IE780518L - Cephem and cepham compounds - Google Patents

Description

46674 This invention relates to new cephem and cepham1 compounds. Wore particularly, it relates to new 7-substituted-3-cephem(or cepham)-4-carboxylic acid, its pharmaceutical^ . acceptable salt and pharmaceutically acceptable bioprecursor] thereof, which have antimicrobial activities, 1 and processes for preparation thereof, and to pharmaceutical composition comprising the same and methods of using the same prophylactically and therapeutically for i j treatment of infectious diseases in non-human animals. ii Si' ' Accordingly, the objects of this invention are ' ■ to provide new 7-substituted-3-cephem(or cepham)-4-carboxylic acid, its pharmaceutically acceptable salt and pharmaceutically acceptable bioprecursor thereof, which exhibit excellent antimicrobial activities against a wide variety of pathogenic microorganisms including Gram negative and Gram positive bacteria, j processes for preparation of the same, 1 pharmaceutical composition comprising one of the j same as an active ingredient, and ! / a method of using the same prophylactically and \. therapeutically for treatment of infectious diseases caused ® by pathogenic microorganisms in non-human animals. 4 6674 The cephem and cepham compounds provided by this invention can be represented by the formula (I) 1 The compound useful as an antimicrobial agent can be represented by the formula (I1):- 4 6674 R1-A-CONH & (I') wherein R* is thiadiazolyl or thiazolyl of the formula; in which in which Ru is as defined above, and 3 4 5 A, R , R and R are each as defined above.

On the other hand, the compound useful 5 as an intermediate for preparing the above compound (I1) can be represented by the formula (I") :- R^-A'-CONH r ' "3 (I * ') wherein R^ is haloacetyl, 10 4 R is hydroqen, halogen, lower alkyl or a group of SL 1 1 the formula :-0-R in which R is lower alkyl, A' is methylene or a group of the formula: 2 -C- in which R is as defined above, II N and S 2 0-R 3 5 R and R are each as defined above.

And further, it is to be noted that the compound (!') wherein R^ is thiazolyl of the formula;- m, J> ' < r6 "s" in which R is protected amino, R^ is a group of the formula: 7 7 5 -0-R in which R is hydrogen or acyl and/or R is functionally 2q modified carboxy is also useful as an intermediate for preparing the more active compound as explained below.

Accordingly, the more preferred active compound can be represented by the formula (I'•1) :— 4 -5- 46674 R1-A-CONH c (I'* ) COOH wherein is thiadiazolyl or thiazolyl of the formula: ■ and 2 3 4 R , R , R and A are each as defined above. a 5 The terms and definitions described in this specification and claims are illustrated as follows. a) Partial structure of the formula: R1-C-CO- I Lr2 is intended to mean both of the geometric formulae: R1-C-CO- and R1-C-CO- N-O-R2 R2—0-N 10 (S) The geometry of the formula (S) is referred to as "syn" and another formula (A) is referred to as " anti".

Accordingly, one isomer of the compound having the partial structure shown by the above formula (S) is 15 referred to as "syn isomer" and another isomer of the compound having the alternative one shown by the above formula (A) is referred to as "anti isomer", respectively. 46674 From the view point of structure-activity relationship, it is to be noted that a syn isomer of the compound (I') tends to be of much higher antimicrobial activity than the corresponding anti isomer, and accordingly the syn isomer ^ of the compound (I') is more preferable antimicrobial agent than the corresponding anti isomer in the prophylactic and therapeutic value. b) The thiazolyl group of the formula : ,«-G-(wherein R is as defined above) is well known 10 to lie in tautomeric relation with a thiazolinyl group of the formula : JO 6' (wherein R is imino or protected imino).

The tautomerism between the said thiazolyl and 15 thiazolinyl groups can be illustrated by the following equilibrium : 6 6' (wherein R and R are each as defined above).

Accordingly, it is to be understood that both of the said groups are substantially the same, and the 20 tautomers consisting of such groups are regarded as the same compounds, -7- 466*74 especially in the manufacturing chemistry. Therefore, both of the tautomeric forms of the compounds having such groups in their molecule are included in the scopc of this invention and designated inclusively with one expression "thiazolyl" and represented by the formula: R6j,sjF (wherein is as defined above) only for the convenient sake throughout this specification and claims. c) It is well known that the 3-hydroxy-3-cephem compound having the partial structure of the formula: r8- XI -OH 0^ " R5 lies in a tautomeric relation with the 3-oxo-cepham compound; of the formula: .S, m . e RS | cach of which is referred to as the enol- or keto-tautomer, and that the enol-tautomer is usually the stabilized one.

Accordingly, both of the compounds having such tautomeric structures are included within the same scope of the compound, and therefore, the structure and nomenclature of such tautomers are expressed inclusively with one expression of the stabilized enol tautomer, i.e. 3-hydroxy-3-cephem compound throughout this specification and claims.

In the above and subsequent descriptions of this specification, suitable examples and illustration of the various definitions which this invention intends to include within the scope thereof are explained in detail as follows. -8- 466 The term "lower" is used to intent! a group having 1 to 6 carbon atoms, unless otherwise provided.

"Thiadiazolyl" for R* may be 1,2,3-thiadiakolyl (e.g. J ,2, 3-thiadiazol-4-yl or 1', 2 , 3-thiadiazol-5-yl) ; 1.3,4-thiadiazolyl or 1,2,4-thiadiazolyl, preferably 1,2,3-thiadiiazolyl, and more preferably 1,2 , 3-thiadiazol-4-yl. 2 "Aliphatic hydrocarbon residue "for R may include a monovalent radical of a saturated or unsaturated, and ! ; straight, branched or cyclic aliphatic hydrocarbon, and particularly may include alkyl, alkenyl, alkynyl, cycloalkyl and the like, the details of which are explained below. i "AJkyl" may include a residue of straight or bronched alkane having 1 to 12 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, neopenty l, hexyl, heptyl, octyl, nonyl, dccyl, undecyl, dodecyl and the like, preferably lower alkyl, and more preferably the one having 1 to 4 carbon atoms.

"Alkenyl" may include a residue of a straight or branched alkene having up to 12 carbon atoms, preferably lower alkenyl such as vinyl, allyl, 1-propenyl, isopropenyl, butenyl, isobutenyl, pentenyl, hexenyl and the like, and more preferably the ones having up to 4 carbon atoms.

"Alkynyl" may include a residue of a straight or branched alkyne- having up to 12 carbon atoms, preferably lower alkynyl such.as ethynyl, propargyl, 1-propynyl, 3-butynyl, 2-butynyl, 4-pentynyl, 3-pentynyl, 2-pentynyl, 1-pentynyl, 5-hexynyl and the like, and more preferably the ones having up to 4 carbon atoms. 4 6674 f "Cycloalkyl" may include a residue of a cycloalkane having up to 8 carbon'atoms, preferably lower cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, and more preferably cyclohexyl.

These aliphatic hydrocarbon residues may be substituted with halogen atom(s), carboxy or esterified carboxy ' i group(s). Accordingly, "aliphatic hydrocarbon residue substituted with halogen atom(s), carboxy or esterified carboxy group(s)" can also be alternatively expressed as "halogen-substituted aliphatic hydrocarbon residue", "carboxy-substituted aliphatic hydrocarbon residue" and "esterified carboxy-substituted aliphatic hydrocarbon residue", respectively, which may include more particularly halo-alkyl, alkenyl, alkynyl and cycloalkyl; carboxy-alkyl, alkenyl, alkynyl and cycloalkyl; and esterified carboxy-alkyl, alkenyl, alkynyl and cycloalkyl, respectively.

Suitable examples of the "halogen" may include chlorine, bromine, iodine and fluorine; suitable examples of the "esterified carboxy" may be alkoxycarbonyl or the like; and preferred examples of the "alkyl", "alkenyl", "alkynyl", "cycloalkyl" and alkyl moiety of the "alkoxycarbonyl" are the corresponding "lower" ones as mentioned above.

Preferred examples of the "halo-alkyl, alkenyl, alkynyl and cycloalkyl" may be chloromethyl, bromomethyl, iodomethyl, fluoromethyl, trichloromethyl, trifluoromethyl, 2-chloroethyl, 1,2-dichlorocthyl, 2,2,2-trifluoroethyl, 3-chloropropyl, 4-iodobutyl, 5-fluoropentyl, 6-bromohexyl, 3-fluoroallyl, 3-chloropropargyl, 4-fluorocy.clohexyl, or the like. -10- 46674 Preferred examples of the "carboxy-alkyl, alkenyl, alkynyl and cycloalkyl" may be carboxymethy1,-1-carboxyethy1, 2-carboxyethyl , 1-carboxypropy 1, 3-cnrboxypropy.1 , 4-carboxy-butyl, 5-carboxypcntyl, 6-carboxyhexyl, 1 carboxyisopropyl, 1-ethyl-1-carboxyethy1, 2-mcth/l- 2-carboxypropyl, 3-carboxyallyl, 3-carboxypropargy1, 4-carboxycyclohexyl, or the like.

Preferred examples of the "esterified carboxyalkyl, alkenyl, alkynyl and cycloalkyl" may be lower alkoxycarbonyl-(lower)alkyl (e.g. methoxycarbonylmethyl, ethoxycaTbonylmethy1, propoxycarbonylmethyl, t-butoxycarbony linethyl, 2-ethoxycarbonyl-ethyl, 2-ethoxycarbonylpropyl, 4-ethoxycarbonylbutyl, 1-t-butoxycarbonylisopropyl, 1-t-butoxycarbonyl-1-methyl-propyl, 4-t-butoxycarbonylbutyl, 5-t-butoxycarbonylpentyl, 6-butoxycarbonylhexyl, etc.), lower alkoxycarbonyl(lower)-alkenyl (e.g. 3-methoxycarbonylally1, etc.), lower alkoxycarbonyl (lower) alkynyl (e.g. 3-methoxycarbonylpropargyl, etc.), lower alkoxycarbonyl(lower)cycloalkyl (e.g. 4-methoxycarbonyl-cyclohexyl, etc.) or the like, and more preferably lower alkoxycarbonylinethyl as exemplified above.

I "Lower alkyl." for and R^ is to be referred to those as exemplified in the term of the aliphatic 2 hydrocarbon residue for R , preferably may be the ones having up to 4 carbon atoms and more preferably methyl.

"Halogen" for R^ may be chlorine, bromine, iodine or fluorine, and preferred one is chlorine or bromine. 7 "Acyl" for R may be lower alkanoyl (e.g. forinyl, -11- 46674 acetyl, propionyl, butyryl, isobutyryl, isovaleryl, pivaroyl, etc.)j aroyl (e.g. benzoyl, etc.), lower alkanesulfonyl (e.g. mesyl, ethanesulfonyl, 1-methylethanesulfonyl, propanesulfonyl, butanesulfonyl, etc.), arenesulfonyl (e.g. benzenesulfonyl, tosyl, etc.) or the like.

"Protective group" in the "protected amino" for may be the conventional N-protective group such as substituted or unsubstituted ar(lower)alkyl (e.g. benzyl, benzhydryl, trityl, 4-methoxybenzyl, 3,4-dimcthoxybenzyl, etc.), halo-(lower)alkyl (e.g. trichloromethyl, trichlorocthy1, trifluoro-methyl, etc.), tetrahydropyranyl, substituted phcuylthio, substituted alkylideno, substituted arnlkylidene, substituted cycloalkylidene, acyl, or the like.

Suitable acyl for the protective group may be substituted or unsubstituted lower alkanoyl (e.g. formyl, acetyl, chloroacetyl, trifluoroacetyl, etc.), substituted or unsubstituted lower alkoxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, 1-cyclopropylethoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, t-butoxycarbonyl, pentyloxycarbonyl, t-pentyloxy-carbonyl, hexyloxycarbonyl, trichloroethoxycarbonyl, 2-pyridyl-methoxycarbonyl, etc.), substituted or unsubstituted ar(lower)-alkoxycarbonyl (e.g. benzyloxycarbonyl, benzhydryloxycarbonyl, 4-nitrobenzyloxycarbonyl, etc.), lower cycloalkoxycarbonyl (e.g. cyclopentyloxycarbonyl, cyclohexyloxycarbonyl, etc.), 8-quinolyl-oxycarbonyl, succinyl, phthaloyl, or the like.

And further, the reaction product of a silicon, boron, aluminium or phosphorus compound with the amino group may also be included in the protective group. Suitable examples of such compounds may be trimethylsilyl chloride, 46674 trimethoxysilyl chloride, boron trichloride, butoxyboron dichloride, aluminum trichloride,diethoxy aluminum chloride, phosphorus dibromide, phenylphosphorus dibromide, or the like.

"Functionally modified carboxy" for R** may be an ester, amide or the like.

Suitable examples of the ester may be alkyl ester (e.g. methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, t-butyl ester, pentyl ester, t-pentyl ester, hexyl ester, heptyl ester, octyl ester, 1-cyclopropylethyl ester, etc.); alkenyl ester (e.g. vinyl ester, allyl ester, etc.); alkynyl ester (e.g. ethynyl ester, propynyl ester, etc.); alkoxyalkyl ester (e.g. metlioxymethyl ester, cthoxymethyl ester, isopropoxymethyl ester, 1-methoxyethyl ester, 1-ethoxyethyl ester, etc.); alkylthioalkyl ester (e.g. methylthiomcthyl ester, ethylthiomethyl ester, ethylthioethyl ester,isopropylthio-methyl ester, etc.); haloalkyl ester (e.g. 2-i.odoethyl ester, 2,2,2-trichloroethy1 ester, ctc.) ; alkanoyloxyalkyl ester (e.g. acetoxymethyl ester, propionyloxyinethyl ester, butyryloxyinethyl ester, valeryloxy-methyl ester, pivaloyloxymethyl ester, hexnnoyloxymethyl ester, 2-acetoxyethyl ester, 2-propionyloxyethyl ester, palmi toyloxymethyl ester, etc.); alkanesulfonylalkyl ester (e.g. mesylmethyl ester, 2-mesylethyl ester, etc.); -13- 46674 substituted or unsubstituted aralkyl ester (e.g. benzyl ester, 4-methoxybenzyl ester, 4-ni.trobenzyl ester, phenethyl ester, trityl ester, benzhydryl ester, bis(methoxy-phenyl)methyl ester, 3,4-dimethoxybenzyl ester, 4-hydroxy-3,5-di-t-butylbenzyl ester, etc.); substituted or unsubstituted aryl ester (e.g. phenyl ester, tolyl ester, t-butylphenyl ester, xylyl ester, mesityl ester, cumenyl ester, salicyl ester, etc.); an ester with a silyl compound such as trialkylsilyl compound, dialkylalkoxysilyl compound or trialkoxysilyl compound, for example, trialkylsilyl ester (e.g. triinethyi silyl ester, triethylsilyl ester, etc.), dialkylalkoxy silyl ester (e.g. dimethylmethoxysilyl ester, dimethyletiioxy-■; silyl ester, diethylmethoxysilyl ester, etc.) or trialkoxysilyl ester (e.g. trimethoxysilyl ester, triethoxysilyl ester, etc.) or the like.

With regard to the terms "protected amino" for and "functionally modified carboxy" for R^, it is to be understood that these groups bear the meaning not only in synthetic manufacture of the object compound by chemical process(es), but also in physiological and pharmaceutical properties of the. object compound per se.

That is, in the meaning of the synthetic manufacture, free amino group for R^ and/or free carboxy group for R^ may be transformed into the "protected amino" and/or "functionally modified carboxy" as mentioned above before conducting the process(es) for preventing any possible undesired side reaction(s), and the "protected amino" and/or "functionally modified carboxy" group in the resultant compound may be -14- 46674 transformed into free amino and/or carboxy group after the reaction is conducted. This will be apparent from the explanation of the processes in the following.

