxy, 2-(carboethoxycarbamoyl) benzoyloxy and 2-(carboethoxysulfamoyl) benzoyloxy. The halogen represented by R4 may for example be chlorine, bromine or iodine.
The residue of a nucleophilic compound represented by R5 in the formula (V) means the residue of a nucleophilic compound corresponding to the residue of a nucleophilic compound represented by R3 excluding the acyloxy represented by R4 or carbamoyloxy. For the purposes of this reaction, however, it is generally advantageous to employ a compound (IV) having an acyloxy gr~up derived from lower aliphatic carboxylic acid such as acetyloxy. The nucleophilic compound employed in this reaction is a compound corresponding to the residue of a nucleophilic compound designated by the symbol R5 in the formula (V). Particularly preferred are the heterocyclic thiol compounds i.e. mercapto compounds which may contain a substituent. Among the nucleophilic compounds corresponding to the residue represented by R5, mercapto compounds may be employed in their free form, although it is advantageous to use them in the form of alkali metal salts, e.g.
sodium or potassium salts. This reaction is preferably conducted in a solvent. For example, use is made of water, deuterium 'I 15 `" 1 3 ,r '~; ? O ~

or an organic solvent that is readily miscible with water and does not react with the reactants, e.g. dimethylformamide, dimethylacetamide, dioxane, acetone, alcohol, acetonitrile, dimethylsulfoxide and tetrahydrofuran. While the reaction temperature and time vary with such factors as the particular starting material and solvent employed, it is generally selected from the range of O to 100 C, preferably 30 to 70 C and the range of 2 to 48 hours, preferably 3 to 15 hours, respectively.
The reaction is preferably carried out in the neighborhood of neutrality and feasible within the range of about pH 2 to 8, preferably pH 5 to 80 The progress of this reaction may some-times be rendered smooth by the addition of a quaternary ammon-ium salt having surface activity, such a~ trimethylbenzylammonium bromide or triethylbenzylammonium bromide or triethylbenzylammon-ium hydroxide. Moreover, more satisfactory results are obtained when the reaction is conducted in an inert gaseous atmosphere such as nitrogen in order to prevent atmospheric oxidation of the mercapto compound.
(3) The cephalosporin derivative of the formula (I) may also be produced by subjecting a 7-(2-(2-amino-thiazol-4-yl)-2-(syn)-hydroxyiminoacetamido)cephalosporin derivative (VI):

RzH ~ C-CONH ~ OH~3 (VI) OH OOH

wherein R and R2NH are as previously defined, to O-methyla-tion. The O-methylation is conducted by reacting the compound I ~'`` ,;'(3~

~VI) with a methylating agent (Process 3).
This 0-methylation reaction is normally conducted in a solvent under ice-cooling or in the neighborhood of room temperature (0 to 40 C, preferably 5 to 30 C) and, in many cases, goes to completion within about S minutes to about 5 hours, preferably 5 minutes to 2 hours. The solvent may be any solvent that will not interfere with the reaction, such as ethers5 e.g. tetrahydrofuran, dioxane, etc.; lower alcohols e.g. methanol, ethanol, etc.; halogenated hydrocarbons, e.g., chloroform, methylene chloride, etc.; esters, e.g. ethyl ace-tate, butyl acetate, etc.; amides, e.g. N,N-dimethylformamide, N,N-dimethylacetamide, etc.; water; and mixtures of such solvents. The methylating agent may be a methylating agent which is generally employed in organic chemicstry, such as methyl halide (e.g. methyl iodide, methyl bromide), dimethyl sulfate, diazomethane or the like.
This reaction may proceed smoothly in the presence of a suitable base except in the case of diazomethane. As such base, use is normally made of an inorga~ic base such as the alkali metal salts of carbonic acid (e.g. sodium carbonate, potassium carbonate), alkali metal hydroxides (e.g. sodium hydroxide, potassium hydroxide). Where the stability of com-pound (VI) is a consideration, however, sodium carbonate, potassium carbonate or the like is preferably employed. This reaction may also be conducted in a buffer at about pH 7.5 to 8.5.
The cephalosporin compounds (I) which are produced by the several production processes described hereinbefore _ 17 -I'' 1 3"^70~

may each be purified by procedures known per se, such as column chromatography, extraction, precipitation, recrystal-lization and so forth. If necessary, each of those compounds may be treated by per se known procedures to obtain the desired salts, esters, etc.
One of the starting materials ~or this in~ention, i.e. 2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetic acid derivative (III) may be produced, for example by the several alternative processes described hereinafter in detail.
(I) In the first place, a 4-halogeno-~-o~o-2-oxyimino-butyric acid derivative of the formula (VII):
XCH COC-COOR
2 " 7 N (VII) wherein X is halogen, e.g. chlorine or bromine; ~6 is hydrogen or methyl; R7 is a lower alkyl of 1 to 3 carbon atoms, e.g. methyl, ethyl or propyl is reacted with thiourea to obtain a 2-(2-aminothiazol-4-yl)-2-oxyiminoacetic acid derivative of the formula (VIII):

H2 ~ ' ¦¦
N C-COOR7 (VIII) N

wherei~ R6 and R7 are a~ pre~i~u~ly defi~ed. In both the cases where R6 is hydrogen and methyl, re~p~ctively, the compound (VIII) is normally obtained as a mixture of s~n-a~d anti-isomers thereof. This reaction is normally t~ 1 C! ~

conducted by reacting a compound of the formula (VII) with thiourea in an organic solvent such as ethanol, methanol or tetrahydrofuran at room temperature or elevated temperature (0 to 100 C, preferably 10 to 50 C). The reaction time is selected from the range of 1 to 30 hours, preferably 1 to 5 hours. To isolate the desired syn-isomer from the resultant mixture of syn- and anti-forms of compound (VIII), one of the following procedures may be successfully followed. Thus, these procedures include the procedure of fractional crystal-lization which takes advantage of the differential crystalli-zabilities or solubilities ofthe isomers of the compound (VIII) as such, a salt of the compound (VIII) of hydrogen halide (HBr or HC~ salt) or a derivative of the compound (VIII) with a protective group on its 2-amino group, the pro-tective group (e.g. monochloroacetyl or dichloroacetyl) having been introduced by a procedure known per ~j isolation by chromatography and a procedure such that when the compound (VIII) or the compound (VIII) with a protective group on its 2-amino group is hydrolyzed, at its ester position, by a E~
se known process to a carboxylic acid derivative of formula (III), the syn-isomer alone is selectively isolated by util-izing the difference in the rate of hydrolysis between the syn- and anti-isomers.
In the last-mentioned procedure, because of the higher rate of hydrolysis for the anti-isomer than for the syn-isomer, the anti-isomer may be selectively hydrolyzed and removed. The reaction for hydrolyzing the ester link-age of the compound (VIII) with or without a substituent on its 2-amino group is normally conducted in , -~ , .

1 3 r~

the presence of 1 to several molar equivalents of an alkali metal hydroxide, e.g potassium hydroxide or socLium hydroxide at a temperature ranging from 0C to room temperature and in water or a mixture of water with an organic solvent miscible with water, e.g. methanol, ethanol, acetone, tetrahydro~uran, dioxane, ~ dimethyl-formamide or N,N-dimethylacetamide. Where R6 în the compound (VIII) is hydrogen, the s~n-isomer isolated may be converted to syn-isomer of the compound (VIII) in which R6 is methyl, by subJecting the former compound (VIII) to methylation. This methylation reaction is normally carried out in a solvent under ice-cooling or at temperatures near room temperature and, in many instances, goes to completion in a few minutes to several hours.
The solvent for this purpose may be any type of solvent only if it does not interfere with the reaction. ~hus, for example, tetrahydrofuran, dioxane, methanol, ethanol, chloroform, methylene dichloride, ethyl acetate, butyl acetate, N,N-dimethylformamide, N,N-dimethylacetamide and water as well as mixtures of such solvents may be mentioned.
~s the methylation agent may be mentioned methyl halides, e.g. methyl iodide and methyl bromide; dimethyl sulfate;
and diazomethane; to name but a few. In all cases except that diazomethane is employed, the compound (VIII) in which R6 is hydrogen is reacted with said methylating agent in the presence of a base such as an alkali metal carbonate (e.g. sodium carbonate, potassium carbonate, etc.) or an alkali metal hydroxide (e.g. sodium hydroxide, 1 3 ~

pot;assium hydroxide, etc.). Some of the physical constants of the syn-isomers of compounds ~III) and (VIII) thus obt;ained are shown below in comparison with the physical constants of the corresponding anti-isomers (See Table 1).
~able Structure NMR spectru~ Melting (ppm) point(C) H2N ~ S~ In d6-DMSO
s~n-N~ 11 C-COOC2H5 6,80s(5-H) 18505 isomerN~ 11,6s(OH) OH

H2N ~ ~ In d6-DMSO
anti- N C-COOC2H5 7.50s(5-H) 145.3 isomer N 12,5s(OH) HO

H2N ~ S~ In CDC~3 s~n- N C-COOC2H5 6,74s(5-H)163 to isomer N~ 4.02s(0CH3)164 H2N ~ S~ In CDC~3 anti-N 11 C-COOC2H5 7.43s(5~H)114 to isomer N 4.07s(0CH3)115 H2N ~ ~ In CDC~3 syn- N C-COOCH3 6.74s(5-H),164.9 isomer N~ 4.02s(0CH3) , _ H2N ~ S~ In CDC~3 anti- N C-COOC~ 7.48s(5~H), isomer N 4.06s(OCH3) :, ~ ! ~

~ 3~J~7 08 Structure NMR spectrum Melting (ppm)point(C) __ _ C~CH2CONH~f S~ In CDC~3 s;yn- ~ C-COOC2H5 7.15s(5-H)111 to isomer N 4000s(0CH3) 112 _ C~CH2CONH ~S~I In CDC~3 anti- N C-GOOC2H5 7.94s(5-H)81 to isomer N 4.10s(OCH3) 82 C~CH2CONH~ S~ In d6-DMSO
~~ N--`C-COOH 7.57s(5-H)170 to isomer ~J~ 3.95s(0CH3) 171 _~_ _ _ C~CH2CONH ~f ~1 In d6-DMSO
~nti- ~ C-COOH 8,00s(5-H)182 to isomer N 4.00s(0CH3) 183 C~CH2CONH~-- 11 In CDC~3 s;yn- N C-COOCH3 7~24s(5-H),130.8 isomer N~ 4.02s(0CH3) _ C~CH2CONH ~S 11 In CDC~3 .
anti- N C-COOCH3 8.02s(5-H) isomer N 4,12s(0CH3) :~ CH30' Remarks s: singlet ~he methoxyimino (hydro~yimino) group in ~sYnllisomey is cis t~o the carboxyl function~ and ~n "a~ti"
isomer trans to the carboxyl function.

:~ :
.~ :
" ' 1 3"'``10~

(II) The procedure for selective production of compound (III) (s~n-isomer) will hereinafter be described. Whereas thle aforementioned reaction of the compound (VII) with thiourea yields a mixture of syn- and anti-isomers of compound (VIII) t in many instances the anti isomer of the compound (VIII) predominates~ The inventor's study of the conditions of this cyclization reaction shed light on the conditions to conduce to a selective formation of the desired syn-isomer. Thus, if the reaction of the compound (VII) witn thiourea to produce the compound (VIII) is conducted under the conditions described hereinbefore the s~n- and anti-isomers are normally produced in a ratio in the ran~e of 2:98 to 50:50.
It has been found, however, that if this cyclization reaction is carried out in water or a mixture of water and a water-miscible solvent such as methanol, ethanol, acetone, tetrahydrofuran, dioxane, ~,N-dimethylformamide, N,~-dimethylacetamide or N-methylpiperidone and in the presence of a basic substance, the s~n-isomer of the compound (~III) is selectively produced (normally in a ratio of about 85:15 to lO0:0). As the basic substance useful for the purposes of this reaction, there may be mentioned alkali or alkaline earth metal salts of lower aliphatic carboxylic acids, and inorganic or organic bases having pKa values of not less than 9.59preferably within the range of 9~8 to 12 0. As examples of said lower aliphatic carboxylic acid salts may be mentioned the salts of lower aliphatic carboxylic acids of 1 to 6 carbon , . ~

1 3~`70~

atoms such as sodium acetate, potassium acetate, calcium acetate, barium acetate, sodium formate, sodium propionate, potassium hexanoate~ etc.; while the inorganic bases mentioned above in-clude alkali metal salts of carbonic acid such as sodium carbon-ate, potassium carbonate, etc. As said organic bases may be mentioned tri-lower aLkyl-substituted amines whose lower alkyl is that of 1 to 4 carbon atoms such as trimethylamine, triethyl-amine, tributylamine, etc. and 5- to 6-membered cyclic amines substituted in N-position by lower alkyl of 1 to 2 carbon atoms such as N-methylpyrrolidine, N-ethylpyrrolidine, N-methylpiper-azine, N-ethylpiperazine~ etc. Where said N,N-dimethylformamide, NjN-dimethylacetamide or N-methylpyrrolidone is employed as the solvent, it is not always necessary to add the a~oresaid basic substance. The reaction temperature and time are generally selected from the range of O to 50 & (preferably O to 30 C) and the range of 1 to 30 hours ~preferably 1 to 5 hours), res-pectively.
(III) The compound (VIII) (syn-isomer) may also be selectively produced by the following procedure. Thus, in a further search for a method for selective production of the syn-isomer, we have discovered that by reacting a 2-amino-thiazol-4-ylglyoxyl acid derivative of the formula (IX) with O-methylhydroxylamine, the ~y~-isomer of the methoximino compound may be selectively obtained.

R2NH~

wherein R2 and R7 are as previously defined.
Normally this reaction may be conducted smoothly in a suitable solvent at pH about 4.0 to 9Ø The solvent mentioned 1! _ 24 -1 3 '` ~ 7 0 ~
:
may be any type of solvent unless it interferes with the reaction.
Thus, for example, ethers such as ethyl ether, tetrahydrofuran, dioxane, etc.; lower alcohols such as methanol, ethanol, etc.;
halogenated hydrocarbons such as chloroform, methylene dichloride, etc.; esters such as ethyl acetate, butyl acetate, etc.; water;
and mixtures of such solvents may be mentioned. ~hile this reaction proceeds in the neighborhood of room temperature, it may be accel-erated by heating. This reaction temperature and time are generally selected from the range of O to 100 C (preferably O to 50 & ) and the range of 1 to 10 hours (preferably 1 to 5 hours), respectively.
The starting compound (IX) for this reaction may be produced by the reaction described hereinafter. Thus, the hydrol-ysis of a nitron compound of the formula (X):

R2NH ~ ~ C-COOR7 (X) + 3 wherein R2 and R? are as previously defined yields the compound (IX).
This hydrolysis reaction takes place smoothly in the presence of a mineral acid, and is normally conducted in a solvent. As examples of said mineral acid may be mentioned hydrogen chloride, sulfuric acid, phosphoric acid, etc. The solvent may be of any desired type that will not interfere with the reactionO Thus, there may be men-tioned ethers, e.g. tetrahydrofuran, dioxane, etc.; alcohols, e.g.
methanol, ethanol, etc.; ketones, e.g. acetone, methyl ethyl ketone;

water, and mixtures of such solvents. Normally this reaction may be conducted under ice-cooling or at room temperature. The starting I'' 1 3r'!'`7~

compound (X) may be obtained by subjecting a compound of the formula (VIII) w~erei.n R6 is hydrogen and whose amino group in 2-position has been protected9 to methylation.
The conditions of this methylation reaction are essentially the same as the conditions under which the aforesaid compound (VIII) wherein R6 is hydrogen is methylated. (cf. the aforesaid method (I)) Under the described conditions of methylation, the methylation of the ~ isomer of the compound (VIII) wherein R6 is hydrogen does not give any substantial amount of this nitron compound (X) but the methylation of the a -isomer of the compound (VIII) wherein R6 is hydxogen yields the nitron compound (X) as a dominant product.
The compound of the ~o~r~.ula (~II) may be produced, for example by the methods described in Journal of Medicinal Chemistry, 16, 978(1973), Helvetica Chimica Acta, 49, 26(1966), Journal of the American Chemical Society7 60, 1328(1938) and West German Patent Application Laid Open (Offenlegungsschrift) No.2556736, or by procedures similar to such methods. The compound of fo~mula (II) used in this invention may be produced,for example by a suitable method selected from the methods described in U.S. Patent Nos 3875151 and 3697515, West German Patent Application ~aid Open ~o,2461478, West German Patent Application ~aid Open No.2607C64 (Dutch Patent Application No 7601902), West German Patent Application 1aid Open No 2619243, - 2~ -1 J ~J ~? j~ t3 ,.~

Japanese Patent Application ~aid Open No. 52083/1~75, West Gerrnan Patent Application Laid'Open No~, 246~] ~nd 2~60332, or by a process analogous to such methods, Among others, the compound (I) wherein R3 is carbamoyloxy or monohaloacetylc~rbamoyloxy group may also be produced, for example, by the method described below:

Ro H ~ ~ > RoNH ~ O O
N CH20H X'CH2CONCO ~ CH20CNHCCH2X' COOH monohalogenoacetyl COOH
(A)isocyanate ~ -~ (C) (B) el~mination of the acyl elimination up at the 7-po~ition ~f the ~ protecting H2N -r~ 1 group o ,~ N ~ CH20C-NHC-CH2X ' (COCH2X ' ) (d) RoNH I l,S~
¦ acylation at the O ~ N ~ CH20C-NH2 S ~ 7-positiOn (g) COOH
2 1 ~ elimination - ' C-CONH
_ ~ ~ of the acyl N~ O _ N ~ - CH20C-NHCCH2X' / group at the (e) OCH3 COOH O ` 7-position H2N I ~ ~
T ,~-CH OC-NH
elimination \~ 'r 2 " 2 of the ~ ~ (h) COOH
protecting R2NH ~acylation at the 7-group(C--CH2X ) ~ ~? C--CONH FS~ position O N~CH20CONH2 (f) I ! ~
, , .

1 3"~`7~8 wherein Ro is hydrogen or an acyl ~roup, X' is halogen such as chlorine9bromine or iodine and R2NH is as previously defined.
The reaction of the 3-desacetyl-cephalosporanic acid derivative of formula (A) w;th a mcnohalogenoacetyl isocyanate (B) is normally conducted smoothly by contacting the two reactants in a suitable solvent, either under ice-cooling or at a temperature near room temperature. The solvent employed for this purpose may be any solvent that will not interfere with this reaction. ~hus, for examples, ethers such as ethyl ether, tetrahydrofuran, dioxane, etc.;
ketones such as acetone, methyl ethyl ketone, etc.;
halogenated hydrocarbons such as chloroform, methylene dichloride, trichloroethane, etc ; esters such as ethyl acetate, butyl acetate, etc.; and mixtures of such solvents may be mentioned The amount of said monohalogenoacetyl isocyanate (B) is about 1 to several moles per mole of the starting compound (A), ~he monohalogenoacetyl isocyanate (B) may be produced, for example, by the method described in Journal of Organic Chemistry, 27, ~742 (1962) or a method analogous thereto.
The reaction for removing the 7-acyl group from the compound of formul~ or (g) J may be any of the reactions used generally for the deacylation of penicillins and cephalosporins ~hus, for example, the procedures described in West German Patent Application 1aid Open Nos, 2460331 and 2460332, Japanese Patent Publication Nos.13862/1966, 40899/1970 and No,34387/1972 1 3r`n-~70~

