GB1580189A - Cephalosporin derivatives and the preparation thereof - Google Patents

Description

(54) CEPHALOSPORIN DERIVATIVES AND THE PREPARATION THEREOF (71) We, FUJISAWA PHARMACEUTICAL CO. LTD., a Japanese Company of No. 3, 4-chome Doshomachi, Higashi-ku, Osaka, Japan, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement: The present invention relates to new 2-lower alkyl-7-substituted-2 or 3-cepEem- 4-carboxylic acid compounds and pharmaceutically acceptable salts thereof. More particularly, it relates to new 2-lower alkyl-7-substituted-2 or 3-cephem-4-carboxylic acid compounds and pharmaceutically acceptable salts thereof which have antimicrobial activities and to process for the preparation thereof, to pharmaceutical composition comprising the same, and to a method of using the same therapeutically in the treatment of infectious diseases in non-human animals.

Accordingly, it is one object of the present invention to provide 2-lower alkyl-7substituted-2 or 3-cephem-4-carboxylic acid compounds and pharmaceutically acceptable salts thereof, which are active against a number of pathogenic microorganisms.

Another object of the present invention is to provide processes for the preparation of 2-lower alkyl-7-substituted-2 or 3-cephem-4-carboxylic acid compounds and pharmaceutically acceptable salts thereof.

A further object of the present invention is to provide pharmaceutical composition comprising, as active ingredients, said 2-lower alkyl-7-substituted-2 or 3-cephem4-carboxylic acid compounds and pharmaceutically acceptable salts thereof.

Still further object of the present invention is to provide a method for the treatment of infectious-diseases caused by pathogenic bacteria in non-human animals.

The object 2-lower alkyl-7-substituted-2 or 3-cephem-4-carboxylic acid compounds are novel and can be represented by the following general formula (I).

wherein R1 is lower alkyl, R2 is carboxy or a protected carboxy group, Rl is amino or a protected amino group and A is carbonyl, hydroxy (lower) alkylene, hydroxyimino (lower) alkylene or lower alkoxyimino (lower)alkylene.

According to the present invention, the 2-lower alkyl-7-substituted-2 or 3-cephem4-carboxylic acid compounds (I) can be prepared by various processes which are illustrated by the following schemes.

Process 1.

R3 X A-CoOHt E ) H N S 5-R1 ~ or its reactive R34%Ni N S)l it; reactive J N\i: derivative at R2 the carboxy R2 group or a salt thereof (11) (I) or its reactive derivative at the amino group of a salt thereof or a salt thereof Process 2 Elimination of the albino protective group

or a salt thereof or a salt thereof Process 3

Reduction R3J3Co-colsl4 R1 S OH 41 R R2 (Id) (Ic) or a salt thereof or a salt thereof Process 4 4 H2N-OR4 (IV) or a salt thereof

or a salt thereof or a salt thereof Process 5

or a salt thereof or a salt thereof Process 6 Alkylating agent

or a salt thereof or a salt thereof Process 7 Elimination of the carboxy

3 protective group N CONH N. t R1 A-CON S:I 0 ON R2a COOH CIj) CIh) or a salt thereof or a salt thereof Process 8

Esterification R38 > A-CONH; < R1 R3A)h A- CON > ff4 COOH COOR5 (th) (Ij) or a salt thereof or a salt thereof wherein R1, R2, R3 and A are each as defined above, R2" is a protected carboxy group, R31 is a protected amino group, R4 is hydrogen or lower alkyl, R4" is lower alkyl, Ro is an ester moiety of an esterified carboxy group represented by the formula: --COOR5 and Y is a residue of an acid.

The starting compound (II) in the present invention can be prepared according to the methods described in W. German Offenlegungsschrift No. 2,412,513.

From the starting compounds (III) and (V) in the present invention, novel compounds can be prepared by the conventional processes which are illustrated by the following schemes. The starting compound (V) is the subject of copending Application No. 35083/79 (Serial No. 1,580,190).

Amino-protecting 3aN Oxidation H2NCH2-Z agent R a R3a~ N (VII) ('aha) or its reactive derivative at the amino group or a salt thereof

Elimination of the carboy protective 3aN7i h,~ R at C0- Z tE Y-Q42cO-c-z S N [mb}\ /4IlRc) oR4 H2N-0R4 ('V) or a salt thereof \ / a sait ORrIV) or a Hzon a salt thereof J, RJCNlO)(1i H2N S6-Z / N N / \ oR4 A.mino- Cg) (m,) \crotect- (mg) agent Elimination Elimination of the of of the carboy carboy protective protective group group \ , group SaN f N H2N53C-(X H ofl N N oR4 oR4 (mud) (elf) cmh) HZN-ISR1 O Xf RZ ('I) or its reactive derivative at the amino group or a salt thereof

Y-CH2COCH2COOll (IX) or its reactive derivative at the carboxy group Y- t S < R1 R R2 (x) Nitrosating agent Y-CHZCO-C-CONH-R1 R2 (Va) Alkylating agent Y-CH,CO-C N OR4a R2 (Vb) wherein R', R2, R2a, R3a, R4, R4a and Y are each as defined above, and Z is a protected carboxy group.

Regarding the object compounds (I) and (Ia)-(Ij) and the starting compounds (III), (IIIa)-(IIIh) and (VII), it is to be understood that they include tautomeric isomers. That is, in case that the group of the formula:

(R3 is as defined above) is contained in the molecules of said object and starting compounds, said group of the formula can be also alternatively represented by its tautomeric formula:

(R" is imino or a protected imino group). That is, both of said groups are in the state of equilibrium with each other and such tautomerism can be represented by the following equilibrium.

wherein R3 and R3' are each as defined above.

These types of tautomerism between the amino-compound and the corresponding imino-compound as stated above have been well known in the literature, and it is obvious to be skilled in the arts that both of the tautomeric isomers are easily convertible reciprocally and are included within the same category of the compound per se. Accordingly, the both of the tautomeric forms of the object compounds (I) and (Ia)-(Ii) and the starting compound (III), (IIIa)(IIIh) and (VII) are clearly included within the scope of the present invention. In the present specification and claims, the object and starting compounds including the group of such tautomeric isomers are represented by using one of the expressions therefor, that is the formula:

only for the convenient sake.

Furthermore, regarding the object compounds (I), (Ia)-(Ib) and (Ie)-(Ij) and the starting compounds (III), (IIIe)-(IIIh), (V), (Va)(Vb) and (VIII), it is to be understood that said object arid Tartmg compounds include syn lsomer, anti isomer and a mixture thereof. That is, in case that the hydroxyimino or lower alkoxyimino group is contained in the molecules of said object and starting compounds, said object and starting compounds can be optionally obtained as syn isomer or anti isomer or a mixture thereof. Accordingly, in this specification, syn isomer means one geometrical isomer havmg the partial structure represented by the following formula:

and anti isomer means the other geometrical isomer having the partial structure represented by the following formula:

wherein R4 and Z are each as defined above.

Suitable pharmaceutically acceptable salts of the object compounds (I) are conventional non-toxic salts and include a metal salt such as an alkali metal salt (e.g., sodium salt or potassium salt) and an alkaline earth metal salt (e.g., calcium salt or magnesium salt), an ammonium salt, an organic base salt (e.g., trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt or N,N'-dibenzylethylenediamine salt), an organic acid salt (e.g., acetate, maleate, tartrate, methanesulfonate, benzenesulfonate or toluenesulfonate), an inorganic acid salt (e.g., hydrochloride, hydrobromide, sulfate or phosphate), or a salt with an amino acid (e.g., arginine, aspartic acid or glutamic acid.

In the above and subsequent descriptions of the present specification, suitable examples and illustrations of the various definitions which the present invention include within the scope thereof are explained in details as follows.

The term "lower" is intended to mean 1 to 6 carbon atoms, unless otherwise indicated.

Suitable lower alkyl may include methyl, ethyl, propyl, isopropyl, butyl, pentyl and hexyl.

Suitable protected carboxy may include an esterified carboxy and the like, and suitable examples of the ester moiety in said esterified carboxy may be the ones such as lower alkyl ester (e.g., methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, pentyl ester, hexyl ester or 1-cyclopropylethyl ester) which may have at least one suitable substituent(s), for example, lower alkanoyloxy(lower)alkyl ester (e.g., acetoxymethyl ester, propionyloxyrnethyl ester, butyryloxymethyl ester, valeryloxymethyl ester, pivaloyloxymethyl ester, 2-acetoxyethyl ester or 2-propionyloxyethyl ester), lower alkanesulfonyl(lower)alkyl ester (e.g., 2-mesylethyl ester) or mono(or di or tri)-halo(lower)alkyl ester (e.g., 2-iodoethylester or 2,2,2-trichloroethyl ester; lower alkenyl ester (e.g., vinyl ester or allyl ester); lower alkynyl ester (e.g., ethynyl ester or propynyl ester); ar(lower)alkyl ester which may have at least one suitable substituent(s) (e.g., benzyl ester, 4-methoxybenzyl ester, 4-nitrobenzyl ester, phenethyl ester, trityl ester, diphenylmethyl ester, bis(methoxyphenyl)methyl ester, 3,4-dimethoxybenzyl ester or 4-hydroxy-3,5-ditertiarylbutylbenzyl ester); and aryl ester which may have at least one suitable substituent(s) (e.g., phenyl ester, 4-chlorophenyl ester, tolyl ester, tertiarybutylphenyl ester, xylyl ester, mesityl ester or cumenyl ester).

Suitable protected amino may include an amino group substituted by a conventional protecting group such as acyl as mentioned below or ar(lower)alkyl which may have at least one suitable substituent(s) (e.g., benzyl, 4-methoxybenzyl, phenethyl, trityl or 3,4-dimethoxybenzyl).

Suitable acyl may include carbamoyl, aliphatic acyl group and acyl group containing an aromatic or heterocyclic ring. And, suitable examples of the said acyl may be lower alkanoyl (e.g., formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, oxalyl, succinyl or pivaloyl); lower alkoxycadbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, 1cyclopropylethoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tertiarybutoxycarbonyl, pentyloxycarbonyl or hexyloxycarbonyl); lower alkanesulfonyl (e.g., mesyl, ethanesulfonyl, propanesulfonyl, isopropanesulfonyl or butanesulfonyl); arnesulfonyl (e.g., benzenesulfonyl or tosyl); aroyl (e.g., benzoyl, toluoyl, naphthoyl, phthaloyl or indancarbonyl); ar(lower)alkanoyl (e.g., phenylacetyl or phenylpropionyl); and ar( lower) alkoxycarbonyl (e.g., benzyloxycarbonyl).

The acyl moiety as stated above may have at least one suitable substituent(s) such as halogen (e.g., chlorine, bromine, iodine or fluorine), cyano, lower alkyl (e.g., methyl, ethyl, propyl, isopropyl or butyl) or lower alkenyl (e.g., vinyl or allyl), suitable examples of which may be mono(or di or tri)halol(lower)alkanoyl (e.g., trifluoroacetyl).

Suitable lower alkylene moiety in the terms "hydroxy(lower)alkylene", "hydroxyimino(lower)alkylene" and "lower alkoxyimino (lower) alkylene" may include methylene, ethylene, trimethylene, propylene and tetramethylene.

Suitable lower alkoxy moiety in the term "lower alkoxyimino(lower)alkylene" may include methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentyloxy and hexyloxy.

Suitable ester moiety of an esterified carboxy may include the ester exemplified for protected carboxy.

Suitable residue of an acid may include halogen (e.g., chlorine, bromine, iodine or fluorine).

The various processes for preparing the object compounds of the present invention are explained in details, in the following.

Process 1: The object compound (I) or a salt thereof can be prepared by reacting the compound (II) or its reactive derivative at the amino group or a salt thereof with the compound (III) or its reactive derivative at the carboxy group or a salt thereof.

Suitable reactive derivative at the amino group of the compound (II) may include Schiff's base type imino or its tautomeric enamine type isomer formed by the reaction of the compound (Il) with a carbonyl compound such as acetoacetic acid; a silyl derivative formed by the reaction of the compound (II) with a silyl compound such as bis(trimethylsilyl)acetamide; a derivative formed by reaction of the compound (II) with phosphorus trichloride or phosgene.

Suitable salt of the compounds (II) and (III) may include an acid addition salt such as an organic acid salt (e.g., acetate, maleate, tartrate, benzenesulfonate or toluenesulfonate) or an inorganic acid salt (e.g., hydrochloride, hydrobromide, sulfate or phosphate); a metal salt (e.g., sodium salt, potassium salt, calcium salt or magnesium salt); ammonium salt; and an organic amine salt (e.g., triethylamine salt or dicyclohexylamine salt).

Suitable reactive derivative at the carboxy group of the compound (III) may include an acide halide, an acid anhydride, an activated amide and an activated ester.