On the other hand, in the meaning of the physiological and pharmaceutical properties of the object compound, the compound bearing the "protected amino"and/or "functionally modified carboxy" group is optionally used for improving the properties such as solubility, stability, absorbability, toxicity of the particularly active object compound bearing the free amino and/or carboxy group.

Suitable "pharmaceutically acceptable salt" of the object compound (I') may be conventional non-toxic salt, and may include a salt with an inorganic base or acid, for example, a metal salt such as an alkali metal salt (e.g. sodium salt, potassium salt, etc.) and an alkaline earth metal salt (e.g. calcium salt, magnesium salt, etc.), ammonium salt, an inorganic acid salt (e.g. hydrochloride, hydrobromide, sulfate, phosphate, carbonate, bicarbonate, etc.), a salt with an organic base or acid, for example, an amine salt (e.g. trimethylamine salt, triethylamine salt, pyridine salt, procaine salt, picoline salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, N-methylglucamine salt, diethanolamine salt, triethanolamine salt, tris-(hydroxymethylamino)methane salt, phenethylbenzylamine salt, etc.), an organic carboxylic or sulfonic acid salt (e.g. acetate, maleate, lactate, tartrate, mesylate, benzene-sulfonate, tosylate, etc.), a basic or acidic amino acid salt (e.g. arginine salt, aspartic acid salt, glutamic acid salt, lysine salt,serine salt, etc.) and the like.

It is well known in the pharmaceutical field that -15- 4667 4 the active drug, when it has any undesired physiological or pharmaceutical property such as solubility, stability, absorbability, etc., is converted into modified derivative thereof for improving such undesired properties, and then said derivative, upon administration to a patient, exhibits the active efficacy by being converted in the body to the parent drug. In this meaning, the term "pharmaceutically acceptable bioprecursor" used throughout this specification and claim is intended to fundamentally mean all of the modified derivatives, which have structural formulae different from those of the active compounds of this invention, but are converted in the body to the active compounds of this invention upon administration, and also to mean the derivatives which are sometimes derived physiologically from the compounds of this invention in the body and exhibit antimicrobial efficacy. -16- The compounds (I) of this invention can be prepared by processes as shown in the following schcme Process A : N-Acylation 'Yr3 r1'A'C00H ("1} R'-A-coniW- //-NNf R* R" (H) Process B : C-Nitrosation (I) Rv -CH^CONIH f S>- R3 Nitrosating R?-C-CONH"]—-f" 2 1 a£v c?u 0 (lb) R* Process C : Etherification R1-Jp-CONH-j ( SY"R3 N Jr- NY^~R4 OH 0 R5 (V) Etherifying R -C-CONH- i£ent ^ « 1 - - \ j 0-R ^ N R* (Ic) Process D : Thiazole ring formation -C-CONJI-1 ^ b ? 'S^_R3 R6-i-NII2 (VI) S 0-R' R~ ■ CONH R Xjl o S i-R»° (VI) (Id) -17- 10 15 25 30 4 6 6 7 4 Process E : Elimination of amino-protective group ft "-jf-C-CONH 0-R— I M-Ul RS (VIII) Ue) Reductive formation of 3-hydroxycepha,,, ^Rl-C-CONH-p-i-Ss / h o^-~Ny^~OH o-R2 r5. i; (IX) (if) £l°?Fss q : O-Acylation * I .( -IflkllT ✓ V Rg "OH (X) Ra-C-C0NH-j Ra-C-CONH. —S' D^.nu /-V-, R*-r-rn\ru --S 20 N ^ N 0-R 5 0 (If) Process_H : 3-Cpphem formation (Ig) Ra'J"C0NHl f*\ ? Base kJ-C-CONH-,— 0-RZ R ' 7 5 0-R R (Ig) -18- (Ih) 4 6 6 7 4 Process I ; Halogenation 1 / R - C - CDNHi ( > r1 - r rrern ^ II I ' Halocrenatim Agent a |j 0001 | [ N J N ^ 2 0—R N <\j o O—R J- N -OH R (XI) Process J ; Oximation R (Ii) R R*- (j: - CONH T(^X R o 1 2 Rj; - r - CCNH d R - ONH- (XIII) x Ra " 9 ? .4 ^ » N r\j p O-R R~ (XII) (Ij) Process K ; Reductive formation of aminomethylene ,3 £-f-°a«nf'sVK L2 o^nn^-: R (Ij) R> CH - CCNH a i NH_ OZ*—N L S v R R (Ik) PffQCSSS L »_ Reductive formation of hydroxymethylene S- R*- C - CCNH .—R3 I 0^lN R RI- CH - CCNH—, / a i ^ r CH R R" (XII) (XI) -19- 4 6 6 7 4 Process M : Esterification S 4 R - A - OONH ,—S R . r1- a — CCNH ^ Esterifyinq agent ^ A ujnm R ^p | (J NNj/ COOH (XIV) Process N ; Carboxy formation c R"*"- A - OONH R1- A - CONH-r—j/ SsS—R3 0^~N COCH (XV) (In) wherein Ra is an aliphatic hydrocarbon residue which may be substituted with halogen, carboxy or esterified carboxy, 10 "b is halogen, < is esterified carboxy, is functionally modified carboxy, Ra is protected amino, •: is acyl, and -20- 4 6 67 4 R1, rI, rJ, R2, R3, R4, r1, R5 and A are each as defined above.

The above processes will be explained in detail in the following. 5 Process A N-Acylation A compound (I) and its salt can be prepared by reacting a 7-amino-3-cephem (or cepham) compound (II), its reactive derivative at the amino or a salt thereof with a 10 carboxylic acid (III), its rcactive derivative at the carboxy or a salt thereof according to a conventional manner of so-called amida.ti.on reaction well known in g-lactam chemistry.

The starting compound (III), includes both of known and new ones, and the new compound (III) can be prepared 15 according to the methods as explained hereinafter in this specification.

Suitable reactive derivative at the amino group of the compound (II) may include a conventional reactive derivative as used in a wide variety of amidation reaction, 20 for example, isocyanato, isothiocyanato, a derivative formed by the reaction of a compound (II) with a silyl compound (e.g. trimethylsilylacetamide, bis(trimethylsilyl)acetamide, etc.), with an aldehyde compound (e.g. acetaldehyde, isopentaldehyde, benzaldehyde, salicylaldchyde, phenylacetaldehyde, p-nitro-25 benzaldehyde, m-chlorobenzaldehyde , p-chlorobenzaldehyde, hydroxynaphthoaldehyde, furfural, thiophenecarboaldehyde, etc., or the corresponding hydrate, acetal, hemiacetal or enolate thereof), with a ketone compound (e.g. acetone, methyl ethyl ketone, methyl isobutyl ketone, acetylacetone,ethyl acetoacetate, etc., or 30 the corresponding ketal, hemiketal or enolate thereof), with -21- 4 6 674 phosphorus compound (e.g. phosphorus oxychloride, phosphorous chloride, etc.), or with a sulfur compourid (e.g. thionyl chloride, etc.), and the like.

Suitable salt,bf the compound (II) may be referred to the one as exemplified for the compound (I).

Suitable reactive derivative at the carboxy group of the compound (III) may include, for example, an "acid halide, an acid anhydride, an activated amide, an activated ester, and the like, and preferably acid halide such as acid chloride, acid bromide; a mixed acid anhydride with an acid such as substituted phosphoric acid (e.g. dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric' acid, dibenzylphosphoric acid, halogenated phosphoric acid, etc.), dialkylphosphorous acid, sulfurous acid, thiosulfuric acid, sulfuric acid, alkylcarbonic acid, aliphatic carboxylic acid (e.g. pivalic acid, pentanoic acid, isopentanoic acid, 2-ethylbutyric acid, trichloroacetic acid, etc.), aromatic carboxylic acid (e.g. benzoic acid, etc.); a symmetrical acid anhydride; an activated acid amide with imidazole, 4-substituted imidazole, dimethylpyrazole, triazole or tetrazole; an activated c^or (e.g. cyanomethyl ester, methoxymethyl ester, dimethylaminomcthyl ester, vinyl ester, propargyl ester, p-nitrophenyl ester, 2,4-dixiitrophcny] ester, trichlorophenyl ester, pentachlorophenyl ester, mesylphenyl ester, phenylazophenyl ester, phenyl thioester, p-nitrophenyl thioester, p-cresyl thioester, carboxymcthyl thioester, pyranyl ester, pyridyl ester, piperidyl ester, 8-quinolyl thioester, an ester with a N-hydroxy compound such as N,N-dimethylhydroxylamine, 4 6 6 7 4 1 -hydroxy-2- (III)-pyridone, N-hydroxysuccinimide , N-hydroxyphthalimide, 1-hydroxybenzotriazole, 1-hydroxy-6-chlorobenzotriazole, etc.), and the like.

-The suitable reactive derivatives of the compounds (II) and (III) can be optionally selected from the above according to the kind of the compounds (II) and (III) to be used practically, and to the reaction conditions.

Suitable salt of the compound (III) may include a salt with an inorganic base such as alkali metal salt (e.g. sodium salt, potassium salt,etc.) and an alkaline earth metal salt. (e.g. calcium salt, magnesium salt, etc.), a salt with an organic base such as tertiary amine (e.g. trimethylamine salt, trietliylaminc salt, N,N-dimethylaniline salt, pyridine salt, etc.) , a salt with an inorganic acid (e.g. hydrochloride, hydrobromide, etc.) and the like.

The reaction is usually carried out in a conventional solvent such as water, acetone, dioxane, acetonitrile, chloroform, benzene, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, NjN-1 dimethylformamide, pyridine or any other solvent which does not adversely influence to the reaction, or an optional mixture thereof.

When the acylating agent (III) is used in a form of free acid or salt in this reaction, the reaction is preferably carried out in the prcsencc of a condensing agent such as a carbodiimide compound (e.g. N,NVdicyclo-hexylcarbodiimide, N-cyclohexyl-N1-morpholinoethylcarbodiimide, N-cyclohexyl-N1 -(4 -diethylaminocyclohexyl)carbodi imide, N,N'-diethylcarbodiimide, N,N'-diisopropylcarbodiimide, N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide, etc.), -23- 4067 4 a bisimidazolide compound (e.g. N,N'-carbonylbis(2-methylimidazole), etc.), an imine compound (e.g. pentamethyleneketene-N-cyclohexylimine, diphenylketene-N-Cyclohexylimine, etc.), an olefinic or acetylenic etlier compound (e.g. ethoxyacetylcne, B-chlorovinylethyl ether, etc.), 1- (4-chlorobenzencsulfonyloxy)-6-chloro-lH-benzotriazole, N-ethylbenzisoxazolium salt, N-ethyl-5-phcnylisoxazolium-3'-sulfonate, a phosphorus compound (e.g. polyphosphoric acid, trialkyl phosphite, ethyl polyphosphate, isopropyl polyphosphate, phosphorus oxychloride, phosphorus trichloride, diethylchlorophosphite, orthophenylene chlorophosphjto, etc.), thionyl chloridc, oxalyl chloride, Vilsmeier reagent prepared by the ■ reaction of dimcthylformaniide with thionyl chloride, I phosphorus oxychloride, phosgene or the like.

With regard to the geometry of the compound (I) wherein A is a group of the formula: -C- [ hereinafter •1 referred to as oxyimino compound" CO ] - o-ir produced by this process, it. is to be noted that there seems to be stereoselectivity between syn and anti isomers, as explained as follows.

In case that the reaction is conducted by reacting a compound (II) or its reactive derivative at the amino group or a salt thereof with a compound (III) wherein A is a group of the formula: -j> [ hereinafter referred to as oxyimino acylating ^ 7 0-R agent (III) ] in the presence of a condensing agent, for example, phosphorus pentachloride, thionyl chloride, etc., an anti isomer of the oxiini.no compound (1) tends to be produced as the dominant product and the corresponding -24- syn isomer thereof can be hardly isolated from the reaction product even when a syn isomer of the oximino acylating agent (III) is used. It may be understood that the tendency of such a isomerization in the reaction conducted by the method as explained above is due to the fact that the less stable syn isomer tends to isomerize partially or wholly to the corresponding more stable anti isomer in the course of such reaction, for example, in so-called activation step of the oximino acylating agent (III) so that more stable isomer, i.e. the anti isomer of the oximino compound (I) may be isolated as the reaction product.

Accordingly, in order to obtain a syn isomer, of the oximino compound (I) selectively and in high yield, it is preferable to use a syn-isomer of the oximino acylating agent (III), and to conduct the reaction under a selected reaction condition. That is, a syn isomer of the oximino compound (I) can be obtained selectively and in high yield by conducting the reaction of a compound (II) with a syn isomer of the oximino acylating agent (III), for example, in the presence of a Vilsmeier reagent as mentioned above and under around neutral condition.

The object compound (I) and salt thereof are useful as an antimicrobial agent, and a part thereof can be also used as a starting material in the following processes.

Process B : C-Nitrosation An object compound (lb) and its salt can be prepared by reacting a compound (IV) or its salt with a 4667 4 nitrosating agent.

The starting compound (IV) corresponds'to the 3-cephem compound (I) wherein R* is haloacetyl, R^ is hydrogen, halogen, lower alkyl or a group of the formula: 7 7 5 -0-R in which R is lower alkyl and A is methylene, and can be prepared by the above Process A, preferably by reacting a compound (II) with diketene and halogen (e.g. chlorine, bromine, etc.). Thus prepared starting compound (IV) can be used in this process without any isolation 10 and/or purification.

Suitable nitrosating agent may include nitrous acid and its conventional derivatives such as nitrosyl halide (e.g. nitrosyl chloride, nitrosyl bromide, etc.), alkali metal nitrite (e.g. sodium nitrite, potassium 15 nitrite, etc.), alkyl nitrite (e.g. butyl nitrite, pentyl nitrite, etc.) and the like.

In case that a salt of nitrous acid is used as a nitrosating agent, the reaction is preferably carried out in the presence of an acid such as an inorganic or 20 organic acid (e.g. hydrochloric acid, sulfuric acid, formic acid, acetic acid, etc.). And also, in case that an ester of nitrous acid is used, the reaction is preferably carried out in the presence of a strong base such as alkali metal alkoxide or the.like. 25 This reaction is usually conducted in a solvent such as water, acetic acid, benzene, methanol, ethanol, tetrahydrofuran or any other solvent which does not adversely influence the reaction. The reaction temperature is not critical and the reaction is preferably conducted 30 within the range of cooling to an ambient temperature. -26- 4 6 6 7 4 Thus prepared compound (lb) and salt thereof can be used as a starting material in the following Processes C and D.

Process C : Etherification An object compound (Ic) and its salt can b'j prepared by reacting a compound (V) or its salt with an etherifying agent.

The starting compound (V) corresponds to the compound (I) wherein A is hydroxyiminomethylene group, and can be prepared by the above Process A and B and also by the following Process D.

Suitable examples of the etherifying agent may include a conventional alkylating agent such as dialkyl sulfate (e.g. dimethyl sulfate, diethyl sulfate, etc.), diazoalkane (e.g. diazomethane, diazoethane, etc.), alkyl halide (e.g. methyl iodide, ethyl iodide, ethyl bromide, etc.), alkyl sulfonate (e.g. methyl tosylate, etc.), the corresponding alkenylating-, alkynylating- or cycloalkylating agent, in which the aliphatic hydrocarbon moiety may be substituted with halogen, carboxy or esterified carboxy, for example, alkenyl halide (e.g. allyl iodide, etc.), alkynyl halide (e.g. propargyl bromide, etc.), cycloalkyl halide (e.g. cyclohexyl bromide, etc.), lower alkoxycarbonylalkyl halide (e.g. ethoxycarbonylmethyl iodide, etc.)and the like.