and United States Patent No. 3,632,578, etc. may be successfully employed. By way of illustration, the compound (C) (or (g)) is treated with an imide halide-forming agent to obtain the corres-ponding imide halide in the first place and the latter compound is then treated with an alcohol to obtain the corresponding imide ether. This imide ether is hydrolyzed to the corresponding 7-amino derivative (d) (or (h)).
As said imide halide-forming agent, there may be employed one of the halides derived from carbon, phosphorus or/and sulfur and the acid halides derived from their oxy-acids (e.g. phosphorus oxychloride, phosphorus pentachloride, phos-phorus trichloride, thionyl chloride, phosgene, oxalyl chloride, protocatechuoyl-phosphorus trichloride, p-toluenesulfonyl chloride, etc.), for instance. This imide-halide-forming reac-tion is normally conducted with advantage in a solvent. The solvents for this purpose include not only the common inert sol-vents (such as methylene dichloride, chloroform, etc.) but tertiary amines (e.g. triethylamine, pyridine, dimethylaniline, etc.) and other solvents as well as mixtures of such sol~ents.
The imide ether-forming reaction is accomplished by contacting the imide halide reaction mixture with an alcohol. The alcohols that may be normally employed include lower alkanols containing 1 to 4 carbon atoms such as methanol, ethanol and n-butanol. The aforementioned hydrolysis is accomplished by contacting the reac-tion mixture containing the product imidoether with water. In order to preclude ,., ~ ~ 3 C t~ 7 ~ 8 24205-339 side reactions, the aforementioned reactions are preferably carried out under cooling.
The reaction for removing the monohaloacetyl group from the compounds (c) [or (e)] is substantially the same reaction as that for removing the same group from the compound (I), which is described before.
Referring to the above formulas (A) and ~B), the acyl groups represented by Ro may be any of the following exemplary groups5 via acyl groups derived from straight-chain aliphatic carboxylic acid containing up to 10 carbon atoms and acyl groups derived from cycloaliphatic carboxylic acid of up to 6 carbon atoms, e.g. formyl, acetyl, propionoyl, hexanoyl, butanoyl, heptanoyl, octanoyl, cyclopentanoyl, etc.; acyl groups derived from phenyl- or phenyl-substituted lower (up to 4 carbon atoms) allphatic carboxylic acid, e.g phenylacetyl, phenoxyacetyl, a-phenoxypropionyl, a-phenoxybutyryl, p-nitrophenylacetyl, etc.;
acetyl or thioacetyl groups subgtituted by a 5- or 6-membered heterocyclic group including one N, S or 0 hetero-atom or a 5- or 6-membered heterocyclic group lncluding said hetero-atom and an additional 1 to 3 hetero-atoms selected from the class consisting of N, S and 0, which latter heterocyclic group, in turn, may optionally be substituted by amino or hydroxyl, or by the corresponding heterocyclicoxy group, e.g. 2-thienylacetyl, tetrazolylacetyl, tetrazolylthioacetyl, a-(2-pyridyloxy)acetyl, a-(3-pyridyloxy)acetyl, a(4-pyridyloxy)acetyl, 2-(2-hydroxy thiazol-4-yl)acetyl, 2-(2-amlnothiazol-4-yl)acetyl,4-pyridylthioacetyl, l-pyrazolylacetyl, 2-furylacetyl, 6-(2'-oxo-3'-~ 3 rl, 7 !3 8 methylpyridazinyl)thioacetyl, etc.; acyl groups derived from mono-substituted aliphatic carboxylic acid, e.g. cyanoacetyl, acetoacetyl, ~-halogenoacetoacetyl, 4-methylthio-3-oxobutyryl, 4-carbamoylmethylthio-3-oxo-butyryl, etc.; a-substituted phenylacetyl groups, e.g. mandelyl, a-carboxylphenylacetyl, a-aminophenylacetyl, a-sulfophenylacetyl, a-sulfo-(p-aminophenyl)acetyl, a-(~-methylsulfonylethoxycarbonyl)aminophenyl-acetyl, etc.; glycyl groups substituted in a-position by a 5- or 6-membered ring including one 0 or S atom as the hetero-atom or a 5- or 6-membered ring including said hetero-atom and one N atom as an additional hetero-atom, which latter ring is substituted by amino or hydroxyl, e.g. phenylglycyl, 1-cyclohexenylglycyl, cyclohexadienylglycyl, thienylglycyl, p-hydroxyphenylglycyl, furylglycyl, 2-amlnothiazol-4-ylglycyl, etc.; acyl groups derived from di-substituted aliphatic carboxylic acid such as 5-amino-5-carboxyvaleryl, etc.; and heterocyclic acyl groups, e.g. 5-methyl-3-phenyl-4-isooxazolylcarbonyl, 3-(2,6-dichlorophenyl)-5-methyl-4-isooxazolylcarbonyl, etc.
The compound (A) may be produced generally ~D by acylating 7-aminocephalosporanic acid (7-ACA) with an acylating agent corresponding to the acyl group represented by Ro by Per se ~nown method for acylation of an amino group at 7-position of cephalosporin compound mentioned hereinbefore, and removing the 3-acetyl group enzymatically from the same cephalosporin having a 3-acetoxymethyl 1 3f~~7 0 Qf grou.p (Biochemical Journal 81, 591(1961)) or ~2? by the ferm.entative production of 7-(D-5-aminoadipinamido)~3-hydroxymethyl-3-cephem-4-carboxylic acid (cephalosporadesic acid., desacetylcephalosporin C, DCP~)(Nature 246, 154(1973);
Japanese Patent Laid Open No~491/1974)), for instance f~he optionally substituted heterocyclic thiol compound R5SH, wherein R5 is defined hereinbefore,which is employed as a nucleophilic compound in accordance with this inven-tion may be synthesized, for example by the methods described in Journal f~r praktische Chemie, N~ 133 (1932), Heterocyclic Compounds, 8, edited by Robert C.
Elderfield (John Wiley & Sons) and Advances in Hetero-cyclic, Chemistry, edited by A R Katritaky, A, J.
Boulton (Academic Press) or by processes analogousf thereto fIfhe compound (IV) may be produced,for example, by the method described in Belgian Patent No 719710 or a process analogous thereto As a~ alternative, it may be produced by the application of the aforementioned Process (1) to the compound (III) and the compound (II) wherein -f~H2R~ is -CH2R4, which is obtainable by one of the methods mentioned hereinbefore as the methods for the production of the compound (II) or processes analogous thereto. fThe compound (VI) may be produced, for example, by a procedure analogous to the method described in West German Patent ; Application ~aid Open No.2556736, or by reacting the compound (II) with the s~n-isomer of the compound (VIII) wherein R6 is hydrogen.
f~he present invention is illustrated in further detail below with reference to examples, but it is to be understood that the examples are solely for the purpose of illustration and not to be construed as limitations of the invention, and that many variations may be resorted to without departing from the spirit and scope of the invention. In this specification, "g", "mg", "kg", "m~", "cm", "ppm", "Hz", "MHz", 'tmol", "m mol", "mcg", "Calcd.", "DMS0", "nm" and "decomp." are abbreviations of "gram", "milligram", "kilogram", "milliliter", "centimeter", "part per million", "Herz", "mega Herz", "Mole", "milli-Mole", "microgram", "Calculated", "dimethylsulfoxide", "Nano meter", and "decomposed", respectively. Resins named "Amberlite" are products manufactured by Rohm &
Haas Co, in U,S,A. All the temperatures are uncorrected and the percentages are all on the weight basis except speficically defined The NM~ spectra given therein were measured using a Varian Model ~ 100 (100 MHz) or ~60 (60 MHz) spectrometer with tetramethylsilane as the internal or external reference and all ~ values are in ppm. ~ye symbol s stands for a singlet, d a doublet, t a triplet, q a quartet, m a multiplet, and J a coupling constant - ~3 -1 3C'~70~

Reference Example 1 In a solution of 13.3 g of sodium carbonate in 120 m~
of water is dissolved 10 g of ethyl 3-oxo-2-hydroxyimino-butyrate, followed by addition of 30 m~ of methanol. The mixture is cooled with ice and, under stirring, 15.8 g of dimethyl sulfate is added dropwise over a period of 3 minutes. After the dropwise addition has been completed, the ice-bath is removed and the mixture is stirred at room temperature for 40 minutes The reaction mixture (pH 8 or higher) is extracted twice with ethyl acetate and the extracts are pooled, washed with water and dried The solvent is then evaporated off under reduced pressure and the residue is subjected to distillation under reduced pressure. By the above procedure is obtained 9 g of ethyl 3-oxo-2-methoxyiminobutyrate as a pale-yellow oil boiling at 56-61C/0 3-0.4 mmHg.
Elemental analysis, for C7Hl1N04 Calcd C, 48.54; H, 6.40; ~, 8 08 Found C, 48.41; H, 6.51; N, 7,96 ~?IR spectrum (60 MHz, in CDC~3):
2.40 ppm(3H, singlet, CH3CO), 4 10 ppm(3H, singlet, =NOCH3) Reference ~xamPle 2 (1) In 120 m~ of chloroform is dissolved 27 3 g of ethyl 3-oxo-2-methoxyiminobutyrate and the solution is warmed to 40C. Then, a solution of 25.3 g of bromine in 30 m~ of chloroform is added dropwise over a period of 30 minutes. ~he mixture is stirred and reacted at I !

1 3!~,~7 ~ ~

room temperature for l^hour. The reaction mixture is washed with a 5 /0 aqueous solution of sodium hydrogen carbonate and water in that order and the organic layer is dried. The solvent is then distilled off under reduced pressure to obtain 36.2 g of ethyl 4-brom-3-oxo-2-methoxy-iminobutyrate as an oily product.
NMR spectrum (60 MXz, in CDC~3):
4.16 ppm(3H, singlet, OCH3), 4.36 ppm(2H, singlet, BrCH2CO) (2) In 20 m~ of ethanol is dissolved 5 g of the above product~ followed by addition of 1.8 g of thiourea. The mixture is heated under reflux for 3 hours. After cooling, the precipitate is collected by filtration and dissolved in 20 mR of water, to which sodium hydrogen carbonate is added ~he oil that has separated is extracted with ethyl acetate ~he ethyl acetate layer is washed and dried Thereafter, the ethyl acetate is evaporated off to obtain white crystals. Recrystallization from ethanol yields 2.6 g (57.2 %) of ethyl 2-(2-aminothiazol-4-yl)-2-(anti)-methoxyiminoacetate as white crystals, melting point: 114-115C
Elemental analysis, for C8HllN303S
Calcd C, 41.91; H, 4 84; N, 18 33 ~ ound C, 41 71; H, 4 75; N, 18.07 MMR spectrum (60 MHz, in CDC~3):
4.07 ppm(3H, s., OCH3), 5.80 ppm(2H, br s., NH2~, 7.43 ppm (lH, s , thiazole 5H) (3) The filtrate obtained upon collection of the first 1 3r ~ $

crop of precipitate is concentrated under reduced pressure and sodium hydrogen carbonate is added to the residue.
The mixture is extracted with ethyl acetate and the oil obtained from the ethyl acetate layer is purified by column chromatography on silica gel. By the above procedure is obtained 59 mg (1.~ %) of ethyl 2-(2-amino-thiazol-4-yl)-2-(syn)-methoxyiminoacetate as white crystals, melting point: 163-164C.
Elemental analysis, for C8HllN303S
Calcd. C, 41.91; H, 4.84; N, 18.33 ~ ound C, 41.57; H, 4.76; N, 18.07 NMR spectrum (60 MHz, in CDC~3):
4.02 ppm(3H, s,, OC~ ), 5.8~ ppm(2H, br, ~., NH2), 6,74 ~pm(lH, s " thiazole 5E~
Reference ~xample 3 To 600 m~ of ethanol is added 121 g of ethyl 4-chloro-3-oxo-2-hydroxyiminoacetate together with 47.6 g of thiourea and the mixture is s~irred at room temperature for 3 hours. The ethanol is then evaporated off under reduced pressure and 350 m~ of water is added. ~he water layer is washed with ether,neutralized with sodium hydrogen carbonate (to pH 7.5) and extracted with ethyl acetate-tetrahydrofuran (1~ he organic layer is washed with water and dried. The solvent is then distilled off to obtain 45 g of crystalline product.
A 1 g por~ion of the above product is taken and purified by column chromatography on silica gel (eluting solvent: ethyl acet~te-n-he~ane). The first fraction ~3~ 7~,S

gives 650 m~ of the anti-isomer OI ethyl 2-(2-amino-thiazol~-yl)-2-hydroxyiminoacetate and 150 mg of the s;~n-isomer is obtained from the second fraction.
Anti-isomer: white crystals, melting point:l45,3C
S;gn-isomer : pale yellowish white crystals, meltin~;
point: 185.5C
~lemental analysis, for C7H9N~03S
Calcd. C, ~59.06; H, 4 21; N, 19.52 ~ound(Anti-) C, 38.81; H, 4.20; ~, 19.62 (S~n-) C, 39.28; H, 4 10; N, 19~63 NMR spectrum (60 MHz, in d6-DMSO):
Anti-isomer: 7.10 ppm(2H, br, s, NH2), 7.50 ppm(lH, s.~ thiazole 5-H~, 12,5 ppm(lH, s., OH).
S;,m-isomer: 6 80 ppm(lH, sO, thiazole 5-H), 7.12 ppm(2H, br. s , NH2), 11.6 ppm(lH, s, OH) Reference Example 4 In 15() m~ of water is dissolved 10 6 g of sodium carbonate, followed by addition of a solution of 10.7 g of ethyl 2-(2-aminothiazol~-yl)-2-(syn)-hydroxyimino-acetate in a mixture of 150 m~ of tetrahydrofuran and 50 m~ of methanol Under ice-cooling, 12~6 g of dimethyl sulfate is added dropwise over a period of 5 minutes. After the dropwise addition has been completed, the ice-bath is removed a~d the mixture is stirred at room temperature While stirring, white crystals start separating out After 3 hours, most of the organic solvent is distilled off un~ler reduced pressure and the residue is cooled with ice. ~he resultant precipitate ~ 37 --1 3C~7~

is colle~ted by filtration, washed with water and dried.
By the above procedure is obtained 5 g of ethyl 2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetate as white crystals. In NMR spectr~m and other properties, this product is identified with the ethyl 2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetate Reference Example 5 In 10 m~ of N,N-dimethylacetamide is dissol~ed 2.15 g of ethyl 2-(2-aminothiazol-4-yl)-2-(syn)-methoxy-iminoacetate (melting point: 16~-164C) and, under ice-cooling, 1 27 g of chloroacetyl chloride is added dropwise.
The mixture is stirred under ice-cooling for 30 minutes and, then, at room temperature for 30 minutes. ~he reaction mixture is diluted with 50 m~ of water and extracted twice with 100 m~ portions of ethyl acetate ~he extracts are pooled, washed with a 5 /0 aqueous solution of sodium hydrogen carbonate and a saturated aqueous solution of sodium chloride in the order mentioned and finally dried. The solvent is then evaporated off to obtain 2.04 g of ethyl 2-(2-chloroacetamidothiazol-4-yl)-2-(s~)-methoxyiminoacetate as a crystalline product, melting point~ 112C.
~lemental analysis, for CloH12N304SC~
Calcd. C, 39.29; H, 3 96; N, 13.74 ~ ound C, 39.15; H, 3 91; N, 13~69 NMR spectrum (60 MHz, in CDC~3):
4.00 ppm(3H, s., =NOC ~ )~ 4.24 ppm(2H, s, C~CH2CO), 7.15 ppm(lH, s., thiazole 5-H) 1 3"~708 Reference ~xample 6 To a solution of 9 g of potassium hydroxide in a mixt;ure of 85 m~ of water and 452 m~ of ethanol is added 9 62 g of ethyl 2-(2-chloroacetamidothiazol-4-yl)-2-(s~n)-methoxyiminoacetate and the mixture is stirred at room temperature for 2 hours. The ethanol is distilled off under redueed pressure and, following addition of 85 m~
of water, the residue is washed with 10~ m~ of ethyl acetate. The water layer is adjusted to pH 2 with 10 %
hydrochloric acid and extracted twice with 200 mR portions of ethyl acetate The extracts are combined, washed with a saturated aqueous solution of sodium chloride and dried.
The solvent is then distilled off to obtain 7,63 g of 2-(2-chloroacetamidothiazol-4-yl)-2-(s~n)-methoxyimino-acetic acid as crystals meltin~ at 170-171~C.
Elemental analysis~ for C8H8N304~C~
Calcd. C, 34.60; X, 2.90; N, 15.13 ~ ound C, 34,97; H, 3 03; N, 14.74 NMR spectrum (60 MHz, in d6-DMSO): 3 95 ppm(3H, singlet, =~OCH3), 4.40 ppm(2H, singlet, C~CH2CO), 7 57 ppm (lH, singlet, thiazole 5-H) Reference ~xample 7 2 38 g of a 7:8 mixture of the s~n- and anti-isomers of ethyl 2-(2-aminothiazol-4-yl)-2-methoxy-iminoacetate is chloroacetylated with chloroacetyl chloride as in Reference ~xample 5, and 30 m~ of ether is added to the resultant mixture of the s~n- and anti- forms of ethyl 2-(2-chloroacetamidothiazol-4-yl)-2-methoxyimino-- 39 ~

. .~ , .

1 3"Q`70~

acet;ate. The crystals that ha~e separated out are col~ected by filtration ~Product (A)) In NMR spectrum and other properties, this product is identified with the sample of ethyl 2-(2-chloroacetamidothiazol-4-yl)-2-~ )-methoxyiminoacetate obtained in Reference Example 5 Yield 600 mg.
~ he oil obtained upon concentration of the filtrate (2 42 g., a mixture of s~n- and anti-isomers) is added to a solution of 879 mg potassium hydroxide in a mixture of 5 m~ water and 80 m~ ethanol under ice-cooling and the entire mixture is stirred at that temperature for 15 minutes The ethanol is distilled off under reduced pressure and the residue is diluted with 50 m~ of water and extracted twice with 100 m~ portions of ethyl acetate~ The ethyl acetate layer is washed with water and dried, The ethyl aceta.te is then distilled off to obtain 577 mg of ethyl 2-(2-chloroacetamidothiazol-4-yl)-2-(s~n)-methoxyimino-acetate (Product (B~). In-NM~ spectrum and other properties, this product is identified with the syn-isomer according to Reference Example 5. Products (A) and (B) give a total yield of 1076 g or a recovery rate of 96.8 %.
Reference Example 8 In 600 m~ of 50 % aqueous tetrahydrofuran is dissolved 67 8 g of ethyl 4-chloro-3-oxo-2-hydroxyiminoacetate, followed by addition of 155 g of sodium acetate trihydrate and 53.2 g of thiourea~ ~he mixture is stirred at room temperature for 4 hours, ~he reaction mixture is adjusted to pH 7.0 with sodium hydrogen carbonate and, following ' ' 0 ~

addition of sodium chloride, it is extracted twice with 300 m~ of tetrahydrofuran. The extracts are combined, washed (with water) and dried. The tetrahydrofuran is then distilled off to obtain 27.5 ~ of ethyl 2-(2-amino-thiazol-4-yl)-2-hydroxyiminoacetate as crystals. Based on l~MR and other data, this product is found to be a 82:18 mixture of syn- and anti-isomers.
A similar reaction is carried out without usin~
sodium acetate. Based on the same criteria, the resultant product is found to be a 25075 mixture of s~n- and anti-isomers.
Reference Example 9 The reaction of Reference ~xample 8 is repeated except that 50 % aqueous ethanol is used in lieu of 50 %
aqueous tetrahydrofuran. In this case, too, where sodium acetate is employed, there is obtained an 83:17 mixture of s~n- and anti-isomers of ethyl 2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetate In contrast, where sodium acetate is not employed, the above reaction yields a 50:50 mixture of s~n- and anti-isomers. ~he proportions of s~n and anti-isomers are determined by NMR spectra and other methods.
Reference Example 10 ~ he reaction of Reference Example 9 is repeated except that N,N-dimethylacetamide is used in lieu of 50 %
aqueous tetrahydrofuran-sodium acetate. This procedure yields an 85:15 mixture of s~n- and anti-isomers of ethyl 2-(2-amincthiazol-4-yl)-2-hydroxyiminoacetate, I 3r~jQ7~8 Reference ~xample 11 In 10 m~ of 50 % aqueous ethanol is dissolved 200 mg of ethyl 2-aminothiazol-4-yl-glyoxylate, followed by the addition of 166 mg of 0-methylhydroxylamine hydrochloride and, then? 168 mg of soclium hydrogen carbonate. ~he mixture is stirred in a closed vessel at 70C for 5 hours The reaction mixture is concentrated under reduced pressure and the residue is diluted with 10 m~ of water and extracted with ethyl acetate~ The ethyl acetate layer is washed with water and dried. The ethyl acetate is then distilled off to obtain ethyl 2-(2-aminothiazol-4-yl)-2-methoxyiminoacetate as crystals. Based on NMR and other data, this product is found to be an 83:17 mixture of s~n-and anti-isomers Reference ~xample 12 In 70 m~ of ethanol containing 10 % of HC~ is suspended 2.44 g of the methylnitron of ethyl 2-(2-aminothiazol-4-yl)-2-(anti)- hydroxyiminoacetate, which is ~-(2-aminothiazol-4-yl-ethoxycarbonyl)methylenemethylamine ~-oxide, melting point: 184-185C. The mixture is stirred at room temperature for 16 hours. ~he reaction mixture is concentrated under reduced pressure and, following addition of 10 m~ of water, the residue is adjusted to pH 7.5 with a 5 %
aqueous solution of sodium hydrogen carbonate and extracted with ethgl acetate. ~he ethyl acetate layer is washed with water and dried. ~he ethyl acetate is then distilled off and the residue is recrystallized from ethanol. By the above procedure is obtained 1.54 g of ethyl 2-amino-_ 42 -13`~ ,70~

thiazol-4-ylglyoxylate as yellow crystals melting at 14~.3C.
Elemental analysis, for C7H8N203S
Calcd. C, 41,98; H, 4.02; N, 13,99 Found C, 41 83; H, 4.14; N, 13 98 Reference ExamPle 1~
In 50 m~ of lN-hydrochloric acid is dissolved 1 g of the same N-(2-aminothiazol-4-yl-ethoxycarbonyl)methylene-methylamine N-oxide as used is Reference Example 12 and the solution is stirred at room temperature for 5 hours.
The reaction mixture is neutralized with sodium carbonate and extracted with ethyl acetate. Thereafter, the procedure of Reference Example 12 is repeated to obtain O 5 g of ethyl 2-aminothiazol-4-ylglyoxylate. Based on NMR and other data, this product is identified with the product obtained in Reference Example 12 Reference Example 14 In 20 m~ of ethanol containing 10 % of HC~ is suspended 1.2 g of the methylnitron of 2-(2-ami~othiazol-4-yl)-2-(~)-hydroxyiminoacetate, i.e. ~-(2-aminothiazol-4-yl-ethoxycarbonyl)methylenemethylamine N-oxide, melting point: 111.6C and the suspension is stirred at room ; temperature for 16 hours, ~hereafter, the procedure of Reference Example 12 is repeated to obtain 0.7 g of ethyl 2-aminothiazol-4-ylglyoxylate as yellow crystals, In ~MR and other properties, this product is identical with the product according to Reference ~xample 12.