The suitable example may be an acid chloride, an acid azide, a mixed acid anhydride with an acid such as substituted phosphoric acid (e.g., dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid, dibenzylphosphoric acid or halogenated phosphoric acid), dialkylphosphorous acid, sulfurous acid, thiosulfuric acid, sulfuric acid, alkylcarbonic acid, aliphatic carboxylic acid (e.g., pivalic acid, pentanoic acid, isopentanoic acid, 2-ethylbutyric acid or trichloroacetic acid) or aromatic carboxylic acid (e.g., benzoic acid); a symmetrical acid anhydride; an activated amide with imidazole, 4-substituted imidazole, dimethylpyrazole, triazole or tetrazole; or an activated ester (e.g., cyanomethyl ester, methoxymethyl ester dimethyliminomethyl [(CH,) 2N=CH-] ester, vinyl ester, propargyl ester, p-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, mesyl phenyl ester, phenylazophenyl ester, phenyl thioester, p-nitrophenyl thioester, p-cresyl thioester, carboxymethyl thioester, pyranyl ester, pyridyl ester, piperidyl ester or 8-quinolyl thioester), or an ester with a N-hydroxy compound (e.g., N,N-dimethylhydroxylamine, 1-hydroxy-2-(lH)-pyridone, N-hydroxysuccinimide, N-hydroxyphthalimide or l-hydroxy-6-chloro-lH-benzotriazole. These reactive derivatives can be optionally selected from them according to the kind of the compound (III) to be used.

The reaction is usually carried out in a conventional solvent such as water, acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine or any other organic solvent which does not adversely influence the reaction. These conventional solvents may be also used in a mixture with water.

When the compound (III) is used in free acid form or its salt form in the reaction, the reaction is preferably carried out in the presence of a conventional condensing agent such as N,N' - dicyclohexylcarbodiimide, N - cyclohexyl - N' - morpholinoethylcarbodiimide, N - cyclohexyl - N' - (4 - diethylaminocyclohexyl)carbodiimide, N,N' - diethylcarbodiimide, N,N' - diisopropylcarbodiirnide, N - ethyl - N' (3 - dimethylaminopropyl) - carbodiimide, N,N - carbonylbis - (2 - methylimidazole), pentamethyleneketene - N - cyclohexylimine, diphenylketene - N - cyclohexylimine, ethoxyacetylene, 1 - alkoxy 1 - chloroethylene, trialkyl phosphite, ethyl polyphosphate, isopropyl polyphosphate, phosphorus oxychloride, phosphorus trichloride, thionyl chloride, oxalyl chloride, triphenylphosphine, 2 - ethyl - 7 - hydroxybenz isoxazoliurn salt, 2 - ethyl - 5 - (m - sulfophenyl) - isoxazolium hydroxide intramolecular salt, (chloromethylene) - dimethylammonium chloride or 1 - (p - chlorobenzenesulfonyloxy) - 6 - chloro - 1H - benzotriazole.

The reaction may also be carried out in the presence of an inorganic or organic base such as an alkali metal bicarbonate, tri(lower)alkylamine, pyridine, N-(lower)alkylmorphorine or N,N-di (lower) alkylbenzylamine. The reaction temperature is not critical, and the reaction is usually carried out under cooling or at ambient temperature.

It is to be noted that, in order to prepare a syn isomer of the object compound (I) selectively and in high yield, it is advisable and preperable to select a suitable condition. For example, a syn isomer of the object compound (I) can be obtained selectively and in high yield by conducting the present reaction of the compound (II) with the corresponding syn isomer of the starting compound (III) in the presence of a Vilsmeier reagent such as the one prepared from dimethylformamide and phosphorus oxychloride. Especially, a syn isomer of the object compound (I) wherein R3 is amino can be obtained in good results by conducting the present reaction in the presence of more than two molar equivalents of phosphorus oxychloride to each amount of the corresponding syn isomer of the starting compound (III), wherein R3 is amino, and dimethylformamide, and more preferable results can be achieved by conducting a step of activation of the syn isomer of the starting compound (III) wherein R3 is amino in the presence of a silyl compound such as bis-(trimethylsilyl')- acetamide or trimethylsilylacetamide.

Process 2: The object compound (Ia) or a salt thereof can be prepared by subjecting the compound (Ib) or a salt thereof to elimination reaction of the amino protective group.

Suitable salt of the compound (Ib) can be referred to the metal salt, ammonium salt and organic amine salt exemplified for the compound (II).

The elimination reaction is carried out in accordance with a conventional method such as hydrolysis or reduction. The hydrolysis may also include a method using an acid or base or hydrazine. These methods may be selected depending on the kind of the protective groups to be eliminated.

Among these methods, hydrolysis using an acid is one of the most common and preferable method for eliminating the protective groups such as substituted or unsubstituted alkoxycarbonyl, cycloalkoxycarbonyl, substituted or unsubstituted aralkoxycarbonyl, aralkyl (e.g., trityl), substituted phenylthio, substituted aralkylidene, substituted alkylidene or substituted cycloalkylidene. Suitable acid includes an organic or inorganic acid such as formic acid, trifluoroacetic acid, benzenesulfonic acid, ptoluenesulfonic acid and hydrochloric acid, and the most suitable acid is an acid which can be easily removed from the reaction mixture by a conventional manner such as distillation under reduced pressure, for example, formic acid or trifluoroacetic acid.

The acids can be selected according to the kind of protected group to be eliminated.

When the elimination reaction is conducted with an acid, it can be carried out in the presence or absence of a solvent. Suitable solvent includes water, a conventional organic solvent or a mixture thereof. The hydrolysis using hydrazine is commonly applied for eliminating a phthaloyl type amino-protective group.

The reductive elimination is generally applied for eliminating the protective group, for example, haloalkoxycarbonyl (e.g., trichloroethoxycarbonyl), substituted or unsubstituted aralkoxy carbonyl (e.g., benzyloxycarbonyl) or 2-pyridylmethoxycarbonyl. Suitable reduction may include, for example, reduction with an alkali metal borohydride (e.g., sodium borohydride), reduction with a combination of a metal (e.g., tin, zinc or iron) or the said metal together with a metal salt compound (e.g., chromous chloride or chromous acetate etc.) and an organic or inorganic acid (e.g., acetic acid, propionic acid or hydrochloric acid); and catalytic reduction. Suitable catalyst includes a conventional one, for example, Raney nickel, platinum oxide and palladium on charcoal.

Among the protective groups, the acyl group can be generally eliminated by hydrolysis. Especially, trifluoroacetyl group can be easily eliminated by treating with water even in around neutral condition, and halogen substituted-alkoxycarbonyl and 8-quinolyloxycarbonyl groups are usually eliminated by treating with a heavy metal such as copper or zinc.

Among the protective groups, the acyl group can also be eliminated by treating with an iminohalogenating agent (e.g., phosphorus oxychloride) and an iminoetherifying agent such as lower alkanol (e.g., methanol or ethanol), if necessary, followed by hydrolysis.

The reaction temperature is not critical and may be suitably selected in accordance with the kind of the protective group for the amino group and the elimination method as mentioned above, and the reaction is preferably carried out under a mild condition such as under cooling or at slightly elevated temperature.

The present invention includes, within its scope, the cases that the protected carboxy is transformed into the free carboxy group during the reaction or the posttreating step of the present process.

Process 3: The object compound (Ie) or a salt thereof can be prepared by reducing the compound (Id) or a salt thereof.

Suitable salt of the compound (Id) can be referred to the ones exemplified for the compound (Il).

The present reduction is conducted by a conventional method such as a method of using an alkali metal borohydride (e.g., sodium borohydride or potassium borohydride).

The present reduction is usually carried out in a solvent which does not adversely influence the reaction, for example, water, methanol, ethanol, tetrahydrofuran and dicxane. The present reduction can also be carried out in the presence of an inorganic or an organic base such as an alkali metal (e.g., sodium or potassium), an alkaline earth metal (e.g., magnesium or calcium), the hydroxide or carbonate or bicarbonate thereof, tri(lower)alkylamine (e.g., trimethylamine or triethylamine), picoline, N methylpyrrolidine, N-methylmorphcline, 1,5-diazabicyclo [4,3,0]none-5-ene, 1,4-diaza bicyclo[2,2,2] octane or 1,8-diazabicyclo [5,4,0] undecene-7.

The reaction temperature is not critical and the present reaction is preferably carried out under a mild condition such as under cooling or slightly warming.

Process 4: The object compound (Ie) or a salt thereof can be prepared by reacting the compound (Id) or a salt thereof with the compound (IV) or a salt thereof.

Suitable salts of the compound (Id) can be referred to the ones exemplified for the compound (II), and suitable salts of the compound (IV) may include an inorganic acid salt (e.g., hydrochloride, hydrobromide or sulfate) and an organic acid salt (e.g., acetate, maleate or p-toluenesulfonate).

The present reaction is usually carried out in a solvent such as water, an alcohol (e.g., methanol or ethanol) or any other solvent which does not adversely influence the present reaction.

The present reaction is preferably carried out in the presence of a base, for example, an inorganic base such as alkali metal (e.g., sodium or potassium), alkaline earth metal (e.g., magnesium or calcium), the hydroxide or carbonate or bicarbonate thereof, and an organic base such as alkali metal alkoxide (e.g., sodium methoxide or sodium ethoxide), trialkylamine (e.g., trimethylamine or triethylamine), N,N-dialkylaniline (e.g., N,N-dimethylaniline) or pyridine.

The reaction temperature is not critical and the reaction is usually carried out under cooling to heating.

Process 5: The object compound (Ie) or a salt thereof can be prepared by reacting the compound (V) or a salt thereof with the compound (VI).

Suitable salt of the compound (V) can be referred to the ones exemplified for the compound (II).

The present reaction is usually carried out in a solvent such as water, an alcohol (e.g., methanol or ethanol), benzene, dimethylformamide, tetrahydrofuran or any other solvent which does not adversely influence the reaction.

The reaction temperature is not critical and the reaction is usually carried out from at ambient temperature to under heating.

Process 6: The object compound (If) or a salt thereof can be prepared by reacting the compound (Ig) or a salt thereof with an alkylating agent.

Suitable salts of the compound (Ig) can be referred to the ones exemplified for the compound (II).

Suitable alkylating agent used in the present reaction may include di(lower)alkyl sulfate (e.g., dimethyl sulfate or diethyl sulfate), diazo(lower)alkane (e.g., diazomethane or diazoethane), lower alkyl halide (e.g., methyl iodide, ethyl iodide or ethyl bromide) and lower alkyl sulfonate (e.g., methyl p-toluenesulfonate).

The reaction using diazo-(lower)alkane is usually carried Out in a solvent such as diethyl ether, dioxane or any other solvent which does not adversely influence the reaction under cooling or at ambient temperature.

The reaction using other alkylating agent is usually carried out in a solvent such as water, acetone, ethanol, diethyl ether, dimethylformamide or any other solvent which does not adversely influence the reaction under cooling to heating, and the reaction is preferably carried out in the presence of a base such as an inorganic base or an organic base as aforementioned.

Process 7: The object compound (Ih) or a salt thereof can be prepared by subjecting the compound (Ii) or a salt thereof to elimination reaction of the carboxy protective group.

Suitable salts of the compound (Ij) can be referred to the acid addition salts exemplified for the compound (it).

In the present elimination reaction, all conventional methods used in the elimination reaction of the carboxy protective group, for example, hydrolysis or reduction are applicable.

When the carboxy protective group is an ester, it can be eliminated by hydrolysis.

The hydrolysis is preferably carried out in the presence of a base or an acid. Suitable base may include an inorganic base and an organic base as aforementioned in Process 2.

Suitable acid may include an organic acid (e.g., formic acid, acetic acid or propionic acid) and an inorganic acid (e.g., hydrochloric acid, hydrobromic acid or sulfuric acid). The reduction can be applicable to elimination of the protective group such as 2-iodoethyl ester or 2,2,2-trichloroethyl ester. The reduction applicable to the elimination reaction of the present invention may include, for example, reduction using a combination of a metal (e.g., zinc or zinc amalgam) or a chrome salt compound (e.g., chromous chloride or chromous acetate) and an organic or inorganic acid (e.g., acetic acid, propionic acid or hydrochloric acid), and reduction in the presence of a metallic catalyst.

The metallic catalysts for the catalytic reduction include, for example, platinum catalyst (e.g., platinum wire, spongy platinum, platinum black or platinum colloid), palladium catalyst (e.g., palladium spongy, palladium black, palladium oxide, palladium on barium sulfate, palladium on barium carbonate, palladium on charcoal, palladium on silica gel or palladium colloid) and nickel catalyst (e.g., reduced nickel, nickel oxide, Raney nickel or Urushibara nickel).

The reaction temperature is not critical, and it may be suitably selected in accordance with the kind of the protective group of the carboxy and the elimination method.

Process 8: The object compound (Ij) or a salt thereof can be prepared by subjecting the compound (Ih) or a salt thereof to esterification reaction.

Suitable salt of the compound (Ih) can also be referred to the ones exemplified for the compound (II).

The esterifying agent to be used in the present reaction may be a compound of the formula: X - R5 (XI) wherein R5 is as defined above and X is hydroxy or reactive derivatives thereof.