In case of using diazoalkane as an etherifying agent, the reaction is usually conducted in a solvent such as diethyl ether, dioxane or any other solvent which In case of using the other etherifying agent, the reaction is usually conducted in a solvent such as water, acetone, ethanol, diethyl ether, dimethylformamide or any other solvent which does not adversely influence the reaction within a temperature range of cooling to heating, preferably in the presence of a base such as an inorganic or organic base, suitable examples of which are referred to the ones used for the basic hydrolysis in the Process E as illustrated below.

Some of the object compound (Ic) ami salt thereof are useful as an antimicrobial agent, and some of them, especially the compound where R* is haloacetyl can be used as a starting material in the following Process D.

This process is an alternative one for preparing the compound (Ic) where R* is haloacetyl group, and further this process is particularly preferable and advantageous for preparing the compound (Ic) where R^" is 2 . haloacetyl and Ra is substituted- or unsubstituted-lower alkyl, lower alkenyl o,r lower alkynyl, more preferably lower alkyl.

Proccss D : Thiazole ring formation A compound (Id) and.its salt can be prepared by reacting a compound (VI) or its salt with a thiourea compound (VII).

The starting compound (VI) corresponds to the 3-cephem compound (I) wherein R* is haloacetyl, R4 is 7 hydrogen, halogen, lower alkyl or a group of the formula:-0-R -28- 4 6 6 7 7 in which R is lower alkyl and A is methylene or a group of the formula: N * 2 0 R 2 in which R is as defined above, and prepared by the above Process(es) A, B and/or C.

The reaction is usually conducted in a solvent such as water, alcohol (e.g. methanol, ethanol, etc.), benzene, dimethylformamide, tetrahydrofuran or any other solvent which does not adversely influence the reaction within a temperature range of an ambient temperature to heating.

This process is an alternative and highly advantageous one for providing the active compound (Id), especially (a) the compound (Id) where A' is a group of the formula: N s 2 0—R -29- 46 67 4 2 6 ' " v in which R is hydrogen and R is amino from the compound (IV) via the Process B, and (b) the compound (Id) where A' is a group of the formula: —C 1 i-R2 2 6 in which R is lower alkyl and R is amino from the compound (IV) via the Processes B and C.

I Process E: Elimination of amino-protective group A compound (Ie) and its salt can be prepared by subjecting a comptmd (VIII) or its salt to elimination reaction of the protective group in the protected amino group for R6. a The starting Compound (VIII) corresponds to the compound (I) wherein R^- is thiazolyl of the formula: in which R^ is protected amino, and can be prepared, for example, by the above Process A.

The elimination reaction may be conducted in accordance with a conventional method such as hydrolysis, reduction or the like. These methods may be selected -30- 4 6 674 according to the kind of the protective group to be eliminated.

The hydrolysis may include a method using an acid (acidic hyd'rolyfeis), a base (basic hydrolysis) .or 5 hydrazine, and the like.

Among these methods, hydrolysis using an acid is one of the common and preferable methods for eliminating the protective group such as an acyl group, for example, substituted or unsubstituted lower alkanoyl, 10 substituted or unsubstituted lower alkoxycarbonyl, substituted or unsubstituted ar (lower)alkoxycarbonyl, lower cycloalkoxycarbonyl, substituted phcnylthio, substituted alkylidene, substituted aralkylidene, substituted cyclo- alkylidene or the like, particulars of which are to be | IS referred to those as illustrated for the N-protective group, respectively.

Suitable acid to be used in this acidic hydrolysis may include an organic or inorganic acid such as formic acid, trifluoroacetic acid, benzenesulfonic acid, p-20 toluenesulfonic acid, hydrochloric acid, cation-exchange resin, and the like. Preferable acid is the one which can be easily separated out from the reaction product by a conventional manner such as neutralization or distillation under reduced pressure, for example, formic acid, 25 trifluoroacetic acid, hydrochloric acid or the like. The acid suitable for the reaction can be selected in consideration of the chemical property of the starting compound and the product as well as the kind of the protective group to be eliminated. The acidic hydrolysis can be 30 conducted in the presence or absence of a solvent. -31- 46674 Suitable solvent may be a conventional organic solvent, water or a mixture thereof, which does not adversely influence this reaction. Particularly, when the hydrolysis is conducted with trifluoroacetic acid, the reaction may be accelerated by addition of anisole.

The hydrolysis using a base can be applied for eliminating the protective group such as an acyl group, preferably, for example, haloalkanoyl (e.g. trifluoroacety 1, etc.) and the like. Suitable base inay include, for example, an inorganic base such as alkali metal hydroxide (e.g. sodium hydroxide, potassium hydroxide, etc.), alkaline earth metal hydroxide (e.g. magnesium hydroxide, calcium hydroxide, etc.), alkali metal carbonate (e.g. sodium carbonate, potassium carbonate, etc.), alkaline earth metal carbonate (e.g. magnesium carbonate, calcium carbonate, etc.), alkali metal bicarbonate (e.g. sodium bicarbonate, potassium bicarbonate, etc.), alkaline earth metal phosphate (e.g. magnesium phosphate, calcium phosphate, etc.), alkali metal hydrogen phosphate (e.g. disodium hydrogen phosphate, dipotassium hydrogen phosphate, etc.), or the like, and an organic base such as alkali metal acetate (e.g. sodium acetate, potassium acetate, etc.), trialkylamine (e.g. trimethylamine, triethylamine, etc.), picoline, N-methylpyrrolidine, N-methylmorpholine, 1,5-diazabicyclo[4,3,0]-5-nonene, 1,4-diazabicyclo[2,2,2]octane, 1,5 -diazabicyclo [5,4,0]- 7-undecene7anion-exchange resin or the like. The hydrolysis using a base is often carried out in water or a conventional organic solvent or a mixtur-e thereof. -32- 46674 The hydrolysis using hydrazine can be applied for eliminating the protective group such as dibasic acyl, for example, succinyl, phthaloyl or the like.

The reduction can be applied for eliminating 5 the protective group such as acyl, for example, halo (lower)alkoxycarbonyl (e.g. trichloroothoxycarbonyl, etc.), substituted or unsubstituted ar(lower)alkoxycarbonyl ! (e.g. benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, etc.), 2-pyridylmethoxycarbonyl, etc., aralkyl (e.g. benzyl, 10 benzhydryl, trityl, etc.) and the like. Suitable reduction may include, for example, reduction using an alkali metal borohydride (e.g. sodium borohydride, etc.), conventional catalytic hydrogenolysis and the like.

And further, the protective group such as 15 halo(lower)alkoxycarbonyl or 8-quinoly]oxycarbonyl can be eliminated by treatment with a heavy metal such as copper, zinc or the like.

The reaction temperature is not critical and may be optionally selected in consideration of the 20 chemical property of the starting compound and reaction product as well as the kind of the N-protective group and the method to be applied, and the reaction is preferably carried out under a mild condition such as under cooling, at ambient temperature or slightly elevated temperature. 25 The process includes in its scope the cases that the functionally modified carboxy for R** is simultaneously transformed into the free carboxy group in the course of the above reaction or in the post-treatment.

As to this process, it is to be understood that 3^ the purpose of this process lies, in providing the -33- 4 6 6 7 4 generally more active compound (I1) wherein R* is aminof thiazolyl by eliminating the protective group in the protected amino group of the compound (VIII) prepared by the other processes as mentioned above or below. i Process F : Reductive formation of 3-hydroxycepham A compound (If) and its salt can be prepared by reducing a compound (IX) or its salt. i The starting compound (IX) corresponds to the ;3-c.ephem compound (I) wherein R"'" is thiadiazolyl or thiazolyl of the formula : R^ {j1 ~7j|_ in which R^ is as defined above, R is hydrogen, ' R is a group of the 7 7 formula:-O-R in which R is hydrogen and A is a group of the formula : -|J- in which R is as defined above, and can be s ? prepared, for example, by the 0-R above Process A.

The method of reduction applied to this proces may include a conventional one which is applicable for reduction of ketonic carbonyl group including its tautomeric enol form into hydroxymethylene group, and the preferable method may be reduction using an alkali metal borohydride (e.g. sodium borohydride, etc.) or a combination of an acid (e.g. hydrochloric acid, sulfuric acid, formic acid, acetic acid, etc.) and a metal (e.g. zinc, iron, copper, etc.), catalytic reduction using a conventional catalyst (e.g. palladium on carbon, palladium sponge, Raney nickel, platinum, platinum black etc.) or the like.

The reaction is usually carried out in a conventional solvent such as water, alcohol (e.g. -34- methanol, ethanol,, etc. ) , dimethylformamide, tetrahydro-furan or any other solvent which does not adversely influence the; reaction within a temperature range from i cooling to somewhat elevated temperature.

Although! thus prepared compound (If) and salt thereof have antimicrobial activities, they are also useful mainly as an intermediate, especially as a starting material in the following Process G and successively Process H for preparing the more active 3-cephem compound (Ih). ! I Process G : O-acylation A compound (Ig) and its salt can be prepared by reacting a compound (If) or its srilt. with a compound (X), its salt or its ronctive derivative.

As to the compound (X), suitable examples of J the acyl moiety for Rfl are to be referred to those as 7 exemplified above for the acyl group for R of the compound (I).

The reactive derivative of the compound (X) may be.an acyl halide, anhydride, azide, activated ester, activated amide and the like, which are to be referred to those as exemplified above for the compound (III) in the Process A, preferably an acyl halide such as lower alkanoyl halide (e.g. acetyl chloride, etc.), aroyl halide (e.g. benzoyl chloride, etc.), lower alkanesulfonyl halide (e.g. mesyl chloride, mesyl bromide, ethanesulfonyl chloride, etc.), arenesulfonyl halide (e.g. tosyl chloride, etc.), an acyl azide such as lower alkanesulfonyl azide (e.g. mesyl azide, etc.), arenesulfonyl azide (e.g. 4 6 6 7 4 | j i tosyl azide, etc.) or the like, and more preferably lower alkanesulfonyl halide or arenesulfonyl halide., • The reaction is usually carried out in a conventional solvent such as dimethylformamide, ; chloroform, methylene chloride or any other solvent which does not adversely influence the reaction, under cooling or at an ambient or somewhat elevated temperature.

In case that the acyl halide is used as an \ acylating agent, the reaction is generally conducted in the presence of a base as exemplified in the above Process E.

This process is the first activation step for ; preparing a more active 3-cephem compound (Ih) from the ; 3-hydroxycepham compound (If) via the 3-acyloxyccpham i compound (Ig), which is successively treated with a base in the following Process H.

Process 11 : 3-Cephcm formation This process is the final step to transform the 3-hydroxycephem compound (IX) into the more active 3-cephem compound (Ih) or its salt. That is, a compound; (Ih) or its salt can be prepared by treating a compound 1 (Ig) as prepared in the above Process G or its salt ! with a base.

The preferable base includes an inorganic base such as metal hydroxide (e.g. sodium hydroxide, potassium hydroxide, etc.), metal carbonate (e.g. sodium carbonate, potassium carbonate, magnesium carbonate, etc.) metal bicarbonate (e.g. sodium bicarbonate, potassium bicarbonate, etc.), organic base such as tertiary amine -36- (e.g. triraeihyl amine, triethyl amine, pyridine, etc.) alkali metal alkoxide (e.g. sodium methoxide, sodium ethoxide, etc.) and the like.

The reaction is usually carried out in a conventional solvent such as an alcohol, dimethylformamide, chloroform, methylene chloride or any other solvent which does not adversely influence the reaction, under cooling or at an ambient or somewhat elevated temperature.

Process I : Halogenation ■ A compound (Ii) or its salt can be prepared by halogenating a compound (XI) or its salt.

The starting compound (XI) corresponds to the compound (I) wherein R* is thiadiazolyl or thiazolyl of the formula : R6 h1 151— in which R6 is as defined above, 3 S 4 7 R is hydrogen, R is a group of the formula:-0-R in which R is hydrogen and A is a group of the formula: 2 in which R is as defined above, and. can be prepared N c , by the processes as explained above. 6-R Suitable halogenating agent may include a conventional halogen compound such as phosphorus halide (e.g. phosphorus trichloride, phosphorus pentachloride, phosphorus tribromide, phosphorus pentabromide, phosphoryl chloride, etc.), thionyl chloride and the like.

The reaction is usually carried out in a conventional solvent such as chloroform, methylene chloride, dimethylformamide or any other solvent which does not adversely influence the reaction a^d preferably under cooling or at ambient or somewhat elevated temperature. -37- 4 6 674 i i Process J: Oximation .

A compound (Ij) and its salt can be prepared by reacting a compound (XIII) or its salt with a compound (XII) or its salt. 1 The starting compound corresponds to the 3-cephem compound (I) where R^" is thiadiazolyl or thiazolyl of the in which R is as defined above and A is oxomethylene, and 10 can be prepared by the above Process A.

The suitable examples of the compound (XIII) may be hydroxylamine, lower alkoxylamine, lower alkenyloxyamine, lower alkynyloxyamine or cycloalkoxylamine in which the lower alkyl-, lower alkenyl-, lower alkynyl- and cycloalkyl-15 moiety may be substituted with halogen, carboxy or esterified carboxy, and preferably lower alkoxylamine. In the above suitable examples, the lower-alkyl, alkenyl and alkynyl moiety, cycloalkyl moiety, halogen and esterified carboxy J are to be referred to those as exemplified above. 20 The salt of the compound (XIII) may be acid salit such as hydrochloride, hydrobromide, sulfate or the like.

This reaction is usually conducted in a solvent such as water, alcohol or any other solvent which does not adversely influence the reaction, within a temperature range from 25 cooling to heating.

When a salt of the compound (XIII) is used, the reaction is preferably conducted in the presence of a base as -38- I 4 6 6 7 4 exemplified in the Process E.

Process K: Reductive Formation of Aminomethylene A compound (Ik) and its salt can be prepared by • reacting a compound (Ij) or its salt, which can be prepared, 5 for example, by the above Process A.

The reduction in this process may be conducted^ by a conventional method, for example, catalytic reduction using a conventional catalyst (e.g. Raney nickel, platinum oxide, palladium on carbon, ruthenium on carbon, rhodium on alumina, 10 copper chromium oxide, etc.); chemical reduction using a combination of an acid (e.g. hydrochloric acid, sulfuric acid, formic acid, acetic acid, etc.) and a metal or a metal salt (e.g. iron, zinc, tin, chromium chloride, chromium acetate, etc.), a combination of a metal or an 15 aimalgam (e.g. sodium, zinc amalgam, sodium amalgam, aluminum amalgam, etc.) and a solvent (e.g. water, methanol, ethanol, etc.), or a reducing agent such as a complex of metal hydride (e.g. sodium borohydride, alkyl - tin - hydride, lithium aluminum hydride, diethyl aluminum hydride, etc.); 20 electrolytic reduction or the like. The reaction conditions such as temperature, pressure, time and solvent can be selected according to the kinds of the starting compound (Ij) and the reduction method to be applied.

In case that the compound (Ij) having hydroxy group 4 25 for R is used as a starting material in this process, a 3 -hydroxycepham compound corresponding to the compound (Ik) may be occasionally produced according to the reduction -39- 4667 4 method to be applied, and such a case is also included in 1 this process.

Process L: Reductive Formation of Hydroxymethylene A compound (II) and its salt can be prepared by, 5 reducing a compound (XII) or its salt.

The starting compound (XII) corresponds to the 3-cephem compound (I) where R^" is thiadiazolyl or thiazolyl of the formula: N R6 I ""I" (■ 10 in which is as defined above and A is oxomethylene, and can be prepared by the above Process A.

The reduction method of this process may be a conventional one which can be applied for the reduction of oxo group into hydroxy group, and particulars of which is 15 substantially the same as those explained in the above : Process K. i In case that the compound (XII) having hydroxy 4 group for R is used as a starting material in this process, 3-hydroxycephem compound corresponding to the compound (II) 20 may be occasionally produced according to the reduction method to be applied, and such a case is also included in this process.