- 4~ -~, ~ 3~310~

Reference E;xample 15 To a mixture of 10 m~ tetrahydrofuran and 5 m~
eth1yl acetate is added lg of ethyl 2-(2-aminothiazol-4-yl)-2-(anti)-hydroxyiminoacetate (melting point: 145,3C), followed by addition of an excess of diazomethane-ether solution. The mixture is allowed to stand at room temperature for 2 days. After the residual diazomethane is decomposed with acetic acid, the reaction mixture is concentrated under reduced pressure and the residue is recrystallized from ethyl acetate. By the above procedure is obtained 0 8 g of the methylnitron compound, i.e. N-(2-aminothiazol-4-yl-ethoxycarbonyl)methylenemethylamine N-oxide as yellow crystals melting at 184-185C.
E;lemerLtal analysis, for C8Hl1N303S
Calcd C, 41.91; H, 4.84; N, 18.~3 ~ ound C, 41.86; H, 4.75; N, 18.35 spectrum (60 MHz, in CDC~3): ~ 82 ppm(3H, singlet, N-CH3), 5.27 ppm(2H, br. singlet, NH2), 8.49 ppm (lH, singlet, thiazole 5-H) ~a~e~
~ o a solution of 23 mg sodium in 8 m~ methanol is added 215 mg of ethyl 2-(2-aminothiazol-4-yl)-2-(anti)-hydroxyiminoacetate (melting point: 145.3C) and, at room temperature, 280 m~; of methyl iodide is added. The mixture is stirred for 45 minutes, after which it is concentrated under reduced pressure. ~he residue is diluted with water (pH 7 or higher) and extracted with ethyl acetate. The ethyl acetate layer is washed with -: .

1 3~j~70~

water, dried and concentrated. The residue is recrystallized from tetrahydrofuran-ethyl acetate. By the above procedure is obtained 160 mg of the methylnitron compound as yellow crystals. This product is completely identical with the product obtained in Reference Example 15.
_eference Example 17 The filtrate after collection o~ the precipitated ethyl 2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetate from the concentrated reaction mixture in the procedure of Reference Example 4 is extracted with tetrahydrofuran-ethyl acetate (1:1) and the extract is washed with water, dried and concentrated ~o the residual brown-colored oil is added 20 m~ of tetrahydrofuran and the mixture is allowed to stand in a refrigerator overnight, ~he result-ant cr~stals are collected by filtration and recrystal-lized from ethyl acetate. By the above procedure is obtained 1.3 g of the methylnitron of ethyl 2-(2-amino-thiazol-4-yl)-2-(~)-hydroxyiminoacetate, i.e. ~-(2-aminothiazol-4-yl-ethoxycarbonyl)methylenemethylamine N-oxide as yellow crystals melting at 111.6C.
Elemental analysis, for C8HllN303~
Calcd C, 41.91; H, 4.84; N, 18.33 ~ ound C, 41.89; H, 4 91; N, 18.44 ~MR spectrum (60 MXz, in CDCe3): 4 14 ppm(3H, singlet, *

N-CH3), 5 34 ppm(2H, br. singlet, ~H2), 6.62 ppm (lH, singlet, thiazole 5-H) Reference Exam~le 18 In 10 m~ of tetrahydrofuran is dissolved 1.5 g of J ~ O ~

ethyl 4-brom-3-oxo-2-methoxyiminobutyrate and, after 7 m~
of water is added, 2 4 g of sodium acetate trihydrate and 0 9 g of thiourea are further added ~he mixture is stirred at room temperature for 17 hours, after which it is concentrated under reduced pressure The concentrate is adjusted to pH about 1.5 with dilute hydrochloric acid and washed with ethyl acetate. The water layer is neutra-lized with sodium hydrogen carbonate and extracted with ethyl acetate The ethyl acetate layer is washed with water, dried and concentrated under reduced pressure to obtain 0 8 g of yellowish crystals This product is the ethyl 2-(2-aminothiazol-4-yl)-2-(syn)-methoxyimino-acetate. Based on ~MR and other data, this product is identified with the sXn-isomer obtained i~ Reference Example 2 R ference Example 19 In 10 m~ of dimethylformamide is dissolved 2 g of ethyl 4-brom-3-oxo-2-methoxyiminobutyrate, followed by addition of 1.2 g of thiourea. The mixture is reacted at room temperature for 5 hours. To the reaction mixture is added 20 m~ of a saturated aqueous solution of sodium chloride and, then, the pH of the mixture is adjusted to pH about 1.5 with dilute hydrochloric acid, Thereafter, the procedure of Reference Ex~mple 18 is followed to obtain 1.1 g of pale-yellow crystals. Based on its NMR
and other data, this product is identified to be an 87:13 mixture of the s~n- and anti-isomers of ethyl 2-(2-amino-thiazol-4-yl)-2-methoxyiminoacetate. Washing the product _ 46 -1 3r` ,7 Q~

with a small quantity of ether gives the s~n-isomer substantially free of the anti-isomer.
Reference Example 20 (1) In 80 m~ of anhydrous acetone is dissolved 20 g of 7-(5-carboxy-5-benzamidovalerylamido)desacetylcephaiosporanic acid, followed by addition of 7 g of chloroacetyl isocya-nate. The mixture is stirred at 20C for 40 minutes, after which 200 mR of ether is added The precipitate is collected by filtration and washed with 50 m~ of ether.
By the above procedure is obtained 19.6 g of 7-(5-car~oxy-5-benzamidovalerylamido)-3-(N-chloroacetyl)carbamoyloxy-methyl-3-cephem-4-carboxylic acid as white powder.
NMR spectrum (60 MHz, in d6-DMSO): 3 54 ppm(2H, quartet, 2-CH2~, 4 50 ppm(2H, singlet, -NHCOCH2GR), 4.98 ppm (2H, quartet, ), 5 04 ppm(lH, doublet, 6-H), 5 77 ppm(lH, doublet, 7-H) (2) In 80 mR of methylene dichloride containing 7.6 mR
of N,N-dimethy~aniline is suspended 6 g of 7-(5-carboxy-5-benzamidovalerylamido)-3-(N-chloroacetyl)carbamoyloxy-methyl-3-cephem-4-carboxylic acid. The mixture is cooled to -50C, at which temperature 2.25 me of phosphorus trichloride is added. It is then stirred at -30C for 1.5 hours to obtain a clear solution. To this solution is added 4 17 g of phosphorus pentachloride and the mixture is stirred at -25C for 2.5 hours, after wh;ch it is cooled to -40C and 37 mR of cold methanol is promptly added.
~he mixture is then stirred at -5C for 25 minutes and, following addition of 22 mR of water, it is ad~u~ted to ~ 3,~ Q 7 o~

pH 3.5 with dilute aqueous ammonia. The reaction mixture is allowed to stand at 5C for l hour and the precipitate is collected by filtration. By the above procedure is obtained 1.76 g of 7-amino-3-(N-chloroacetyl)carbamoyloxy-methyl-3-cephem-4-carboxylic acid as colorless crystals.
Elemental analysis, for CllHl2~N~6S
Calcd. C, ~7.78; H, ~.46; N, 12.01 Found C, 38.02; H, ~.86; Ng 11.81 MMR spe~trum (60 MHz, in CF3COOH): ~.78 ppm(2H, br.
singlet, 2-CH2), 4.~5 ppm(2H, singlet, -~HCOCH2C~), 5 42 ppm(2H, br. singlet, 6-H, 7-H)~ 5,46 ppm(2H, quartet, -CH20COMH) Reference Example 21 While a mixture of sodium azide, ethanol and water is stirred under reflux, an ethanolic solution of N,N-dimethylaminoethyl isothiocyanate is added dropwise. The mixture is further refluxed for 45 minutesS after which time the ethanol is distilled off under reduced pressure.
The residual solution is made acidic with l~-hydrochloric acid and extracted with ethyl acetate. ~he extract is dried and concentrated to dryness and the crystalline residue is stirred with n-hexane~ recovered by filtration and recrystallized from toluene By the above procedure is obtained 1-(2-N,N-dimethylaminoethyl)-lH-tetrazol-5-thiol.
melting point: 217-219C(recrystallized from aqueous ethanol) NMR (60 MHz, in D20+~aHCO~ O~(s~ N(CH3)2), ~.58 1 3 ~i 3 7 ~ 8 (t, CH2), 4.70(t, CH2) Reference Example 22 (1) While a mixture of glycine-N,N-dimethylamide, triethylamine and methylene chloride is stirred, carbon disulfide and methyliodide are added in the order mentioned.
~he mixture is stirred at room temperature for 1 hour, after which it is shaken vigorously with a 5 % aqueous solution of phosphoric acid. The organic layer is taken, washed with water, dried and concentrated to dryness under reduced pressure. ~he crystalline residue is stirred with n-hexane, recovered by filtration and dried. By the above procedure is obtained methyl 2-(N,N-dimethyl-carbamoylmethyl)dithiocarbamate, IR (KBr, cm 1): 1626, 1543 NMR(60 MHz, in d6-DM~0) ~: 2.62(s, CH~S), 3.02(s, N(C ~ )2), 4,42(d, J=4Hz, CH2~, 8.30(br s.~ NH) (2) A mixture of methyl 2-(N,N-dimethylcarbamoylmethyl)-dithiocarbamate, sodium azide and ethanol is stirred under heating at 80C for 6.5 hours. The reaction mixture is adjusted to pH 2.5 with 10 % hydrochloric acid and, then, concentrated to dryness under reduced pressure. ~he residue is extracted with 100 m~ of methanol and the methanol extract is treated with activated carbon and dried, ~he residual powder is recrystallized from water.
By the above procedure i~ obtained l-N,N-dimethylcarbamoyl-methyl-lH-tetrazol-5-thiol. melting poi~t: 195-198C
(decomp.) NMR (60 MHz, in d6-DMS0) ~ : 2 87 & 3 07 (each ~, N(CH~)2), 1 3~ 7~

5.21(s, CH2CO) (3) Using a solution of sodium hydroxide, l-N,N-dimethylcarbamoylmethyl-lH-tetrazole-5-thiol is hydrolyzed to obtain l-carboxymethyl-lH-tetrazole-5-thiol.
melting point: 156-160C(decomp.) IR(KBr, cm 1): 171~
NMR(60 MHz, in d6-DMSO) 6 : 5.03(s, CH2CO), 12.09(br. s, NH ~ -COOH) Reference ~xample 2~
To 200 m~ of water are added 38 g of sodium nitrite and 53 g of methyl acetoacetate and, under ice-cooling and stirring, 200 m~ of 4N-sulfuric acid is added dropwise over a period of about an hour. During this dropwise addition, the temperature of the reaction mixture is maintained at 5-8C. The mixture is further stirred within that temperature range for 2 5 hours, after which it is extracted twice with 300 m~ portions of ethyl acetate. The extracts are pooled and washed twice with a saturated aqueous solution of sodium chloride. Then, a solution of 96 7 g sodium carbonate in 1 ~ of water is divided into 3 equal portions, with which 3-oxo-2-hydroxy-iminobutyrate is extracted from the above ethyl acetate layer (~ times). To the water layer (1 ~) is added 200 m~ of methanol and, after cooling with ice, 150 g of dimethyl sulfate is added dropwise with stirri~g over a period of 10 minutes. After the dropwise addition has been completed, the mixture is stirred at room temperature for 1,5 hours and extracted twice with 300 m~ portions of 1 3~ 708 ethyl acetate. The extracts are pooled, washed with water and dried. The ethyl acetate is then distilled off and the residue is cooled with ice, whereupon it solidifies.
The solid residue is collected by filtration and washed with a small amount of water. By the above procedure is obtained 52.3 g of methyl 3-oxo-2-methoxyiminobutyrate as white crystals melting at 64.4Co Elemental analysis, for C6HgN04 Calcd C, 45.28; H, 5.70; N, 8.80 Found C, 44.9~; H, 5.61; N, 8.71 NMR spectrum (60 MHz, in CDC~3) : 2 40 ppm(3H, singlet, -C-CH3), 3.86 ppm(3H, singlet, COOCH3), 4.10 ppm (3H, singlet, =NOCH3) Reference Example 24 In 150 m~ of chloroform iæ dissolved 40 g of methyl 3-oxo-2-methoxyiminobutyrate and the solution is heated to 40C. Then, a solution of 40 g bromine in 50 m~
chloroform is added dropwise over a period of an hour.
~hereafter, the reaction is continued under stirring at room temperature for an hour. The reaction mixture is washed with a 5 % aqueous solution of sodium hydrogen carbonate and water in the order mentioned, and the organic layer is dried. ~he solvent is then distilled off to obtain 52.1 g of methyl 4-bromo-3-oxo-2-methoxy-iminobutyrate as an oil.
~MR spectrum (60 MHz, in CDC~3) : 3 82 ppm(3H~ si~glet, COOCH~), 4.09 ppm(3H, singlet, =~-OC~ ), 4.27 ppm (2H, singlet, BrCH2CO) : ` :

. : -1 3"370~

In 350 ml of tetrahydrofuran is dissolved 52 g of methyl 4-bromo-3-oxo-2-methoxyiminobutyrate, followed by addition of 250 m~ of water and, further, by the addition of 89 1 g of sodium acetate trihydrate and 33.2 g of thiourea. The mixture is stirred at room temperature for 18 hours. ~o the reaction mixture is added 200 m~ of a 5 % aqueous solution of sodium hydrogen carbonate, followed by extraction with ethyl acetate.
The organic layer is washed with water, dried and concent-rated under reduced pressure to remove the solvent. ~o the concentrate is added 200 m~ of ether and the resultant precipitate is collected by filtration. By the a~ove procedure is obtained 24.8 g of methyl 2-(2-aminothiazol-4-yl)-2-(s~n~-methoxyiminoacetate as crystals melting at Elemental analysis, for C7H9~30~
Calcd C, 39 06; H, 4.21; N, 19.52 Found C, 38.78; H, 4.15; ~, 19.33 ~MR ~pectrum (60 MHz, in CDC~3) : 3.84 ppm(3H, singlet, COOCH3), 4.02 ppm(3H, singlet, =NOC~ ), 5.74 ppm (2H, br. singlet, ~H2), 6.74 ppm(lH, singlet, thiazole 5-H) Reference ExamPle 25 In 90 m~ of N,N-dimethylacetamide is dissolved 21.5 g of methyl 2-(2-aminothiazol-4-yl)-2-(s~n)-methoxyimino-acetate and, under ice-cooling, 1~ 6 g of chloroacetyl chloride i~ added dropwiseO ~he mixture i~ stirred under ice-cooling for 30 minutes and, then, at room temperature for ~0 minutes. Following the addition of 500 m~ of water, - 5~ -1 3~`~`7~

the reaction mixture is extracted twice with ethyl acetate, The extracts are pooled, washed with a 5 % aqueous solution of sodium hydrogen carbonate and water in that order and dried. The solvent is then distilled off to obtain 25 g of methyl 2-(2-chloroacetamidothiazol-4-yl)-2-(s~n)-methoxyiminoacetate as crystals melting at 130 8C
Elemental analysis, for CgHllN304~C~
Calcd. C, 37.03; H, 3.45; N, 14 40 Found C, 37 30; H, 3.40; N, 14.35 NMR spectrum (60 MHz, in CDC~3) : 3.90 ppm(3~, singlet, C~OC ~ ), 4.02 ppm(3H, singlet, =NOC~ ), 4.26 ppm (2H, singlet, C~CH2CO), 7.24 ppm(lH, singlet, thiazole 5-H) Reference Example 26 ~ o a solution of 19,2 g of potassium hydroxide in a mixture of 170 m~ water an~ 900 m~ ethanol is added 20 g of methyl 2-(2-chloroacetamidothiazol-4-yl)-2-(s~n)-methoxyiminoacetate and the solution is stirred at room temperature for 2 hours. ~he ethanol is distilled off under reduced pressure and~ following the addition of 170 m~ of water, the residue is washed with 200 m~ of ethyl acetate. The water layer is adjusted to pH 2 with 10 % hydrochloric acid and extracted twice with 300 m~
portions of ethyl acetate.
~ he extracts are pooled, washed with a saturated aqueous solution of sodium chloride and dried. The solvent is distilled off to obtain 16.8 g of 2-(2-chloro-acetamidothiazol-4-yl)-2-(~)-methoxyiminoacetic acid ~ 53 -1 30~708 as crystals. In NMR spectrum and other properties, this product is found to be identical with the product obtained in Reference Example 60 Reference E;x~mple 27 (l) Six grams of the 7-(5-carboxy-5-benzamidovaleryl-amido)-3-(N-chloroacetyl)carbamoyloxgmethyl-3-cephem~-carboxylic acid is suspended in 80 m~ of methylene dichloride containing 7.6 m~ of NjN-dimethylaniline and, under cooling at -50C, 2,25 m~ of phosphoruæ trichloride is added. The mixture is stirred at -30C for 1,5 hours until a clear solution is obtained. 'rO this solution is added 4,17 g of phosphorus pentachloride and the mixture is stirred at -25~C for 2.5 hours, ~hen, it is cooled to ~0C and 37 m~ of cold methanol is promptly added, q'he mixture is ~tirred at -5C for 25 minutes, after which it is diluted with 22 m~ of water and adjusted to pH 3,5 with dilute aqueous ammonia. ~he reaction mixture is allowed to stand at 5C for l hour and the resultant precipitate is collected by filtration, ~r the above procedure is obtained 1,76 g of 7-amino-3-(N-chloroacetyl)-carbamoyloxymethyl-3-cephem~-carboxylic acid as a colorless crystalline product, l~lemental analysis, for Cl1Hl2C eN3o6s Calcd, C, 37.787 H, 3,46; N, 12.01 ~ ound C, 38,02; H, 3,86; N, 11.81 NMR spectrum (60 MHz, in C~3COOH):
3.78 ppm(2H, broad singlet, 2-CH2), 4.35 ppm(2H, singlet, -NHCOCH2C~), 5,42 ppm(2H, broad singlet, .

, ' , , 1 3'','``?0~

6-H, 7-H), 5 46 ppm(2H, quartet, -CH20CONH) (2) In N,N-dimethylacetamide is dissolved 1.05 g of the 7-amino-~-(N-chloroacetyl)carbamoyloxymethyl-3-cephem-4-carboxylic acid obtained in the above (l) and, under ice-cooling, 998 mg of 2-chloroacetamidothiazol-4-yl-~-(anti)-methoxyiminoacetyl chloride hydrochloride is added ~he mixture is stirred under ice-cooling for 15 minutes and, then, at room temperature for 2 hours.
Then, following addition of 50 m~ of water, the reaction mixture is extracted twice with 100 m~ portions of ethyl acetate. The organic layers are pooled, washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The ethyl acetate is then distilled off, By the above procedure is obtained 2,2 ~ of 7-~(2-chloroacetamidothiazol-4-yl)-a-(anti)-methoxyimino~-aceta~ido-3-(~-chloroacetyl)carbamoyloxymethyl-3-cephem-4-carboxylic acid as white powder.
Note: Production of 2-chloroacetamidothiazol-4-yl-~-(anti~-methoxyiminoacetyl chloride (i) In lO0 m~ of dimethylacetamide is dissolved 10 g of ethyl a-(anti)-methoxyimino--(2-aminothiazol-4-yl)-acetate and, under cooling with ice, 5.91 g of chloro-acetyl chloride is added dropwise. ~he mixture is stirred at room temperature for l hour, at the end of which time it is poured in ice-water. ~he mixture is extracted with ethyl acetate and the organic layer is washed, dried and distilled to remove the solvent. By the procedure is obtained 12.66 g of ethyl ~-(anti)-methoxyimino-~-1 3",S70~

(2-(chloroacetamido)thiazol-4-yl )acetate as crystals, melt;ing point: 81-82C.
~;lemental analysis, for CloH12N304SC~
Calcd C, 39.29; H, 3.96 Found C, 38.74; H, 3.58 The nuclear magnetic resonance spectrum(60 MHz, in CDC~3) of this procluct gives singlets, one at 4.10 ppm being assignable to methoxg protons, at 4.24 ppm assignable to chloroacetyl protons and at 7.94 ppm assignable to thiazole 5-hydrogen.
(ii) 12.66 g of ethyl a-(anti)~methoxyimino-a-(2-(chloro-acetamido)thiazol-4-yl )acetate is added to a solution of 11.74 g of potassium hydroxide in a mixture of 25 m~
water and 500 m~ ethanol, ~'he mixture is stirred at room temperature for 20 minutes and ethanol is distilled off under reduced pressure and the residue is diluted with water. The mixture is acidified to l~-hydrochloric acid and the resultant precipitate is collected by filtration.
By the above procedure is obtained 10.54 g of a-(anti)-methoxyimino-a-(2-(chloroacetamido)thiazol-4-yl )acetic acid, meltin~; point: 182-183C.
Elemental analysis, for C8H8N304SC~
Calcd. C, 34.60; H, 2.90; ~, 15.13 ~ound C, 34.53; H, 3.00; N, 14.80 ~ he nuclear magnetic re~onance spectrum (60 MHz, in d6-DMS0) of the above product shows singlets, assignable to methoxy protons at 400 ppm, chloroacetyl protons at 4.~8 ppm and thiazole 5-hydrogen at 8.00 ppm, respectively.

. :

.
~ .