A suitable example of the reactive derivative of hydroxy may include a residue of an acid as aforementioned.

The present reaction is usually carried out in a solvent such as dimethylformamide, pyridine, hexamethylphosphoric triamide, dioxane or other solvents which does not adversely affect the reaction.

In case that the compound (Ih) is used in a form of free acid, the reaction is preferably carried out in the presence of a base such as an inorganic base or an organic base as aforementioned in Process 2.

The reaction temperature is not critical and the reaction is preferably carried out under cooling, at ambient temperature or under warming.

In the aforementioned reactions and/or the post-treating steps of the processes of the present invention, the aforementioned tautomeric isomers may occasionally be transformed into the other tautomeric isomers, and such cases are also included in the scope of the present invention.

In the aforementioned reactions and/or the post-treating steps of the processes of the present invention, the aforementioned syn or anti isomer may occasionally be transformed into the other isomer partially or wholly, and such cases are also included in the scope of the present invention.

In case that the object compound (I) is obtained in a form of the free acid at 4 position and/or in case that the object compound (I) has a free amino group, it may be transformed into its pharmaceutically acceptable salt as aforementioned by a conventional method.

Processes for the preparation of the starting compounds are explained in detail as follows.

The starting compound (IIIa) can be prepared by reacting the compound (VII) or its reactive derivative at the amino group or a salt thereof with an amino-protecting agent, and the starting compound (IIIe) can be prepared by reacting the compound (IIIh) or its reactive derivative at the amino group or a salt thereof with an aminoprotecting agent, respectively.

Suitable reactive derivative at the amino group of the compounds (VII) and (IIIh) and suitable salt of the compounds (VII) and (IIIh) may include the same ones as illustrated in the explanations of the reactive derivative at the amino group of the compound (II) and salt of the compound (II), respectively.

Suitable amino-protecting agent may include acylating agent.

Suitable acylating agent may include an aliphatic, aromatic and heterocyclic isocyanate, and the corresponding isothiocyanate, and an aliphatic, aromatic and heterocyclic carboxylic acid, and the corresponding sulfonic acid, carbonic acid ester and carbamic acid, and the corresponding thio acid, and the reactive derivative of the above acids.

Suitable reactive derivative of the above acids may include the same ones as illustrated in the explanation of "reactive derivatives at the carboxy group of the compound (III)". The example of the protective group to be introduced into the amino group in the compounds (VII) and (IIIh) with the above amino-protecting agent may be the same ones as illustrated in the explanation of the protective group in the terms "a protected amino group".

The present reaction is carried out in the similar manner as illustrated in the reaction of the compound (II) or its reactive derivative at the amino group or a salt thereof with the compound (III) or its reactive derivative at the carboxy group.

The starting compound (IIIb) can be prepared by oxidizing the compound (IIIa).

The present oxidation reaction is conducted by a conventional method which is applied to the transformation of so-called activated methylene group into carbonyl group. That is, the present oxidaton is conducted by a method, for example, by using a conventional oxidizing agent such as selenium dioxide or trivalent manganese compound (e.g. manganous acetate and potassium permanganate). The present oxidation is usually carried out in a solvent which does not adversely influence the reaction, for example, water, dioxane and tetrahydrofuran.

The reaction temperature is not critical and the reaction is preferably carried out under warming to heating.

The starting compound ( IIIe ) can be prepared by subjecting the compound (IIIb) to elimination reaction of the carboxy protective group, the starting compound (IIIe) can be prepared by subjecting the compound (III,) to elimination reaction of the carboxy protective group, and the starting compound (IIIh) can be prepared by subjecting the compound (lug) to elimination reaction of the carboxy protective group, respectively.

The elimination reaction is carried out in the similar manner to that illustrated for the elimination reaction of Process 7.

The starting compound (IIId) can be prepared by reducing the compound (ll).

The present reduction is carried out in the similar manner to that illustrated for the reduction of Process 3.

The starting compound (IIIe) can be prepared by reacting the compound (IIIc) with the compound (IV) or a salt thereof, and the starting compound (III)f) can be prepared by reacting the compound (IIIb) with the compound (IV) or a salt thereof, respectively.

The present reaction is carried out in the similar manner to that illustrated in the reaction of Process 4.

The starting compound (IIIf;) can be prepared by reacting the compound (VIII) with thiourea.

The present reaction is carried out in the similar manner to that illustrated in the reaction of Process 5.

The compound (X) can be prepared by reacting the compound (II) or its reactive derivative at the amino group or a salt thereof with the compound (IX) or its reactive derivative at the carboxy group.

Suitable reactive derivative at the carboxy group of the compound (IX) may include the same ones as illustrated in the explanation of "reactive derivative at the carboxy group of the compound (III)".

The present reaction is carried out in the similar manner to that illustrated in the reaction of Process 1.

The starting compound (Va) can be prepared by reacting the compound (X) with a nitrosating agent.

Suitable nitrosating agent may include nitrous acid, alkali metal nitrite (e.g., sodium nitrite and lower alkyl nitrite (e.g., amyl nitrite).

The present reaction is usually carried out in a solvent such as water, acetic acid, benzene, methanol, ethanol br any other solvent which does not adversely influence the reaction.

The reaction temperature is not critical and the reaction is usually carried out under cooling or at ambient temperature.

The starting compound (Vb) can be prepared by reacting the compound (V,) with an alkylating agent.

The present reaction is carried out in the similar manner to that illustrated in the reaction of Process 6.

The object compounds (I) and pharmaceutically acceptable salt thereof of the present invention exhibit high antibacterial activity and inhibit the growth of a number of microorganisms including Gram-positive and Gram-negative bacteria.

Especially, the syn isomers of the object compounds (I) and pharmaceutically acceptable salt thereof exhibit generally much higher antibacterial activity than that of the corresponding anti isomers of the object compounds (I) and pharmaceutically acceptable salt thereof. For therapeutic purpose, the compounds according to the present invention can be used in the form of pharmaceutical preparation which contain said compounds, as an active ingredient, in admixture with a pharmeceutically acceptable carriers such as an organic or inorganic solid or liquid excipient suitable for oral, parenteral ot external administration. The pharmaceutical preparaticns may be capsules, tablets, dragees, ointments or suppositories, solutions, suspensions, emulsions, and the like. If desired, there may be included in the above preparations auxiliary substances, stabilizing agents, wetting or emulsifying agents, buffers and other commonly used additives.

While the dosage of the compounds will vary depend upon the age and condition of the patient, an average single dose of about 10 mg., 50 mg., 100 mg., 250 mg., 500 mg., and 1000 mg. of the compounds according to the present invention was proved to be effective for treating infectious diseases caused by pathogenic bacteria.

In order to illustrate the usefulness of the object compounds, anti-microbial activities of some representative compounds of the present invention against some test strains of pathogenic bacteria are shown in their minimal inhibitory concentrations below.

Test Method In vitro antibacterial activity was determined by the two-fold agar-plate dilution method as described below.

One loopful of an overnight culture of each test strain in Trypticase-soy broth (108 viable cells per ml) was streaked on heart infusion agar (HI-agar) containing graded concentrations of representative test compound, and the minimal inhibitory concentration (MIC) was expressed in terms of,ug/ml. afrer incubation at 37bC for 20 hours.

Test compounds (1) 2 - Methyl - 7 - [2 - (2 - aminothiazol - 4 - yl)glyoxylamido] - 3 - cephem 4 - carboxylic acid (Test compound (1)) (2) 2 - Methyl - 7 - [2 - hydroxy - 2 - (2 - aminothiazol - 4 - yl)acetamido] 3 - cephem - 4 - carboxylic acid (Test compound (2)) (3) 2 - Methyl - 7 - [2 - methoxyimino - 2 - (2 - aminothiazol - 4 - yl) - acet amido] - 3 - cephem - 4 - carboxylic acid (syn isomer) (Test compound (3)) (4) Pivaloyloxymethyl 2 - methyl - 7 - [2 - methoxyimino - 2 - (2 - aminothiazol- 4 - yl)acetamido] - 3 - cephem - 4 - carboxylate (syn isomer) (Test Com pound (4)) TEST RESULTS

Organism Test Test Test Test compound compound compound compound (1) (2) (3) (4) E.coli No. 324 0.78 0.78 0.05 0.2 No. 341 0.2 0.39 0.2 0.78 Kl.aerogenes No. 417 0.39 0.39 0.2 0.2 No. 418 0.39 0.78 0.1 0.78 No.427 0.1 0.39 0.05 0.2 No. 428 0.78 1.56 0.2 1.56 Pr.minabilis No. 501 0.78 1.56 0.05 0.2 No. 520 0.39 1.56 0.05 0.1 No. 525 6.25 1.56 0.05 0.2 The present invention is illustrated by the following examples.

Preparation of the starting compounds: Preparation 1 (a) A mixture of 2,2,2 - trichloroethyl 2 - methyl - 7 - amino - 3 - cephem - 4carboxylate hydrochloride (0.38 g.), trimethylsilylacetamide (1.1 g.) and methylene chloride (10 ml.) was stirred for 30 minutes at room temperature, and thus obtained solution was cooled to 150C. To the solution was added dropwise 3-oxo-4-bromobutyryl bromide (1.0 m mole) in carbon tetrachloride (13 ml.) under cooling to -15 C, and the mixture was stirred for 1.5 hours at the same temperature and for 30 minutes without external cooling. The mixture was poured into cold water, and then the organic layer was separated therefrom. The organic layer was washed with 2N hydrochloric acid (8 mix3) and the water (10 mlX2) in turn, dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure. The residue was pulverized in diisopropyl ether, collected by filtration and then dried to give pale brown powder of 2,2,2 - trichloroethyl 2 -methyl - 7 - (3oxo - 4 - bromobutyramido) - 3 - cephem - 4 - carboxylate (0.31 g.), mp 78 to 83"C (dec.).

I.R. Spectrum (Nujol) 3320, 1785, 1735, 1675, 1284, 1210 cm-I N.M.R. Spectrum (CDCl,, ) 1.54 (3H, d, J=7Hz) 3.65 (1H, m) 3.76 (4/5H, s) 4.11 (6/5H, s) 4.90 (2H, s) 5.00 (1H, d, J=6Hz) 5.95 (1H, m) 6.72 (1H, d, J=6.8Hz) 7.05 (2/5H, d, J=9Hz) 7.73 (3/5H, d, J=9Hz) (b) To a solution of 2,2,2 - trichloroethyl 2 - methyl - 7 -(3 - oxo - 4 - bromobutyramido) - 3 - cephem - 4 - carboxylate (2.54 g.) in glacial acetic acid (25 ml.) was added dropwise a solution of sodium nitrite hydrate (0.33 g.) in water (1 ml.) over 3 minutes with stirring at 10 to 150C, and then the mixture was stirred for 1 hour at the same temperature. After the reaction mixture was poured into cold water (70 ml.), the precipitates were collected by filtration and then dried to give brown powder of 2,2,2 - trichloroethyl 2 - methyl - 7 - (2 - hydroxyimino - 3 - oxo 4 - bromobutyramido) - 3 - cephem - 4 - carboxylate (a mixture of syn and anti isomers) (2.0 g.), mp 76 to 800C (dec.).

I.R. Spectrum (Nujol) 1670-1710, 1540, 1280, 1215, 715 cm-1 N.M.R. Spectrum (de-dimethylsulfoxide, 8) 1.44 (311, d, J=7Hz) 3.2-3.8 (2H, broad) 3.91 (1H, m) 4.57 (1H, s) 5.02 (211, s) 5.16 (1H, d, J=5Hz) 5.91 (1H, dd, J=5 and 9Hz) 6.74 (1H, d, J-6.5Hz) 9.32 (1H, d, J=9Hz) Preparation 2 To a solution of 2,2,2 - trichloroethyl 2 - methyl - 7 - (2 - hydroxyimino - 3oxo - 4 - bromobutyramido) - 3 - cephem - 4 - carboxylate (a mixture of syn and anti isomers) (1.2 g.) in ethanol (20 ml.) was added dropwise a solution of diazomethane (0.1 mole) in diethyl ether under stirring and ice-cooling to complete the reaction. After the reaction mixture was concentrated under reduced pressure, the residue was pulverized in diisopropyl ether, collected by filtration and then dried to give brown powder of 2,2,2 - trichloroethyl 2 - methyl - 7 - (2 - methoxyimino - 3oxo - 4 - bromobutyramido) - 3 - cephem - 4 - carboxylate (a mixture of syn and anti isomers) (1.1 g.), mp 80 to 830C (dec.).