Process M: Esterification This process is to provide an ester compound (Im) and -40- 4 6 6 7 4 its.salt for improving the chemical, physiological and/or pharmaceutical properties of the corresponding free carboxy compound (XIV), which corresponds to the 3-cephem compound (I) wherein R5 is carboxy, or its salt. 5 The esterification is conducted by reacting a free carboxy compound (XIV), its reactive derivative at the carboxy or a salt thereof with an esterifying agent.

The preferred reactive derivative at the carboxy group of the compound (XIV) is to be referred to those of 10 the compound (III) as exemplified in the Process A.

The esterifying agent may include a hydroxy | compound and its reaction equivalent.

Suitable examples of the hydroxy compound may be a a substituted or unsubstituted alcohol such as alkanol, aralkanol, 15 arenol or the like, particulars of which may be substituted alcohol such as alkanoyloxy(lower) alkanol (e.g. acetoxymethanol, propionyloxymethanol, butyryloxymethanol, pentanoyloxymethanol, hexanoyloxymethanol, acetpxyethanol, propionyloxyethanol, 20 butyrylcoQTOethanol , pentanoyloxyethanol, hexanolyoxyethanol, acetoxypropanol, propionyloxypropanol, hexanoyloxypropanoic _ * hexanoyloxyhexanol, palmitoyloxymethanol, etc.), halo(lower) alkanol (e.g. mono-,, di- or tri-chloroethanol, etc.), lower cycloalkyl(lower)alkanol (e.g. 1- cyclopropylethanol, etc.), 25 substituted ar(lower) alkanol (e.g. 4 - nitrobenzyl alcohol, 4 - chlorobenzyl alcohol, 4 - methoxybenzyl alcohol, 3,5 di - tert - butyl - 4 - hydroxybenzyl alcohol, bis (methoxyr-phenyl)methanol, etc.) substituted arenol (e.g. 4 - methoxy-phenol, etc.), the corresponding unsubstituted alcohol or -41- & i 4 6 6 7 4 the like.

Suitable readtive equivalent of the hydroxy compound may include a conventional one such as halide, alkanesulfohate, arenesulfonate or salt of the hydroxy compound, diazoalkane, ^ diazoaralkane, and the like.

Preferable halide of the hydroxy compound may be chloride, bromide or iodide.

Preferable alkane- or arene- sulfonate of the hydroxy compound may be methanesulfonate, ethanesulfonate, benzene-sulfonate, tosylate or the like.

Preferable salt of the hydroxy compound may be an alkali metal salt such as lithium salt, sodium salt, potassium salt or the like.

Preferable diazoalkane and diazoaralkane may be ^ diazomethane, diazoethane, diazopropane, diphenyldiazomethane or the like.

The reaction can be carried out in the presence or absence of a solvent such as N,N ^dimethylformamide, dimethylsulfoxide or any other solvent which does not 2q adversely influence the reaction, and within a temperature range of cooling to heating. The liquid hydroxy compound can be also used as a solvent in this reaction.

This reaction can be preferably conducted in th0 presence of an inorganic or organic base as exemplified In case of preparing a substituted- or unsubstituted-aryl ester (Im), particularly substituted- or unsubstituted-phenyl ester, this reaction is to be conducted by reacting a) a compound (XIV) or its salt with phenol or its salt in -42- 4 6 6 7 4 the presence of a condensing agent as exemplified in the above Process A, or b) a reactive derivative of the compound (XIV) preferably a mixed acid anhydride of the compound (XIV) with phenol or its salt in the presence of a base.

In case thst a compound (XIV), where A is a group of the formula: ~T~ N ^ R2 2 in which R is an aliphatic hydrocarbon residue substituted with carboxy, is used as a starting material in this reaction, the said carboxy group 10 may be also esterified in accordance with the reagent and the reaction conditions, and this mode of the reaction is included within the scope of this process.

!' And further, in case that the 2-cephan compound corresponding to I the compound (Im) is produced, the said 2-cephem compound can be i • j 15 transformed into the 3-rcephem ccmpcund (Dn) by acidizing and then reducing the resultant S cxide compound in a conventional manner. This mode of the reactions is also included within the scope of this process.

Process N: Carbcrcy Formation.

This process is to provide a free carboxy compound (In) or its 20 salt, especially the compound (In) wherein R1 is thiadiazolyl or thiazolyl of the formula: ,dnt- in which R® is as defined above and A is a group of the formula: II N % 2 0 R 2 in which R is as defined above, which generally exhibits higher antim- -43- 4 6674 crobial activities as compared with the corresporuiing ' I functionally modified, carboxy compound (XV) Accordingly, the meaning of the functionally modified carboxy in the compound (XIII) lies in mainly synthetic manufacture by chemical process(es) as illustrated hereinabove.

This process is conducted by transforming the functionally modified carboxy group of the starting compound (XIII) into free carboxy group, and the preferred functionally modified carboxy for in the compound (XIII) may be an esterified carboxy group as exemplified for of the compound (I).

The method to be applied to this process includes conventional ones such as hydrolysis, reduction and the like.

The method of hydrolysis includes a conventional one using an acid, base, enzyme or enzymatic preparation, and the like.

Suitable examples of the acid and base are to be referred to those as exemplified in the above Process E, and the acidic or basic hydrolysis can be carried out in a similar manner to that of the Process E.

Suitable enzyme includes an esterase* and esterase preparation which exhibits an esterase activity such as a cultured broth of microorganism or processed materials of microorganism, the preparation of animal or plant tissues, or the like, and preferably a cultured broth of microorganism or processed material thereof.

An esterase to be used in the enzymatic hydrolysis may be used not only in a purified state, but also in a crude state. -44- 46674 Such' an esterase is frequently found to exist widely, for example, in various kind of microorganisms, which can be easily isolated from a soil sample and other sources by conventional means, and further can be ' !• ' 5 easily selected from the collected cultures available in public facilities for culture collection such as ATCC (American Type Culture Collection, Maryland, USA), IAM (Institute of Applied Microbiology, University of Tokyo, Japan), IFO (Institute For Fermentation, Osaka, Japan), 10 IID (The Institute for Infectious Diseases, University of Tokyo, Tokyo, Japan), CBS (Ccntraalbureau voor Schimmelcultures, Beam, Netherlands), FERM (Fermentation Research Institute, Agency of Industrial Science and Technology, Chiba, Japan) and NRRL (Northern Utilization • i 15 Research and Development Division, U.S. Department of Agriculture, Illinois, U.S.A.) and the like.

As to th? microorganism having an esterase activity, there may be exemplified one belonging to the genus, Bacillus, Corynebacterium, Micrococcus, 20 Flavovacterium, Salmonella, Staphylococcus, Vibrio, Microbacterium, Escherichia, Arthrobacter, Azotobacter, Alcaligenes, Rhizobium, Brevibacterium, Kluyvera, Proteus,; Sarcina, Pseudomonas, Xanthomonas, Protaminobacter, Comamonus and the like. 25 Examples of the above microorganisms may be Bacillus subtilis IAM-1069, IAM-1107, IAM-1214, Bacillus ; sphaericus IAM-1286, Corynebacterium equi IAM-1308, Micrococcus varians IAM-1314., Flavobacterium rigeus IAM-1238, Salmonella typhimurium IAM-.1406, Staphylococcus 30 epidermidis IAM-129-6, Microbacterium flavum IAM-1642, -45- 46674 i Alcaligenes faecalis ATCC-8750, Arthrobacter simplex ATCC-6946, Azotobacter vinelandii IAM-1078, Escherichia coli IAM-1101, Rhizobium japonicum IAM-0001, Vibrio metchnikovii IAM-1039, Brevibacterium helvolum IAM-1637, Protaminobacter alboflavum IAM-1040, Comamonas terrigena IFO-12685, Sarcina lutea- IAM-1099, Pseudomonus schuylkilliensis IAM-1055, Xanthomonas trifolii ATCC-12287 or the like.

In the enzymatic hydrolysis, the esterase can be preferably used in a form of a cultured broth obtained by culturing microorganisms having an esterase activity in a suitable manner, or of its processed material.

Cultivation of microorganisms can be generally conducted in a conventional manner. As a culture medium to be used, there may be used a nutrient one containing sources of assimilable carbon and nitrogen and inorganic salts. The preferred sources of carbon are, for example, glucose, sucrose, lactose, sugars, glycerol and starch. The preferred sources of nitrogen are, for example, meat extract, peptone, gluten meal, corn meal, cotton-seed meal, soybean meal, corn steep liquor, yeast extracts, casein hydrolysate and amino acids, as well as inorganic and organic nitrogen such as ammonium salts (e.g. ammonium sulfate, ammonium nitrate, ammonium phosphate, etc.), sodium nitrate or the like. If desired, mineral salts such as calcium carbonate, sodium or potassium phosphate, magnesium salts and copper salts, and various vitamines can be also used.

Suitable pH of the culture medium, suitable cultivation temperature and suitable cultivation time -46- vary with the kind of the microorganisms to be used. A desirable pH usually lies in a range of pH 5 to 8. The temperature is usually selected from about 20°C to about 35°C. The cultivation time is usually selected from 20 hours to 120 hours.

The cultured broth per se thus obtained and its processed material may be employed for enzymatic hydrolysis of this process. The "processed material" of cultured broth means any preparation having esterase activity, which is processed by conventionally suitable means for increasing said esterase activity.

The esterase activity of the cultured broth is present in cells (intracellularly) and/or out of cells (extracellularly).

When the activity exists mainly in cells, the following preparation, for example, may be used as a processed material of the cultured broth. (1) raw cells; separated from the cultured broth in conventional manners such as filtration and centrifugation, (2) dried cells; obtained by drying said raw cells in conventional manners such as lyophilization and vacuum drying, (3) a cell-free extract; obtained by destroying said raw or dried cells in conventional manners (e.g. grinding the cells with almina, sea sand, etc. or treating the cells with super sonic waves), or (4) an enzyme solution; obtained by purification or partial purification of said cell-free extract in a conventional manner.

When the activity exists mainly out of cells, the following preparation, for example, may be used as a. processed material. • (1) a supernatant or a filtrate; obtained from the cultured broth in a conventional manner; or (2) an enzyme solution; obtained: by purification-or partial purification of said supernatant; or filtrate in a conventional manner.

The enzymatic hydrolysis is conducted by . contacting the compound (XIII) with the cultured broth of the microorganism or its processed material in an aqueous medium such as water or. 'a buffer solution (e.g. phosphate buffer, etc.), preferably in the presence of conventional surf ace - active agenjt. That is, the reaction is usually conducted by adding tie compound (XIII) to the : v - '• cultured broth of the microorganism or its liquid processed material (e.g. supernatant, filtrate, enzyme solution, etc.), or to the solution or suspension of the cultured broth or its processed material in an aqueous medium. Sometimes, an agitation of the said reaction mixture is preferable.

Preferred pH of reaction mixture, concentration of substrates, reaction time and;reaction temperature may vary with characteristics of the cultured broth or its processed material to be used, or the compound (XIII) to be used. However, the reaction conditions are preferably selected from a range of at pH 4 to 10, more preferably at pH 6 to 8, at 20 to 50°C, more preferably at 25 to 35°C for .L to 100 hours. The concentration of the starting compound (XIII) to be used as a substrate in the reaction mixture may be in a range of 0.1 to 100 mg per m£, -48- 466 i ' preferably 1 to 20.mg per m£.

The method of the reduction for this process may be carried out in a similar manner to that of the above i Process E.

This process includes within its scope the cases that the protective grou.v in the protected .mino for R^, which is a substituer.t on the thiazolyl group for R*, is eJiminated and/or the esterified carboxy group, which is ft an optional substituent on the aliphatic hydrocarbon 2 residue for R in the group A, is transformed into free carboxy group in the course of the reaction or the post-treatment. 1 i The compound obtained in accordance with the processes as explained above can be isolated and purified in a conventional manner.

; | In case that the object compound (I) has free carboxy for R^ and/or free amino for R^, it may be transformed into its pharmaceutically acceptable salt by a conventional method.

Among the object compound (I), the compound (I'),! its pharmaceutically acceptable salt and bioprecursor thereof exhibit high antimicrobial activities inhibiting the growth of a wide variety of pathogenic microorganisms including Gram-positive and Gram-negative bacteria and are useful as antimicrobial agents.

And further, the compound (I") and its salt are novel and useful as an intermediate for preparing the active compound (I') , its pharmaceutically acceptable salt or 46 67 4 bioprecursor thereof.