1 3C~7~

(iii) In 5 m~ of methylene chloride is suspended 555.4 mg of a-(anti)-methoxyimino-a-~2-(chloroacetamido)thiazol-4-yl)acetic acid and, under ice-cooling, 416.3 mg of phosphorus pentachloride is added. The mixture is reacted under stirring for 30 minutes. To the reaction mixture is added n-hexane and theresultant precipitate is collected by filtration By the above procedure is obtained 620 mg of ~-(anti)-methoxyimino-~-~2-(chloroacetamido)thiazol-4-yl)acetyl chloride hydrochloride.
Elemental analysis, for C8H7~303SC~2-HC~
C, 28.89; H, 2.42; N, 12.63 C, 28.35; H, 2.81; ~, 12.00 (3) In 50 m~ of tetrahydrofuran is dissolved 2.2 g of the 7-~2-chloroacetamidothiazol-4-yl)-~-(anti)-methoxy-imino~acetamido-3-(N-chloroacetyl)carbamoyloxymethyl-3-cephem-4-carboxylic acid obtained in the above (2), followed by the addition of 913 mg of finely powdered thiourea and 1 63 g of sodium acetate trihydrate. The mixture is stirred at room temperature for 17 hours. The precipitate is collected by filtration, washed with ethyl ether and dissolved in 10 m~ of water. The solution is made to pH 7 with sodium hydrogen carbonate and passed through a column of Amberlite XAD-2 By the above procedure is obtained 360 mg of sodium 7-~(2-aminothiazol-4-yl)-a-(anti)-methoxyimino)acetamido-3-carbamoyloxgmethyl-3-cephem-4-carboxylate as white powder, Elemental analysiS, for C15H15~67~2Na 5 2 Calcd. C, 34.42; H, 3 85; N, 16.05 ~ound C, 34,43; H~ 3.70; N, 15.68 ~a~n~rk ~ 57 ~

1 3C~7C~

NMR spectrum (60 MHz, in D20):
3.55 ppm(2H, quartet, 2-CH2), 4.11 ppm(3H, singlet, =NOC ~ ), 4.81 ppm(2H, quartet, -CH20CONH2), 5r21 ppm(lH, doublet, 6-H), 5 82 ppm(lH, doublet, 7-H), 7.55 ppm(lH, singlet, H2~ ~ ~ H

The antibacterial activity (MIC (~/m~)) of the sodium 7-~(2-aminothiazol-4-yl)-a-(anti)-methoxyimino)acetamido-3-carbamoyloxymethyl-3-cephem-4-carboxylate according to this example is shown below.
Microorganism MIC(y/m~) Escherichia coli 0-111 0 78 Klebsiella pneumoniae D~ 1,56 Klebsiella pneumoniae GN 3835 6.25 Serratia marcescens IFO 12648 12.5 ~erratia ~N0024 6.25 Proteus vulgaris IFO 3988 0.39 Proteus mirabilis GI~ 4359 0.78 Proteus morganii I~O 3168 0.78 Proteus rettgeri 8 T~O 336 ~ 0.2 Proteus rettgeri GN 473~ 0.78 Enterobacter cloacae I~O 12937 25 Citrobacter freundii G~ 99 1.56 Citrobacter freundii GN 1706 3 13 ; Reference_~xample 28 (1) In 20 m~ of N,N-dimethylacetamide is dissolved 1 05 g of 7-amino-3-(N-chloroacet~l)carbamoyloxymethyl-3-cephem-: `~
:

`~3~i7~

4-carboxylic acid and, under ice-cooling, 869 mg of 2-chloro~cet~midothiazol-4-ylacetyl chloride hydro-chloride is added The mixture is stirred under ice-cooling for 15 minutes and, then, at room temperature for 2 houxs After this reaction, the mixture is diluted with 50 m~ of water and extracted twice with 100 m~
portions of ethyl acetate ~he organic layers are pooled, washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The ethyl acetate is then distilled off to obtain white powder of 7-(2-chloroacetamidothiazol-4-yl)acetamido~ -chloro-acetyl)carbamoyloxymethyl-~-cephem-4-carboxylic acid.
Yield 1.6 g.
Note: Production of 2-chloxoacetamidothiazol-4-ylacetyl chloride In 15 m~ of dimethglacetamide is dissolved 4 g of ethyl 2-aminothiazol-4-ylacetate and, under ice-cooling, ~.62 g of chloroacetyl chloride is added dropwise, The mixture is stirred under ice-cooling for 30 minutes and, then, at room temperature for another 30 minutes. Then, following the addition of 50 m~ of water, the mixture is extra¢ted twice with 100 m~ portions of ethyl acetate-tetrahydrofuran. ~he extract is washed with 100 ml of a 5 % aqueous solution of sodium hydrogen carbonate and, then, with 100 m~ of a saturated aqueous solution of sodium chloride, followed by drying The solvent is then distilled off By the above procedure is obtained 2.95 g of ethyl 2-chloroacetamidothiazol-4-ylacetate as ~ 59 -1 3a~7~

an oily product. The entire amount of this oil is suspended in l00 m~ of methanol and, under ice-cooling~ 12 m~ of water containing 761 mg of sodium hydroxide is added.
~he mixture is stirred at room temperature for 30 minutes, at the end of which time a major portion of the methanol as distilled off under reduced pressure. To the residue is added lO m~ of water. The water layer is washed with 50 m~ of ethyl acetate and after the addition of 20 m~
of ethyl acetate, it is adjusted to pH 2 with lO % hydro-chloric acid. ~he mixture is shaken well and the organic layer is taken, washed with a saturated aqueous solution of sodium chloride and dried. The solvent is then distilled off. By the a~ove procedure is obtained 1,51 g of 2-chloroacetamidothiazol-4-ylacetic acid as colorless crystals~ melting point: 202-203C, ~lemental analysis, for C7H~C~N203S
Calcd. C, 35,83; H, 3.01; N, 11.94 Found C, ~6,01; H, 2.96, N, 11,61 In 20 m~ of methylene dichloride is suspended 938 mg of the above product and, under ice-cooling, l g of phosphorous pentachloride i8 added. ~he mixture is stirred at room temperature for 30 minutes. Following addition of 50 m~ of petroleum ether, the precipitate is collected by filtration and washed with 10 m~ of petroleum ether, By the above procedure is obtained 1.06 g of 2-chloro-acetamidothiazol-4-ylacetyl chloride hydrochloride as colorless crystals~

~ 3 ~, ~, 7 C 8 Elemental analysis, for C7H6C~2N202S HC~
Calcd C, 29.04; II, 2 44; N, 9.67 Found C, 28.96; H, 2 24; N, 9.61 IR spectrum (KBr): 1780 cm l(-Co~) (2) In 40 m~ of tetrahydrofuran is dissolved 1,6 g of the 7-(2-chloroacetamidothiazol-4-yl)acetamido-3--(N-chloroacetyl)carbamoyloxymethyl-3-cephem-4-carboxylic acid obtained in the above (1). ~o this solution is added 860 mg of thiourea, follo~ed by addition of sodium acetate trihydrate The mixture is stirred at room temperature overnight The precipitate is collected by filtration, washed with ethyl ether and dissolved in 10 m~
of water The solution is brought to pH 7 with sodium hydrogen carbonate and purified by column chromato~raphy on Amberlite XAD-2 By the above procedure is obtained 152 mg of sodium 7-(2-aminothiazol-4-yl)acetamido-3-carbamoyloxymethyl-3-cephem-4-carboxylate as white powder.
Elemental analysis, for C14H14N506S2Na 2H20 Calcd C, 35.67; H, 3.85; N, 14,85 ~ ound C, 35 97; H, 3.88; N, 14.64 NMR spectrum (60 MHz, in D20):
3.52 ppm(2H, quartet, 2-CH2), 3.61 ppm(2H, singlet, ~ ~ ), 4 78 ppm(2H, quartet, -CH20CONH-), 5.14 ppm(lH, doublet, 6-H), 5.68 ppm(lH, doublet, 7-H), 6.52 ppm(lH, singlet,`~ S

~xample 1 (1) In 6 mæ of N,N-dimethylaceta-mide is dissolved 290 mg 1 3"37~

of 7-amino-3-(N-chloroacetyl)carbamoyloxymethyl-~-cephem-4-carboxylic acid and, under ice-cooling, 276 mg of 2-(2-chloroacetamidothiazol-4-yl)-2-(s~n)-methoxyiminoacetyl chloride hydrochloride is added. The mixture is stirred under ice-cooling for 15 minutes and at room temperature for 2 hours. Thereafter, the reaction mixture is diluted with 30 m~ of water and extracted twice with 50 m~
portions of ethyl acetate. The extracts are pooled, washed with 50 m~ of a saturated aqueous solution of sodium chloride and dried over c~nhydrous magnesium sulfate. The ethyl acetate is distilled off to obtain 402 mg of 7-(2-(2-chloroacetamidothiazol ~I-yl)-2-(~)-methoxyimino)-acetamido-3-(M chloroacetyl)carbamoyloxymethyl-~-cephem-4-carboxylic acid as a viscous oil NMR spectrum (60 MHz5 in CDC~3): ~.50 ppm(2H, quartet, 2-CH2), ~.99 ppm(3H, singlet, NOCH3), 4.04, 4 ~0 ppm (2Hx2, singletx2, C~CH2COx2), 5 10 ppm(lH, doublet, 6-H), 5.73 ppm(lH, doublet, 7-H), 7.32 ppm(lH, singlet, thiazole, 5-H) (2) ~he entire amount of the above product is dissolved in 9 m~ of tetrahydrofuran~ followed by addition of 168 mg of thiourea and 300 mg of sodium acetate trihydrate The mixture is stirred at room temperature for 4 hours The precipitate is collected by filtration, washed with ether and dissolved in 5 mR of water The solution is adjusted to pH about 7 with sodium hydrogen carbonate and purified by columri chromatography on Amberlite XAD-2, ~y the above procedure is obtained 58 mg of sodium 7-~2-(2-aminothiazol-, , . ' ' 1 3 ~i ~ ! 7 ~ ~3 4-yl)-2-(s~n)-methoxyiminoacetamido)-~-carbamoyloxymethyl-~-cephem-4-carboxylate as white powder Elemental analysis, for C15H15N607S2Na 3H20 Calcd C, 33.84; H, 3 98; N, 15.78 Found C, ~3.94; H, 3.82; N, 15.42 NMR spectrum (60 MHz, in D20): ~ 47 ppm(2H, quartet, 2-CH2), 3.92 ppm(3H, singlet, =NOCH3), 4.68 ppm (2H, quartet, -CH20CONH2), 5.27 ppm(lH~ doublet, 6-H), 5.72 ppm (lH, doublet, 7-H), 6.95 ppm(lH, singlet, thiazole 5-H) Method for production of 2-(2-chloroacetamidothiazol-4-yl)-2-(s~n)-methoxyiminoacetyl chloride.
In 5 m~ of methylene chloride is suspended 278 mg of the 2-(2-chloroacetamidothiazol-4-yl~-2-(s~n)-methoxy-minoacetic acid obtained in Reference Example 6, and, under ice-cooling, 208 mg of phosphorus pentachloride is added. The mixture is stirred at room temperature for 30 minutes, after which it is washed with petroleum ether.
By the above procedure is obtained 276 mg of 2-(2-chloro-acetamidothiazol-4-yl)-2-(s~n)-methoxyiminoacetyl chloride as powders.
Elemental analysis, for C8H7 ~ O~SC~2 HC~
Calcd. C, 28.89; H, 2.42; N, 12.6~
~ound C, 28.47; H, 2.73; N, 12.12 Example 2 In 22 m~ of dry tetrahydrofuran is dissolved 500 mg of the 2-(2-chloroacetamidothiazol-4-yl)-2-( ~ -methoxy-iminoacetic acid and, under stirring, 182 mg of triethyl-- 6~ -:

1 3C~70~

amine is added. This mixture is cooled to -10C and 245 mg of isobutyl chloroformate is added dropwise. The mixture is stirred at that temperature for 2 hours. To the resultant solution of mixed acid anhydride is added 182 mg of tri-ethylamine together with a solution (ice-cooled) of 590 mg of 7-amino-~ methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid in 18 m~ of a 50 % aqueous tetra-hydrofuran. The mixture is stirred under ice-cooling for 1 hour and at room temperature for 2 hours. Thereafter, most of the tetrahydrofuran is distilled off under reduced pressure and the residue is diluted with 100 m~ of water and with 40 m~ of ethyl acetate Then, under stirring, the aqueous layer is adjusted to pH about 2 with l~-HC~.
The layers are separated ard the water layer is extracted with 60 m~ of ethyl acetate, ~he ethyl acetate layers are pooled, washed with 50 m~ of a saturated aqueous solution of sodium chloride and dried~ The ethyl acetate is distilled off to obtain 70G mg of 7-(2-(2-chloro-acetamidothiazol-4-yl)-2-(s~n)-methoxyiminoacetamido)-3-C (l-methyl-lH-tetrazol ~-yl)thiomethyl-3-cephem-4-carboxylic acid as a viscous oil.
(2) The entire amount of the above product is dissolved in 15 m~ of tetrahydrofuran, followed by the addition of 226 mg of thiourea and 406 mg of sodium acetate trihydrate The mixture is stirred at room temperature for 4 hours After the reaction, the precipitate is collected by filtra-tion, washed with ether and di~solved in 10 m of water. ~he solution is adjusted to pH about 7 0 with sodium hydrogen ~ ; ~

1 3 ~ O~'3 carbonate and purified by column chromatogra~hy on hmberlite XAD--2. By the above procedure is obtained 125 mg of sodium 7-~2-(2-aminothiazol-4-yl)-2-(syn)-methoxyimino-acetamido~-3-(1-methyl-lH-tetrazol-~-yl)thiomethyl-3-cephem~-carboxylate as white powder.
Flemental analysis, for C16H16N905S3Na 2H20 Calcd. C, 33.74, H, 3.54; N, 22 13 ~ound C, 34.18; H, 3.57; N, 21,79 NMR spectrum (60 MHz, in D20): 3.59 ppm(2H, quartet, 2-CH2), 3 93 ppm(3H, singlet, =NOCH3), 3.98 ppm(3H, singlet, N-CH3), 4008 ppm(2H, quartet, 3-CH2), 5,12 ppm(lH, doublet, 6-H), 5.72 ppm(lH9 doublet, 7-H~, 6 93 ppm(lH, singlet, thiazole 5-H) 13xample 3 (1) In 15 m~ of N,N-dimethylacetamide is dissolved 762 mg of 7-aminocephalosporanic acid and, under ice-cooling, 931 mg of 2-(2-chloroacetamidothiazol-4-yl)-2-methoxy-iminoacetyl chloride hydrochloride (prepared from s:~n-isomer) is added. The mixture is stirred under ice-cooling for 15 minutes and at room temperature for 2 hours. ~he reaction mixture is diluted with 10 m~ of water and extracted with 100 m~ portions of ethyl acetate. ~he extracts are pooled, washed wîth 100 m~ of a saturated aqueous solution of sodium chloride and dried. The ethyl acetate is distilled off to obtain 1.4 ~ of 7-(2-(2-chloroacetamidothiazol-4-yl)-2-(s;Yn)-methoxyiminoacetamido ~-cephalosporanic acid as an oil.
(2) In 30 m~ of tetrahydrofuran is dissolved the entire , 7 ~ ~3 amount of the above product, followed by the addition of 500 mg of thiourea and, then, of 895 mg of sodium acetate trihydrate The mixture is stirred at room temperature for 4 hours. The resultant precipitate is collected by filtration, washed with ether and dissolved in 6 m~ of water. The solution is adjusted to pH about 7.0 with sodium hydrogen carbonate and purified by means o~ column chromatography on Amberlite XAD-2. By the above procedure is obtained 78 mg of sodium 7-~2-(2-aminothiazol-4-yl)-2-(s~n)-methoxyiminoacetamido)cephalosporanate as white powder Elemental analysis, for C16H16N507S2Na 2.5H20 Calcd. C, 36.78; H, 4.05; N, 13.40 Found C, 36.93; H, 3.80; N, 12.68 ~MR spectrum (60 MHz, in D20): 2 07 ppm(3H, singlet, COCH3), 3 53 ppm(2H, quartet, 2-CH2)~ 3 98 ppm(3H, singlet, =NOC~ ), 4.75 ppm(2H, quartet, 3-CH2), 5.21 ppm(lH, doublet, 6-H), 5.81(1H, doublet, 7-H), 7.01 ppm(lH, singlet, thiazole 5-H) Example 4 To 10 m~ of water are added 1 g of the sodium 7-~2-(2-aminothiazol-4-yl)-2-(s~n)-methoxyiminoacetamido)-cephalosporanate obtained in ~xample 3, 270 mg of 2-methyl-1,3,4-oxadiazole-5-thiol potassium salt and 7 mg of triethylbenzylammonium bromide. The mixture is stirred in nitrogen gas streams at 60C for 6 hours, After cooling, the reaction mixture is purified by means of column chromatography on Amberlite XAD-2. By the above procedure , 1 3'`3708 is obtained llC) mg of sodium 7-~2-(2-aminothiazol~-yl)-2-(sgn)-methoxyiminoacetamido )-3-(2-methyl-1,3,4-oxadiazol-5-yl)thiomethyl-3-cephem~-carboxylate as white powder.
~;lemental analysis, for C17H16N706S3Na2H20 Calcd. C, 35.85; H, 3.54; N, 17.21 Found C, ~5.73; H, 3.72; N, 17.01 N~ spectrum ~60 MHz, in D20): 8.42 ppm(3H, singlet, oxadiazole 2-CH3), ~.55 ppm(2H, quartet, 2-CH2), 4.02 ppm(3H, singlet, =NOCH3), 5.13 ppm(lH, doublet, 6-H), 5.73 ppm(lH~ doublet, 7-H), 6.97 ppm(lH, singlet, thiazole 5-H) ~ xample 5 (1) To 10 m~ of tetrahydrofuran are added 83~ mg of 2-(2~chloroacetamidothiazol-4-yl)-2-(s~n)-methoxyimino-acetic acid, ~80 m~; of N-hydroxysuccinimide and 630 mg oî dicyclohexylcarbodiimide and the mixture is stirred at room temperature for 45 minutes. The precipitate is filtered off and the filtrate is cooled to 5C. It is then added to a mixed solution of 650 mg 7-aminodesacetoxy-cephalosporanic acid and 2 m~ bis(trimethylsilyl)acetamide in methylene chloride, which has been previously cooled.
The mixture is stirred at room temperature overnight and, then, the solvent is distilled off under reduced pressure.
To the resultant oil is added 50 m~ of water together with 50 m~ of ethyl acetate, and the mixture i8 adjusted to pH about 2.5 with lN-hydrochloric acid. 'rhe two layers are separated, followed by extractions with two 50 m~
portions of ethyl acetate. The ethyl acetate layers are pooled, washed with water and dried. ~he ethyl acetate is t;hen distilled off to obtain 1.1 g of 7-(2-(2-chloro-acet;amidothiazol-4-yl)-2-(s~n)-methoxyiminoacetamido)-desacetoxycephalosporanic acid as an oil.
(2) The entire amount of the above product is dissolved in 25 me of tetrahydrofuran, followed by the addition of thiourea and, then, of 632 mg of sodium acetate trihydrate.
The mixture is stirred at room temperature for 4 hours.
The precipitate is collected by filtration, washed with ether and dissolved in 10 m~ of water. ~he solution is adjusted to pH about 7.0 with sodium hydrogen carbonate and purified by means of column chromatography on Am~erlite XAD-2 By the above procedure is obtained 120 mg of sodium 7-~2-(2-aminothiazol-4-yl)-2-(syn)~methoxyimino-acetamido)desacetoxyc~phalosporanate as white powders.
Elemental analysis, for C14H14N505~2Na 1 5H20 Calcd C, 37,67; H, 3.84; N, 15.68 ~ound C, 37 37; H, 3.98; ~, 15,38 NMR spectrum (60 MHz, in D20) ~ : 1.94 ppm (3H, singlet, 3-CH3), 3.46 ppm(2H, quartet, 2-CH2), 4 00 ppm(3H, singlet, =NOCH3), 5.17 ppm(lH, doublet, 6-H), 5.76 ppm (lH, doublet, 7-H), 6.99 ppm(lH, singlet, thiazole 5-H) ~he minimal inhibitory concentration~ (~g/m~) of some of the compounds according to the above Examples are as follows.