I.R. Spectrum (Nujol) 3300, 1785, 1737, 1650-1710, 1535, 1280, 1210, 1160, 1045, 715 crn N.M.R. Spectrum (d^-dimethylsulfoxide, ) 1.46 (3H, d, J=7Hz) 4.0 (1H, m) 4.04 (3H, s) 4.62 (1H, s) 5.05 (2H, s) 5.29 (1H, d, J=5Hz) 5.95 (1H, m) 6.74 (1H, m) 9.48 (1H, d, J=9Hz) Preparation 3 (a) To acetic anhydride (384 ml.) was added dropwise formic acid (169.2 ml.) over 15 to 20 minutes under cooling below 350C, and the mixture was stirred for 1 hour at 55 to 600 C. To the mixture was added ethyl 2 - (2 - aminothiazol - 4yl)acetate, which can be represented as ethyl 2 - (2 - imino - 2,3 - dihydrothiazol - 4yl)acetate, (506 g.) over 15 to 20 minutes under ice-cooling and stirring, and then the mixture was stirred for 1 hour at room temperature. After the reaction, the solvents were distilled off. To the residue was added diisopropyl ether (2500 ml.), and the mixture was stirred for 1 hour at room temperature. The precipitates were collected by filtration, washed with diisopropyl ether and then dried to give ethyl 2 - (2 - formylaminothiazol - 4 - yl)acetate, which can be represented as ethyl 2 (2 - formylimino - 2,3 - dihydrothiazol - 4 - yl)acetate, (451.6 g.), mp 125 to 1260C. The remaining filtrate was concentrated, and the residue was washed with diisopropyl ether (500 ml.) and then dried to give further the same object compound (78.5 g.).

I.R. Spectrum (Nujol) 1737, 1700 cm-l N.M.R. Spectrum (CDCl3, 3) 1.25 (3H, t, J=811z) 3.7 (2H, s) 5.18 (2H, q, J=8Hz) 6.9 (1H, s) 8.1 (1H, s) (b) A mixture of manganous acetate tetrahydrate (120 g.), acetic acid (1000 ml.) and acetic anhydride (100 ml.) was stirred for 20 minutes in an oil bath heated at 130 to 135"C, and to the mixture was added potassium permanganate (20 g.) over 5 minutes at 105 to 110 C with stirring and then the mixture was further stirred for 30 minutes at 130 to 1350C. The mixture was cooled to room temperature, and to the mixture was added ethyl 2 - (2 - formylaminothiazol - 4 - yl)acetate, which can be represented as ethyl 2 - (2 - formylimino - 2,3 - dihydrothiazol - 4yl)acetate, (53.5 g.), and then the mixture was stirred for 15 hours at 38 to 40"C under introduction of air at the rate of 6000 ml. per minute. After the reaction, the precipitates were collected by filtration. The precipitates were washed with acetic acid and water in turn and then dried to give ethyl 2 - (2 - formylaminothiazol - 4yl)glyoxylate, which can be represented as ethyl 2 - (2 - formylimino - 2,3 - dihydrothiazol - 4 - yl)glyoxylate, (41.5 g.), mp 232 to 2330C (dec.).

(c) To a suspension of ethyl 2 - (2 - formylaminothiazol - 4 - yl)glyoxylate, which can be represented as ethyl 2 - (2 - formylimino - 2,3 - dihydrothiazol - 4 - yl) g]yoxylate, (281 g.) in water (1100 ml.) was added an 1N sodium hydroxide aqueous solution (2.23 1.) under stirring and ice-cooling, and then the mixture was stirred for 5 minutes at 10 to 15 C. After the reaction mixture was filtered, the filtrate was adjusted to pH 1 with concentrated hydrochloric acid with stirring. The precipitates were collected by filtration, washed with water and then dried to give 2 - (2 - formylaminothiazol - 4 - yl)glyoxylic acid, which can be represented as 2 - (2 - formylimino - 2,3 - dihydrothiazol - 4 - yl)glyoxylic acid, (234 g.), mp 133 to 136"C (dec.).

N.M.R. Spectrum (NaDCO3, 6) 8.27 (1H, s) 8.6 (1H, s) Preparation 4 To a suspension of 2 - (2 - formylaminothiazol - 4 - yl)glyoxylic acid, which can be represented as 2 - (2 - formylimino - 2,3 - dihydrothiazol - 4 - yl)glyoxylic acid, (20 g.) in water (400 ml.) was added sodium bicarbonate (8.4 g.) under icecooling and stirring, and the mixture was stirred for 10 minutes at the same temperature, and then ethanol (10 ml.) was added thereto. To the mixture was added sodium borohydride (1.52 g.) over 10 minutes with stirring at the same temperature, and the mixture was stirred for 1 hour and 50 minutes at the same temperature.

After the reaction, the reaction mixture was filtered. The filtrate was adjusted to pH 4.0 with 10% hydrochloric acid and then concentrated under reduced pressure till the volume became 100 ml. The concentrated filtrate was adjusted to pH 1 with 10% hydrochloric acid, and crystallization was induced by scratching. The concentrated filtrate was stirred for 1 hour at room temperature and then allowed to stand overnight in a refrigerator. The precipitates were collected by filtration, washed with ice-water twice and then dried under suction to give 2 - hydroxy - 2 - (2formylaminothiazol - 4 - yl)acetic acid, which can be represented as 2 - hydroxy - 2 (2 - formylimino - 2,3 - dihydrothiazol - 4 - yl)acetic acid, (14.8 g.), mp 188 to 189 C. (dec.).

I.R. Spectrum (Nujol) 1730, 1635 cm~1 N.M.R. Spectrum (NaDCO3, 6) 5.07 (1H, s) 7.15 (1H, s) 8.5 (1H, s) Preparation 5 (a) A solution of ethyl 2 - methoxyimino - 4 - bromoacetoacetate (a mixture of syn and anti isomers) (17.4 g.) and thiourea (5.4 g.) in ethanol (100 ml.) was refluxed for 4 hours. The reaction mixture was allowed to stand in a refrigerator to precipitate crystals. The crystals were collected by filtration, washed with ethanol and dried to give ethyl 2 - methoxyimino - 2 - (2 - aminothiazol - 4 - yl)acetate hydrobromide (anti isomer) (9.5 g.). The filtrate and the washings were put together and concentrated under reduced pressure. Water (100 ml.) was added to the residue and the mixture was washed with ether. The aqueous layer was alkalized with a 28% aqueous solution of ammonia and extracted with ethyl acetate. The extract was washed with water and a saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to give crystalline substance of ethyl 2 - methoxyimino - 2 (2 - aminothiazol - 4 - yl)acetate (syn isomer), which can be represented as ethyl 2 - methoxyimino - 2 - (2imino - 2,3 - dihydrothiazol - 4 - yl)acetate (syn isomer), 5.2 g.).

I.R. Spectrum (Nujol) 3400, 3300, 3150, 1725, 1630, 1559 cm-1 N.M.R. Spectrum (CDCl,, 8) 1.38 (3H, t, J=7Hz) 4.03 (3H, s) 4.38 (2H, q, J=7Hz) 5.91 (2H, broad s) 6.72 (1H, s) (b) Ethanol (10 ml.) was added to a suspension of ethyl 2 - methoxyimino - 2 - (2aminothiazol - 4 - yl)acetate (syn isomer), which can be represented as ethyl 2methoxyimino - 2 - (2 - amino - 2,3 - dihydrothiazol - 4 - yl)acetate (syn isomer), (2.2 g.) in a 1N aqueous solution of sodium hydroxide (12 ml.) and the mixture was stirred for 15 hours at ambient temperature. The reaction mixture was adjusted te pH 7.0 with 10% hydrochloric acid and ethanol was distilled off under reduced pressure. The residual aqueous solution was washed with ethyl acetate, adjusted to pH 2.8 with 10% hydrochloric acid and stirred under ice-cooling to precipitate crystals. The crystals were collected by filtration, washed with acetone and recrystallized from ethanol to give colorless needles of 2 - methoxyimino - 2 - (2 - aminothiazol - 4 - yl)acetic acid (syn isomer), which can be represented as 2-methoxyimino - 2 - (2 - imino - 2,3 - dihydrothiazol - 4 - yl)acetic acid (syn isomer), (1.1 g.).

I.R. Spectrum (Nujol) 3150, 1670, 1610, 1585 cm-1 N.M.R. Spectrum (d,-dimethylsulfoxide, ) 3.83 (3H, s) 6.85 (1H, s) 7.20 (2H, broad s) Preparation 6 Pyridine (5 ml.) was added to a suspension of 2 - methoxyimino - 2 - (2aminothiazol - 4 - yl)acetic acid (syn isomer) which can be represented as 2-methoxyimino - 2 - (2 - imino - 2,3 - dihydrothiazol - 4 - yl)acetic acid (syn isomer), (2.0 g.) in ethyl acetate (20 ml.). A solution of bis(2,2,2-trifiuoroacetic)anhydride (2.5 g.) in ethyl acetate (3 ml.) was added dropwise thereto with stirring at 5 to 70C and the mixture was stirred for 30 minutes at 3 to 50C. Water (30 ml.) was added to the reaction mixture and the ethyl acetate layer was separated. The aqueous layer was further extracted with ethyl acetate and two ethyl acetate layers were combined together, washed with water and a saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to give 2 - methoxyimino - 2 - [2 - (2,2,2 - trifluoroacetylamino)thiazol - 4 - yl]acetic acid (syn isomer), which can be represented as 2 - methoxyimino - 2 - [22,2,2 - trifluoroacetylimino) - 2,3 - dihydrothiazol - 4 - yl]acetic acid (syn isomer), (0.72 g.).

I.R. Spectrum (Nujol) 1725, 1590 cm-1 N.M.R. Spectrum (de-dimethylsulfoxide, 6) 3.91 (3H, s) 7.68 (1H, s) Similarly, the following compound was obtained.

i) 2 - Methoxyimino - 2 - (2 - formylaminothiazol - 4 - yl)acetic acid (syn isomer), which can be represented as 2 - methoxyimino- 2 - (2 - formylimino - 2,3 - di hydrothiazol - 4 - yl)acetic acid (syn isomer), mp 152"C dec.).

I.R. Spectrum (Nujol) 3200, 2100--2800, 1950, 1600 cm-1 N.M.R. Spectrum (de-dimethylsulfoxide, 3) 3.98 (1H, s) 7.62 (1H, s) 8.60 (1H, s) Example 1.

To dimethylformamide (0.54 g.) was added dropwise phosphorus oxychloride (1.13 g.) under stirring and ice-cooling, and the mixture was stirred for 30 minutes at 40"C, and then dried ethyl acetate (13 ml.) was added thereto. To the mixture was gradually added 2 - methoxyimino - 2 - (2 - trifluoroacetylaminothiazol - 4 - yl)acetic acid (syn isomer), which can be represented as 2 - methoxyimino - 2 - (2trifluoroacetylimino - 2,3 - dihydrothiazol - 4 - yl)acetic acid (syn isomer), (2.0 g.) under cooling at 3 to 5"C, and the mixture was stirred for 40 minutes at the same temperature. Thus obtained solution was added to a solution, which was prepared by stirring a mixture of 2 - methyl - 7 - amino - 3 - cephem - 4 - carboxylic acid (1.44 g.) and trimethylsilylacetamide (9.78 g.) in dried ethyl acetate (30 ml.) for 5 to 10 minutes at 35 to 40"C, under cooling at -25 to -200C with stirring. The mixture was stirred for 1 hour at the same temperature, and cold water was added thereto under ice-cooling, and then the mixture was stirred for about 5 minutes at the same temperature. The ethyl acetate layer was separated from the reaction mixture, and the remaining aqueous layer was extracted with ethyl acetate (20 ml. X 2). The ethyl acetate layers were combined together, washed with water and then water (50 ml.) was added thereto. The mixture was adjusted to pH 7.5 with a saturated aqueous solution of sodium bicarbonate, under ice-cooling and stirring, and the aqueous layer was separated therefrom. After washing the aqueous layer with ethyl acetate, ethyl acetate (70 ml.) was added thereto. The mixture was adjusted to pH 2.5 with 10% hydrochloric acid under ice-cooling and stirring. The ethyl acetate layer was separated from the mixture, and the remaining aqueous layer was extracted with ethyl acetate (30 ml.). The ethyl acetate layers were combined together, washed with an aqueous solution of sodium chloride, dried and then concentrated till the total volume became about 10 ml. To the residue was added diethyl ether (20 ml.) and the mixture was stirred for about 1 hour. The precipitates were collected by filtration, washed with diethyl ether and then dried to give 2 - methyl7 - [2 6.62 (1H, d, J6Hz, 3-H) 7.56 (1H, s, 5-H on thiazole ring) 9.81 (1H, d, J=7Hz, 7-CONH) Example 2.