According to the aforementioned processes, more specifically the following compounds can be prepared. 5 7 - [2 -(2-amino-4-thi azolyl)- 2-methoxyiminoacetamido]- 3-methoxy-3-cephem-4-carboxylic acid (syn isomer) 7-[2-(2-amino-4-thiazolyl)- 2-methoxyiminoacetamido]-2,3-dimethyl-3-cephem-4-carboxylic acid (syn isomer) 7- [2-(2-amino-4-thiazolyl)- 2-mcthoxyiminoacetamido]-10 3-chloro-3-cephcm-4-carboxy 1 ic acid (.anti isomer) 7-[2-(l,2,3-thiad:iazol-4-yl)-2 -ine thoxy imino ace tami do ] -3-cephem-4-carboxylic acid (syn isomer) 7-[2-(2-amino-4-thiazolyl)-2-hydroxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer) 15 7- [2- (2-amino-4-thiazolyl) - 2-methoxyiminoacetamido] - 3-tosyloxy-3-cephem-4-carboxylic acid (syn isomer) 7- [2-(2-arnino-4-thiazolyl)- 2 -ethoxyiminoacc tami do ] -3-ce'phem-4-carboxylic acid (syn isomer) 7 - [2-(2-ami no-4-thiazolyl)- 2-ethoxyiminoacctamido] -20 3-chloro-3-cephcm-4-carboxylic acid (syn isomer) 7- [2 - (2 - amino - 4 - thi azolyl) - 2- isopropoxyiminoa.ee tami do ] -3-cephem-4-carboxylic acid (syn isomer) 7-[2-(2-amino-4-thiazolyl)-2-propoxyiminoacetamido]-3-chloro-3-cephem-4-carboxylic acid (syn isomer) 25 7-[2-(2-amino-4-thiazolyl)-2-propoxyiminoacetamido]- 3-cephem-4-carboxylic acid (syn isomer) 7-[2-(2-amino-4-thiazolyl)- 2-isobutyloxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer) 7-[2-(2-amino- 4-thiazolyl)- 2-n-butoxyiminoacetamido]-30 3-cephem-4-carboxylic acid (syn isomer) -50- 4 6674 7- [2- (2-amino-4-thiazolyl) -2-n-hexyloxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer) 7-[2-(2-amino-4-thiazolyl) -2-cyclohexyloxyimino-acetamido] - 3-cephem-4-carboxylic acid (syn isomer) 7-[2-(2-amino-4-thiazolyl)-2-allyloxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer) 7-[2-(2.-amino-4-thiazolyl)-2-propargyloxyimino-. acetamido]-3-cephem-4-carboxylic aci^ (syn isomer) 7- [2-(2-amino-4-thiazolyl)-2-ethoxycarbonylmethoxyiminoacetamido] -3-cephem-4-carboxylic acid (syn isomer) 7- [2- (2-ainino-4-thiazolyl) - 2^carboxymethoxyimino-acetamido]-3-cephem-4-carboxylic acid (syn isomer) 7- [2-(2-amino-4-thiazolyl)-2-n-pentyloxyimino-acetamido]-3-cephem-4-carboxylic acid (syn isomer) 7- [2-i- (2-amino-4-thiazolyl)-2-(2 ,2 , 2-trifluoro-ethoxyimino)acltamido]-3-cephem-4-carboxylic acid (syn isomer) 7- [21 (2-amino-4-thiazolyl) -2-(2-chloroethoxyimino) -acetamido]-3-cephem-4-carboxylic acid (syn isomer) 7- [2-(2-amino-4-thiazolyl)-2-(2,2,2-trifluoroethoxy-imino)acetamido]-3-chloro-3-cephem-4-carboxylic acid (syn isomer) 7- [2- (2-formamido-4-thj.azolyl) -2-methoxyimino-acetamido]-3-cephem-4-carboxylic, acid (syn isomer) 7-[2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid (anti isomer) 7-[2'(2-amino-4-thiazolyl)-2-n-octyloxyimino-acetamido]-3-cephem-4-carboxylic acid (syn isomer) 7- [2-(2-amino-4-thiazolyl)- 2-(2,3,3-trifluoro-2-propenyloxyimino)acetamido]-3-cephem-4-carboxylic acid (syn isomer) 4 6 6 7 4 7 - £1 - (2 - amino - 4 - thiazolyl) - 2 -lauroyloxymethoxyim inoacetamido7 - 3 - cephem - 4 - carboxylic acid (syn isomer) 7 - fl ~ (1,2,3 - thiadiazol - 4 - yl)- 2 - n -5 hexyloxyiminoacetamidg7 - 3 - cephem - 4 - carboxylic acid (syn isomer) 1 - £2 - (2 - amino - 4 - thiazolyl) - 2 - n -butoxyiminoacetamido7 - 3 - chloro - 3 - cephem - 4 - carboxylic acid(syn isomer) 10 7 - /2 - (2 - amino - 4 - thiazolyl) - 2 - n - butoxyiminoacetamidg7 - 3 methoxy - 3 - cephem - 4 -carboxylic acid (syn iscmer) 7 - £& - (2 - amino - 4 - thiazolyl) - 2 - propargy-loxyiminoacetamidq7 — 3 — methoxy — 3 - cephem - 4 - carboxylic acid (syn isomer) 1 - fl - (2 - amino - 4 - thiazolyl) - 2 - trifluoro-methoxyiminoacetamido/ - 3 - cephem - 4 - carboxylic acid (syn isomer) 7 - £2 - (2 - amino - 4 - thiazolyl) acetamidoj? -2o 3 - cephem - 4 - carboxylic acid 7 - /2 - (2 - amino - 4 - thiazolyl)oxalylamino7 ~ 3 - cephem - 4 - carboxylic acid 7 - /2 - (2 - amino - 4 - thiazolyl) - 2 - hydraxy-acetamidg7 - 3 - cephem - 4 - carboxylic acid 25 the corresponding functionally modified derivative such as h ex a n oy1oxyme thy1 7 - £2 - (2 - amino - 4 - thiazolyl)' 2-methoxyiminoacetamido7 3 - cephem - 4 - carboxylate (syn isomer) 52 ! 4 6 6 7 4 i • pivaloyloxymethyl 7 - fl - (2 - amino - 4 - thiazolyl) - 2 - methoxyiminoacetamido7 - 3 - cephem - 4 - carboxylate(syn isomer) 4 - nitrobenzyl 7 - - (2 - amino - 4 - thiazolyl) ■ - 2 - methoxyiminoacetamido7 - 3 - cephem - 4 - carboxy- late(syn isomer) 4 - nitrobenzyl 7 -fl - (2 — amino - 4 - thiazolyl) - 2 - methoxyiminoacetamidoT" - 3 - hydroxy - 3 - cephem - 4 carboxylate(syn Isomer) ; 10 4 - nitrobenzyl 7 - £l - (2 - amino - 4 - thiazolyl) - 2 - ethoxy - iminoacetamido7 - 3 - cephem - 4 - carboxy-late (syn isomer) 4 - nitrobenzyl 7 - (2 - amino - 4 - thiazolyl) -2-n - propoxyJLminaacetamido7 - 3 - hydroxy - 3 -15 cephem - 4 - carboxylate (syn isomer) 4 - nitrobenzyl 7 - /2 - (2 - amino - 4 - thiazolyl) - 2 - isobutoxyiminoace*amido7 - 3 - hydroxy - 3 - cephem -4 - carboxylate (syn isomer) the corresponding salt such as sodium 7-/2 - (2 - amino - 4 - thiazolyl) - 2 -20 methoxyiminoacetamido7 - 3 - cephem - 4 - carboxylate (syn isomer) | calcium 7 - - (2 - amino - 4 - thiazolyl) - 2 methoxyiminoacetamido7 - 3 - cephem - 4 - carboxylate (syn isomer) * 25 magnesium 7 - - (2 - amino - 4 - thiazolyl) - 2 - methoxyiminoacetamido7 ~ 3 - cephem - 4 - carboxylate (syn isomer) agrinine salt of 7 - /2 - (2 - amino - 4 - thiazolyl) - 2 - methoxyiminoacetamidc/ - 3 - cephem - 4 - carboxylic acid (syn isomer) 4 667 4 t, v, % : ■ <. ,/ '"V lysine salt of 1 - - (2 - amino -4 _ thiazolyl) - 2 - methoxyiminoacetamido7 - 3 - cephem -4 - carboxylic acid (syn isomer) 7 - - (2 - amino - 4 - thiazolyl) - 2 - methoxy-5 iminoacetamidq7 - 3 - cephem - 4 - carboxylic acid hydrochloride (syn isomer) 7 - /2 - (2 - amino - 4 - thiazolyl) glycinamidg7 - 3 - cephem - 4 - carboxylic acid formate In order to show the utility of the active compound 10 (I')» the test data of some representative compounds (I1) are shown in the following 1. In vitro Antibacterial Activity 1 (1) Test Method: In vitro antibacterial activity was determined by 15 the two-fold agar-plate dilution method as described below.

One loopful of the overnight culture or lOO-fold dilution of an overnight culture of each test strain in Trypticase-soy broth was streaked on heart infusion agar (HI-agar) containing graded concentrations of the test compound 20 and incubated at 37°C for 20 hours. The minimal inhibitory concentration (MIC) was expressed in ug/ml. (2) Test compounds.

No % 1. 7 - {1 - (2 - amino - 4 - thiazolyl) - 2 - 25 methoxyiminoacetamido7 - 3 - cephem - 4 - carboxyic acid (syn isomer) 2. 7 - fl - (2 - amino - 4 - thiazolyl) - 2 - hydroxy-iminoacetamido7 - 3 - cephem - 4 - carboxylic acid (syn isomer) "4 4 6 6 7 4 3 7 - £2 - (2 - amino - 4 - thiazolyl) - 2 -ethoxyiminoacetamido7 - 3 - cephem - 4 - carboxylic acid (syn isomer) 4 7 - £2 - (2 - amino - 4 - thiazolyl) - 2 - methoxy-5 iminoacetamid,Q73i — chloro — 3 — cephem — 4 carboxylic acid (syn isomer) 5 1 - £l - (2- amino - 4 - thiazolyl) - 2 - n -propoxyiminoacetamido7 - 3 - cephem - 4 - carboxylic acid (syn isomer) 10 6 7 - £2 - (2 - amino - 4 - thiazolyl) - 2 - n - butoxyiminoacetamido7 — 3 — cephem - 4 — carboxylic acid (syn isomer) 7 7 - £2 - (2 - amino - 4 - thiazolyl) - 2 - ally-loxyiminoacetamido7 _ 3 — cephem - 4 - carboxylic acid 15 (syn isomer) < ' 8 7 - £ 2 - (2 - amino - 4 - thiazolyl) - 2 - prop-argyloxyiminoacetamido/ — 3 — cephem — 4 - carboxylic acid (syn isomer) 9 7 - - (2 - amino - 4 - thiazolyl) -2-n - 20 pentyloxyiminoacetamidg7 - 3 - cephem - 4 - carboxylic acid (syn isomer) 10 7 - £2 - (2 - amino - 4 - thiazolyl) - 2 - n -hexyloxyiminoacetamidg7 - 3 - cephem - 4 - carboxylic acid (syn isomer) 25 11 7 - £l - (2 - amino - 4 - thiazolyl) - 2 - cyclohexyloxyiminoacetamidg7 - 3 - cephem - 4 - carboxylic acid (syn isomer) 55 4 667 4 (2) Test Compounds: No. 12. 1 - fl - (2 - amino - 4 - thiazolyl) - 2 - (2 - chloroethoxyimino) - acetamido7 - 3 - cephem - 4 -carboxylic acid (syn isomer) 13. 7 - /2 - ( 2 - amino - 4 - thiazolyl) - 2 -(2,2,2 - trifluoroethoxyiminoacetamido/ - 3 - cephem - 4 -carboxylic acid (syn isomer) 14 7 - - (2 - amino - 4 - thiazolyl)oxalylamino7 -3 - cephem - 4 - carboxylic acid 15 7 - - (2 - amino - 4 - thiazolyl)acetamido/ -3 - cephem - 4 - carboxylic acid f 16 7 - /"2 - (2 - amino - 4 - thiazolyl)glycinamido/ t - 3 - cephem - 4 - carboxylic acid formate 17 7 - - (2 - amino - 4 - thiazolyl) - 2 - hydroxy acetamidq7 - 3 - cephem - 4 - carboxylic acid r6 > t- (O (3) Test results Test Strains 1 j 1 1 2 ! 3 4 5 . 1 ^ 1 i 8 Staphylococcus aureus 209P JC-1 6.25 j 0.39 ! 3.13 i 5 12.5 | 1.56 1 0.78 1.56 1.56 Escherichia coli. NIHJ JC-2 <0.025 ' 0.1 0.0.5 ■ 0.39 0.2 0.39 0.2 0.1 Proteus vulgaris IAM-1025 <0.025 0.1 <0.025 <0.025 <0.025 0.05 <0.025 • <0.025 Klebsiella pneumoniae 20 <0.025 <0.025 <0.025 0.1 £0.025 i 0.2 ! <0.025 r <0.025 Proteus mirabilis 18 <0.025 <0.025 <0.025 0.0125 0.1 0.2 <0.025 <0,025 Pseudomonus aeruginosa NCTC-1G490 0.39 6.25 <1.56 6.25 <1.56 <1.56 <1.56 <1.56 Serratia ; marcescens 35 1.56 12.5 0.78 50 3.13 i I ' ' 6.25 1.56 3.13 * 100-fold dilution of an overnight culture MIC (g/ml)* i- •f. t-(0 ~^Compound No. Test Strains 9 10 11 12 13 Staphylococcus aureus 209P JC-1 0.39 1.56 0.39 1,56 1.56 Escherichia coli NIIIJ JC-2 3.13 1.56 3.13 0.1 0.2 Proteus vulgaris IAM-1025 0.39 0.2 0.78 <0.025 <0.025 Klebsiella pneumaniae 20 0.2 0.05 0. 39 0.1 0.05 Froteus niirabilis 18 1.56 0.78 1.56 0.2 0.2 Pseudomonus aeruginosa NCTC-10490 3.13 <1.56 •ssS <1. 56 <1.56 <1.56 Serratia narcescens 35 . 3.13 12.5 12.5 12.5 6.25 CO LC, * lOO-fold dilution of an overnight culture ® MIC (ug/ml)* Compound No. 14 15 16 17 Salmonella enteritidis 1.56 1.56 3.13 3.13 Escherichia coli 324 1.56 1.56 0.78 1.56 Klebsiella aergenes 417 0.1 0.2 0.39 0.78 Proteus mirabilis 520 0.78 0.39 0.78 1.56 Proteus vulgaris 616 12.5 6.25 1.56 12.5 I v , * Overnight culture 46674 ■ 2. Protecting effect against experimental infections in mice : .

CI) Test method Male ICR strain mice aged 4 weeks, each weighing 18.5 -521.5 g. were used in groups of 10 mice. The test bacteria were cultured overnight at 37°C on Trypticase-soy agar and then suspended in 55 mucin to obtain the suspension corresponding to cach challenge cells. Micc were- inoculated intraperitoneally with 0.5 ml. of the suspension. A solution containing each test compound: was given subcutaneously to the mice in various dosage one hour after the challenge. The ED,jq values were calculated from the number of surviving mice for each dosage after four days of observation. (2) Test compounds No. 1 7-[2-(2-Ainino-4-thiazolyl)-2-mcthoxyiminoacetamido] - 3-cephem-4-carboxylic acid (syn isomer) reference --- 7- [2-(2-Am.ino-4-thiazolyl) -2-methoxyimino-acetamido]cephalospolanic acid (syn isomer) 60 46674 (3) Test results : Test Bacteria Inoculated Cells/mouse ED50(s.c.)(mg/kg) MIC (pg/ml.) Test Compounds Inoculum Size Test Compounds 1 reference 1 reference Escherichia coli 54 1.1 x 107 0.95 2.8 0 *1 10u \ 0.78 3.13 10"2*2 0.05 0.1 Klebsiella pneumoniae 39 I f 8 x 106 <0.93 0.995 10° 0.39 3.13 10"2 <0.025 0.05 Proteus rettgeri 24 9.9 x 106 0.39 1.171 10° 1.56 50 10~2 <0.025 0.1 Serratia Ma rcos cms 58 1.2 x 107 3.562 A * ^ 31.427 15 10° 25 50 10"2 0.39 ,1.56 * 1 : overnight culture * 2 : 100-fold dilution of the overnight culture * 3 : treated with two divisional doses at 1 hr. and 3 hrs. after infection 3. Acute toxicity : (1) Test method : Ten male and 10 female rats aged 6 weeks (JCL-SD j strain) were used per group. Test compound dissolved in distilled water was given subcutaneously and intraveneously to the animals. These animals were observed for 7 days after dosing. The LD^q values were calculated from the number of dead animals by the Litchfield-Wilcoxon method. (2) Test compound : 7- [2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido]- 61 4 6 6 7 4 3-cephem-4-carboxylic acid (syn isomer) (3) Test results : ... . _ .

Test animal - Sex LD50 Cmg./kg.) s ,'C. i. v.

Rat Male Female >8000 >8000 about 8000 >8000 4. Absorbability (1) Test method : Test compound was given orally to a group of 5 ra'.s (JCL-SD strain, 6-week-old, male) which had been fasted. Bile and urine samples were collected at 0^6 and 6^24 hrs. The concentrations of the test compound in the samples were determined by bioassay (disk method) using Batillus subtilis ATCC-6633 as test organism, and the recoveries in bile and.urine were calculated. (2) Test compound : 7- [2- (2-amino - 4- thiazolyl) - 2-n-penty.loxyimino-acctamido]-3-cephem-4-carboxylic acid (syn isomer) (3) Test result : Total recovery in bile and urine in 24 hrs. was 22.8%.

For prophylactic and/or therapeutic administration, the active compound (I') of the present invention is used in 62 466 74 the form of conventional pharmaceutical preparation which contains said compound, as an active ingredient, in admixture with pharmaceutically acceptable carriers such as an organic pr inorganic solid or liquid excipient which is suitable for oral, parenteral or external administration. The pharmaceutical preparations may be in solid form such as capsule, tablet dragee, ointment or suppository, or in liquid form such as solution, suspension, or emulsion. If needed, there may be included in the above preparations auxiliary substances, stabilizing agents, wetting or emulsifying agents, buffers and the other commonly used additives.

While the dosage of the compounds may vary from and also depend upon the age and conditions of the patient/ a kind of disease and a degree of the infection, and further a kind of the active compound (I') to be applied, etc., an average single dose of about 50 mg., 100 mg., 250 mg. and 500 mg. of the active compound (I') is sufficient for treating infectious diseases caused by pathogenic bacteria. In general, the active compound (I\) can be administered in an amount between 1 mg/kg and 100 mg/kg, preferably 5 mg/kg and 50 mg/kg.