~ ' , 1 3n3708 C ompound Microorgani sm Compound Compound Compound Compound of ~x 1 of Ex.3 of E~ 2 of ~x 5 E, coli NIHJ 0.10 0.20 0.10 0.78 E;, coli 0-111 0.024 0.05 0.024 0.39 E. coli T-7 0.39 0.78 0.78 6.25 K.pneumonia DT ~ 0.012 0.024 0~024 0,20 K.pneumonia GN 3835 0,05 0.05 0,20 0.20 Ps. aeruginosa Pd 1 5 25 12.5 ~ 100 Ps. aeruginosa PM 3 3.13 1.56 0078 25 Ps. aeruginosa P2 25 50 5 > 100 Ps. aeruginosa G~3407> 100 50 50 > 100 Serr,marcescens IFO 12648 1.56 3.13 0.78 12.5 Serratia 'r~ 00240.20 0.78 0.20 1.56 P, vulgaris IF0 3988~ 0,020.024 0.024 0.20 P. vulgaris GN 4413 1.56 0,78 0.39 1,56 P. mirabilis GN 4359 ~0.02 0.05 0.10 0.10 P. morganii I~031680,39 0.20 0.05 12.5 P.rettgeri 8(TN0336)< 0.012< 0~012 _ 0.012~ 0.012 P.rettgeri 8 GN 4733 0.05 0.20 0.20 0.10 Ent.cloacae TN1282 6.25 6.25 1.56 50 Cit. freundii G~ 99 0.20 0.20 0.10 3.13 Cit. freundii GN1706 0.39 0.39 0.20 6,25 Acinetobacter anitratus6.25 25 25 12,5 ~ote) The followin~ abbreviations are used to denote the microorganisms employed.
E: Escherichia K: Klebsiella Ps: Pseudomonas Serr: Serratia P: Proteus ~nt: Enterobacter Cit: Citrobacter 1 3 '"' 7 0~

Example 6 (1) In 20 m~ of dry tetrahydrofuran is dissolved 500 mg of 2-(2-chloroacetamidothiazol-4-yl)-2-(s~n)-methoxy-iminoacetic acid and, under stirring, 182 mg of triethyl-amine is added. The mixture is cooled to -10C, after which 245 m~ of isobutyl chloroformate is added dropwise.
The mixture is stirred at that temperature for 2 hours.
To the resultant mixed acid anhydride solution is added a solution (ice-cooled) of 180 mg of triethylamine and 492 mg 7-amino-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid in a 50% ~queous tetrahydro uran, ~he mixture is stirred under ice-cooling for 1 hour and, then, at room temperature for 2 hours, Most of the tetrahydrofuran is distilled off under reduced pre~sure, and 100 m~ of water and 40 m~ of ethyl acetate are added to the residue.
~he mixture is adjusted to ~H about 2 with l~-hydrochloric acid. ~he two layers are separated and the water layer is extracted twice with 50 m~ portions of ethyl acetate.
~he ethyl acetate layers are pooled, washed with water, dried and concentrated. By the above procedure is obtained 650 mg of 7-~2-(2-chloroacetamidothiazol-4-yl)-2-(s~n)-methoxyiminoacetamido)-3-carbamoyloxymethyl-~-cephem-4-carboxylic acid as an oil.
(2) ~he entire amount of the above product is dissolved in 15 m~ of tetrahydrofuran, followed by the addition of 226 mg of thiourea and 406 mg of sodium acetate trihydrate.
~he mixture is stirred at room temperature for 4 hours ~he precipitate is collected by filtration, dis~olved in 1 3C~ 7`~

10 m~ of water, adjusted to pH about 7 with sodium hydrogen carbonate and purified by column chromatography on Amberlite XAD-2. By the above procedure is obtained 120 mg of sodium 7-(2-(2-aminothiazol-4-yl)-2-(s~n)-methoxyimino-acetamido)-3-carbamoyloxymethyl-3-cephem-4-carboxylate as white powders. In NMR spectrum and other properties, this product is found to be identical with the product obtained in Example 1.
~ xample 7 (1) In 45 m~ of dry tetrahydrofuran is dissolved 1.11 g of 2-(2-chloroacetamidothiazol-4-yl)-2-(s~n)-methoxy-iminoacetic acid and, under stirring, 815 mg of tri-n-butylamine is added. ~he mixture is cooled to -10C
and 544 mg of isobutyl chloroformate is added dropwise.
The mixture is stirred at -10C for 2 hours, after which a cold solution of 741 mg tri-n-butylamine and 1.4 g 7-amino-3-(~-chloroacetyl)carbamoyloxymethyl-3-cephem-4-carboxylic acid in 40 m~ fa 50% aqueous tetrahydrofuran is added, The mixture is stirred under ice-cooling for 1 hour and at room temperature for 2 hours. Most of the tetrahydrofuran is distilled off under reduced pressure and the residue is diluted with 25 m~ of water and washed with 40 m~ of ethyl acetate. The water layer is taken and, following addition of 50 m~ of ethyl acetate, it is adjusted to pH about 2.5 with lN-hydrochloric acid. The mixture is separated into two layers, The water layer is further extracted twice with 50 m~ portions of ethyl acetate. ~he extracts are pooled, washed with 100 m~ of : :
.

3 ~ 3 7 o ~

a saturated aqueous solution of sodium chloride, dried and Einally concentrated. By the above procedure is obtained 1 g of 7-(2-(2-chloroacetamidothiazol-4-yl)-2-(s~n)-methoxyiminoacetamido)-3-(N-chloroacetyl)carbamoyloxy-methyl-3-cephem-4-carboxylic acid as an oil.
(2) ~he entire amount of the above product is dissolved in 22 ml of tetrahydrofuran; f~llowed by the addition of 499 mg of thiourea and then, of 892 mg of sodium acetate tri-hydrate. The mixture is stirred at room temperature for 4 hours. The precipitate is collected by filtration, washed with ether and dissolved in lO m~ of water. ~he solution is adjusted to pH about 7 with sodium hydrogen carbonate and purified by means of column chromatography on Amberlite XAD-2. ~y the above procedure is obtained 153 mg of sodium 7-(2-(2-aminothiazol-4-yl)-2-(s~n)-methoxyiminoacetamido)-~-carbamoyloxymethyl-3-cephem-4-carboxylate as white powders. Based on NMR and other data, this product is identical with the compound obtained in Example l ExamPle 8 In 20 m~ of tetrahydrofuran are dissolved 277 mg of 2-(2-chloroacetamidothiazol-4-yl)-2-(syn)-methoxyimino-acetic acid and 270 mg of t-butyl 7-aminodesacetoxy-cephalosporanic acid, followed by the addition vf 206 mg of dicyclohexylcarbodiimide. The mixture is reacted under stirring at room temperature for 6 hours. The precipitated urea derivative is filtered off and the filtrate is poured in 50 m~ of water and extracted with ethyl acetate. The 1 3r~70~

ethyl acetate layer is washed with O.5N-hydrochloric acid, water and a saturated aqueous solution of sodium chloride in the order mentioned, dried and finally concentrated By the above procedure is obtained 320 mg of t-butyl 7-~2-(2-chloroacetamidothiazol-4-yl)-2-(syn)-methoxyimino-acetamido)desacetoxyc~phalosporanate as an oil.
NMR spectrum (60 MHz, in CDC~3) : 1.53 ppm(9H, singlet, t-C4H9), 2.13 ppm(3H, singlet, 3-CH3), 3.39 ppm (2H, quartet, 2-CH2), 4.06 ppm(3H, singlet, =NOCH3), 4 29 ppm(2H, singletS C~CH2CO). 5.06 ppm(lH, doublet, 6-H), 5.86 ppm(lH, doublet of doublet, 7-H), 7.20 ppm(lH, singlet, thiazole 5-H), 8.14 ppm(lH, doublet, 7-CONH) ~2) The entire amount of the above product is dissolved in 12 mR OL' tetrahydrofuran, followed byt~e addition of 100 mg thiourea and 200 mg sodium acetate trihydrate. The mixture is stirred at room temperature for 8 hour~. ~he reaction mixture is diluted with 30 m~ of water and extracted with ethyl acetate. The ethyl acetate layer is washed with water, dried and concentrated The resultant oil is purified by chromatography on silica gel. By the above procedure is obtained 128 mg of t-butyl 7-~2-(2-amino-thiazol-4-yl)-2-(s~n)-methoxyiminoacetamido)desacetoxy-cephalosporanate as powders.
NMR spectrum (60 MHz, in CDC~3) : 1.52 ppm(9H, singlet, t-C4H9), 2.10 ppm(3H~ singlet,3-CH3)s 3.40 ppm(2H, quartet, 2-CH2), 4.00 ppm(3H, singlet, =~OCH3), 5 05 ppm(lH, doublet, 6-H), 5.98 ppm(lH, doublet of doublet, 7-H), 6.66 ppm(lH, singlet, thiazole - 73 ~

1 3~, ,70~

5-H), 8.28 ppm(lH, doublet, 7-CONH) (3) The entire amount of the above product is dissolved in a mixture OI 1 m~ trifluoroacetic acid and 0.1 m~
anisole and the solution is stirred at room temperature for 1.5 hours, after which time ether is added. The resultant precipitate is collected by filtration and washed with ether. By the above procedure is obtained 70 mg of 7-(2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamido)-desacetoxycephalosporanic acid trifluoroacetate as powders.
In NMR spectrum (60 MHz, in D20 including NaHC03), this product is identical with the product obtained in Example 5.
ExamPle 9 By the acylation of the 7-amino group of the corres-ponding cephalosporin compounds in a manner similar to that described in Example 2 (Process A~, and by using sodium 7-(2-(2 aminothiazol-4-yl)-2-(s~n)-methoxyimino-acetamido)cephalosporanate and heterocyclic thiol compounds in a manner similar to that described in Example 4 (Process B), the following compolln~s are produced.
(a) Sodium 7-(2-(2-aminothiazol-4-yl)-2-(s~n)-methoxy-iminoacetamido3-3-(2-methyl-1,3,4-thiadiaæol-5-yl)thio-methyl~3-cephem-4-carboxylate (Process B) NMR spectrum (60 MHz, in D20): 2 57 ppm(3H, singlet, thiazole 2-CH3), 3.52 ppm(2H, quartet, 2-CH2), 3 95 ppm(7H, singlet, =NOCH3), 5.18 ppm(lH, singlet, 6-H), 5 73 ppm(lH, singlet, 6-H), 5.73 ppm(lH, singlet, 7-H), 6 95 ppm(lH, singlet, thiazole 5-H) 1 3^",70~

(b) Disodium 7-(2-(2-aminothiazol~-yl)-2-(s n)-meth,oxyiminoacetamido )-~-(2-carboxymethyl-l~Z,4-thiadiazol-5-yl)thiomethyl-3-cephem~-carboxylate (Process B) NMR spectrum (60 MHz, in D20): 3.56 ppm(2H, quartet, 2-CH2), 3.96 ppm(3H, singlet, =NOCH3), 4 18 ppm (2H, singlet, CH2COONa), 5.20 ppm(lH, doublet, 6-H), 5.74 ppm(lH, doublet, 7-H), 6.97 ppm(lH, singlet~
thiazole 5-H) (c) Sodium 7-(2-(2-aminothiazol-4-yl)-2-(syn)-methoxy-iminoacetamido )-3-(1,2,3-triazol-5-yl)thiomethyl-3-cephem-4-carboxylate (Process B) ~MR spectrum (60 MHz, in D20): 3.57 ppm(2H, quartet, 2-CH2), 3.94 ppm(3H, singlet, =NOCH3), 5,21 ppm (lH, doublet, 6-H), 5.72 ppm(lH, doublet, 7-H), 6.94 ppm(lH, singlet, thiazole 5-H), 7.95 ppm(lH, singlet, triazole 4-H) (d) Disodium 7-(2-(2-aminothiazol~-yl)-2-(s;~,rn)-methoxy-iminoacetamido)-3-(1-carboxymethyl-1,2,3,4-tetrazol-5-yl)-thiomethyl-3-cephem~-carbo~ylate (Process B) l~lMR spectrum (60 MHz, in D20): 3.55 ppm(2H, quartet, 2-CH2), 3.96 ppm(3H, singlet, =NOCH3), ~.72 ppm(2H, singlet, -~-CH2COO~a), 5.18 ppm(lH, doublet, 6-H), 5.72 ppm(lH, doublet,7-H), 6.95 ppm(lH, singlet, thiazole 5-H) (e) 7-(2~(2-Aminothiazol-4-yl)-2-(sgn)-methoxyimino-acet~mido )~3-(1-(2-N,N-dimethylaminoethyl)-1,2~3,4-tetrazol-5-yl ~thiomethyl-3-cephem-4-carboxylic acid betaine (Proces~ A, B) ~ 75 ~

.

~ 3",~70~

NMR spectrum (60 MHz, in D20~: 3.01 ppm(6H, singlet, ,CH
-N~ 3 ), 3.50 ppm(2H, quartet, 2-CH2), 3.98 ppm (3H, singlet, =NOCH3)9 5.18 ppm(lH, doublet, 6-H), 5.74 ppm(lH, doublet, 7-H), 6.96 ppm(lH~ singlet, thiazole 5-H) (f) Sodium 7-(2-(2-aminothiazol-4-yl)-2-(s~n)-methoxy-iminoacetamido)-3-(6-methyl-1-oxopyridazin-3-yl)thiomethyl-3-cephem-4-carboxylate (Process B) NMR spectrum (60 MHz, in D20): 2.60 ppm(3H, singlet, pyridazine 6-CH3), 3.52 (2H, quartet, 2-CH2~, 3.98 ppm(3H, singlet, =NOCH3), 5.21 ppm(lH, doublet, 6-H), 5.76 ppm(lH, doublet, 7-H), 6.95 ppm(lH, singlet, thiazole 5-H) The minimum inhibi~ory concentration (~g/m~) of some of the obtained compounds as mentioned above are as follows.
Com~ound Microorgani~m (a) (e) E. coli ~IHJ 0,20 0.20 E, coli 0-111 0.10 0.024 E, coli T-7 1.56 1.56 K. pneumoniae DT 0.05 0.10 K. preumoniae GN 3835 0.39 0.20 Serr. marcescens I~O 12648 0.78 1.56 Serratia TN 0024 0.78 0.78 P. vulgaris I~O 3988 0.10 0.20 P. vulgaris GN 4413 1.56 1.56 P, mirabilis GN 4359 0.20 o.39 P. morganii IFO 3168 0.10 0.20 P. rettgeri 8(~N0 336) ~ 0~012 0.024 P. rettgeri GN 4733 .39 0.78 ~nt, cloacae I~012937 3.13 6.25 Cit, freundii GN 99 0.20 0.20 Cit. freundii GN 1706 0.78 0,78 ' ' 1 3C~)70~

Exam~le 10 In a mixture of 20 m~ water and 10 m~ methanol is dissolved 280 mg of sodium carbonate, followed by addition of 477 m~ of 7-(2-(2-aminothiazol-4-yl)-2~(s~n)-hydroxy-iminoacetamido)cephalosporanic acid To this mixed solution is added 300 mg of dimethyl sulfate dropwise under ice-cooling and stirring. ~hen, after 25 minutes, 300 mg of potassium carbonate and 300 mg of dimethyl sulfate are added After another 25 minutes, the reaction mixture is concentrated under reduced pressure and subjected to column chromatography on Amberlite XAD-2, elution being carried out with water. By the above procedure is obtained sodium 7-(2-(2-aminothiazol-4-yl)--2-(s~n)-methoxyiminoacet-amidG)cephalosporanate. In NMR spectrum, etc., this product is identical with the compound obtained in ~xample 3.
~ xample 11 (1) To a suspension of 5.54 g of 2-(2-chloroacetamido-thiazol-4-yl)-2-~ )-methoxyiminoacetic acid in 70 m~
of methylene chloride is added 2.42 g of triethylamine to obtain solution. Under ice-cooling and ~tirring, 4.16 g of phosphorus pentachloride i8 added in a single dose to the above solution. After 5 minutes the ice-bath is removed and the mixture is stirred at room temperature for 20 minutes, after which it is concentrated under reduced pressure. To the residue is added 150 m~ of hexane~ followed by decantations (twice). After the addition of 90 m~ of anhydrous tetrahydrofuran, the precipitated ~ 77 --I J ~ ~i . r, ~

triethylamine hydrochloride is filtered of~, whereupon a solution of 2-(2-chloroacetamidothiazol-4-yl)-2~
methoxyiminoacetyl chloride in tetrahydrofuran is obtained On the other hand, to a suspension of 4,28 g of 7-aminodesacetoxycephalosporanic acid (7-ADCA) in a mixture of 50 m~ water and 50 m~ tetrahydrofuran is added, under ice-cooling, 4.44 g of triethylamine to prepare a homogeneous solution Under ice-cooling, the previously prepared acid chloride solution is added dropwise to the above solution over a period of 15 minutes. ~he mixture is stirred at room temperature for 2 hours, after which a saturated aqueous solution of sodium chloride is added.
The mixture is adjusted to pH about 2 with dilute hydro-chloric acid and extracted with ethyl acetate. The ethyl acetate layer is wa~hed with a saturated a~ueous solution of sodium chloride, dried over magnesium sulfate and concentrated to obtain 8 g of yellowish white powders.
The powders are washed with 50 m~ of methanol and the insolubles are collected by filtration. By the above procedure is obtained 4.6 g ol 7-~2-(2-chloroacetamido-thiazol-4-yl)-2-(s~n)-methoxyiminoacetamido)desacetoxy-cephalosporanic acid as white powders.
~MR spectrum (60 MHz, in d6-DMSO): 2.04 ppm(3H, singlet, 3-CH3), 3.50 ppm(2H, broad singlet, 2-CH2)~ 3.92 ppm (3H, singlet, OCH3), 4,40 ppm(2H, singlet, C~CH2CO), 5.18 ppm(lH, doublet, 6-H), 5.78 ppm(lH, doubletx2 7-H), 7.50 ppm(lH, singlet, thiazole 5-H).
(2) The above product is reacted and treated in the same ~ 3"`''7C~

manner as E~xample 5-(2) to obtain sodium 7-~2-(2-amino-thiazol-4-yl)-2-(syn)-methoxyiminoacetamido`)desacetoxy-cephalosporanate as white powders In N~IR spectra and other properties, this product is identical with the product obtained in Example 5.
13~ample 12 In 25 m~ of dimethylformamide is suspended sodium 7-~2-(2-aminothiazol-4-yl)-2-(s~n)-methoxyiminoacetamido)-desacetoxycephalosporanate and, under ice-cooling, 3.75 g of iodomethyl pivalate is added with 3 m~ of dimethyl-formamide being further added. After 17 minutes, 100 mR
of ethyl acetate is added to the reaction mixture and the insolubles are filtered off, The filtrate is washed with water, a 5 % aqueous solution of sodium hydrogen carbonate and a saturated aqueous solution of sodium chloride in the order mentioned and dried over magnesium sulfate.
The ethyl acetate is then distilled off and the resultant oil (2 4 g) is purified by chromatography on silica gel.
By the above procedure is obtained 1 g of pivaloylox~J-methyl 7-(2-(2-aminothiazol-4-yl)-2-(s:sn)-methoxyimino-acetamido ~desacetoxycephalosporanate as white powders.
Elemental analysis, for C20H25N507S2 Calcd. C, 46"95; H, 4.92; N, 13.69 Found C, 46.92; H~ 4.88; N, 13.13 ~IMR spect~um (60 MHz, in CDC~3): 1.24 ppm(9H, singlet, -C(CH3)3), 2.16 ppm, 3.44 ppm(2H, doublet, 2-CH2), 4.10 ppm(3H, singlet, OCH3), 5 16 ppm(lH, doublet, 6-H), 5.94 ppm(2H, singlet, -OCH20)~ 6.86 ppm(lH, singlet, thiazole, 5-H) ~ 3 i~`70$

xample 13 0.7 g of th~ 7-L2-(2-chloroacetamido-thiaz~l-4-yl)-2-( SY~ methoxyiminoacet~mido~-des~cetoxycephalosporanic acid obtained by the procedure of ~xample 11-(1) is dissolved in ice-cooled solution of 149 mg of triethylamine in 7 m~ of dimethyl-formamide, Following the addition of 715 mg of iodomethyl pivalate, the mixture is stirred for 15 minutes. ~o this reaction mixture is added 40 m~ of ethyl acetate and the mixture is washed with water, a 5 /c aqueous solution of sodium hydrogen carbonate and a saturated aqueous solution of sodium chloride in the order mentioned, followed by drying over magnesium sulfate, ~he ethyl acetate is distilled off to obtain 0,8 g of crude pivaloyloxymethyl 7-(2-(2-chloroacetamidothiazol-4-yl)-2-(s~n)-methoxyimino-acetamido~desacetoY.ycephalosporanate as a brown oil, ~ his product is dissolved in ~ m~ of dimethyl-acetamide, followed by the addition of 206 mg of thiourea, The mixture is stirred at room temperature overnight, ~o this is added 40 m~ of ethyl acetate, and the mixture is washed twice with 30 m~ portions of a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The ethyl acetate is distilled off and the resultant brown-colored oil (0.4 g) is purified by chromato-graphy on silica gel, By the above procedure is obtained 0.2 g of pivaloyloxymethyl 7-(2-(2-aminothiazol Jl-yl)-2-(s~n)-methoxyiminoacetamido)desacetoxycephalosporanate as white powders.

:
~ .