To dimethylformamide (78 ml.) was added dropwise phosphorus oxychloride (11.9 g.) under stirring and ice-cooling, and the mixture was stirred for 30 minutes at 40"C. To the mixture was added 2 - (2 - formylaminothiazol - 4 - yl)glyoxylic acid, which can be represented as 2 - (2 - formylimino - 2,3 - dihydrothiazol - 4yl)glyoxylic acid, (7.8 g.) under cooling at 200 C, and then the mixture was stirred for 30 minutes under cooling at '--20 to - 150C. Thus obtained mixture was added to a solution, which was prepared by stirring a mixture of 2 - methyl - 7 - amino - 3cephem - 4 - carboxylic acid (8.35 g.) and bis(trimethylsilyl)acetamide (19.5 ml.) in dried methylene chloride (170 m].) at room temperature, under cooling at -50 to --45"C with stirring. The mixture was stirred for 1 hour at -45 to -400C and then the reaction mixture was poured into a solution of sodium bicarbonate (32 g.) in water (1.5 1) with shaking. The aqueous layer was separated and washed with ethyl acetate. The aqueous solution was layered with ethyl acetate and then adjusted to pH 1 to 2 with concentrated hydrochloric acid. The ethyl acetate layer was separated from the mixture, and the remaining aqueous layer was extracted with ethyl acetate (200 ml.X2). The ethyl acetate layers were combined together, washed with water and then concentrated to a small volume. The precipitates were collected by filtration, washed with a small amount of ethyl acetate and then dried to give 2 - methyl - 7 - [2 - (2 - formylaminothiazol - 4 - yl)glyoxylamido] - 3 - cephem- 4 - carboxylic acid, which can be represented as 2 - methyl - 7 - [2 - (2 - formylimino - 2,3 - dihydrothiazol - 4 - yl)glyoxylamido] - 3 - cephem - 4 - carboxylic acid, (7.9 g.), mp 210 to 215"C (dec.).

I.R Spectrum (Nujol) 3300, 3150, 1780, 1713, 1660, 1625, 1533 cm'-l N.M.R. Spectrum (d,-dimethylsulfoxide, ) 1.45 (3H, d, J=7Hz, 2-CH,) 3.7-4.1 (1H, m, 2-H) 5.17 (1H, d, J=5Hz, 6-H) 3.91 (1H, dd, J=5 and 8Hz, 7-H) 6.59 (1H, d, J=Hz, 3H) 8.40 (1H, s, 5-H on thiazole ring) 8.57 (1H, s, OHC-N=) 9.83 (1H, d, J=8Hz, 7-CONH) Example 3.

To a solution of thionyl chloride (3.01 g.) in methylene chloride (45 ml.) were added dimethylformamide (0.928 g.) and 2 - (2 - formylaminothiazol - 4 - yl) glyoxylic acid, which can be represented as 2 - (2 - formylimino - 2,3 - dihydrothiazol - 4 - yl)glyoxylic acid, (3.71 g.) in turn, and the mixture was stirred for 4 hours at room temperature. Thus obtained mixture was added over 5 minutes to a solution, which was prepared by stirring a mixture of 2 - methyl - 7 - amino3 - cephem - 4 - carboxylic acid (3.3 g.) and trimethylsilylacetamide (16.2 g.) in methylene chloride (60 ml.) at room temperature for 40 minutes, with stirring under cooling to -25 to -200C. The mixture was stirred for 30 minutes at -25 to ---20"C, for 30 minutes at - 10 to OOC, and then for 30 minutes at room temperature. To the reaction mixture was added water (30 ml.), and the mixture was stirred for 10 minutes. After a saturated aqueous sodium bicarbonate solution was added to the mixture in order to dissolve the precipitates, the aqueous layer was separated.

To the aqueous layer was added ethyl acetate, and the mixture was adjusted to pH 2 with 2N hydrochloric acid, and then the ethyl acetate layer was separated.

The remaining aqueous layer was further extracted with ethyl acetate. The ethyl acetate layers were combined together, washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate and then concentrated. Thus obtained crystalline residue was pulverized in diethyl ether, collected by filtration and then dried to give yellow crystalline powder of 2 - methyl - 7 - [2 - (2 - formylaminothiazol - 4 - yl)glyoxylamido] - 3 - cephem - 4 - carboxylic acid, which can be represented as 2 - methyl - 7 - [2 - (2 - formylimino - 2,3 - dihydrothiazol - 4 - yl)glyoxylamido] - 3 - cephem - 4 - carboxylic acid, (3.81 g.).

I.R Spectrum (Nujol) 3475, 3315, 3200, 1788, 1655, 1620, 1530, 1293, 1240 1185 cm-' N.M.R. Spectrum (de-dimethylsulfoxide, ) 1.48 (3H, d, J=7Hz) 3.7.17 (1H, m) 5.21 (1H, d, J=5HZ) 5.96 (1H, d, J=5Hz) 6.63 (1H, d, J=6Hz) 8.44 (1H, s) 8.62 (1H, s) Example 4.

To dimethylformamide (6.42 g.) was added dropwise phosphorus oxychloride (12.5 g.) over 20 minutes with stirring under cooling to 5 to 100C, and the mixture was stirred for 30 minutes at 400C, and then ethyl acetate (200 ml.) was added thereto with vigorous stirring. After the mixture was cooled to 3"C, 2 - methoxyimino - 2 - (2 - formylaminothiazol - 4 - yl)acetic acid (syn isomer), which can be represented as 2 - methoxyimino - 2 - (2 - formylimino - 2,3 - dihydrothiazol - 4yl)acetic acid (syn isomer), (18.34 g.) was added thereto, and then the mixture was stirred for 40 minutes at 3 to 5"C. Thus obtained solution was added to a solution, which was prepared by stirring a mixture of 2 - methyl - 7 - amino - 3cephem - 4 - carboxylic acid (17.1 g.) and trimethylsilylacetamide (84 g.) in ethyl acetate (300 ml.) for 1 hour at room temperature, with vigarous stirring under cooling to -250C. The mixture was stirred for 1 hour at -20 to --1SOC and for 30 minutes at - 10 to -50C. To the mixture was added water (200 ml.) at room temperature, and the mixture was further stirred for 20 minutes at the same temperature. After a saturated aqueous sodium bicarbonate solution was added to the mixture in order to dissolve the precipitates, the aqueous layer was separated. To the aqueous layer was added ethyl acetate, and the mixture was adjusted to pH 2 with 2N hydrochloric acid, and then the ethyl acetate layer was separated. The remaining aqueous layer was further extracted with ethyl acetate. The ethyl acetate layers were combined together, washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate, treated with an activated charcoal and then concentrated. Thus obtained crystalline residue was pulverized in diethyl ether, collected by filtration and then dried to give white crystals of 2 - methyl - 7 - [2 - methoxyimino - 2 - (2formylaminothiazol - 4 - yl)acetamido] - 3 - cephem - 4 - carboxylic acid (syn isomer), which can be represented as 2 - methyl - 7 - [2 - methoxyimino - 2 - (2formylimino - 2,3 - dihydrothiazol - 4 - yl)acetamido] - 3 - cephem - 4 - carboxylic acid (syn isomer), (32.2 g.). This compound was recrystallized from methanol to give white crystals of the pure object compound, mp 174 to 2040C (dec.).

I.R Spectrum (Nujol) 3270, 1780, 1655, 1285, 1040 cm-1 N.M.R. Spectrum (de-dimethylsulfoxide, ) 1.44 (3H, d, J=7Hz) 3.68-4.12 (1H, m) 3.90 (3H, s) 5.14 (1H, d, J=5Hz) 5.90 (1H, d, J=SHz) 6.56 (1H, d, J=6Hz) 7.40 (1H, s) 8.50 (1H, s) Similarly, the following compounds were obtained.

1) 2 - Methyl - 7 - [2 - hydroxy - 2 - (2 - aminothiazol - 4 - yl)acetamidoj - 3 cephem - 4 - carboxylic acid hydrochloride, which can be represented as 2 - methyl 7 - [2 - hydroxy - 2 - (2 - imino - 2,3 - dihydrothiazol - 4 - yl)acetamidoj- 3 - cephem - 4 - carboxylic acid hydrochloride, mp > 250 C.

2) 2 - Methyl - 7 - [2 - methoxyimino - 2 - (2 - aminothiazol - 4 - yl)acetamido]- 3 - cephem - 4 - carboxylic acid (syn isomer), which can be represented as 2 methyl - 7 - [2 - methoxyimino - 2 - (2 - imino - 2,3 - dihydrothiazol - 4 - yl) acetamido] - 3 - cephem - 4 - carboxylic acid (syn isomer), dp > 2410C.

3) 2 - Methyl - 7 - [2 - (2 - aminothiazol - 4 - yl)glyoxylamido] - 3 - cephem - 4 carboxylic acid hydrochloride, which can be represented as 2 - methyl - 7 - [2 (2 - imino - 2,3 - dihydrothiazol - 4 - yl)glyoxylamido] - 3 - cephem - 4 carboxylic acid hydrochloride, mp > 270 C.

4) 2,2,2 - Trichloroethyl 2 - methyl - 7 - [2 - methoxyimino - 2 - (2 - amino- thiazol - 4 - yl)acetamido] - 3 - cephem - 4 - carboxylate (syn isomer), which can be represented as 2,2,2 - trichloroethyl 2 - methyl - 7 - [2 - methoxyimino 2 - (2 - imino - 2,3 - dihydrothiazol - 4 - yl)acetamido] - 3 - cephem - 4 carboxylate (syn isomer), mp 128 to 1490C (dec.).

5) Pivaloyloxymethyl 2 - methyl - 7 - [2 - methoxyimino - 2 - (2 - aminothiazol 4 - yl)acetamido] - 3 - cephem - 4 - carboxylate (syn isomer), which can be represented as pivaloyloxymethyl 2 - methyl - 7 - [2 - methoxyimino - 2 - (2 imino - 2,3 - dihydrothiazol - 4 - yl)acetamido] - 3 cephem - 4 - carboxylate (syn isomer), mp 165 to 1700C (dec.).

Example 5.

A suspension of 2 - methoxyimino - 2 - (2 - aminothiazol - 4 - yl)acetic acid (syn isomer), which can be represented as 2 - methoxyimino - 2 - (2 - imino - 2,3dihydrothiazol - 4 - yl)acetic acid (syn isomer), (26 g.) in ethyl acetate (250 ml.) was cooled to 5 C, and phosphorus oxychloride (25 g.) was added dropwise thereto with stirring under ice-cooling, and then the mixture was stirred for 30 minutes at 4 to 6"C. To the mixture was added dropwise a solution of trimethylsilylacetamide (22 g.) in ethyl acetate (20 ml.) with stirring under ice-cooling, and the mixture was stirred for 30 minutes at 4 to 60C, and then phosphorus oxychloride (25 g.) was further added thereto with stirring under ice-cooling. The mixture was stirred for 15 minutes at the same temperature, and dimethylformamide (10.6 g.) was added dropwise thereto at the same temperature. The mixture was stirred for 40 minutes at the same temperature, and the resulting clear solution was cooled to - 100C. On the other hand, to a solution of 2 - methyl - 7 - amino - 3 - cephem - 4 - carboxylic acid (23.9 g.) in a solution of sodium bicarbonate (25 g.) and water (400 ml.) was added acetone (300 ml.), and the mixture was cooled to -50C. To the mixture was added dropwise the above prepared clear solution at -5 to 0 C, and then the mixture was stirred for 2 hours, all the while the mixture was kept to pH 6 with 15% aqueous sodium bicarbonate solution. Insoluble materials were filtered off, and the aqueous layer was separated. The aqueous layer was adjusted to pH 3 with 20% hydrochloric acid, and precipitated crystals were collected by filtration, washed with water and acetone in turn and then dried under reduced pressure to give 2 - methyl7 - [2 - methoxyimino - 2 - (2 - aminothiazol - 4 - yl)acetamido] - 3 - cephem - 4carboxylic acid (syn isomer), which can be represented as 2 - methyl - 7 - [2 - methoxyimino - 2 - (2 - imino - 2,3 - dihydrothiazol - 4 - yl)acetamido] - 3 - cephem- 4 - carboxylic acid (syn isomer), (39.4 g.). This object compound was identified with the object compound prepared in Example 6 by IR and NMR determination.

The sodium or ammonium salt of this object compound can be obtained by a conventional manner, and physical properties of each compound are as follows.

1 y Sodium salt, powder.

IR Spectrum (Nujol): 1770, 1660, 1560, 1500 cm NMR Spectrum (d6-dimethylsulfoxide, 8) 1.37 (3H, d, J=7.0 Hz) 3.64 (1H, m) 3.84 (3H, s) 4.97 (1H, d, J=5.0 Hz) 5.74 (1H, m) 6.21 (1H, d, J=6.0 Hz) 6.70 (1H, s) 7.30 (2H, m) 9.63 (1H, m) 2) Ammonium salt, powder.

IR Spectrum (Nujol): 1775, 1660, 1580, 1530 cm' NMR Spectrum (dG-dimethylsulfoxide, #) 1.37 (3H, d, J=7.0 Hz) 3.64 (1H, m) 3.83 (3H, s) 4.99 (1H, d, J=5.0 Hz) 5.8 (5H, m) 6.17 (1H, d, J=6.0 Hz) 6.87 (1H, s) 7.27 (2H, m) 9.55 (1H, m) Example 6.