The starting compounds (III) some of which are disclosed and claimed in Patent Specification No. can be prepared as illustrated below. 4 6 674 x-ch,co-c-cooz (Ilia) 1 II n ) oh x - ci l co-c-cooz (iii.) i. || b' N ? 2 O-R r"-c-nh? a I. l (v"a>: N—TV c-cooz (i lip Vjfnh2 (viia) ) oh n c-cooz (iii.) it a Ra^S^ N o-r: n' H2N-S c-cooz I n > 2 o-r: (ine) c-cooh (IIIf) O-R' h a:J! c-cooh o-r a (HIg) r^-onh2 (xiv) n~ Ra"^S^ -c-cooh (iii.) II ^ 0 nnh-y h,cco-c-cooz (xv) J ti N > 2 O-R^ a N r c-cooz (iii.) iJ" n I O-R a y-nhnh- (xvi) h,c-c-c-cooz 1 ^ ■ J n ) , sx2 (xviii) O-R n—r c «' J 11 a c-cooh ) 2 o-r' (xvii) (inp 64 46674 2 wherein Ra is an aliphatic hydrocarbon residue which may be substituted with halogen,' carboxy or esterified carboxy is protected amino X is halogen Y is lower alkoxycarbonyl, and Z is lower alkyl Each of the above processes are explained in the following.

Process 1 : F.thcrif i cat ion The compound (II1^) and (II1^) can be prepared by reacting a compound (III ) or (III ) with an etherifying H C agent, respectively.

This reaction may be conductcd substantially in the same manner as the aforementioned Process C.

Process 2 : Thiazole ring formation The compound (IIIc) and (III^) can be prepared by reacting a compound (III ) or (III.) with a thiourea compound s d (VIIa), respectively, and further the compound (IIIe) can be prepared by reacting a compound (II1^) with thiourea.

This reaction may be conductcd substantially in the same manner as the aforementioned Process D.

Process 3 : Elimination of amino-protective group The compound (111 e) an-d (III ) can be prepared by subjecting a compound (III^) or (III£•) to elimination reaction of the protective group in the protected amino group for R^, 65 46674 j respectively. ! This reaction may be conducted substantially in the same manner as the aforementioned Process E.

Process 4 : Carboxy formation The compound (Hlf) , (III ) and (III.) can be 8 3 prepared by transforming the esterified carboxy group of a compound (III^), (IIIe) or (III^) into free carboxy group, respectively.

This reaction may be conducted substantially in the same manner as the aforementioned Process K. i • ' Process S : Oximation i The compound (Ijr) can be also prepared by jreacting a compound (111j) with a hydroxylamine derivative (XIV) or its salt.

The hydroxylamine derivative (XIV) may be hydroxylamine substituted with an aliphatic hydrocarbon residue which may be substituted with halogen, carboxy or esterified caiboxy, particulars of which are to be referred to those as exemplified before. Suitable salt of the hydroxylamine derivative (XIV) may be hydrochloride, . hydrobromide, sulfate or the like. ! The reaction is usually conducted in a conventional solvent such as water, alcohl, tetrahydrofuran, acetonitrile, dimethylsulfoxide, pyridine or any other solvent which does not adversely influence the reaction, or a mixture thereof, and the reaction temperature is not critical.

In case that a salt of the hydroxylamine derivative (XIV) is used as a reagent, the reaction is preferably 46674 conducted in the presence of a conventional base.

Proccss 6 : Thiadiaaol ring formation The compound (III^) can be prepared by reacting a compound (XV) with a hydrazine derivative (XVI), and then reacting the resultant compound (XVII) with sulfur dihalide (XVIII).

Among the starting compound (III), the compound of the formula R1-C-COOR8 a II N (III') ) 21 °"Ra I wherein R* is thiadiazolyl or thiazolyl of the formula: N R<>Js Jj in which R^ is amino or protected amino, 2' ^ Rq is alkyl, alkenyl or alkynyl having more than one carbon atom or cycloalkyl which may be substituted with halogen, carboxy or esterified carboxy, 8 R is hydrogen or lower alkyl, provided that R6 is amino which may be protected with formyl, 8 2' and R is hydrogen, when R is ethyl, isopropyl or allyl, a is novel and useful as a starting material in the aforementioned Process A.

Particulars of each definition in the above are to be referred to those as explained before.

Following examples are given only for explaining this invention in more detail. n 46674 i i ! .! Preparation of the startling compounds Example A (1) A solution of-ethyl 2-methoxyiminoacetoacetate (a mixture of syn and anti isomers) (34.6 g.) and t-butoxy-5 carbonylhydrazine (26.4 g.) in ethanol (200 ml.) was stirred for 7.5 hours at ambient temperature and allowed to stand overnight to precipitate crystals. The crystals were collected by filtration, washed with ethanol and dried to give ethyl 2-methoxyimino-3-t-butoxycarbonylhydrazonobutyrate 10 (a mixture of syn and anti isomers) (41.7 g.), mp 144 to 145°C. : 3200, 1750, 1705, 1600, 1520 cm"1! N.M.R. «ppjn (CDCS.3) : 8.52 (IH, broad s), 4.35 (211, q, J=7Hz), 4.10 (3H, s) , 15 2.00 (3H, s), 1.50 (9H, s), 1.33 (3H, t, J=7Hz) (2) Sulfur dichloride (15.9^ml.) was added with stirring / at ambient temperature to a solution of ethyl 2-methoxyimino-3-t-butoxycarbonylhydrazonobutyrate (a mixture of syn and 2o isomers) (14.36 g.) in methylene chloride (150 ml.), and the mixture was stirred for 1 hour at ambient temperature. To the reaction mixture was added ice-water (300 ml.), and the methylene chloride layer was washed with water, with a saturated aqueous solution of sodium bicarbonate and with a 25 saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The solvent was distilled off to give an oil. The oil was purified by column chromatography on silica gel using a mixture of benzene and n-hexane (19:1) as on eluent to firstly give ethyl 2-methoxyimin.o-2-(1,2,3- M 4 6674 thiadiazol-4-yl)acetate (syn isomer) (1.8 g.), mp 77 to 79°C.

I.R. v ^j01 : 1720, 1595 cm"1 N.M.R. 6ppjn (CDCH3) : 8.92 (IH, s), 4.46 (2H, q, J«7Hz), 4.06 (3H, s), 1,38 (3H, t, J=7Hz) From subsequent fractions, ethyl 2-methoxyimino-2-(1,2,3-thiadiazol-4-yl)acetate (anti isomer) (0.7 g.) was obtained as an oil. 10 I.R. v £*lm : 1730, 1590 cm'1 N.M.R. 6ppm (CDCA3) : 9.38 (IH, s), 4.47 (2H, q, J»7Hz), 4.20 (3H, s), 1.40 (3H, t, J«7Hz) (3) IN Aqueous solution of sodium hydroxide (6.7 ml.) 15 was added to a solution of ethyl 2-methoxyimino-2-(1,2,3- ' , • thiadiazol-4-yl)acetate (syn isomer) (1.2 g.) in methanol (10 ml.) and the mixture was stirred for 1.5 hours at ambient temperature. Methanol was distilled off from the reaction mixture and water was added to the residue. The 2o mixture was washed with ether, adjusted to pH 1 with 10% hydrochloric acid and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The solvent was distilled off to give prisms of 2-methoxyimino-25 2-(1,2,3-thiadiazol-4-yl)acetic acid (syn isomer) (0.7 g.), m.p. 110 to 113°C. 1 .R. v : 2750-2150, 1730, 1595 cm'1 N.M.R. 6ppm (dg-DMSO) : 9.47 (IH, s), 4.01 (3H, s) 69 4 6 6 7 4 I W i i Example B I (1) Pulverized potassium carbonate (160 g.) was added to a solution of ethyl 2-hydroxyiminoacetoacetate (a mixture of syn and anti isomers) (152 g.) in acetone (500 ml'.). Dimethyl sulfate (130 g.) was dropwise added thereto with stirring over 1 hour at 45 to 50°C and the mixture was stirred for 2 hours. An insoluble material was filtered off and the filtrate was concentrated under reduced pressure. The filtered insoluble material was dissolved in water (500 ml.) and this solution was added to the residue. The mixture was extracted twice with ethyl acetate (300 ml.). The extract was washed twice with water (200 ml.) and with a saturated sodium chloride aqueous solution (200 ml.) and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was distilled under reduced pressure to give colorless oil of ethyl 2-methoxyiminoacetoacetate (a mixture of syn and anti isomers) (145.3 g.), bp 55 to 64®C/0.5 mm Hg.

I.R. v £*1,n : 1745, 1695, 1600 cm"1 N.M.R. «ppjn CCDGA3) : 4.33 (4H, q, J=8Hz), 4.08 (3H, s), 3.95 (3H, s) , 2.40 (3H, s), 1.63 (3H, s), 1.33 (6H, t, J=8Hz) (2) Sulfuryl chloride (235 ml.) was dropwise added over 20 minutes with stirring and ice-cooling to a solution of ethyl 2-methoxyiminoacetoacetate (syn isomer) (500 g.) in acetic acid (500 ml.), and the mixture was stirred overnight under cooling with water. Nitrogen gas was 70 466 introduced to the reaction mixture for 2 hours, and the j resulting mixture was poured into water (2.5 £..) After | I I extracting with methylene chloride (500 ml.) and twice j with methylene chloride (200 ml.), the extracts were combined. The combined extract were washed with a saturated aqueous solution of sodium chloride, and adjusted to pH 6.5 by adding water (800 ml.) and sodium bicarbonate. Methylene chloride layer was separated, washed with an aqueous solution of sodium chloride and dried over magnesium sulfate. The solvent was distilled off to give ethyl 2-methoxyimino-4-chloroacetoacetate (syn isomer) (559 g.). 1.R. v £*lm : 1735, 1705 cm"1 (3) Ethyl 2-methoxyimino-4-chloroacetoacetate (syn isomer) (50 g.) was added over 3 minutes with stirring at ambient temperature to a solution of thiourea (18.4 g.) i and sodium acetate (19.8 g.) in a mixture of methanol (250 ml.) and water (250 ml.). After stirring for 35 minutes .1 at 40 to 45°C, the reaction mixture was cooled with ice and adjusted to pH 6.3 with a saturated aqueous solution of i sodium bicarbonate!. After stirring for 30 minutes at the same temperature, precipitates were collected by filtration, • j washed with water i(200 ml.) and then with diisopropyl ether | (100 ml.), and dried to give colorless crystals of ethyl • i 2-methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetate (syn isomer) (37.8 g.), m.p. 161 to 162°C. 1 .R. v JJjJ*01 : 3400, 3300, 3150, 1725, 1630, 1559 cii)'1 N.M.R. 6ppm (CDCJt3) : 6.72 (IH, s), 5.91 (2H, broad s), 4.38 (2H, q, J=7Hz), 4.03 (3H, s), 1.38 (3H, t, J=7Hz) 71 46674 (4) Ethanol (10 ml.) was added to a suspension of ethyl 2-methoxyimino-2-(2-amino-l,3-thiazol-4-yl)acetate (syn isomer) (2.2 g.) in: a IN aqueous solution of sodium hydroxide (12 ml.) and the mixture was stirred for 15 hours at ambient temperature. The reaction mixture was adjusted to 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-amino-1,3-thiazol-4-yl)acetic acid (syn isomer) (1.1 g.) ; I,R' v max01 : 3150> 1670, 1610, 1585 cm"1 j N.M.R. 6ppm (dg-DMSO) : 7.20 (2H, broad s), 6.85 (IH, s), 3.83 (3H, s) 72 Example C 46674 (1) Sulfuryl chloride (35.2 g.) was added all at once to the stirred solution of ethyl 2-ethoxyimino-3-oxobutyrate (syn isomer, 48.9 g.) in acetic acid (49 ml.) 5 at room temperature, and stirred at the same temperature for an hour. After adding the resultant solution into water (200 ml.), the solution was extracted with methylene chloride. The extract was washed with a saturated aqueous solution of sodium chloride, neutralized with 10 an aqueous solution of sodium bicarbonate and washed with water. The solution was dried over magnesium sulfate and concentrated under reduced pressure to give ethyl 2-ethoxyimino-3-oxo-4-chlorobutyrate (syn isomer, 53.8 g.), pale yellow oil. 15 (2) A mixture of ethyl 2-ethoxyimino-3-oxo-4-chlorobutyrate (syn isomer 38.7 g.), thiourea (13.2 g.), sodium acetate (14.3 g.), methanol (95 ml.) and water (95 ml.) was stirred at 48°C foT 40 minutes. After the resultant solution was adjusted to pH 6.5 with an aqueous solution 2o of sodium bicarbonate, the appeared precipitates were collected by filtration and washed with diisopropyl ether to give ethyl 2-(2-amino-4-thiazolyl)-2-ethoxyiminoacetate (syn isomer, 14.7 g.), mp 130 to 131°C.

I.R.v : 3450, 3275, 3125, 1715, 1620 cm"1 73 4 6 674 , (3) Ethyl 2-(2- I. R. vj^jo1 3625, 3225 (shoulder), 3100, 1650, 1615 cm"1 N.M.R. fippm (DMSO-dg) : 1.20 (3H, t, J»7Hz), 4.09 (2H, q, J=7Hz), 6.82 (IH, s), 7.24 (2H; broad s) (4) 2-(2-Aminothiazol-4-yl)-2-ethoxyiminoacetic acid (syn isomer, 100 g.), formic acid (85.5 g.) and acetic anhydride (190.1 g.) were treated in a similar manner to that of Example F-(5) to give 2-(2-formamidothiazol-4-yl)-2-ethoxyiminoacetic acid (syn isomer, 99.1 g.).

!-R- v max01 : 3200» 3140> 3050» 1700 cm"1 N.M.R. 6.(DMSO-d6, ppm) : 1.18 (3H, t, J-6Hz), i 4.22 (2H, q, J=6Hz), 7.56 (IH, s), 8.56 (IH, s), 12.62 (IH, broad s) 74 10 Example D j 4 6 6 7 4 (l) To a suspensionof ethyl 2-hydroxyimino-3-oxobutyrate (syn isomer, 15 g.) and potassium carbonate (19.8 g.) in acetone (75 ml.) was added dropwise propyliodide (16.2 g.) with stirring, and the mixture was stirred at ambient temperature for 1,5 hours. The insoluble substance was collected by filtration and washed with acetone. The washings and the filtrate were combined and evaporated to dryness under reduced pressure.To th^resultant residue was added water and the aqueous solution was extracted twice with chloroform. The extract was washed with an aqueous solution of sodium chloride, dried over magnesium sulfate, and then evaporated to dryness under reduced pressure to give ethyl 3-oxo-2-propoxyiminobutyrate 15 (syn isomer, 15.4 g.), oil. (2), Ethyl 3-oxo-2-propoxyiminobutyrate (syn isomer, 15.4 g.) and sulfuryl chloride (10.6 g.)were dissolved in acetic acid (15.4 ml.), warmed at 35 to 40°C for 10 minutes with stirring and then stirred at ambient temperature for on additional 6 hours. The reaction mixture was poured into / ice-water (200 ml.) andthe resultant mixture was extracted twice with chloroform. The extract was washed with an aqueous solution of sodium chloride, twice a saturated aqueous solution of sodium bicarbonate and once with water 2^ in turn, dried over magnesium sulfate, and then evaporated to dryness under reduced pressure to give ethyl 4-chloro-3-oxo-2-propoxyiminobutyrate (syn isomer, 15.4 g.), oil. I.R. i^x"1 = "40, 1710, 169S, 1455 cm"1 75 46674 (3) Ethyl 4-chloro-3-oxo-2-propoxyiminobutyrate (syn isomer, 15.4 g.), thiourea (4.97 g.) and sodium acetate hydrate (8.89 g.) were dissolved in a mixture of water (40 ml.) and ethanol (50 ml.), and stirred at 40°C for an hour. 5 The reaction mixture was adjusted to pH 6.5 with a saturated aqueous solution of potassium carbonate under cooling and stirred at the same temperature for half an hour. The precipitating crystals were collected by filtration, washed with water and diisopropyl ether, and then dried to give crystalline ethyl 10 2-(2-amino-4-thiazolyl)-2-propoxyiminoacetate (syn isomer, 10.55 g.), mp 142 - 144°C.