~ J'~ 7 ~ ~

In NMR spectrum and other properties, this product is :identical with the product obtained in ~xample 12.
~xam~le 14 To a suspension of 831 mg of 2-(2-chloroacetamido-thiazol-4-yl)-2-(s~n)-methoxyiminoacetic acid in lO m~
of methylene chloride are added 360 mg of triethylamine and 624 mg of phosphorus pentachloride. The mixture is stirred at room temperature for 20 minutes, after which lOO me of hexane is added, The oil that has separated out is obtained by the decantation of the hexane and dissolved in 15 m~ of tetrahydrofuran, whereby a solution of 2-(2-chloroacetamidothiazol-4-yl)-2-(syn)-methoxyimino-acetyl chloride is obtained, On the other hand, 984 m~ of 7-amino-3-(l-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid and 660 mg of triethylamine are dissolved in 15 m~ Of a 50%
aqueous tetrahydrofuran and, under ice-cooling, the previously prepared acid chloride solution is added dropwise to this solution, ~he mixture is stirred under ice-cooling for 2 hours, after which the reaction mixture is diluted with water, adjusted to pH about 2 with dilute hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer is washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate, The ethyl acetate is distilled off and the residue is treated with ether, The resultant crystals are collected by filtration, By the above procedure is obtained 1.3 g of 7-(2-(2-chloroacetamidothiazol-4-yl)-2-(s~n)-methoxyimino-1 3^S70~

acet;amido)-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-4-carboxylic acid.
This product is identical with the intermediate obtained by the first part of the process described in Example 2. 5,8 g of the product prepared as above is dissolved in 20 m~ of dimethylacetamide and, under ice-cooling, 1,53 g of thiourea is added. ~he mixture is stirred at room temperature for 15 hours. To this reaction mixture is added 200 m~ of ice-water and the pH of the mixture is adjusted to pH 3.5 with sodium hydrogen carbonate.
The resultant precipitate is collected by filtration and dissolved in a 10 % aqueous solution of sodium hydrogen carbonate, The solution is then passed through a column packed with Amberlite XAD-2, By this purification procedure i~ obtained 1,58 g of sodium 7-(2-(2-amino-thiazol-~-yl)-2-(s~n)-metho~yiminoacetamido)-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-~-cephem-4-carboxylate as white powders.
In NMR spectrum and other properties, this product is identical with the product obtained in Example 2.
Example 15 In 10 m~ of dimethylformamide is dissolved 1 g of sodium 7-(2-(2-aminothiazol-4-yl)-2-(~)-methoxyimino-acetamido)-~-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylate and, under ice-cooling and stirring, 0,85 g of iodomethyl pivalate is added, The mixture is stirred for 15 minutes. ~ollowing the addition of 40 m~
of ethyl acetate, the reaction mixture is washed with 1 ~"`370~

water, a 5 % aqueous solution of so~ium hydrogen carbonate and a saturated aqueous solution of sodium chloride in the order mentioned and, then, dried over magnesium sulfate. The ethyl acetate is distilled off under reduced pressure and the residue is dissolved in a small amount of ethyl acetate and filtered ~o the filtrate is added ether, followed by cooling. The resultant precipitate is collected by filtration. ~y the above procedure is obtained 0.4 g of pivaloyloxymethyl 7-(2-(2-aminothiazol-4-yl)-2-(s~n)-methoxyiminoacetamido)-~-(l-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylate as white powders.
Elemental analysis, for C22H27N907S3 Calcd. C, 42 27; H, 4.34 Found C, 42,29; H, 4 40 NMR spectrum (60 MHz, in CDC~3): 1 22 ppm(9H, singlet, -C(CH3)3), 3 80 ppm(2H, broad singlet, 2-CH2), 3 94, 4 06 ppm(3Hx2, singletx2, N-CH
OCH~), 5 94 ppm(2H, singlet, -OCH20), 5 12 ppm (lH, doublet, 6-H), 6,06 ppm(lH, doubletx2, 7-H), 4 44 ppm(2H, doublet, 3-CH2), 6 81 ppm(lH, singlet, thiazole 5-H) Example 16 In 20 m~ of methylene chloride are dis~olved 2 776 g of 2-(2-chloroacetamidothiazol-4-yl)-2-(s~n)-methoxy-iminoacetic acid and 1 2 g of triethylamine, followed by the addition of 2 08 g of phosphorus pentachloride, ~he mixture is stirred at room temperature for 20 minutes, after which 150 m~ of hexane is added ~he resultant oily precipitate is separated and dissolved in 20 m~ of tetra-hydrofuran to prepare a solution of-2-(2-chloroacetamido-thia~zol-4-yl)-2-(syn)-methoxyiminoacetyl chloride. On the other hand, 3.143 g of 7-amino-3-acetylacetoxymethyl-3-cephem-4-carboxylic acid and 2.2Q g of triethylamine are dissolved in 50 m~90f a 50~ aqueous tetrahydrofuran. To this is added dropwise, under ice-cooling and stirring, the previously prepared acid chloride solution. ~he mixture is stirred under ice-cooling for 2 hours, after which water is added. ~he mixture is adjusted to pH 2.0 with dilute hydrochloric acid and extracted with ethyl acetate The ethyl acetate layer is washed with a saturated a~ueous solution of sodium chloride and dried over magnesium sulfate, The ethyl acetate is then distilled off and ether is added to the residue. ~he resultant crystalline product is collected by filtration. By the above procedure is obtained 4.168 g of 7-~2-(2-chloro-acetamidothiazol-4-yl)-2-(s~n)-methoxyiminoacetamido)-3-acetylacetoxymethyl-3-cephem-4-car~oxylic acid ~MR spectrum (60 MHz, in d6-DMSO): 2.14 ppm(3H, singlet, -C-CH3), 3 60 ppm(4H, broad singlet, -C-CH2-C- &
O O O
2-CH2)~ 3 86 ppm(3H, singlet9 OCH3), 4.34 ppm(2H, singlet, C~CH2CO), 4.91 ppm(2H, quartet, 3-CH2), 5.13 ppm(lH, doublet, 6-H), 5 80 ppm(lH, doubletx2, 7-H), 7.40 ppm(lH, singlet, thiazole 5-H) ~xample 17 In 20 m~ of dimethylacetamide is dissolved 4.00 g 1 3 ~ ~ ~ fJ ~

of the 7-l2-(2-chloroacetamidothiazol-4-yl)-2-(s~n)-methoxyiminoacetamido)-3-~cetylacetoxymethyl-3-cephem ll-carboxylic acid obtained in ~xample 16, followed by the addition of 1.06 g of thiourea~ r~he mixture is stirred at room temperature for 17 hours, after which 100 m~ of ether is added. The oily precipitate is separated and dissolved in a 5 % aqueous solution of sodium hydrogen carbonate. ~he solution is lyophilized and the resultant powdery product is added to 50 m~ of methanol. The insolubles are filtered off and the filtrate is added to 300 m~ of ether. The precipitate is collected by filtra-tion, By the above procedure is obtained 3.150 g of sodium 7-(2-(2-aminothiazol-4-yl)-2-( ~ -methoxyimino-acetamido)-3-acetylacetoxymethyl-3-cephem-4-carboxylate, In 10 m~ of water are dissolved 933 mg of the above product, 350 mg of 1-(2-N,N-dimethylaminoethyl)-lH-tetrazol-5-thiol and 168 mg of sodium hydrogen carbonate, The mixture is stirred at 55C for 1 hour and, then, the reaction mixture is directly passed through a column packed with Amberlite XAD-2 for purification. By the above procedure is obtained 170 ~ of sodium 7-(2-(2-aminothiazol-4-yl)-2-(~)-methoxyiminoacetamido)-3-~1-(2-~ dimethylaminoethyl)-lH-tetrazol-5-yl~thiomethyl-3-cephem-4-carboxylate as white powders, In NMR spectrum and other properties, this product is identical with the product obtained in ~xa~ple 9, The following table shows the protective effect (~D50 , mg/kg) of the compounds prepared by the above `1 J ~ 7 0 3 Examples on infected mice.
Table rOf Sample Administration L_ 5 _ _ 1 SC 0.015 (CER : 1.25) 2 SC 0.022 (C~R : 1.25) 3 SC 0.018 (CER : 1.25) 5 SC 0.111 (C~R : 1.25) 15Oral 0.11 (CEX : 2.51) 17Oral Q.27 (CEX : 2.51) Test animals: male mice (ICR/SLC) 5 mice per group per single dose Infection : intraperitoneally with E, ¢oli 0-111 Observation period: 7 days ( ) ; control SC = subcutaneous CER= cephaloridine ~L CH2CONH ~ S~ +
N ~ CH2 COO

CEX= cephalexin ~c~co F~-COOH

Example 18 (1) To a suspension of 55.6 g of 2-(2-chloroacetamido-.

1 3~70~

thiazol-4-yl)-2-(s~n) methoxyiminoacetic acid in 600 m~
of !methylene chloride is added 24.3 g of triethylamine to obtain a solution Under ice-cooling and stirring, 41.8 g of phosphorus pentachloride is added in two doses to the above solution After 5 minutes the ice-bath is removed and the mixture is stirred at room temperature for 20 minutes, after which it is concentrated under reduced pressure. To the residue is added 1 ~ of hexane, followed by decantations (twice). After addition of 600 m~ of anhydrous tetrahydrofuran, the precipitated triethylamine hydrochloride is filtered off 7 whereupon a solution of 2-(2-chloroacetamidothiazol-4-yl)-2-(s~n)-methoxyimino-acetyl chloride in tetrahydrofuran is obtained, On the other hand, to a suspension of 54,7 g of 7-amino-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid in a mixture of 400 m~ water and 400 m~ tetrahydrofuran is added 61 g of triethylamine under ice-cooling to prepare a homogeneous solution Under ice-cooling, the previously prepared acid chloride solution is added dropwise to the above solution over a period of 30 minutesO ~he mixture is stirred at room temperature for 2 hours, after which a saturated aqueous solution of sodi~m chloride is added.
The mixture is adjusted to pH about 2 with dilute hydro-chloric acid and extracted with ethyl acetate, The ethyl acetate layer is washed with a saturated ag.leou.s solution of sodium chloride, dried over magnesium sul~ate and concentrated to obtain 97,3 g of 7-(2-(2-chloroacetamido-thiazol-4-ylj-2-(s~n)-methoxyiminoacetamido)-3-carbamoyloxy-1 3~

methyl-3-cephem-4-carboxylic acid In NMR spectrum and other properties, this product is identical with the product obtained in (1) of Example 6.
NMR spectrum (60 MHz, in d6-DMS0): 3 56 ppm(2H, broad singlet, 2-CH2), 3.93 ppm(3H, singlet, OCH3) 7 4.35 ppm (2H, singlet, C~CH2C0), 4.78 ppm(2H, quartet, 3-CH2), 5 19 ppm(lH, doublet, 6-H), 5.84 ppm(lH, doubletx2, 7-H), 6.56 ppm(2H, singlet, OCONH2), 7.46 ppm(lH, singlet, thiazole 5-H) (2) 97.3 g of the product prepared as above (1) is dissolved in 500 m~ of N,N-dimethylacetamide and, under ice-cooling,to the solution is added 31.2 g of thiourea.
The mixture is stirred at room temperature for 15 hours.
To this reaction mixture i~ added 2 ~ of ether and then~
the oily product is separated. A suspension of this oily product in 300 m~' of water i8 adjusted to pH 7.0 with sodium hydrogen carbonate. Thus obtained solution is passed through a column packed with Amberlite XAD-2.
By this purification procedure is obtained 20.2 g of sodium 7-(2-(2-aminothiazol-4-yl)-2-(s~n)-methoxyimino-acetamido~-3-carbamoyloxymethyl-3-cephem-4-carboxylate as white powders. In NMR spectrum and other properties~
this product is identical with the product obtained in Example 1 or 6.
The structures and properties (IR spectrum) of the compounds (No.l - 33) obtained according to the above processes of this invention are listed in the ~ollowing table. In this table, I~ spectruI~. (cm~l, KBr) means 1 3~`7~8 characteristic absorption band due to ~-lactam moiety.
Table R2NH c~
N 11 C-CONH ~ S
N O ~N~CH2:~

~ _ Compound R M IR
No . 2 3 ( cm l,KBr) 1 H S 1~ S~ Na 1760 _ _ _ _ 2 H --S ~ ~,U Na 1763 _ ~ ~. -.____ 3 JI S~NJL CH3 :~a 1758 _ 4 H --S ~l~Y Na 1760 CJ.I3 H S ~ CR3 Na 1763 6 H --S ~ S ~L NH2 Na 1765 _ __ _ 7 H S J~ S~L NHCOOCH3 ~a 1760 -~ ~ 89 _ 1 J'J~)7~8 ____ _ .
Compound R R M IR
No . 2 3 (cm , KBr) 8 H N - N Na 1765 - S ll SJL CH2CONH2 __ _ 9 H N - N ~a 1758 --S N~N

_CH2CONH2 H N - Na1768 11 H -OH Na 1760 _ __ _ ,_ 12 H-S~ S~ CH2N/ 3 Na 1765 13 H ~?~ 3 _ 14 H -N~ CONH2 3 1765 H N - N Na 1768 --sll $J~L ~CH2COONa 16 H N - ~ ~a 1765 _~N,N
CH2COONa 1 7 ~ ;7 (3 ~

_ ~ ~
Compound R2 R3 M (cm 1, KBr) 17_ -SJ~ N,IN Na 1765 __ CH2SO~,Na CH3 18 H-OCOCH3 - CH20COC-CH~; 1760 C, H3 j 19 H 2 ~O~ 1763 H -S ¢NH'N CH3 1765 _ --_ _ _ GH3 _ 21 H , CH3 -CH20COC--CH3 1768 CH2CH2N' 22 H H . -CEOCOOC2H5 1760 C~ H3 24 H -OCO~H2 -CHOCOC-CH3 1763 : _ ~
I ~SJ~H3 - IIOCOOC2~ L

3 3 V ~ 7 ! ~.

__ .
CmIP~oU. nd R2 3 Tp '26 H -S¢N,N -CHOCOOC2H5 17~c CH2cH2N~ 3 CH3 CH3, .
28 H H \~ 1760 29 H -OCOCH3 0~/~ 176~
_ O_ H -OCO~I2 `~ 1763 _ 31 H ~ ~,IT o~OI`' ~ 1765 3 2 H - S ¢~,11 ~ 1763 : H O

33 H S~,N CH ~ 1768 :: _ CH2CH2N' 3 -' 0~

Injectable composition 250 mg of sodium 7-[2-(2-aminothiazol-4-yl)-2-(syn)-metho~riminoacetamido]-3-carbamoylox~methyl-3-cephem-4-carboxylate, or sodium 7-[2-(2-aminothiazol-4-yl)-2-(synj-metho~yiminoactamidoJ-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylate, or sodium 7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoactamido]cephalosporanate is dissolved in 1 m~ of sterilized water before use.

- 93 ~

Claims (123)

1. A process for producing a 7-[2-(2-aminothiazol-4-yl)-

2-(syn-methoxyiminoacetamido]cephalosporin derivative of the formula:

(I) or a pharmaceutically acceptable salt or ester thereof, wherein R3 is hydrogen; hydroxy; mercapto; an acyloxy; carbamoyloxy;
cyano; azido; amino; carbamoylthio; thiocarbamoyloxy;
carbamoyloxy whose amino group is protected; phenylglycyloxy;
a substituted hydroxy, mercapto or amino, the substituent being a lower alkyl of 1 to 3 carbon atoms or acyl derived from a lower aliphatic carboxylic acid having 2 to 4 carbon atoms; a quaternary ammonium group; or a heterocyclicthio group whose group is unsubstituted or substituted by one or more substituents selected from the group consisting of lower alkyl of 1 to 3 carbon atoms, lower alkoxy of 1 to 3 carbon atoms, halogen, trihalogeno-lower alkyl, hydroxyl, mercapto, amino, carboxyl, carbamoyl, di-lower alkyl (having 1 to 3 carbon atoms) amino lower alkyl of 1 to 3 carbon atoms, carboxymethyl, carbamoyl-methyl, carboxymethylthio, sulfomethyl and methoxycarbonylamino, provided that when R3 is hydrogen; hydroxyl; acetoxy;

carbamoyloxy; 1,3,4-thiadiazol-2-ylthio; 5-amino-1,3,4-thiadiazol-2-ylthio; 1,3,4-triazol-2-ylthio; 1,5-dimethyl-1,3,4-triazol-2-ylthio; 1-methylimidazol-2-ylthio; 5-methyl-1,3,4-oxadiazol-2-ylthio; 5-methyl-1,3,4-thiadiazol-2-ylthio; or l-methyltriazol-5-ylthio, then the derivative (I) is in the form of the pharmaceutically acceptable ester, which process comprises:
(1) reacting a 7-aminocephalosporin derivative of the formula:

wherein R3 has the meanings defined above, or a salt or ester thereof, with a compound of the formula:

wherein the amino qroup may be protected, or a reactive derivative thereof, if necessary followed by removing protective group present; or (2) reacting a compound of the formula:

wherein the amino group may be protected and R4 is acyloxy, carbamoyloxy or halogen, or a salt or ester thereof, with a tertiary amine or heterocyclicthiol compound or its salt, if necessary followed by removing any protective group present; or (3) O-methylating a compound of the formula:

wberein the amino group may be protected and R3 has the meaning defined above, or a salt or ester thereof, by reaction with a methyl halide, dimethyl sulfate or diazomethane, if necessary followed by removlng any protective group present, and where required converting any free carboxylic acid of formula (I) into a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable ester thereof.

2. A process as claimed in claim 1, wherein R3 is a quaternary ammonium group.

3. A process as claimed in claim 1, wherein R3 is (1) mercapto; (2) cyano; (3) azido; (4) amino;
(5) carbamoylthio; (6) thiocarbamoyloxy; (7) phenylglycyloxy;
(8) substituted hydroxyl, mercapto or amino, the substituent being lower alkyl of 1 to 3 carbon atoms or acyl derived from lower aliphatic carboxylic acid having 2 to 4 carbon atoms; or (9) a quaternary ammonium group.

4. A process as claimed in claim 1, wherein R3 is an acyloxy derived from an aromatic carboxylic acid which is substituted by hydroxy, carboxy, carboethoxycarbamoyl or carboethoxysulfamoyl group.

5. A process as claimed in claim 1, wherein R3 is an acyloxy derived from a lower aliphatic carboxylic acid having 2 to 4 carbon atoms which is substituted by oxo, carboxyl or ethoxycarbamoyl.

6. A process as claimed in claim 1, wherein R3 is a substituted pyridyl-thio, N-oxidopyridyl-thio, pyrimidyl-thio, pyridazinyl-thio, N-oxidopyridazinyl-thio, pyrazolyl-thio, imidazolyl-thio, thiazolyl-thio, thiadiazolyl-thio, oxazolyl-thio, oxadiazolyl-thio, triazolyl-thio or tetrazolyl-thio group, the substituent being lower alkoxyl, trihalogeno-lower alkyl, hydroxyl, mercapto, carboxyl, carbamoyl, di-lower alkylamino-lower alkyl, carboxymethyl, carbamoylmethyl, carboxymethylthio, sulfomethyl or methoxycarbonylamino.

7. A process for preparing a pharmaceutically acceptable ester of 7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyimino-acetamido]-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid, which comprises reacting 7-amino-3-(N-unprotected or protected) carbamoyloxymethyl-3-cephem-4-carboxylic acid, or its salt or ester, with 2-(2-protected aminothiazol-4-yl)-2-(syn)-methoxy-iminoacetic acid, or its reactive derivative, and if necessary removing the protective group(s) from thus obtained compound or/and converting it into a pharmaceutically acceptable ester.

8. A process for preparing a pharmaceutically acceptable ester of 7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyimino-acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid, which comprises (1) reacting 7-amino-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid, or its salt or ester, with 2-(2-protected aminothiazol-4-yl)-2-(syn)-methoxyiminoacetic acid, or its reactive derivative, and removing the protective group from thus obtained compound and if necessary converting it into a pharmaceutically acceptable ester or (2) reacting 7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-acyloxymethyl-3-cephem-4-carboxylic acid, or its salt or ester, with l-methyl-lH-tetrazole-5-thiol, or its salt and if necessary converting thus obtained compound into a pharmaceutically acceptable ester.

9. A process for preparing a pharmaceutically acceptable ester of 7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyimino-acetamido]cephalosporanic acid, which comprises reacting 7-amino-cephalosporanic acid, or its salt or ester, with 2-(2-protected aminothiazol-4-yl)-2-(syn)-methoxyiminoacetic acid, or its reactive derivative, and removing the protective group from thus obtained compound and if necessary converting it into a pharmaceutically acceptable ester.

10. A process for preparing a pharmaceutically acceptable ester of 7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyimino-acetamido]-3-(2-methyl-1,3,4-oxadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid, which comprises (1) reacting 7-amino-3-(2-methyl-1,3,4-oxadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid, or its salt or ester, with 2-(2-protected amidothiazol-4-yl)-2-(syn)-methoxyiminoacetic acid, or its reactive derivative and removing the protective group from thus obtained compound and if necessary converting into a pharma-ceutically acceptable ester, or (2) reactlng 7-[2-(2-amino-thiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-acyloxymethyl-3-cephem-4-carboxylic acid, or its salt or ester, with 2-methyl-1,3,4-oxadiazol-5-thiol, or its salt and if necessary converting into a pharmaceutically acceptable ester.

11. A process for preparing a pharmaceutically acceptable ester of 7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyimino-acetamido]desacetoxycephalosporanic acid, which comprises reacting 7-aminodesacetoxycephalosporanic acid, or its salt or ester, with 2-(2-protected aminothiazol-4-yl)-2-(syn)-methoxy-iminoacetic acid, or its reactive derivative, and removing the protective group from thus obtained compound and if necessary converting thus obtained compound into a pharmaceutically acceptable salt.

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12. A process for preparing a pharmaceutically acceptable ester of 7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyimino-acetamido]-3-(2-methyl-1,3,4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid, which comprises (1) reacting 7-amino-3-(2-methyl-1,3,4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid, or its salt or ester, with 2-(2-protected aminothiazol-4-yl)-2-(syn)-methoxyiminoacetic acid, or its reactive derivative, and removing the protective group from thus obtained compound and if necessary converting thus obtained compound into a pharmaceutically acceptable salt, or (2) react-ing 7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-acyloxymethyl)-3-cephem-4-carboxylic acid, or its salt or ester with 2-methyl-1,3,4-thiadiazole-5-thiol, or its salt and if necessary converting thus obtained compound into a pharmaceutically acceptable salt.

13. A process for preparing 7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-(2-carboxymethyl-1,3,4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid, or its pharmaceutically acceptable salt or ester, which comprises (1) reacting 7-amino-3-(2-carboxymethyl-1,3,4-thiadiazol-5-yl)thio-methyl-3-cephem-4-carboxylic acid, or its salt or ester, with 2-(2-protected aminothiazol-4-yl)-2-(syn)-methoxyiminoacetic acid, or its reactive derivative, and removing the protective group from thus obtained compound, or (2) reacting 7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-acyloxy-methyl-3-cephem-4-carboxylic acid, or its salt or ester, with 2-carboxymethyl-1,3,4-thiadiazole-5-thiol, or its salt.