To a solution of sodium acetate (11.6 g.) in water (43 ml) was added 2-methyl 7-[2-methoxyimino - 2 - (2 - trifluoroacetylaminothiazol - 4 - yl)acetamido] - 3cephem - 4 - carboxylic acid (syn isomer), which can be represented as 2 - methyl7 - [2 - methoxyimino - 2 - (2 - trifluoroacetylimino - 2,3 - dihydrothiazol - 4 - yl)- acetamido] - 3 - cephem - 4 - carboxylic acid (syn isomer), (2.1 g.) with stirring, and the mixture was adjusted to pH 6 with 5% aqueous sodium bicarbonate solution.

The mixture was stirred overnight at room temperature. After the reaction, the reaction mixture was adjusted to pH 2.8 to 3 with 10% hydrochloric acid and then cooled. The precipitates were collected by filtration and then dried to give 2 - methyl7 - [2 - methoxyimino - 2 - (2 - aminothiazol 4 - yl)acetamido] - 3 - cephem - 4carboxylic acid (syn isomer), which can be represented as 2 - methyl - 7 - [2methoxyimino - 2 - (2 - imino - 2,3 - dihydrothiazol - 4 - yl)acetamido] - 3cephem - 4 - carboxylic acid (syn isomer), (1.1 g.), dp > 2410C. The same object compound (0.25 g.) was further obtained from the filtrate by a conventional manner.

I.R Spectrum (Nujol) 3470, 3320, 3190, 2380, 1783, 1690, 1655, 1622, 1530 cm'-' N.M.R. Spectrum (dG-dimethylsulfoxide, ) 1.44 (3H, d, J=8Hz, 2--CH,) 3.7-4.0 (1H, m, 2-H) 3.84 (3H, s, OCH3) 5.12 (1H, d, J=6Hz, 6-H) 5.89 (1H, dd, J=6 and 8Hz, 7-11) 6.57 (1H, d, J=7Hz, 3-H) 6.77 (1H, s, 5-H on thiazole ring) 9.62 (1H, d, J=8Hz, 7-CONH) Example 7.

To a suspension of 2 - methyl - 7 - [2 - (2 - formylaminothiazol - 4 - yl)glyoxylamido] - 3 - cephem - 4 - carboxylic acid, which can be represented as 2 - methyl - 7 - [2 - (2 - formylimino - 2,3 - di hydrothiazol - 4 - yl)glyoxylamido]- 3 - cephem - 4 - carboxylic acid, (3.0 g.) in methanol (60 ml.) was added dropwise phosphorus oxychloride (2.55 g.) under ice-cooling and stirring, and the mixture was stirred for 3.5 hours at the same temperature and then for 30 minutes at room temperature. After the reaction, the reaction mixture was poured into diethyl ether (400 ml.). The precipitates were collected by filtration, washed with diethyl ether and then dried to give 2 - methyl - 7 - [2 - (2 - aminothiazol - 4 - yl)glyoxylamido]- 3 - cephem - 4 - carboxylic acid hydrochloride, which can be represented as 2-methyl7 - [2 - (2 - imino - 2,3 - dihydrothiazol - 4 - yl)glyoxylamido] - 3 - cephem - 4carboxylic acid hydrochloride (2.2 g.), mp > 2700C.

I.R. Spectrum (Nujol) 1770, 1700 (shoulder), 1665, 1624, 1515 cm-1 N.M.R. Spectrum (d,;-dimethylsulfoxide, ) 1.44 (3H, d, J=7Hz, 2--CH3) 3.6--4.1(1H, m, 2-H) 5.15 (1H, d, J=SHz, 6-H) 5.82 (1H, dd, J=5 and 8Hz, 7-H) 6.58 (1H, d, J=6Hz, 3-11) 8.17 (1H, s, S--H on thiazole ring) 9.87 (1H, d, J=8Hz, 7-CONH) Example 8.

To a suspension of 2 - methyl - 7 - [2 - methoxyimino - 2 - (2 - formylaminothiazol - 4 - yl)acetamido] - 3 - cephem - 4 - carboxylic acid (syn isomer), which can be represented as 2 - methyl - 7 - [2 - methoxyimino - 2 - (2 - formylimino2,3 - dihydrothiazol - 4 - yl)acetamido] - 3 - cephem - 4 - carboxylic acid (syn isomer), (9.0 g.) in methanol (90 ml.) was added concentrated hydrochloric acid (2.12 ml.) with stirring at room temperature, and the mixture was stirred for 7 hours at the same temperature. To the reaction mixture was gradually added diethyl ether till crystals started to precipitate. The mixture was allowed to stand for 30 minutes, and the precipitated crystals were collected by filtration, washed with diethyl ether and then dried to give white crystals of 2 - methyl - 7 - [2 - methoxyimino - 2 - (2aminothiazol - 4 - yl)acetamido] - 3 - cephem - 4 - carboxylic acid hydrochloride (syn isomer), which can be represented as 2 - methyl - 7 - [2 - methoxyimino - 2 (2 - imino - 2,3 - dihydrothiazol - 4 - yl)acetamidoj - 3 - cephem - 4 - carboxylic acid hydrochloride (syn isomer) (7.9 g.).

The remaining filtrate was concentrated till the total volume became half. To the concentrated filtrate was gradually added diethyl ether till crystals started to precipitate, and the mxture was allowed to stand for 1 hour. The precipitated crystals were collected by filtration, washed with diethyl ether and then dried to give further the same object compound (0.5 g.).

I.R. Spectrum (Nujol) 3300, 3295, 1780, 1720, 1660, 1630, 1300 cam~' N.M.R. Spectrum (d6-dimethylsulfoxide, 8) 1.44 (3H, d, J=7Hz) 3.70-4.14 (1H, m) 3.94 (3H, s) 5.10 (1H, d, J=SHz) 5.84 (1H, d, J=5Hz) 6.39 (1H, d, J=6Hz) 6.94 (1H, s) To a suspension of 2 - methyl - 7 - [2 - methoxyimino - 2 - (2 - aminothiazol4 - yl)acetamido] - 3 - cephem - 4 - carboxylic acid hydrochloride (syn isomer), which can be represented as 2 - methyl - 7 - [2 - methoxyimino - 2 - (2 - imino2,3 - dihydrothiazol - 4 - yl)acetamido] - 3 - cephem - 4 - carboxylic acid hydrochloride (syn isomer), (7.7 g.) in water (77 ml.) was added a saturated aqueous sodium bicarbonate solution (44 ml.). Thus obtained solution was adjusted to pH 3 with 1N hydrochloric acid and then allowed to stand for 1 hour at cold place. The precipitated crystals were collected by filtration, washed with water and then dried to give white powder of 2 - methyl - 7 - [2 - methoxyimino - 2 - (2 - aminothiazol4 - yl)acetamido] - 3 - cephem - 4 - carboxylic acid (syn isomer), which can be represented as 2 - methyl - 7 - [2 - methoxyimino - 2 - (2 - imino - 2,3 - dihydrothiazol - 4 - yl)acetamido] - 3 - cephem - 4 - carboxylic acid (syn isomer) (6.67 g.), mp 196 to 2400C (dec.).

I.R. Spectrum (Nujol) 3470, 3310, 3200, 1790, 1655, 1620, 1530, 1295, 10SS cm~ N.M.R. Spectrum (d6-dimethylsulfoxide, ) 1.48 (3H, d, J=8Hz) 3.63-4.08 (1H, m) 3.84 (3H, s) 3.10 (1H, d, J=SHz) 5.84 (1H, d, J=SHz) 6.54 (1H, d, J=6Hz) 6.72 (1H, s) Similarly, the following compounds were obtained.

1) 2 - Methyl - 7 - [2 - hydroxy - 2 - (2 - aminothiazol - 4 - yl)acetamido] - 3 cephem - 4 - carboxylic acid hydrochloride, which can be represented as 2-methyl 7 - [2 - hydroxy - 2 - (2 - imino - 2,3 - dihydrothiazol - 4 - yl)acetamido] - 3 - cephem - 4 - carboxylic acid hydrochloride, mp > 2SOOC.

2) 2,2,2 - Trichloroethyl 2 - methyl - 7 - [2 - methoxyimino - 2 - (2 - amino thiazol - 4 - yl)acetamido] - 3 - cephem - 4 - carboxylate (syn isomer), which can be represented as 2,2,2 - trichloroethyl 2 - methyl - 7 - [2 - methoxyimino 2 - (2 imino - 2,3 - dihydrothiazol - 4 - yl)acetamido] - 3 - cephem - 4 - carb oxylate (syn isomer), mp 128 to 1490C (dec.).

3) 2,2,2 - Trichloroethyl 2 - methyl - 7 - [2 - hydroxyimino - 2 - (2 - amino thiazol - 4 - yl)acetamido] - 3 - cephem - 4 - carboxylate (syn isomer), which can be represented as 2,2,2 - trichloroethyl 2 - methyl - 7 - [2 - hydroxyimino 2 - (2 - imino - 2,3 - dihydrothiazol - 4 - yl)acetamido] - 3 - cephem - 4 carboxylate (syn isomer), mp 175 to 178"C (dec.).

Example 9.

To a suspension of 2 - methyl - 7 - [2 - (2 - aminothiazol - 4 - yl)glyoxyl- amido] - 3 - cephem - 4 - carboxylic acid hydrochloride, which can be represented as 2 - methyl - 7 - [2 - (2 - imino - 2,3 - dihydrothiazol - 4 - yl)glyoxylamido]- 3 - cephem - 4 - carboxylic acid hydrochloride, (3.80 g.) in methanol (70 ml.) was added 1N sodium hydroxide aqueous solution (18.8 ml.) under ice-cooling and stirring. To the mixture was added sodium borohydride (0.13 g.) over 20 minutes under ice-cooling and stirring and the mixture was stirred for 30 minutes at the same temperature. After the reaction, methanol was distilled off from the reaction mixture. To the residue was added cold water (60 ml.), and the mixture was washed with ethyl acetate, adjusted to pH 2 with 10% hydrochloric acid and then filtered.

The filtrate was subjected to column chromatography (non-ionic adsorption resin, Diaion HP 20 prepared by Mitsubishi Chemical Industries) and the column was washed with water and then eluted with 10% aqueous isopropyl alcohol solution. The eluates containing the object compound were collected and then lyophilized to produce pale yellow powder (1.80 g.). To the powder were added methanol (10 ml.) and 33% hydrochloric acid (0.5 g.) in turn, and thus obtained solution was subjected to column chromatography using activated carbon (2.0 g.) and then the column was eluted with methanol. The eluates containing the object compound were collected and then the solvent was distilled off under reduced pressure. The residue was washed with ethyl acetate and then dried to give 2 - methyl - 7 - [2 - hydroxy - 2 - (2aminothiazol - 4 - yl)acetamido] - 3 - cephem - 4 - carboxylic acid hydrochloride, which can be represented as 2 - methyl - 7 - [2 - hydroxy - 2 - (2 - imino - 2,3dihydrothiazol - 4 - yl)acetamido] - 3 - cephem - 4 - carboxylic acid hydrochloride, (1.10 g.), mp > 250 C.

I.R. Spectrum (Nujol) 3000-3400, 1775, 1690, 1630, 1523 cm'l N.M.R. Spectrum (d-dimethylsulfoxide, ) 1.48 (3H, d. J--8Hz, 2-CH3) 3.5-4.1 (1H, m, 2-H) 3.09 (1H, d, J=5Hz, 6-H) 5.17 (s) and 5.19 (s)

(Total: 1H) 5.78 (1H, dd, J=5 and 9Hz, 7-H) 6.54 (1H, d, J=6Hz, 3-H) 6.76 (1H, s, 5--H on thiazole ring) 8.73 (d, J=9Hz) and 8.81 (d, J=9Hz) (7-CONH) (Total: 1H) Example 10.

To a suspension of 2 - methyl - 7 - [2 - (2 - formylaminothiazol - 4 - yl)glyoxylamido] - 3 - cephem - 4 - carboxylic acid, which can be represented as 2methyl - 7 - [2 - (2 - formylimino - 2,3 - dihydrothiazol - 4 - yl)glyoxylamido] - 3cephem - 4 - carboxylic acid, (792 mg.) in water (20 ml.) was added sodium bi carbonate (168 mg.) with stirring. To thus obtained solution were added sodium acetate trihydrate (272.2 mg.) and O-methylhydroxylamine hydrochloride (334 mg.), and the mixture was stirred for 2 hours at 48 to 300 C. After cooling the reaction mixture, a saturated aqueous sodium bicarbonate solution (10 ml.) and ethyl acetate (1S ml.) were added thereto in order to dissolve the precipitated insoluble material.

The aqueous layer was separated, washed with ethyl acetate, adjusted to pH 1 with 2N hydrochloric acid and then extracted with ethyl acetate. The ethyl acetate extract was washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate and then concentrated. The residue was pulverized in diethyl ether, collected by filtration and then dried to give 2 - methyl - 7 - [2 - methoxyimino - 2 - (2formylaminothiazol - 4 - yl)acetamido] - 3 - cephem - 4 - carboxylic acid (syn isomer), which can be represented as 2 - methyl - 7 - [2 - methoxyimino - 2 - (2formylimino - 2,3 - dihydrothiazol - 4 - yl) - acetamido] - 3 - cephem - 4 - carboxylic acid (syn isomer), (505 mg.). This compound was recrystallized from methanol to give white crystals of the pure object compound.