I-R* Vial01 : 3460' 3260' 3120, 1720, 1620, 1540~cm"1 * max N.M.R. £ ppm (dg-DMSO) : 0.88 (3H, t, J=7Hz), 1.27 (3H, t, J=6Hz), 1.60 (2H, sextet, J=7Hz), 15 4.04 (2H, t, J=7Hz), 4.28 (2H, q, J=6Hz), 6.86 (IH, s), 7.23 (2H, s) (4) A solution of ethyl 2-(2-amino-4-thiazolyl)-2-propoxyiminoacetate (syn isomer, 10 g.) in a mixture of tetrahydrofuran (39 ml.), methanol (39 ml.) and IN sodium hydroxide (75.8 ml.) 20 was stirred at 35 to 40°C for 5 hours.

After the resultant solution was concentrated under reduced pressure, the aqueous residue was adjusted to pH 2.5 with 10% hydrochloric acid. The precipitates were collected by filtration «nd dried to give 2-(2-amino-4-thiazolyl)-2-propoxyiminoacetic icid (synisomer, 6.2 g.), mp 161°C (dec.) I.R. i/„ax01 : 3380' 3120 (broad), 1630, 1610, 1460 cm"1 N.M.R. ^ ppm (DMSO-dg) : 0.89 (3H, t, J=7Hz), 1.63 (2H, sextet, J=7Hz), 4.05 (2H, t, J=7Hz), 6.83 (IH, s), 6.9 - 8.8 (3H, broad) 76 46674 10 (5) 2-(2-Aminothiazol-4-yl)-2-n-propoxyiminoacetic acid (syn isomer, 21.8 g.), acetic anhydride (38.8 g.) and formic acid (17.5 g.) were treated in a similar manner to that of ExampleF-(5), and then the obtained oil was triturated with diisopropyl ether to give 2-(2-formamidothiazol-4-yl)-2-n-propoxyiminoacetic acid (syn isomer, 19.2 g.), mp. 164°C (dec.) I.R. v Nujo1 : 3200, 3120, 3050, 1700, 1550 cm"1 1 * * max ' ' N.M.R. 6(DMSO-d6, ppm) : 0.92 (3H, t, J=7Hz), 1.67 (2H, sextet, J=7Hz), 4.12 (2H, t, J=7Hz), 7.53 (IH, s), 8.54 (IH, s) 77 46 67 4 Example E , (1) Ethyl 2-hydroxyimino-3-oxobutyrate (syn isomer, 30 g.), iso-propyl iodide (32.5 g.), potassium carbonate (39.5 g.) and acetone (150 ml.) were treated in a similar manner to that 5 of ExampleD -(1) to give ethyl 2-iso-propoxyimino-3-oxobutyrate (syn isomer, 35.4 g.), oil.

I,R* v max"1 : 1745» 1690» 1600 cm l N.M.R. 6 (CCJ&4, ppm) : 1.33 (3H, t, J=7Hz), 1.35 (6H, d, J=6Hz), 2.32 (3H, s), 10 4.1^4.7 (3H, m). (2) Ethyl 2-iso-propoxyimino-3-oxobutyrate (syn isomer 35.4 g.), sulfuryl chloride (24.5 g.) and acetic acid (35.4 ml.) were treated in a similar manner to that of Example D- (2) to give ethyl 4-chloro-3-oxo-2-iso-propoxyiminobutyrate 15 (syn isomer, 41.5 g.), oil.

I,R* v max"* : 1745' 1715, 1375 cm"1 (3) Ethyl 4-chloro-3-oxo-2-iso-propoxyiminobutyrate (syn isomer, 41.5 g.), thiourea (13.4 g.), sodium acetate (14.4 g.), water (110 ml.) and ethanol (110 ml.) were treated in a similar 2o manner to that of Example D-(3) to give ethyl 2-(2-aminothiazol-4-yl)-2-iso-propoxyiminoacetate (syn isomer, 27.3 g.), mp. 162 to 164°C. 1 .R. v 5Ja£o1: 3460» 3430» 3260» 3150» 1725» 1^1S 1540 cm"1 25 N.M.R. (DMSO-dg, ppm) : 1.17 (6H, d, J«6Hz), 1.24 (311, t, J=7Hz), 4M.7 (3H, m), 6.86 (IH, s), 7.24 (2H, s) 78 (4) Ethyl 2-(2-aminothiazol-4-yl)-2-iso-propoxyimino-acetate (syn isomer, 26.8 g.), IN aqueous solution of sodium hydroxide (156 ml.), methanol (156 ml.) and tetrahydrofuran (100 ml.) were treated in a similar manner to that of Example D"(4) to give 2-(2-aminothiazol-4-yl)-2-iso-propoxyimino-acetic acid (syn isomer, 15.3 g.), mp. 151°C (dec.).

I .R. v jjj[j01: 3610, 3580, 3080, 1650, 1610 cm"1 N.M.R. 6(DMS0-d6, ppm) : 1.22 (6H, d, J=6Hz), 4.33 (IH, quintet, J=6Hz), 6.80 (IH, s), 7.22 (2H, broad s) (5) 2-(2-Aminothiazol-4-yl)-2-iso-propoxyiminoacetic acid (syn isomer, 4 g.), acetic anhyddride (7.6 g.) and formic acid (3.4 g.) were treated in a similar manner to that of ExampleF-(5) to give 2-(2-formamidothiazol-4-yl)-2riso-propoxyiminoacetic acid (syn isomer, 3.75 g.), mp. 168 to 169°C (dec.). 1 «R. v jjjjj01 : 3200, 3130, 1710, 1600, 1560 cm"1 N.M.R. 6(DMS0-d6, ppm)i : 1.26 (6H, 4), 4.4 (IH, m), 7.54 (IH, s) , 8 i 52 (IH, s), .12.56 (IH, broad s) 7* 4 6674 j Example P (1) n-Butyl iodide (46.9 g.) was added dropwise to a stirred'suspension of ethyl 2-hydroxyimino-3-oxobutyrate (syn isomer, 40 g.), potassium carbonate (52.7 g.) and acetone (200 ml.) under ice-cooling over 5 minutes, and stirred at room temperature for 4 hours. The resultant solution was filtered, and washed with acetone. The filtrate and washing solution were combined together and concentrated in vacuo. After adding water (300 ml.) to the residue, the solution was extracted with methylene chloride three times. The solution was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated in vacuo to give ethyl 2-n-butoxyimino-3-oxobutyrat'e (syn isomer, 48.8 g.), oil.

I.R. v max™ : 1750' 1700» 1470, 1370, 1320cm'1 (2) A solution of etjiyl 2-n-butoxyimino-3-oxobutyrate (syn isomer, 48.8 g.), sulfuryl chloride (31.5 g.) and acetic acid (48.8 ml.) was stirred at 40°C for 10 minutes and further at room temperature for 5.5 hours. After water (300 ml.) was added to the resultant solution under ice cooling, the solution was extracted with methylene chloride three times. The extract was washed with water, an aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride in turn, and dried over magnesium sulfate. The solution was concentrated in vacuo to give ethyl 2-n-butoxyimino-4-chloro-3-oxobutyrate (syn isomer, 52.1 g.), oil.

•E * 1 R" v U! ; 174°. 1710, 1470, 1370 cm"1 80 (3) A solution of ethyl 2-n-butoxyimino-4-chloro-3-oxobutyrate (syn isomer, 52.1 g.), thiourea (15.9 g.), sodium acetate 3 hydrate (28.4 g.), water (130 ml.) and ethanol (180 ml.) was stirred at 40°C for 1.25 hours. The resultant solution was adjusted to pH 6.5 with an aqueous solution of sodium carbonate under ice cooling, and stirred for 20 minutes under ice cooling. The precipitates were collected by filtration, and washed with water and diisopropyl ether in turn to give ethyl 2-(2-aminothiazoi-4-yl)-2j-n-butoxyiminoacetate (syn isomer, 36.1 g.), mp 126 I. R. v max01 : 3460' 3370» 3230' 1720» 1620» 1550 cm"1 N.M.R. '6(DMSO-dg, ppm) : 0.6 - 2.0 (6H, m), 1.28 (3H, t, J=7Hz)| 4.12 (3H, t, J»6Hz), 4.31 (2H, q, J«7Hz), 6.89 (IH, s), 7.24 (2H, s) (4) A solution of ethyl 2-(2-aminothiazol-4-yl)-2-n-butoxyiminoacetate (syn isomer, 36 g.), methanol (133 ml.), tetrahydrofuran (133 ml.) and 2N aqueous solution of"sodium 2o hydroxide (133 ml.) was stirred at 30°C for 5 hours. After the resultant solution was concentrated in vacuo, the residue was dissolved in water. The solution was adjusted to pH 7 with 10% hydrochloric acid and treated with activated charcoal. The solution was adjusted to pH 2.0 with 25 10% hydrochloric acid and stirred for 20 minutes under ice cooling. The precipitates were collected by filtration, washed with water and acetone in turn, and dried to give 2-(2-aminothiazd-4-yl)-2-n-butoxyiminoacetic acid (syn isomer, 25.4 g.). 8! 46674 I. R. v Ny>o1 : 3325, 3190,' 1660, 1620 cm"1 max N.M.R. 6(DMSO-d6, ppm) : 0.88 (3H, t, J=7Hz), 1.0-1.9 (4H, m), 4.06 (2H, t, J=7Hz), 6.81 (IH, s), 7.21 (2H, broad s) ^ (5) Formic acid (18.95 g.) was added dropwise to acetic . anhydride (42.0 g.) under stirring at room temperature over i 5 minutes, and stirred at 50°C for an hour. 2-(2-Aminothiazol-4-yl)-2-n-butoxyiminOacetic acid (syn isomer, 25 g.) was ; added to the solution under ice cooling, and stirred at room 10 temperature for 3 hours and additionally.at 30°C for an hour. After concentrating the resultant solution in vacuo, the \ residue was dissolved in diethyl ether. The solution was j: washed with water and a saturated aqueous solution of sodium3; chloride in turn, dried over magnesium sulfate and concentrated in vacuo. The obtained oil was triturated with a solution of n-hexane (1 part) and diisopropyl ether (1 part), and collected by filtration to give 2-(2-formamidothiazol-4-yl)-2-n-butoxyiminoacetic acid (syn isomer, 20.1 g.).

I.R. v Ua£o1 : 3350» 3160» 3050» 1700, 1680, | 1570 cm"1 j 2Q N.M.R. |6(DM^O-dg, ppm) : 0.91 (3H, t, J«6Hz), 1.0 - 2.2 (4H, m), 4.18 (2H, t, J=6Hz), 7.57 (IH, s), 8.59 (111, s), 12.66 (IH, j broad s) I Example Q 25 (1) Ethyl 2-hydroxyimino-3-oxobutyrate (syn isomer, 40 g.), N,N-dimethylformamide (200 ml.), potassium carbonate (52.7 g.) and iso-butyl bromide (34.94 g.) were treated in a similar manner to that of ExampleF -(1) to give ethyl s? I | . 46674 2-iso-butoxyimijio-3-oxo-butyrate (syn isomer, 42 g.). I. R. v : 1740, 1670 (broad) cm"1 (2) Ethyl 2-iso-butoxyimino-3-oxobutyrate (syn isomer, 42 g.)» acetic acid (42 ml.) and sulfuryl chloride (27.1 g.) 2 were treated in a similar manner to that of Example F-(2) to give ethyl 2-iso-butoxyijnino-4-chloro-3-oxobutyrate (syn isomer, 31.9 g.).

I. R. v fllm« * 1750, 1720, 1680 cm"1 ir.a.x (3)' . Ethyl 2-i'so1-butoxyimino-4-chloro-3-oxobutyrate 10 (syn isomer, 31.9 g.), thiourea (9.72 g.), sodium acetate 3-hydrate (17.4 g.), ethanol (120 ml.) and water (80 ml.) were treated in a similar manner to that of Example F-(3) to give ethyl 2-(2-aminothiazol-4-yl)-2-iso-butoxyimino-acetate (syn isomer, 17.6 g.), mp 122 to 124°C. 15 I. R. v JUj01 : 3470, 3260, 3120, 1730, 1620, 1545 cm"1 N.M.R. 6(DMSO-d6, ppm) : 0.86 (6H, d, J=7Hz), 1.28 (3H, t, J=7Hz), 1.6-2.2 (IH, m), 3.86 (2H, d, J=7Hz), 4.28 (2H, q, J=7Hz), 2o 6.86 (IH, s), 7.22 (2H, s) (4) Ethyl 2-(2-aminothiazol-4-yl)-2-iso-butoxyimino-acetate (syn isomer, 19.6 g.), 2N aqueous solution of sodium hydroxide (72.2 ml.), methanol (72.2 ml.) and tetrahydrofuran (72.2 ml.) were treated in a similar manner to that of 25 ExampleF-(4) to give 2-(2-aminothiazol-4-yl)-2-iso- butoxyiminoacetic acid (syn isomer, 16.1 g.), mp 180°G (dec.).

R- v !J"io1 : 3375, 3300, 3130, 3050, 1640 cm"1 max ' N.M.R. S(DMSO-d6, ppm) : 0.91 (6H, d, J=7Hz), 1.5-2.3 (IH, m), 3.90 (2H, d, J=7Hz), 6.87 (IH, s), 7.26 (2H, broad s) 63 4 667 4 I • (5) 2-(2-Aminothia'zol-4-y.l)-2-iso-butoxyiminoacetic acid (syn isomer, 11.5 g.) , acetic anhydride (19.3 g.) and formic acid (8.7 g.) were treated in a similar manner to that of Example F-(5) to give 2-(2-formamidothiazol-4-yl)- 2-iso-butoxyiminoacetic acid (syn isomer, 11.15 g.), mp 163°C (dec.).

I. R. v : 3175, 3110, 3050, 1695, 1550 cm'1 N.M.R. 6(DMSO-dg, ppm) : 0.91 (6H, d, J=7Hz), 1.7-2.3 (IH, m), 3.92 (2H, d, J=7Hz), 7.52 (IH, s), 8.52 (IH, s:), 12.58 (IH, broad S) Example H (1) Ethyl 2-hydroxyimino-3-oxobutyrate (syn isomer, 30 g.), N,N-dimethylformamide (100 ml.), potassium carbonate (39.5, g.) and cyclohexyl bromide (31.1 g.) were treated in a similar manner to that of Example P-(l) to give ethyl 2-cyclohexyloxy-imino-3-oxobutyrate (syn isomer, 41.8 g.), oil.