14. A process for preparing 7-[2-(2-aminothiazol-4-y1)-2-(syn)-methoxyiminoacetamido]-3-(1,2,3-triazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid, or its pharmaceutically acceptable salt or ester, which comprises (1) reacting 7-amino-3-(1,2,3-triazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid, or its salt or ester, with 2-(2-protected aminothiazol-4-yl)-2-(syn)-methoxyiminoacetic acid, or its reactive derivative, and removing the protective group from thus obtained compound, or (2) reacting 7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-acyloxymethyl-3-cephem-4-carboxylic acid, or its salt or ester, with 1,2,3-triazole-5-thiol, or its salt.

15. A process for preparing 7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-(1-carboxymethyl-1,2,3,4-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid, or its pharmaceutically acceptable salt or ester, which comprises (1) reacting 7-amino-3-(1-carboxymethyl-1,2,3,4-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid, or its salt or ester, with 2-(2-protected aminothiazol-4-yl)-2-(syn)-methoxyiminoacetic acid, or its reactive derivative, and removing the protective group from thus obtained compound, or (2) reacting 7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyimino-acetamido]-3-acyloxymethyl-3-cephem-4-carboxylic acid, or its salt or ester, with l-carboxymethyl-1,2,3,4-tetrazole-5-thiol, orits salt.

16. A process for preparing 7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-[1-(2-N,N--dimethylaminoethyl)-1,2,3,4-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid, or its pharmaceutically acceptable salt or ester, which comprises (1) reacting 7-amino-3-[1-(2-N,N-dimethylaminoethyl)-1,2,3,4-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid, or its salt or ester, with 2-(2-protected aminothiazol-4-yl)-2-(syn)-methoxyiminoacetic acid, or its reactive derivative, and removing the protective group from thus obtained compound, or (2) reacting 7-[2-(2-amino-thiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-acyloxymethyl-3-cephem-4-carboxylic acid, or its salt or ester, with 1-(2-N,N-dimethylaminoethyl)-1,2,3,4-tetrazole-5-thiol, or its salt.

17. A process for preparing 7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-(6-methyl-1-oxopyridazin-3-yl)thiomethyl-3-cephem-4-carbozylic acid, or its pharmaceutically acceptable salt or ester, which comprises (1) reacting 7-amino-3-(6-methyl-1-oxopyridazin-3-yl)thiomethyl-3-cephem-4-carbozylic acid, or its salt or ester, with 2-(2-protected aminothiazol-4-yl)-2-(syn)-methoxyiminoacetic acid, or its reactive derivative, and removing the protective group from thus obtained compound, or (2) reacting 7-[2-(2-aminothiazol-4 y1)-2-(syn)-methozyiminoacetamido]-3-acylozymethyl-3-cephem-4-carbozylic acid, or its salt or ester, with 6-methyl-1-oxopyridazine-5-thiol, or its salt.

18. A process for preparing pivaloyloxymethyl 7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxy-iminoacetamido]desacetoxycephalosporanate, which comprises reacting 7-aminodesacetoxycephalosporanic acid, or its salt, with 2-(2-protected aminothiazol-4-yl)-2-(syn)-methoxyimino-aeetic aeid or its reactive derivative, then (1) removing the protective group and esterizing with halogenomethyl pivalate, or (2) esterizing with halogenomethyl pivalate and removing the protective group.

19. A process for preparing pivaloyloxy-methyl 7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylate, which comprises (1) reacting 7-amino-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid, or its salt, with 2-(2-protected aminothiazol-4-yl)-2-(syn)-methoxyiminoacetic acid, or its reactive derivative, then (i) removing the protec-tive group and esterizing with halogenomethyl pivalate, or (ii) esterizing with halogenomethyl pivalate and removing the protective group, or (2) reacting 7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-acyloxymethyl-3-cephem-4-carboxylic acid, or its salt, with l-methyl-IH-tetrazole-5-thiol, or its salt, and esterizing with halogenomethyl pivalate.

20. A process for preparing 7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-acetyl-acetoxymethyl-3-cephem-4-carboxylic acid, or its pharmaceutical-ly acceptable salt or ester, which comprises reacting 7-amino-3-acetylacetoxymethyl-3-cephem-4-carboxylic acid, or its salt or ester, with 2-(2-protected aminothiazol-4-yl)-2-(syn)-methoxyiminoacetic acid, or its reactive derivative, and removing the protective group from thus obtained compound.

21. A process for preparing a pharmaceutically acceptable ester of 7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyimino-acetamido]-3-(1,3,4-triazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid, which comprises (1) reacting 7-amino-3-(1,3,4-triazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid, or its salt or ester, with 2-(2-protected aminothiazol-4-yl)-2-(syn)-methoxyiminoacetic acid, or its reactive derivative, and removing the protective group from thus obtained compound and if necessary converting thus obtained compound into a pharmaceutically accept-able ester, or (2) reacting 7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-acyloxymethyl-3-cephem-4-carboxylic acid, or its salt or ester, with 1,3,4-triazol-2-thiol, or its salt and if necessary converting thus obtained compound into a pharmaceutically acceptable ester.

22. A process for preparing a pharmaceutically acceptable ester of 7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyimino-acetamido}-3-(1,2-dimethyl-1,3,4-triazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid, which comprises (1) reacting 7-amino-3-(1,2-dimethyl-1,3,4-triazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid, or its salt or ester, with 2-(2-protected aminothiazol-4-yl)-2-(syn)-methoxyiminoacetic acid, or its reactive derivative, and removing the protective group from thus obtained compound and if necessary converting thus obtained compound into a pharmaceutically acceptable ester, or (2) reacting 7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyimino-acetamido]-3-acyloxymethyl-3-cephem-4-carboxylic acid, or its salt or ester, with 1,2-dimethyl-1,3,4-triazole-thiol, or its salt and if necessary converting thus obtained compound into a pharmaceutically acceptable ester.

23. A process for preparing a pharmaceutically acceptable ester of 7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyimino-acetamido]-3-(1-methyl-1,3-diazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid, which comprises (1) reacting 7-amino-3-(1-methyl-1,3-diazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid, or its salt or ester, with 2-(2-protected aminothiazol-4-yl)-2-(syn)-methoxyiminoacetic acid, or its reactive derivative, and removing the protective group from thus obtained compound and if necessary convertlng thus obtained compound into a pharmaceutically acceptable ester, or (2) reacting 7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamidol-3-acyloxy-methyl-3-cephem-4-carboxylic acid, or its salt or ester, with l-methyl-1,3-diazole-2-thiol, or its salt and if necessary converting thus obtained compound into a pharmaceutically acceptable ester.

24. A process for preparing a pharmaceutically acceptable ester of 7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyimino-acetamido]-3-(4,5-dimethyl-1,3-thiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid, which comprises (1) reacting 7-amino-3-(4,5-dimethyl-1,3-thiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid, or its salt or ester, with 2-(2-protected aminothiazol-4-yl)-2-(syn)-methoxyiminoacetic acid, or its reactive derivative, and removing the protective group from thus obtained compound and if necessary converting thus obtained compound into a pharma-ceutically acceptable ester, or (2) reacting 7-[2-(2-amino-thiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-acyloxymethyl-3-cephem-4-carboxylic acid, or its salt or ester, with 4,5-dimethyl-1,3-thiazole-2-thiol, or its salt and if necessary converting thus obtained compound into a pharmaceutically acceptable ester.

25. A process for preparing a pharmaceutically acceptable ester of 7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyimino-acetamldo]-3-(2-amino-1,3,4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid, which comprises (1) reacting 7-amino-3-(2-amino-1,3,4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid, or its salt or ester, with 2-(2-protected aminothiazol-4-yl)-2-(syn)-methoxyiminoacetic acid, or its reactive derivative, and removing the protective group from thus obtained compound and if necessary converting thus obtained compound into a pharmaceutically acceptable ester, or (2) reacting 7-12-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-acyloxy-methyl-3-cephem-4-carboxylic acid, or its salt or ester, with 2-amino-1,3,4-thiadiazole-5-thiol, or its salt and if necessary converting thus obtained compound into a pharmaceutically acceptable ester.

26. A process for preparing 7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamidol-3-(2-methoxycarbonylamino-1,3,4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid, or its pharmaceutically acceptable salt or ester, which comprises (1) reacting 7-amino-3-(2-methoxycarbonylamino-1,3,4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid, or its salt or ester, with 2-(2-protected aminothiazol-4-yl)-2-(syn)-methoxyimino-acetic acid, or its reactive derivative, and removing the protective group from thus obtained compound, or (2) reacting 7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-acyloxymethyl-3-cephem-4-carboxylic acid, or its salt or ester, with 2-methoxycarbonylamino-1,3,4-thiadiazole-5-thiol, or its salt.

27. A process for preparing 7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-(2-carbamoylmethyl-1,3,4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid, or its pharmaceutically acceptable salt or ester, which comprises (1) reacting 7-amino-3-(2-carbamoylmethyl-1,3,4-thiadiazol-5-yl)-thiomethyl-3-cephem-4-carboxylic acid, or its salt or ester, with 2-(2-protected aminothiazol-4-yl)-2-(syn)-methoxyiminoacetic acid, or its reactive derivative, and removing the protective group from thus obtained compound, or (2) reacting 7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-acyloxy-methyl-3-cephem-4-carboxylic acid, or its salt or ester, with 2-carbamoylmethyl-1,3,4-thiadiazole-5-thiol, or its salt.

28. A process for preparing 7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-(1-carbamoylmethyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid, or its pharma-ceutically acceptable salt or ester, which comprises (1) reacting 7-amino-3-(1-carbamoylmethyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid, or its salt or ester, with 2-(2-protected aminothiazol-4-yl)-2-(syn)-methoxyiminoacetic acid, or its reactive derivative, and removing the protective group from thus obtained compound, or (2) reacting 7-[2-(2-aminothiazol-4-yl)-2 (syn)-methoxyiminoacetamido]-3-acyloxymethyl-3-cephem-4-carboxylic acid, or its salt or ester, with l-carbamoylmethyl-1H-tetrazole-5-thiol, or its salt.

29. A process for preparing a pharmaceutically acceptable ester of 7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyimino-acetamido]-3-(1-methyl-2-amino-1,3,4-triazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid, which comprises (1) reacting 7-amino-3-(1-methyl-2-amino-1,3,4-triazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid, or its salt or ester, with 2-(2-protected aminothiazol-4-yl)-2-(syn)-methoxyiminoacetic acid, or its reactive derivative, and removing the protective group from thus obtained compound and if necessary converting thus obtained compound into a pharmaceutically acceptable salt, or (2) reacting 7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamldo]-3-acyloxymethyl-3-cephem-4-carboxylic acid, or its salt or ester, with l-methyl-2-amino-1,3,4-triazole-5-thiol, or its salt and if necessary converting thus obtained compound into a pharma-ceutically acceptable salt.

30. A process for preparing 7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamidol-3-[2-(N,N-dimethylaminomethyl)-1,3,4-thiadiazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid, or its pharmaceutically acceptable salt or ester, which comprises (1) reacting 7-amino-3-[2-(N,N-dimethylaminomethyl)-1,3,4-thiadiazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid, or its salt or ester, with 2-(2-protected aminothiazol-4-yl)-2-(syn)-methoxyiminoacetic acid, or its reactive derivative, and removing the protective group from thus obtained compound, or (2) reacting 7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-acyloxymethyl-3-cephem-4-carboxylic acid, or its salt or ester, with 2-(N,N-dimethylaminomethyl)-1,3,4-thiadiazole-5-thiol, or its salt.

31. A process for preparing 7-12-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamido-3-pyridiniummethyl-3-cephem-4-carboxylic acid, or its pharmaceutically acceptable salt or ester, which comprises (1) reacting 7-amino-3-pyridiniummethyl-3-cephem-4-carboxylic acid, or its salt or ester, with 2-12-protected aminothiazol-4-yl)-2-(syn)-methoxyiminoacetic acid, or its reactive derivative, and removing the protective group from thus obtained compound, or (2) reacting 7-[2-(2-amino-thiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-acyloxymethyl-3-cephem-4-carboxylic acid, or its salt or ester, with pyridine.

32. A process for preparing 7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-(4-car-bamoylpyridinium)methyl-3-cephem-4-carboxylic acid, or its pharmaceutically acceptable salt or ester, which comprises (l) reacting 7-amino-3-(4-carbamoylpyridinium)methyl-3-cephem-4-carboxylic acid, or its salt or ester, with 2-(2-protected aminothiazol-4-yl)-2-(syn)-methoxyiminoacetic acid, or its reactive derivative, and removing the protective group from thus obtained compound, or (2) reacting 7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-acyloxymethyl-3-cephem-4-carboxylic acid, or its salt or ester, with 4-carbamoylpyridine.

33 A process for preparing 7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-(2-carboxy-methylthio-1,3,4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid, or its pharmaceutically acceptable salt or ester, which comprises (1) reacting 7-amino-3-(2-carboxymethylthio-1,3,4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid, or its salt or ester, with2-(2-protected aminothiazol-4-yl)-2-(syn)-methoxyiminoacetic acid, or its reactive derivative, and re-moving the protective group from thus obtained compound, or (2) reacting 7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyimino-acetamido]-3-acyloxymethyl-3-cephem-4-carboxylic acid, or its salt or ester, with 2-carboxymethylthio-1,3,4-thiadiazole-5-thiol, or its salt.

34 A process for preparing 7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-(1-sulfo-methyl-IH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid, or its pharmaceutically acceptable salt or ester, which comprises (1) reacting 7-amino-3-(1-sulfomethyl-lH-tetrazol-5-yl)thio-methyl-3-cephem-4-carboxylic acid, or its salt or ester, with 2-(2-protected aminothiazol-4-yl)-2-(syn)-methoxyiminoacetic acid, or its reactive derivative, and removing the protective group from thus obtained compound, or (2) reacting 7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-acyloxy-methyl-3-cephem-4-carboxylic acid, or its salt or ester, with 1-sulfomethyl-1H-tetrazole-5-thiol, or its salt.

35. A process for preparing pivaloyloxy-methyl 7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamido]
cephalosporanate, which comprises reacting 7-amino cephalospora-nic acid, or its salt, with 2-(2-protected aminothiazol-4-yl)-2-(syn)-methoxyiminoacetic acid, or its reactive derivative, then (1) removing the protective group and esterizing with halogeno-methyl pivalate, or (2) esterizing with halogenomethyl pivalate and removing the protective group.

36. A process for preparing pivaloyloxy-methyl 7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-carbamoyloxymethyl-3-cephem-4-carboxylate, which comprises reacting 7-amino-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid, or its salt, with 2-(2-protected aminothiazol-4-yl)-2-(syn)-methoxyiminoacetic acid, or its reactive derivative, then (1) removing the protective group and esterizing with halogeno-methyl pivalate, or (2) esterizing with halogenomethyl pivalate and removing the protective group.

37. A process for preparing pivaloyloxy-methyl 7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-(1H-1,2,3-triazol-5-yl)thiomethyl-3-cephem-4-carboxylate, which comprises (1) reacting 7-amino-3-(lH-1,2,3-triazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid, or its salt, with 2-(2-protected aminothiazol-4-yl)-2-(syn)-methoxyiminoacetic acid, or its reactive derivative, then (i) removing the protective group and esterizing with halogenomethyl pivalate, or (ii) esterizing with halogenomethyl pivalate and removing the pro-tective group, or (2) reacting 7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-acyloxymethyl-3-cephem-4-carboxylic acid, or its. salt, with 1H-1,2,3-triazole-5-thiol, or its salt, and esterizing with halogenomethyl pivalate.

38. . A process for preparing pivaloyloxy-methyl 7-[2 (2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-[1-(2-N,N-dimethylaminoethyl)-1,2,3,4-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylate, which comprises (1) reacting 7-amino-3-[1-(2-N,N-dimethylaminoethyl)-1,2,3,4-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid, or its salt, with 2-(2-protected aminothiazol-4-yl)-2-(syn)-methoxyiminoacetic acid, or its reactive derivative, then (i) removing the protective group and esterizing with halogenomethyl pivalate, or (ii) esterizing with halogenomethyl pivalate and removing the protective group, or (2) reacting 7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyimino-acetamido]-3-acyloxymethyl-3-cephem-4-carboxylic acid, or its salt, with 1-(2-N,N-dimethylaminoethyl)-1,2,3,4-tetrazole-5-thiol, or its salt, and esterizing with halogenomethyl pivalate.

39. A process for preparing 1-propionyloxyethyl 7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxy-iminoacetamido]desacetoxycephalosporanate, which comprises reacting 7-aminodesacetoxycephalosporanic acid, or its salt, with 2-(2-protected aminothiazol-4-yl)-2-(syn)-methoxyimino-acetic acid, or its reactive derivative, then (1) removing the protective group and esterizing with l-propionyloxyethyl halogenide, or (2) esterizing with l-propionyloxyethyl halogenide and removing the protective group.

40. A process for preparing l-propionyloxy-ethyl 7-(2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamido]
cephalosporanate, which comprises reacting 7-aminocephalos-poranic acid, or its salt, with 2-(2-protected aminothiazol-4-yl)-2-(syn)-methoxyiminoacetic acid, or its reactive derivative, then (1) removing the protective group and esterizing with 1-propionyloxyethyl halogenide, or (2) esterizing with l-pro-pionyloxyethyl halogenide and removing the protective group.

41. A process for preparing l-pivaloyloxy-ethyl 7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-carbamoyloxymethyl-3-cephem-4-carboxylate, which comprises reacting 7-amino-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid, or its salt, with 2-(2-protected aminothiazol-4-yl)-2-(syn)-methoxyiminoacetic acid, or its reactive derivative, then (1) removing the protective group and esterizing with halogenoethyl pivalate, or (2) esterizing with halogenoethyl pivalate and removing the protective group.

42. A process for preparing 1-propionyloxyethyl 7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxy-iminoacetamido]-3-(1-methyl-1,2,3,4-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylate, which comprises (1) reacting 7-amino-3-(1-methyl-1,2,3,4-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid, or its salt, with 2-(2-protected aminothiazol-4-yl)-2-(syn)-methoxyiminoacetic acid, or its reactive deriva-tive, then (i) removing the protective group and esterizing with l-propionyloxyethyl halogenide, or (ii) esterizing with l-propionyloxyethyl halogenide and removing the protective group, or (2) reacting 7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-acyloxymethyl-3-cephem-4-carboxylic acid, or its salt, with 1-methyl-1,2,3,4-tetrazole-5-thiol, or its salt, and esterizing with l-propionyloxyethyl halogenide.

43. A process for preparing l-pro-pionyloxyethyl 7-C2-(2-aminothiazol-4-yl)-2-(syn)-methoxy-iminoacetamido]-3-(lH-1,2,3-triazol-5-yl)thiomethyl-3-cephem-4-carboxylate, which comprises (1) reacting 7-amino-3-(lH-1,2, 3-triazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid, or its salt, with 2-(2-protected aminothiazol-4-yl)-2-(syn)-methoxy-iminoacetic acid, or it reactive derivative, then (i) removing the protective group and esterizing with l-propionyloxyethyl halogenide, or (ii) esterizing with l-propionyloxyethyl halogenide and removing the protective group, or (2) reacting 7-[2-(2-aminothiazol-4-y1)-2-(svn)-methoxyiminoacetamido]-3-acyloxy-methyl-3-cephem-4-carboxylic acid, or its salt, with 1H-1,2,3-triazole-5-thiol, or its salt, and esterizing with 1-propionyl-oxyethyl halogenide.

44 A process for preparing 1-pivaloyloxyethyl 7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxy-iminoacetamido]-3-[1-(2-N,N-dimethylaminoethyl)-1,2,3,4-tetrazol-5-y1]thiomethyl-3-cephem-4-carboxylate, which comprises (1) reacting 7-amino-3-[1-(2-N,N-dimethylaminoethyl)-1,2,3,4-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid, or its salt, with 2-(2-protected aminothiazol-4-yl)-2-(syn)-methoxy-iminoacetic acid, or its reactive derivative, then (i) removing the protective group and esterizing with l-pivaloyloxyethyl halogenide, or (ii) esterizing with l-pivaloyloxyethyl halogenide and removing the protective group, or (2) reacting 7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-acyloxy-methyl-3-cephem-4-carboxylic acid, or its salt, with 1-(2-N,N-dimethylaminoethyl)-1,2,3,4-tetrazole-5-thiol, or its salt, and esterizing with l-pivaloyloxyethyl halogenide.

45- A process for preparing phthalidyl 7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamido]
desacetoxycephalosporanate which comprises reacting 7-amino-desacetoxycephalosporanic acid, or its salt, with 2-(2-protected aminothiazol-4-yl)-2-(syn)-methoxyiminoacetic acid, or its reactive derivative, then (1) removing the protective group and esterizing with halogenophthalide, or (2) esterizing with halogenophthalide and removing the protective group.

46. A process for preparing phthalidyl 7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamido]
cephalosporanate which comprises reacting 7-aminocephalos-poranic acid, or its salt, with 2-(2-protected aminothiazol-4-yl)-2-(syn)-methoxyiminoacetic acid, or its reactive derivative, then (1) removing the protective group and esterizing with halogenophthalide, or (2) esterizing with halogenophthalide and removing the protective group.

47. A process for preparing phthalidyl 7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-carbamoyloxymethyl-3-cephem-4-carboxylate, which comprises reacting 7-amino-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid, or its salt, with 2-(2-protected aminothiazol-4-yl)-2-(syn)-methoxyiminoacetic acid, or its reactive derivative, then (1) removing the protective group and esterizing with halogenophthalide, or (2) esterizing with halogenophthalide and removing the protective group.