I.R. Spectrum (Nujol) 3270, 3200, 1775, 1650, 1530, 1280 cmo N.M.R. Spectrum (d6-dimethylsulfoxide, ) 1.44 (3H, d, J=7Hz) 3.504.00 (1H, m) 3.90 (3H, s) 5.12 (1H, d, J=SHz) 5.92 (1H, d, J=5Hz) 6.57 (1H, d, J=6Hz) 7.41 (1H, s) 8.31 (1H, s) Similarly, the following compounds were obtained.

1) 2 - Methyl - 7 - [2 - methoxyimino - 2 - (2 - aminothiazol - 4 - yl)acetamido] 3 - cephem - 4 - carboxylic acid (syn isomer), which can be represented as 2 methyl - 7 - [2 - methoxyimino - 2 - (2 - imino - 2,3 - dihydrothiazol - 4 - yl) acetamido] - 3 - cephem - 4 - carboxylic acid (syn isomer), dp > 241 C.

2) 2,2,2 - Trichloroethyl 2 - methyl - 7 - [2 - methoxyimino - 2 - (2 - amino- thiazol - 4 - yl)acetamido] - 3 - cephem - 4 - carboxylate (syn isomer), which can be represented as 2,2,2 - trichloroethyl 2 - methyl - 7 - [2 - methoxyimino 2 - (2 - imino - 2,3 - dihydrothiazol - 4 - yl)acetamido] - 3 - cephem - 4 carboxylate (syn isomer), mp 128 to 149"C (dec.).

Example 11.

To a solution of 2,2,2 - trichloroethyl 2 - methyl - 7 - (2 - hydroxyimino - 3oxo - 4 - bromobutyramido) - 3 - cephem - 4 - carboxylate (a mixture of syn and anti isomers) (0.51 g.) in ethanol (10 ml.) was added thiourea (0.068 g.), and the mixture was stirred for 1 hour at room temperature. The reaction mixture was concentrated under reduced pressure. To the residue were added ethyl acetate and water with stirring, and the ethyl acetate layer was separated. The remaining aqueous layer was adjusted to pH 7 and extracted with ethyl acetate. The ethyl acetate layer and extract were combined together, washed with water, dried over magnesium sulfate and then concentrated. The residue was pulverized in diethyl ether, collected by filtration and then dried to give pale brown powder of 2,2,2 - trichloroethyl 2methyl - 7 - [2 - hydroxyimino - 2 - (2 - aminothiazol - 4 - yl)acetamido] - 3cephem - 4 - carboxylate (syn isomer), which can be represented as 2,2 5.94 (1H, dd, J=5 and 9Hz) 6.64 (1H, s) 7.08 (2H, broad s) 9.47 (1H, d, J=9Hz) 11.28 (1H, s) Example 12.

To a mixture of 2,2,2 - trichloroethyl 2 - methyl - 7 - (2 - methoxyimino - 3oxo - 4 - bromobutyramido) - 3 - cephem - 4 - carboxylate (a mixture of syn and anti isomers) (0.94 g.) and ethanol (10 ml.) was added thiourea (0.12 g.), and the mixture was stirred for 40 minutes at room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was shaken with ethyl acetate and water. The ethyl acetate layer was separated, and the remaining aqueous layer was neutralized with sodium bicarbonate and then extracted with ethyl acetate. Thus obtained ethyl acetate layers were combined together, washed with water, dried over magnesium sulfate, treated with activated charcoal and then concentrated under reduced pressure. The residue was pulverized in diethyl ether, collected by filtration and then dried to give 2,2,2 - trichloroethyl 2 - methyl - 7 - [2 - methoxyimino2 - (2 - amino thiazol - 4 - yl)acetamido] - 3 - cephem - 4 - carboxylate (syn isomer), which can be represented as 2,2,2 - trichloroethyl 2 - methyl - 7 - [2methoxyimino - 2 - (2 - imino - 2,3 - dihydrothiazol - 4 - yl)acetamido] - 3cephem - 4 - carboxylate (syn isomer), (0.6 g.). This compound was subjected to column chromatography on silica gel using a mixed solvent of benzene, ethyl acetate and acetic acid (10:10:1) as a developer, and the eluates containing the object compound were collected, washed with water, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was pulverized in diethyl ether, collected by filtration and then dried to give pale brown powder of the purified object compound (syn isomer) (0.16 g.), mp 128 to 1490C (dec.).

I.R. Spectrum (Nujol) 3100--3500, 1785, 1735, 1675, 1620, 1530, 1280, 1218, 710 cm~ N.M.R. Spectrum (d6-dimethylsulfoxide, ) 1.45 (3H, d, J=7Hz) 3.82 (3H, s) 3.92 (1H, m) 5.05 (2H, s) 5.20 (1H, d, J=5Hz) 5.97 (1H, dd, J=5 and 9Hz) 6.73 (1H, s) 6.77 (1H, d, J=6Hz) 7.10 (2H, broad s) 9.65 (1H, d, J=9Hz) Similarly, the following compounds were obtained.

1) 2 - Methyl - 7 - [2 - methoxyimino - 2 - (2 - formylamino - thiazol - 4 - yl) acetamido] - 3 - cephem - 4 - carboxylic acid (syn isomer), which can be represented as 2 - methyl - 7 - [2 - methoxyimino - 2 - (2 - formylimino - 2,3 dihydrothiazol - 4 - yl)acetamido] - 3 - cephem - 4 - carboxylic acid (syn isomer), mp 174 to 204"C (dec.).

2) 2 - Methyl - 7 - [2 - methoxyimino - 2 - (2 - aminothiazol - 4 - yl)acetamido] 3 - cephem - 4 - carboxylic acid (syn isomer), which can be represented as 2 methyl - 7 - [2 - methoxyimino - 2 - (2 - imino - 2,3 - dihydrothiazol - 4 yl)acetamido] - 3 - cephem - 4 - carboxylic acid (syn isomer), dp > 2410C.

*3) Pivaloyloxymethyl 2 - methyl - 7 - [2 - methoxyimino - 2 - (2 - aminothiazol 4 - yl)acetamido] - 3 - cephem - 4 - carboxylate (syn isomer), which can be represented as pivaloyloxymethyl 2 - methyl - 7 - [2 - methoxyimino - 2 - (2 imino - 2,3 - dihydrothiazol - 4 - yl)acetamido] - 3 - cephem - 4 - carboxylate (syn isomer), mp 165 to 1700C (dec.).

Example 13.

To a solution of 2,2,2 - trichloroethyl 2 - methyl - 7 - [2 - hydroxyimino - 2 (2 - aminothiazol - 4 - yl)acetamido] - 3 - cephem - 4 - carboxylate (syn isomer), which can be represented as 2,2,2 - trichloroethyl 2 - methyl - 7 - [2 - hydroxyimino 2 - (2 - imino - 2,3 - dihydrothiazol - 4 - yl)acetamido] - 3 - cephem - 4 - carboxylate (syn isomer), (125 mg.) in dioxane (5 ml.) was added dropwise 0.1 M solution of diazomethane in diethyl ether till the starting compound disappeared.

After the reaction mixture was concentrated, the residue was pulverized in diethyl ether, collected by filtration and then dried to give brown powder of 2,2,2 - trichloroethyl 2 - methyl - 7 - [2 - methoxyimino - 2 - (2 - aminothiazol - 4 - yl)acetamido]3 - cephem - 4 - carboxylate (syn isomer), which can be represented as 2,2,2 - trichloroethyl 2 - methyl - 7 - [2 - methoxyimino - 2 - (2 - imino - 2,3 - dihydrothiazol - 4 - yl)acetamido] - 3 - cephem - 4 - carboxylate (syn isomer), (110 mg.), mp 128 to 149"C (dec.).

Similarly, the following compounds was obtained.

1) Pivaloyloxymethyl 2 - methyl - 7 - [2 - methoxyimino - 2 - (2 aminothiazol- 4 - yl)acetamido] - 3 - cephem - 4 - carboxylate (syn isomer), which can be represented as pivaloyloxymethyl 2 - methyl - 7 - [2 - methoxyimino - 2 - (2 imino - 2,3 - dihydrothiazol - 4 - yl)acetamido] - 3 - cephem - 4 - carboxylate (syn isomer), mp 165 to 1700C (dec.).

Example 14.

To a solution of 2,2,2 - trichloroethyl 2 - methyl - 7 - [2 - methoxyimino - 2 (2 - aminothiazol - 4 - yl)acetamido] - 3 - cephem - 4 - carboxylate (syn isomer), which can be represented as 2,2,2 - trichloroethyl 2 - methyl - 7 - [2 - methoxyimino2 - (2 - imino - 2,3 - dihydrothiazol - 4 - yl)acetamidoj - 3 - cephem - 4 - carboxylate (syn isomer), (0.1 g.) in tetrahydrofuran (2 ml.) and glacial acetic acid (0.25 ml.) was added zinc powder (0.1 g.) all at once with stirring at keeping the temperature below 25"C in an ice-bath and then the mixture was stirred for 1 hour at room temperature. To the reaction mixture was further added zinc powder (0.1 g.) and the mixture was stirred for 1 hour at the same temperature. The reaction mixture was filtered, and the insoluble material was washed with a small amount of tetrahydrofuran. After the filtrate and the washing were combined together, the solvents were distilled off. To the residue were added 5% aqueous sodium bicarbonate solution and ethyl acetate so that the aqueous layer became pH 7 to 8, and the mixture was filtered, and then the aqueous layer was separated. The aqueous layer was adjusted to pH 2 to 3 with 2N hydrochloric acid and then concentrated slightly. Thus obtained aqueous layer was subjected to column chromatography (non-ionic adsorption resin, Diaion HP 20 prepared by Mitsubishi Chemical Industries) and the column was washed with water and then eluted with 20% methanol and 40% methanol in turn.

The eluates containing the object compound were collected and then lyophilized to give white powder of 2 - methyl - 7 - [2 - methoxyimino - 2 - (2 - aminothiazol4 - yl)acetamido] - 3 - cephem - 4 - carboxylic acid (syn isomer), which can be represented as 2 - methyl - 7 - [2 - methoxyimino - 2 - (2 - imino - 2,3 - dihydrothiazol - 4 - yl)acetamido] - 3 - cephem - 4 - carboxylic acid (syn isomer), (0.015 g.), mp 230 to 235 OC (dec.).

Similarly, the following compound was obtained.

1) 2 - Methyl - 7 - [2 - methoxyimino - 2 - (2 - formylaminothiazol - 4 - yl) acetamido] - 3 - cephem - 4 - carboxylic acid (syn isomer), which can be represented as 2 - methyl - 7 - [2 - methoxyimino - 2 - (2 - formylimino - 2,3 dihydrothiazol - 4 - yl)acetamido] - 3 - cephem - 4 - carboxylic acid (syn isomer), mp 174 to 2040C (dec.).

2) 2 - Methyl - 7 - [2 - hydroxy - 2 - (2 - aminothiazol - 4 - yl)acetamido] - 3 cephem - 4 - carboxylic acid hydrochloride, which can be represented as 2 methyl - 7 - [2 - hydroxy - 2 - (2 - imino - 2,3 - dihydrothiazol - 4 yl)acet amido] - 3 - cephein - 4 -carboxylic acid hydrochloride, mp > 2500C Example 15.

To a suspension of 2 - methyl - 7 - [2 - methoxyimino - 2 - (2 - aminothiazol4 - yl)acetamido] - 3 - cephem - 4 - carboxylic acid (syn isomer), which can be represented as 2 - methyl - 7 - [2 - methoxyimino - 2 - (2 - imino - 2,3 - dihydrothiazol - 4 - yl)acetamido] - 3 - cephem - 4 - carboxylic acid (syn isomer), (4.8 g.) in water (48 ml.) was added dropwise 1N aqueous sodium hydroxide solution at the rate that the pH value of the mixture was not more than 7. The mixture was filtered and then lyophilized to give sodium 2 - methyl - 7 - [2 - methoxyimino - 2 - (2aminothiazol - 4 - yl)acetamido] - 3 - cephem - 4 - carboxylate (syn isomer), which can be represented as sodium 2 - methyl - 7 - [2 - methoxyimino - 2 - (2 - imino 2,3 - dihydrothiazol - 4 - yl)acetamido] - 3 - cephem - 4 - carboxylate (syn isomer), (4.8 g.), mp > 250 C.

This compound is suspended in dried dimethylformamide (20 ml.), and to the suspension was added iodomethyl pivalate (2.30 g.) with vigorous stirring under cooling to 3 to 50C, and then the mixture was stirred for 20 minutes at the same temperature. The reaction mixture was poured into a mixture of ethyl acetate (60 ml.) and ice-water (10 ml.), and the mixture was well shaken. The ethyl acetate layer was separated, washed with a saturated aqueous sodium bicarbonate solution, water and a saturated aqueous sodium chloride solution in turn. After the ethyl acetate layer was dried over magnesium sulfate, ethyl acetate was distilled off under reduced pressure.