48. A process for preparing phthalidyl 7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-(l-methyl-IH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylate, which comprises (1) reacting 7-amino-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid, or its salt, with 2-(2-protected aminothiazol-4-yl)-2-(syn)-methoxyiminoacetic acid, or its reactive derivative, then (i) removing the pro-tective group and esterizing with halogenophthalide, or (ii) esterizing with halogenophthalide and removing the protective group, or (2) reacting 7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-acyloxymethyl-3-cephem-4-carboxylic acid, or its salt, with 1-methyl-IH-tetrazole-5-thiol, or its salt, and esterizing with halogenophthalide.

49 A process for preparing phthalidyl 7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyimino-acetamido]-3-(lH-1,2,3-triazol-5-yl)thiomethyl-3-cephem-4-carboxylate, which comprises (1) reacting 7-amino-3-(lH-1,2,3-triazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid, or its salt, with 2-(2-protected aminothiazol-4-yl)-2-(syn)-methoxyiminoacetic acid, or its reactive derivative, then (i) removing the protective group and esterizing with halogenophthalide, or (ii) esterizing with halogenophthalide and removing the protective group, or (2) reacting 7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyimino-acetamido]-3-acyloxymethyl-3-cephem-4-carboxylic acid, or its salt, with 1H-1,2,3-triazole-5-thiol, or its salt, and esterizing with halogenophthalide.

50. A process for preparing phthalidyl 7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-[1-(2-N,N-dimethylaminoethyl)-1,2,3,4-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylate, which comprises (1) reacting 7-amino-3-[1-(2-N,N-dimethylaminoethyl)-1,2,3,4-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid, or its salt, with 2-(2-protected aminothiazol-4-yl)-2-(syn)-methoxyiminoacetic acid, or its reactive derivative, then (i) removing the protective group and esterizing with halogenophthalide or (ii) esterizing with halogenophthalide and removing the protective group, or (2) reacting 7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-acyloxymethyl-3-cephem-4-carboxylic acid, or its salt, with 1-(2-N,N-dimethylaminoethyl)-1,2,3,4-tetrazole-5-thiol, or its salt, and esterizing with halogenophthalide.

51. A compound of the formula:

[wherein R3 is:
hydrogen;
hydroxy;
mercapto;
acyloxy;
carbamoyloxy;
cyanos azido;
amino;
carbamoylthio;
thiocarbamoyloxy;
carbamoyloxy whose amino group is protected;
phenylglycyloxy;
a substituted hydroxy, mercapto or amino, the substituent being a lower alkyl of 1 to 3 carbon atoms or acyl derived from a lower aliphatic carboxylic acid having 2 to 4 carbon atoms;
a quaternary ammonium group;
or a heterocyclic-thio group whose heterocyclic group is unsubstituted or substituted by one or more substituents selected from the group consisting of lower alkyl of 1 to 3 carbon atoms, lower alkoxy of 1 to 3 carbon atoms, halogen, trihalogeno-lower alkyl, hydroxyl, mercapto, amino, carboxyl, carbamoyl, di-lower alkyl (having l to 3 carbon atoms) amino lower alkyl of 1 to 3 carbon atoms, carboxymethyl, carbamoyl-methyl, carboxymethylthio, sulfomethyl and methoxycarbonylamino]
or a pharmaceutically acceptable salt or ester thereof, provided that when R3 is hydrogen; hydroxyl; acetoxy;
carbamoyloxy; 1,3,4-thiadiazol-2-ylthio; 5-amino-1,3,4-thiadiazol-2-ylthio; 1,3,4-triazol-2-ylthio; 1,5-dimethyl-1,3,4-triazol-2-ylthio; 1-methylimidazol-2-ylthio; 5-methyl-1,3,4-oxadiazol-2-ylthio; 5-methyl-1,3,4-thiadiazol-2-ylthio; or l-methyltriazol-5-ylthio, then the derivative (I) is in the form of the pharmaceutically acceptable ester.

52. A compound as claimed in claim 51, wherein R3 is a quaternary ammonium group.

53. A compound as claimed in claim 51, wherein R3 is (1) mercapto;
(2) cyano;
(3) azido;
(4) amino;
(5) carbamoylthio;
(6) thiocarbamoyloxy;
(7) phenylglycyloxy;
(8) substituted hydroxyl, mercapto or amino, the substituent being lower alkyl of 1 to 3 carbon atoms or acyl derived from lower aliphatic carboxylic acid having 2 to 4 carbon atoms; or (9) quaternary ammonium group.

54. A compound as claimed in claim 51, wherein R3 is an acyloxy derived from an aromatic carboxylic acid which is substituted by hydroxyl, carboxyl, carboethoxycarbamoyl or carboethoxysulfamoyl group.

55. A compound as claimed in claim 51, wherein R3 is an acyloxy derived from a lower aliphatic carboxylic acid having 2 to 4 carbon atoms which is substituted by oxo, carboxyl or ethoxycarbamoyl.

56. A compound as claimed in claim 51, wherein R3 is a substituted pyridyl-thio, N-oxidopyridyl-thio, pyrimidyl-thio, pyridazinyl-thio, N-oxidopyridazinyl-thio, pyrazolyl-thio, imidazolyl-thio, thiazolyl-thio, thiadiazolyl-thio, oxazolyl-thio, oxadiazolyl-thio, triazolyl-thio or tetrazolyl-thio group, the substituent being lower alkoxyl, trihalogeno-lower alkyl, hydroxyl, mercapto, carboxyl, carbamoyl, di-lower alkylamino-lower alkyl, carboxymethyl, carbamoylmethyl, carboxymethylthio, sulfomethyl or methoxycarbonylamino group.

57. A pharmaceutically acceptable ester of 7-[2-(2-amino-thiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-carbamoyloxy-methyl-3-cephem-4-carboxylic acid.

58. A pharmaceutically acceptable ester of 7-[2-(2-amino-thiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid.

59. A pharmaceutically acceptable ester of 7-[2-(2-amino-thiazol-4-yl)-2-(syn)-methoxyiminoacetamido]cephalosporanic acid.

60. A pharmaceutically acceptable ester of 7-[2-(2-amino-thiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-(2-methyl-1,3,4-oxadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid.

61. A pharmaceutically acceptable ester of 7-[2-(2-amino-thiazol-4-yl)-2-(syn)-methoxyiminoacetamido]desacetoxycephalo-sporanic acid.

62. A pharmaceutically acceptable ester of 7-[2-(2-amino-thiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-(2-methyl-1,3,4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid.

63. 7-[2-(2-Aminothiazol-4-y1)-2-(syn)-methoxyimino-acetamido]-3-(2-carboxymethyl-1,3,4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid, or its pharmaceutically acceptable salt or ester.

64. 7-[2-(2-Aminothiazol-4-y1)-Z-(syn)-methoxyimino-acetamidol-3-(1,2,3-triazol-5-y1)thiomethyl-3-cephem-4-carboxylic acid, or the pharmaceutically acceptable salt or ester.

65. 7-12-(2-Aminothiazol-4-yl)-2-(syn)-methoxyimino-acetamido]-3-(1-carboxymethyl-1,2,3,4-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid, or the pharmaceutically acceptable salt or ester.

66. 7-[2-(2-Aminothiazol-4-yl)-2-(syn)-methoxyimlno-acetamido]-3-[1-(2-N,N-dimethylaminoethyl)-1,2,3,4-tetrazol-5-y1]thiomethyl-3-cephem-4-carboxylic acid, or its pharmaceutically acceptable salt or ester.

67. 7-[2-(2-Aminothiazol-4-yl)-2-(syn)-methoxyimino-acetamido]-3-(6-methyl-1-oxopyridazin-3-yl)thiomethyl-3-cephem-4-carboxylic acid, or the pharmaceutically acceptable salt or ester.

68. Pivaloyloxymethyl 7-[2-(2-aminothiazol-4-y1)-2-(syn)-methoxyiminoacetamido]desacetoxycephalosporanate.

69. Pivaloyloxymethyl 7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-y1)thiomethy1-3-cephem-4-carboxylic acid.

70. 7-[2-(2-Aminothiazol-4-yl)-2-(syn)-methoxyimino-acetamido]-3-acetylacetoxymethyl-3-cephem-4-carboxylic acid, or the pharmaceutically acceptable salt or ester.

71. A pharmaceutically acceptable ester of 7-[2-(2-amino-thiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-(1,3,4-triazol-2-y1)thiomethyl-3-cephem-4-carboxyllc acid.

72. A pharmaceutically acceptable ester of 7-[2-(2-amino-thiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-(1,2-dlmethyl-1,3,4-triazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid.

73. A pharmaceutically acceptable ester of 7-[2-(2-amino-thiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-(1-methyl-1,3-diazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid.

74. A pharmaceutically acceptable ester of 7-[2-(2-amino-thiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-(4,5-dimethyl-1,3-thiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid.

75. A pharmaceutically acceptable ester of 7-[2-(2-amino-thiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-(2-amino-1,3,4-thiadLazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid.

76. 7-[2-(2-Aminothiazol-4-yl)-2-(syn)-methoxyimino-acetamido]-3-(2-methoxycarbonylamido-1,3,4-thiadiazol-5-yl)-thiomethyl-3-cephem-4-carboxylic acid, or the pharmaceutically acceptable salt or ester.

77. 7-[2-(2-Aminothiazol-4-yl)-2-(syn)-methoxyimino-acetamido]-3-(2-carbamoylmethyl-1,3,4-thiadiazol-5-y1)thiomethyl-3-cephem-4-carboxylic acid, or the pharmaceutically acceptable salt or ester.

78. 7-[2-(2-Aminothiazol-4 yl)-2-(syn)-methoxyimino-acetamido]-3-(1-carbamoylmethyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid, or its pharmaceutically acceptable salt or ester.

79. A pharmaceutically acceptable ester of 7-[2-(2-amlno-thiazol-4-yl)-2-(syn)-methoxyiminoacetamido]3-(1-methyl-2-amino-1,3,4-triazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid.

80. 7-[2-(2-Aminothiazol-4-yl)-2-(syn)-methoxyimino-acetamido]-3-[2-(N,N-dimethylaminomethyl)-1,3,4-thiadiazol-5-y1]thiomethyl-3-cephem-4-carboxylic acid, or the pharmaceutically acceptable salt or ester.

81. 7-[2-(2-Aminothiazol-4-yl)-2-(syn)-methoxyimino-acetamido]-3-pyridiniummethyl-3-cephem-4-carboxylic acld, or its pharmaceutically acceptable salt or ester.

82. 7-[2-(2-Aminothiazol-4-y1)-2-(syn)-methoxyimino-acetamido]-3-(4-carbamoylpyridinium)methyl-3-cephem-4-carboxylic acidr or the pharmaceutically acceptable salt or ester.

83. 7-[2-(2-Aminothiazol-4-yl)-2-(syn)-methoxyimino-acetamido]-3-(2-carboxymethylthio-1,3,4-thiadiazol-5-yl)thio-methyl-3-cephem-4-carboxylic acid, or the pharmaceutically acceptable salt or ester.

84. 7-[2-(2-Aminothiazol-4-yl)-2-(syn)-methoxyimino-acetamido]-3-(1-sulfomethyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid, or its pharmaceutically acceptable salt or ester.

85. Pivaloyloxymethyl 7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamido]cephalosporanate.

86. Pivaloyloxymethyl 7-[2-12-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-carbamoyloxymethyl-3-cepham-4-carboxylate.

87. Pivaloyloxymethyl 7-12-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-(1H-1,2,3-triazol-5-yl)thiomethyl-3-cephem-4-carboxylate.

88. Pivaloyloxymethyl 7-12-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-11-(2-N,N-dimethylaminoethyl)-1,2,3,4-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylate.

89. l-Propionyloxymethyl 7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamido]desacetoxycephalosporanate.

90. l-Propionyloxyethyl 7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamido]cephalosporanate.

91. l-Pivaloyloxymethyl 7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-carbamoyloxymethyl-3-cephem-4-carboxylate.

92. l-Propionyloxyethyl 7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-methyl-3-cephem-4-carboxylate.

93. l-Propionyloxyethyl 7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-[lH-1,2,3-triazol-5-yl)thiomethyl-3-cephem-4-carboxylate.

94. 1-Pivaloyloxyethyl 7-[2-(2-aminothiazol-4-yl)-2-(syn-methoxyiminoacetamido]-3-[1-(2-N,N-dimethylaminoethyl)-1,2,3,4-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylate.

95. Phthalidyl 7- Z2- (2-aminothiazol-4-yl)-2-(syn)-methoxy-iminoacetamido]desacetoxycephalosporanate.

96. Phthalidyl 7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxy-iminoacetamido]cephalosporanate.

97. Phthalidyl 7-[2-(2-aminothiazol-4-y1)-2-(syn)-methoxy-iminoacetamido]-3-carbamoyloxymethyl-3-cephem-4-carboxylate.

98. Phthalidyl 7-[2-(2-aminothiazol-4-y1)-2-(syn)-methoxy-iminoacetamido]-3-(1-methyl-1H-tetrazol-5-y1)thiomethyl-3-cephem-4-carboxylate.

99. Phthalidyl 7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxy-iminoacetamido]-3-(1H-1,2,3-triazol-5-y1)thiomethyl-3-cephem-4-carboxylic acid.

100. Phthalidyl 7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxy-iminoacetamido]-3-[1-(2-N,N-dimethylaminoethyl)-1,2,3,4-tetrazol-5-y1]thiomethyl-3-cephem-4-carboxylate.

101. A process for the preparation of a cephalosporin of the formula (I) or a salt thereof, which comprises reacting an acid of the formula wherein the amino group is optionally protected, or a reactive derivative thereof, with a 7-aminocephalosporin derivative of the formula or a salt thereof.

102. A compound of the formula (I) or a salt thereof when-ever prepared by the process of claim 101.

103. A process for the preparation of a cepholasporin of the formula (I) or a salt thereof, which comprises reacting a compound of the formula or a salt thereof, with 1-(2-N,N-di-methylaminoethyl)-1,2,3,4-tetrazole-5-thiol.

104. A compound of the formula (I) or a salt thereof whenever prepared by the process of claim 103.

105. A process for the preparation of a cephalosporin of the formula (V) or a salt thereof, which comprises reacting a compound of the formula or a salt thereof, with 1-carboxymethyl-5-mercapto-tetrazole or a salt thereof.

106. A compound of the formula (V) or a salt thereof whenever prepared by the process of claim 105.

107. A process for the preparation of a cephalosporin of the formula (V) or a salt thereof, which comprises reacting an acid of the formula wherein the amino group is optionally protected or a reactive derivative thereof, with an 7-aminocephalosporin of the formula or a salt thereof.

108. A compound of the formula (V) or a salt thereof whenever prepared by the process of claim 107.

109. A process for the preparation of a cephalosporin of the formula (VI) or a salt thereof, whlch comprises reactlng a compound of the formula or a salt thereof, with halomethyl pivalate.

110. A compound of the formula (VI) or a salt thereof whenever prepared by the process of claim 109.

111. A process for the preparation of a cephalosporin of the formula (syn) (VII) or a salt thereof, which comprises reacting a compound of the formula or a salt thereof, with 2-carboxymethylthio-5-mercapto-1,3,4-thiadiazole or a salt thereof.

112. A compound of the formula (VII) or a salt thereof whenever prepared by the process of claim 111.

113. A process for the preparation of a cephalosporin of the formula (VI I ) or a salt thereof, which comprises reacting an acid of the formula (syn) wherein the amino group is optionally protected or a reactive derivative thereof, with an 7-aminocephalosporin of the formula or a salt thereof.

114. A compound of the formula (VII) or a salt thereof whenever prepared by the process of claim 113.

115. A compound as claimed in claim 1, wherein R3 is a quaternary ammonium group selected from the class consisting of:
pyridinium which may optionally have a substituent selected from the class consisting of methyl, halogen, carbamoyl, N-hydroxymethylcarbamoyl, carbomethoxycarbamoyl, cyanocarbamoyl, carboxymethyl, hydroxymethyl and trifluoromethyl;
quinolinium;
picolinium; and lutidinium.

116. A compound as claimed in claim 1, wherein R3 is pyridinium, 3-methylpyridinium, 4-methylpyridinium, 3-chloro-pyridinium, 3-bromopyridinium, 3-iodopyridinium, 4-carbamoyl-pyridinium, 4-(N-hydroxymethylcarbamoyl)pyridinium, 4-(N-carbo-methoxycarbamoyl)pyridlnium, 4-(N-cyanocarbamoyl)pyridinium, 4-(carboxymethyl)pyridinium, 4-(hydroxymethyl)pyridinium, 4-(trifluoromethyl)pyridinium, quinolinium, picolinium or lutidinium.

117. A compound as claimed in claim 1, whlch is in the pharmaceutically acceptable ester form.

118. A compound as claimed in claim 117, wherein the ester contains, as the ester-forming group, a member selected from the class consisting of a lower alkoxymethyl,an .alpha.-lower alkoxyethyl, a lower alkylthiomethyl, a lower alkanoyloxymethyl, ethoxycarbonyloxy-1-methylmethyl, an .alpha.-lower alkanoyloxy-.alpha.-methylmethyl and

119. A pharmaceutical composition which comprises an anti-bacterial effective amount of the compound, salt or ester as defined in any one of claims 51 - 100 or any one of claims 115 -118 together with a pharmaceutically acceptable carrier.

120. The compound, salt or ester as claimed in claim 51, wherein:
R3 is:
(1) hydrogen;
(2) hydroxyl;
(3) mercapto;
(4) acyloxy in which the acyl is derived from a C2 4 aliphatic carboxylic acid optionally substituted by oxo, carboxyl or ethoxycarbamoyl or is benzoyl optionally substituted by hydroxyl, carboxyl, carboethoxycarbamoyl or carboethoxysulfamoyl;
(5) carbamoyloxy;
(6) cyano;
(7) azido;
(8) amino;
(9) carbamoylthio;
(10) thiocarbamoyloxy;

(11) carbamoyloxy whose amino group is protected;
(12) phenylglycyloxy;
(13) a substituted hydroxyl group, the substituent being C1-3 alkyl, or a substituted mercapto or amino group, the substituent being C1-3alkyl or C2-4 aliphatic acyl;
(14) a quaternary ammonium group selected from the class consisting of:
(i) pyridinium which may optionally have a substituent selected from the class consisting of methyl, halogen, carbamoyl, N-hydroxymethylcarbamoyl, carbomethoxycarbam-oyl, cyanocarbamoyl, carboxymethyl, hydroxymethyl and trifluoromethyl, (ii) quinolinium, (iii) picolinium, and (iv) lutidinium; or (15) a heterocyclic-thio group whose heterocyclic group is a 5- or 6-membered ring having 1 to 4 hetero atoms selected from the class consisting of oxygen, sulfur and nitrogen atoms, the said nitrogen atom being optionally ln oxide form, and may optionally be substituted by one or two substituents each independently selected from the class consisting of C1-3alkyl, C1-3alkoxy, halogen, trihalogeno-C1-3 alkyl, hydroxyl, mercapto, amino, carboxyl, carbamoyl, di-C1-3alkylamino-C1-3alkyl, carboxymethyl, carbamoylmethyl, carboxymethylthio, sulfomethyl and methoxycarbonylamino, provided that the compound is in the form of the pharmaceutically acceptable ester when R3 is hydrogen, hydroxyl, acetoxy, carbamoyloxy, 1,3,4-thiadiazol-2-ylthio, 5-amino-1,3,4,-thiazol-2-ylthio, 1,3,4-triazol-2-ylamino, 1,5-dimethyl-1,3,4-triazol-2-ylthio, 1-methylimidazol-2-ylthio, 5-methyl-1,3,4-oxadiazol-2-ylthio, 5-methyl-1,3,4-thiadiazol-2-ylthio or 1-methylthiazol-5-ylthio.

121. The compound, salt or ester as claimed in claim 51, wherein R3 is a heterocyclic-thio group whose heterocyclic group is a 5- or 6-membered ring selected from the class consisting of pyrldyl, N-oxidopyridyl, pyrimidyl, pyridazinyl, N-oxidopyridazin-yl, pyrazolyl, imidazolyl, thiazolyl, thiadiazolyl, oxadiazolyl, triazolyl and tetrazolyl and may optionally be substituted by one or two substituents each independently selected from the class consisting of Cl-3alkyl, Cl-3alkoxy, halogen, trihalogeno-C1-3 alkyl, hydroxyl, mercapto, amino, carboxyl, carbamoyl, di-C1-3 alkylamino-C1-3alkyl, carboxymethyl, carbamoylmethyl, carboxymethylthio, sulfomethyl and methoxycarbonylamino, provided that the compound is in the form of the pharmaceutically acceptable ester when R3 is 1,3,4-thiadiazol-2-ylthio, 5-amino-1,3,4,-thiazol-2-ylthio, 1,3,4-triazol-2-ylamino, 1,5-dimethyl-1,3,4-triazol-2-ylthio, 1-methylimidazol-2-ylthio, 5-methyl-1,3,4-oxadiazol-2-ylthio, 5-methyl-1,3,4-thiadiazol-2-ylthio or 1-ethylthiazol-5-ylthio.

122. The compound, salt or ester as claimed in claim 51, wherein R3 is carbamoyloxy, 1-methyl-1H-tetrazol-5-ylthio, 2-methyl-1,3,4-thiadiazol-5-ylthio or 1,2-dimethyl-1,3,4-triazol-5-ylthio, provided that the compound is in the form of the pharmaceutically acceptable ester when R3 is carbamoyloxy.

123. A pharmaceutical composition which comprises an antibacterial effective amount of the compound, salt or ester as defined in any one of claims 120-122 together with a pharmaceutically acceptable carrier.