The residual oil was pulverized in diethyl ether (25 ml.), collected by filtration and then dried to give pivaloyloxymethyl 2 - methyl - 7 - [2 - methoxyimino - 2 (2 - aminothiazol - 4 - yl)acetamido] - 3 - cephem - 4 - carboxylate (syn isomer), which can be represented as pivaloyloxymethyl 2 - methyl - 7 - [2 - methoxyimino2 - (2 - imino - 2,3 - dihydrothiazol - 4 - yl)acetamido] - 3 - cephem - 4 - carboxylate (syn isomer), (1.44 g.), mp 165 to 1700C (dec.).

I.R. Spectrum (Nujol) 3340, 1787, 1757, 1678, 1637, 1634, 1283, 1218, 1158, 1132, 1098, 1034, 996 cm-1 N.M.R. Spectrum (d6-dimethylsulfoxide, 3) 1.18 (9H, s) 1.47 (3H, d, J=7Hz) 3.64.1 (3H, s) 5.18 (1H, d, J=6Hz) 5.78-5.96 (3H, m) 6.70 (1H, d, J=6Hz) 6.76-6.88 (1H, s) 9.65 (1H, broad d, J=8Hz) WHAT WE CLAIM IS: 1. A compound of the formula:

wherein Rl is lower alkyl R2 is carboxy or a protected carboxy group; R3 is amino or a protected amino group and A is carbonyl, hydroxy (lower) alkylene, hydroxyimino (lower) alkylene or lower alkoxyimino (lower) alkylene, and pharmaceuticallv acceptable salts thereof.

2. The compound of claim 1, wherein R' is lower alkyl, R2 is carboxy or a protected carboxy group, R3 is amino or a protected amino group and A is carbonyl or hydroxy(lower)alkylene.

3. The compound of claim 2, wherein R1 is lower alkyl, R2 is carboxy or an esterified carboxy group, R3 is amino or acylamino and A is carbonyl or hydroxy(lower)alkylene.

4. The compound of claim 3, wherein R1 is lower alkyl, R2 is carboxy, lower alkoxycarbonyl which may have 1 to 3 halogen atom(s) or lower alkanoyloxy(lower) alkoxycarbonyl, Rfl is amino or lower alkanoylamino which may have 1 to 3 halogen atom(s) and A is carbonyl or hydroxy(lower)alkylene.

**WARNING** end of DESC field may overlap start of CLMS **.

Claims (30)

**WARNING** start of CLMS field may overlap end of DESC **. 2,3 - dihydrothiazol - 4 - yl)acetamido] - 3 - cephem - 4 - carboxylate (syn isomer), (4.8 g.), mp > 250 C. This compound is suspended in dried dimethylformamide (20 ml.), and to the suspension was added iodomethyl pivalate (2.30 g.) with vigorous stirring under cooling to 3 to 50C, and then the mixture was stirred for 20 minutes at the same temperature. The reaction mixture was poured into a mixture of ethyl acetate (60 ml.) and ice-water (10 ml.), and the mixture was well shaken. The ethyl acetate layer was separated, washed with a saturated aqueous sodium bicarbonate solution, water and a saturated aqueous sodium chloride solution in turn. After the ethyl acetate layer was dried over magnesium sulfate, ethyl acetate was distilled off under reduced pressure. The residual oil was pulverized in diethyl ether (25 ml.), collected by filtration and then dried to give pivaloyloxymethyl 2 - methyl - 7 - [2 - methoxyimino - 2 (2 - aminothiazol - 4 - yl)acetamido] - 3 - cephem - 4 - carboxylate (syn isomer), which can be represented as pivaloyloxymethyl 2 - methyl - 7 - [2 - methoxyimino2 - (2 - imino - 2,3 - dihydrothiazol - 4 - yl)acetamido] - 3 - cephem - 4 - carboxylate (syn isomer), (1.44 g.), mp 165 to 1700C (dec.). I.R. Spectrum (Nujol) 3340, 1787, 1757, 1678, 1637, 1634, 1283, 1218, 1158, 1132, 1098, 1034, 996 cm-1 N.M.R. Spectrum (d6-dimethylsulfoxide, 3) 1.18 (9H, s) 1.47 (3H, d, J=7Hz) 3.64.1 (3H, s) 5.18 (1H, d, J=6Hz) 5.78-5.96 (3H, m) 6.70 (1H, d, J=6Hz) 6.76-6.88 (1H, s) 9.65 (1H, broad d, J=8Hz) WHAT WE CLAIM IS:

1. A compound of the formula:

wherein Rl is lower alkyl R2 is carboxy or a protected carboxy group; R3 is amino or a protected amino group and A is carbonyl, hydroxy (lower) alkylene, hydroxyimino (lower) alkylene or lower alkoxyimino (lower) alkylene, and pharmaceuticallv acceptable salts thereof.

2. The compound of claim 1, wherein R' is lower alkyl, R2 is carboxy or a protected carboxy group, R3 is amino or a protected amino group and A is carbonyl or hydroxy(lower)alkylene.

3. The compound of claim 2, wherein R1 is lower alkyl, R2 is carboxy or an esterified carboxy group, R3 is amino or acylamino and A is carbonyl or hydroxy(lower)alkylene.

4. The compound of claim 3, wherein R1 is lower alkyl, R2 is carboxy, lower alkoxycarbonyl which may have 1 to 3 halogen atom(s) or lower alkanoyloxy(lower) alkoxycarbonyl, Rfl is amino or lower alkanoylamino which may have 1 to 3 halogen atom(s) and A is carbonyl or hydroxy(lower)alkylene.

5. The compound of claim 4,

wherein R1 is methyl, R2 is carboxy, R3 is amino or formylamino and A is carbonyl or hydroxymethylene.

6. The compound of claim 5, which is 2 - methyl - 7 - [2 - hydroxy - 2 - (2aminothiazol - 4 - yl)acetamido] - 3 - cephem - 4 - carboxylic acid or its hydrochloride.

7. The compound of claim 5, which is 2 - methyl - 7 - [2 - (2 - aminothiazol4 - yl)glyoxylamido] - 3 - cephem - 4 - carboxylic acid or its hydrochloride.

8. The compound of claim 5, which is 2 - methyl - 7 - [2 - (2 - formylaminothiazol - 4 - yl)glyoxylamido] - 3 - cephem - 4 - carboxylic acid.

9. The compound of claim 1, wherein R1 is lower alkyl, R2 is carboxy or a protected carboxy group, R3 is amino or a protected amino group and A is hydroxyimino (lower) alkylene or lower alkoxyimino (lower) alkylene.

10. The compound of claim 9, which is syn isomer.

11. The compound of claim 10, wherein R1 is lower alkyl, R2 is carboxy or an esterified carboxy group, R" is amino or acylamino and A is hydroxyimino(lower)alkylene or lower alkoxyimino(lower)alkylene.

12. The compound of claim 11, wherein R1 is lower alkyl, R2 is carboxy, lower alkoxycarbonyl which may have 1 to 3 halogen atom(s) or lower alkanoyloxy (lower) alkoxycarbonyl, R3 is amino or lower alkanoylamino which may have 1 to 3 halogen atom(s) and A is hydroxyimino (lower) alkylene or lower alkoxyimino (lower) alkylene.

13. The compound of claim 12, wherein R1 is methyl, R2 is carboxy, 2,2,2-trichloroethoxycarbonyl or pivaloyloxymethoxycarbonyl, R3 is amino, formylamino or trifluoroacetylamino and A is hydroxyiminomethylene or methoxyiminomethylene.

14. The compound of claim 13, which is 2 - methyl - 7 - [2 - methoxyimino2 - (2 - aminothiazol - 4 - yl)acetamido] - 3 - cephem - 4 - carboxylic acid (syn isomer) or its hydrochloride, sodium salt or ammonium salt.

15. The compound of claim 13, which is 2 - methyl - 7 - [2 - methoxyimino2 - (2 - formylaminothiazol - 4 - yl)acetamido] - 3 - cephem - 4 - carboxylic acid (syn isomer).

16. The compound of claim 13, which is 2 - methyl - 7 - [2 - methoxyimino2 - (2 - trifluoroacetylaminothiazol - 4 - yl)acetamido] - 3 - cephem - 4 - carboxylic acid (syn isomer).

17. The compound of claim 13, which is 2,2,2 - trichloroethyl 2 - methyl - 7 [2 - methoxyimino - 2 - (2 - aminothiazol - 4 - yl)acetamido] - 3 - cephem - 4carboxylate (syn isomer).

18. The compound of claim 13, which is pivaloyloxymethyl 2 - methyl - 7 - [2methoxyimino - 2 - (2 - aminothiazol - 4 - yl)acetamido] - 3 - cephem - 4 - carboxylate (syn isomer).

19. The compound of claim 13, which is 2,2,2 - trichloroethyl 2 - methyl - 7 [2 - hydroxyimino - 2 - (2 - aminothiazol - 4 - yl)acetamido] - 3 - cephem - 4carboxylate (syn isomer).

20. A process for the preparation of a compound of the formula:

wherein Rl is lower alkyl, R2 is carboxy or a protected carboxy group, Ra is amino or a protected amino group and A is carbonyl, hydroxy(lower)alkylene, hydroxyimino(lower)alkylene or lower alkoxyimino(lower)alkylene, or a salt thereof which comprises reacting a compound of the formula:

wherein R1 and R2 are each as defined above, or its reactive derivative at the amino group or a salt thereof, with a compound of the formula:

wherein R3 and A are each as defined above, or its reactive derivative at the carboxy group or a salt thereof.

21. A process for the preparation of a compound of the formula:

wherein R1 is lower alkyl, R2 is carboxy or a protected carboxy group and A is carbonyl, hydroxy(lower)alkylene, hydroxyimino(lower) alkylene or lower alkoxyimino(lower)alkylene, or a salt thereof which comprises subjecting a compound of the formula:

wherein Rl, R2 and A are each as defined above, and R3a is a protected amino group, or a salt thereof, to elimination reaction of the amino protective group.

22. A process for the preparation of a compound of the formula:

wherein R1 is lower alkyl, R2 is carboxy or a protected carboxy group and R" is amino or a protected amino group, or a salt thereof which comprises reducing a compound of the formula:

wherein R1, R2 and R3 are each as defined above, or a salt thereof.

23. A process for the preparation of a compound of the formula:

wherein R1 is lower alkyl, R2 is carboxy or a protected carboxy group, R3 is amino or a protected amino group and R4 is hydrogen or lower alkyl, or a salt thereof which comprises reacting a compound of the formula:

wherein R1, R2 and R3 are each as defined above, or a salt thereof, with a compound of the formula: H2N-OR4 wherein R4 is as defined above, or a salt thereof.

24. A process for the preparation of a compound of the formula:

wherein R1 is lower alkyl, Ra is carboxy or a protected carboxy group, R3 is amino or a protected amino group and R4 is hydrogen or lower alkyl, or a salt thereof which comprises reacting a compound of the formula:

wherein R1, R2 and R4 are each as defined above, and Y is a residue of an acid, or a salt thereof, with a compound of the formula: H2N-CS-R' wherein R3 is as defined above.

25. A process for the preparation of a compound of the formula:

wherein R1 is lower alkyl, R2 is a protected carboxy group, R3 is amino or a protected amino group and R4" is lower alkyl, or a salt thereof, which comprises reacting a compound of the formula:

wherein R1, R2" and R3 are each as defined above, or a salt thereof, with an alkylating agent.

26. A process for the preparation of a compound of the formula:

wherein R1 is lower alkyl, R is amino or a protected amino group and A is carbonyl, hydroxy(lower ) alkylene, hydroxyimino (lower) alkylene or lower alkoxyimino (lower) alkylene, or a salt therof, which comprises subjecting a compound of the formula:

wherein R1, R3 and A are each as defined above, and R2" is a protected carboxy group, or a salt thereof, to elimination reaction of the carboxy protective group.

27. A process for the preparaton of a compound of the formula:

wherein R1 is lower alkyl, R3 is amino or a protected amino group, Ra is an ester moiety of an esterified carboxy group represented by the formula: -COOR5 and A is carbonyl, hydroxy(lower)alkylene, hydroxyimino(lower)alkylene or lower alkoxyimino(lower)alkylene, or a salt thereof, which comprises subjecting a compound of the formula:

wherein R1, R" and A are each as defined above, or a salt thereof, to esterification reaction.

28. A pharmaceutical composition comprising a compound of claim 1 or pharmaceutically acceptable salt thereif in association with a pharmaceutically acceptable, substantially non-toxic carrier or excipient.

29. A method for producing a pharmaceutical composition which comprises mixing a compound of claim 1 or pharmaceutically acceptable salt thereof as an active ingredient with an inert carrier.

30. A method of treating infectious diseases in non-human animals by the administration of a compound as claimed in claim 1.