I,R* v max*" : 1740' 1680 cm 1 (2)i Ethyl 2-cyclohexyloxyimino-3-oxobutyrate (syn isomer, 41.3 g.), acetic acid (41.3 ml.) and sulfuryl chloride (23.8 g.) were treated in a similar manner to that of Example F-(2) to give ethyl 4-chloro-2-cyclohexyloxyimino-3-oxobutyrate i (syn isomer, 27.8 g.), oil. j I,R" v max"1 : 1745' 1715» 1680 cm 1 ! (3) Ethyl 4-chloro-2-cyclohexyloxyimino-3-oxobutyrate (syn isomer, 27.8 g.), thiourea (7.7 g.), sodium acetate 3-hydrate (13.7 g.), water (70 ml.) and ethanol (140 ml.) were treated in a similar manner to that of ExampleF -(3) to give ethyl 2-(2-aminothiazol-4-yl)-2-cyclohexyloxyiminoacetate (syn isomer, 3.6 g.), mp. 125 to 126°C. 84 46674 1.R. " j v mai01 : 3430' 3250' 3160, 3130' 171S* 1635 cm'1 N.M.R. 6(DMSO-d6, ppm) : 1.28 (3H, t, j=7Hz), 1.0^2.2 (1011, m), 4.22 (IH, m), 4.32 (2H, q, J=7Hz) , 6.88 (IH, s) , _ 7.24 (2H, broad s) D (4) Ethyl 2-(2-aminothiazol-4-yl)-2-cyclohexyloxyiminoacetate (syn isomer, 3.5 g.), 2N aqueous solution of sodium hydroxide (11.8 ml.), methanol (11.8 ml.) and tetrahydrofuran (11.8 ml.) were treated in a similar manner to that of Example F-(4) to 10 give 2-(2-aminothiazol-4-yl)-2-cyclohexyloxyiminoacetic acid (syn isomer, 2.1 g.), mp. 148°C (dec.).

I.R. v max01 : 3110' 1630» 1450 cm 1 N.M.R. 6(DMSO-dg, ppm) : 0.8%2.3 (10H, m), 4.14 (IH, m), 6.86 (IH, s), 15 7,5 (2H, broad s) (5) 2-(2-Aminothiazol-4-yl)-2-cyclohexyloxyiminoacetic acid (syn isomer, 1.5 g.), acetic anhydride (2.27 g.) and formic acid (1.03 g.) were treated in a similar manner to that of Example F-(5), and the oil obtained was suspended in 20 an aqueous solution of sodium bicarbonate. The suspension was adjusted to pH 3.5 with 10% hydrochloric acid. The precipitates were collected by filtration, washed with water and dried to give 2-(2-formamidothiazol-4-yl)-2-cyclohexyloxyiminoacetic acid (syn isomer, 1.0 g.), mp. above 230°C. 25 I.R. v j^j01 : 3175, 3100, 3060, 1680 cm'1 Example I (1) Ethyl 2-hydroxyimino-3-oxobutyrate (syn isomer, 56.7 g.), N,N-dimethylformamide (280 ml.), potassium carbonate (72.3 g.) and propargyl bromide (43 g.) were treated in a similar manner 65 4 6 6 7 4 v.- ■ ; i | to that of ExampleF (1) to give ethyl 2-propargyloxyimino-3-oxobutyrate (syn isomer, 71.2 g.).

I,R* v max"1 : 3280' 3220> 2120' 1735' 1670 cm 1 (2) Ethyl 2-propargyloxyimino-3-oxobutyrate (syn isomer, 5 71.2 g.), acetic acid (81 ml.) and sulfuryl chloride (50.2 g.) were treated in a similar manner to that of Example F-(2) to give ethyl 4-chloro-3-oxo-2-propargyloxyiminobutyrate (syn isomer, 61.6 g.), oil.

I.R. v Jj*11" : 3300, 2130, 1745, 1720, 1675 cm'1 10 N.M.R. 6(CC£4, ppm) : 1.39 (3H, t, J=7Hz), 2.57 (IH, t, J=2Hz), 4.36 (2H, q, J=7Hz), 4.56/ (2H, s), 4.86 (2H, d, J=2Hz) / ' ; (3) Ethyl 4-chloro-3-oxo-^-propargyloxyiminobutyrate (syn isomer, 61 g.), thiourea (20 g.), sodium acetate 3-hydrate (35.8 g.), water (150 ml.) and ethanol (180 ml.) were treated i in a similar manner to that of Example F-(3) to give ethyl 2-(2-aminothiazol-4-yl)-2-propargyloxyiminoacetate (syn isomer, 35.6 g.). 1.R. v max01 : 3290' 2220» 1729 cm 1 2o N.M.R. 6 (DMSO-d^, ppm) : 1.28 (3H, t, J"'.yaa)f 3.49 (IH, t, J=3Hz), . 4.31 (2H, q, J= 7Hz),, 4.76 (2H, d, J»3Hz), 6.95 (IH, s), 7.29 (2H, s)\ (4) Ethyl 2-(2-aminothiazol-4-yl)-2-propargyloxyimino- 25 acetate (syn isomer, 2.8 g.), methanol (23 ml.), tetrahydrofuran (20 ml.) and IN aqueous solution of sodium hydroxide (22.17 ml.) were treated in a similar manner to that of Example F-(4) to give 2-(2-aminothiazol-4-yl)-2-propargyloxyiminoacetic acid (syn isomer, 1.924 g.). 30 r-R- » max"1 : 2190' 1740 06 46674 I j N.M.R. 6(DMSO-dg, ppm) : 3.47 (IH, t, J=1.5Hz), 4.74 (2H, d, J=1.5Hz), 6.90 (IH, s) ?7 4 6 674 v - Example J (l) Ethyl 2-hydroxyimino-3-oxobutyrate (syn isomer, 40 g.), N,N-dimethylformaido (200 ml.), potassium carbonate (52 g.) and n-hexyl bromide (41.4 g.) were treated in a similiafc .mariner ,to that of Example 5 F-(l) to give ethyl 2-n-hexyloxyimino-3-oxob]ncyrate (syn isomer, 60.7 g.), oil.

I. R. J/^"1 s 1740' 1705' 1700 cm"1 N. M. R. ^(CC14> ppm): 0.6-2.1 (14H, m), 2.37 (3H, a), 4.1—4.6 (4H, m) 10 (2) Ethyl 2-n-hexyloxyimino-3-oxobutyrate (syn isomer, 60.7 g.), acetic acid (61 ml.) and sulfuryl chloride (34.7 gO were treated in a similar manner to that of Example F-(2) to give ethyl 2-n-hexyloxyimino-4-chloro-3-oxobutyrate (syn isomer, 55.6 g.).

I* R*, : 1740» 1720» 1470 cm"1 15 N. M.' R. 5(CC14, ppm): 0.6-2.2 (14H, m), 4,1-4.6 <4H, m), 4.47 (2H, s) (3) Ethyl 2-n-hexyloxyimino-4-chloro-3-oxobutyrate (syn isomer, 55.6 g.), thiourea (15.2 g.), sodium acetate 3-hydr^e (27.2 gJ, ethanol (280 ml.) and water (140 ml.) were treated in a similar manner 20 to that of Example F-(3) to give ethyl 2-(2-aminothiazol-4-yl)-2-n-hexyloxyiminoacetate (syn isomer, 29.3 g.), mp 77 to 78 ®C. I. R. : 3460, 3250, 3140, 1720, 1535 cm"1 N. M. R. (DMSO-dg) J 0.85 (3H, t, J=6Hz), 1,0-1.9. (11H, m)* 2.07 (2H, t, J=6Hz), 2,26 (2H, q, J=7Hz), 6.85(1H, s), 7.22(2H, a) (4) Ethyl 2-(2-aminothiazol-4-yl)2-n-hexyloxyiminoacetate (syn' isomer, 29.1 g.)» methanol {97,2 ml.), 2N aqueous solution of sodium hydroxide (97.2 ml.) and tetrahydrofuran (50 ml.) were treated in a 88 4 6 6 7 4 .similar manner to! that of Example p—(4) to give 2-(2- aminothiazol-4-yl)-2-n-hexyloxyiminoacetic acid (syn isomer, 24.0 g.)f mp. 174°C (dec.). I. : 1660, 1625, 1425 cm"1 N.M.R. & (DMS0-d6, ppm) 0.6-2.1 (>1H, m), 4.07 (211, t, J=6Hz), 6.03 (IH, o), 7.19 (2H, s) 46674 Example K i (1) Ethyl 2-hydroxyimino-3-oxobutyrate (syn isomer, 40 g.), N,N-dimethylform^.itiide (200 ml.)1, potassium carbonate (52 g.) and pentyl bromide (37.9 g.) were treated in a similar manner to that of Example F -(1) to give ethyl 2-pentyloxyimino-3-oxobutyrate (syn isomer, 57.5 g.), oil. 1.R. v nix" : 1745> 1680' 1470 cm 1 N.M.R. 6 (CC«-4, ppm): 0.7 - 2.2 (12H, m), 2.36 (3H, s), 4.1 - 4.6 (4H, m) (2) Ethyl 2-pentyloxyimino-3-oxobutyrate (syn isomer, 5 7.5 g.), acetic acid (58.5 ml.) and sulfuryl chloride (20.9 ml.) were treated in a similar manner to that of Example F -(2) to give ethyl 2-pentyloxyimino-4-chloro-3-oxobutyrate (syn isomeT, 51.1 g.), oil. 1 .R. v £*lm : 1750, 1715, 1470 cm"1 N.M.R. 5 (CCJl4, ppm) : 0.7 - 2.1 (11H, m), 4.1 - 4.6 (4H, m), 4.48 (2H, s) (3) Ethyl 2-pentyloxyimino-4-chloro-3-oxobutyrate (syn isomer, 51.1 g.), thiourea (14.7 g.), sodium acetate trihydrate (26.4 g.), ethanol (175 ml.) and water (125 ml.) were treated in a similar manner to that of Example F -(3) to give ethyl 2-(2-aminothiazol-4-yl)-2-pentyloxyiminoacetate (syn isomer, 28.7 g.), mp 86 to 88°C.

I,Rl v max01 ; 3450» 3250' 3130> 171S» 1535 cm"1 90 4 6 6 7 4 N.M.R. 6 (DMSO-d6, ppm) : 0.6 - 2.0 (12H, m), 4.11 (2H, t, J=6Hz), 4.32 (2H, q, J«7Hz) , 6.90 (1H, s), 7.25 (2H, s) (4) Ethyl 2-(2-aminothiazol-4-yl)-2-pentyloxyiminoacetate (syn isomer, 28.6 g.), 2N aqueous solution of sodium hydroxide (100.2 ml.), methanol (100 ml.) and tetrahydrofuran (100 ml.) were treated in a similar manner to that of Example F -(4) to give 2-(2-aminothiazol-4-yl)-2-pentyloxyiminoacetic acid (syn isomer, 22.4 g.), mp 176°C (dec.).

I-R- v I!ai01 : 3160» 1655» 1620» 1460 cm 1 N.M.R. 6 (DMSO-dg, ppm) : 0.6 - 2.2 (9H, m), 4.07 (2H, t, J=6Hz), 6.82 (IH, s), 7.20 (2H, s) (5) 2-(2-Aminothiazol-4-yl)-2-pentyloxyiminoacetic acid (syn isomer, 15 g.), acetic anhydride (23.8 g.) and formic acid (10.7 g.) were treated in a similar manner to that of Example F -(5) to give 2-(2- formamidothiazol-4-yl)-2-pentyloxyiminoacetic acid (syn isomer, 14.7 g.), mp 125°C (dec.).

I.R. v NuJo1 : 3200, 3140, 1700, 1565 cm"1 max ' ' N.M.R. 6 (DMS0-d6, ppm) : 0.6 - 2.0 (9H, m), 4.13 (2H, t * J=6Hz), 7.53 (IH, s), 7.54 (IH, s), 12.66 (IH, s) 91 4 6 674 Example L (1) Allyl bromide (2.91 g^) was added dropwise to a stirre'd suspension of ethyl 2-(2-tritylaminothiazol-4-yl)-2-hydroxyimino-acetate (syn isomer, 10 g.), N,N-dimethylformamide (100 ml.) and potassium carbonate (4.54 g.) under ice cooling over 5 minutes, and stirred at the same temperature for 4 hours. After adding water (200 ml.) to the resultant solution, the solution was extracted with diethyl ether twice. The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The solution was concentrated in vacuo, and the residue was triturated with a solution of n-hexane and diethyl ether. The precipitates were collected by filtration to give ethyl 2-(2-tritylaminothiazol-4-yl)-2-allyloxyiminoacetate (syn isomer, 9.4 g.), mp. -130 to 132°C. 1 .R. v max01 : 3380' 1735> 1520, 1500 cm"1 N.M.R. 6(DMSO-dg, ppm) : 1.08 (3H, t, J=7Hz), 3.96 (2H, q, J=7Hz), 4.54 (2H, broad d, J=5Hz), S.0>5.5' (2H, m), 5.6^6.3 (IH, m), 6.90 (15H, broad s), 7.74 (IH, s) (2) A solution of ethyl 2-(2-tritylaminothiazol-4-yl)-2-allyloxyiminoacetate (syn isomer, 8.7 g.), 50% formic acid (42.5 ml.) and tetrahydrofuran (42.5 ml.) was stirred at 60°C for 40 minutes. After concentrating the resultant solution in vacuo, the residue was dissolved in.ethyl acetate, washed with an aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride in turn, and dried over magnesium sulfate. After concentrating the resultant solution 92 ,46 6 7 4 U 1 10 in vacuo, the residue was subjected to column chromatography on silica gel with benzene and ethyl acetate in turn, to give ethyl 2-(2-aminothiazol-4-yl)-2-allyloxyiminoacetate (syn isomer, 3.7 g.), mp- 102 to 104°C.

I,R* V max01 : 3':50» 3260» 3130 > 1725» 16i!0» 1540, 1460 cm"1 N.M.R. 6 (DMSO-dg, ppm) : 1.25 (3H, t, J=7Hz), 4.30 (2H, q, J-7Hz), 4.61 (2H, dd, J=5Hz, 1Hz), 5.0^5.5 (2H, m) , 5.6^6.5 (IH, m), 6.95 (IH, s), 7.28 (2H, s) (3) A solution of ethyl 2-(2-aminothiazol-4-yl)-2-allyloxy-iminoacetate (syn isomer, 3.6 g.), 2N aqueous solution of sodium hydroxide (14.1 ml.), tetrahydrofuran (14.1 ml.) and ^ methanol (15 ml.) was stirred at 40°C for 1.5 hours. The resultant solution was concentrated in vacuo, and the residue was dissolved in water. After the solution was adjusted to pH 2.8 with 10% hydrodhloric acid under ice cooling, the j precipitates were collected by filtration, washed with water and acetone in turn and dried to give 2-(2-aminothiazol-4-yl)-2-allyloxyiminoacetic acid (syn isomer, 1.91 g.), mp. 187°C (dec.).

I,R* v max01 : 3350' 1630' 1580' 1460 cm 1 N.M.R. 6 (DMS0-d6, ppm) : 4.61 (2H, d, J=6Hz), 5.1^5.5 (2H, m), 5.7^6.2 (IH, m), 6.84 (IH, s), 7.25 (2H, broad s) Example M (1) Propargyl bromide (4.16 g.) was added to a suspension of ethyl 2-(2-tritylaminothiazol-4-yl)-2-hydroxyiminoacetate (syn isomer, 10 g.), potassium carbonate (4.84 g.) and 20 25 30 S3 N,N-dimethylformamide (22 ml.);under atmosphere of nitrogen gas and stirred at room temperature for 100 minutes. The insoluble substance was filtered off and washed with a little of N,N-dimethylformamide. The filtrate and washing solution were combined together, and water (400 ml.) was added to the solution. After the suspension was extracted with ethyl acetate (400 ml.), the extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. After t - ; treating the solution with activated charcoal, the solution was concentrated in vacuo. The residue was triturated with di isopropyl ether. •The precipitates were collected by filtration, and washed .with diisopropyl ether to give ethyl 2- (2-tritylaminothiazol-4-yl),-2-propargyloxyiminoacetate (syn isomer,1 8. 34 g.). 1.R. v : 3290, 2225, 1735 cm"1 N.M.R. 6(DMS0-d6,; ppm) : 1.12 (3H, t, j=>7Hz)f '3.47 (IH, t, J-. ?Hz), 3.97 (2H, q, J= 7Hz), . 4.67 (2H, d, J= 3Hz), 6.95 (IH, s), 7.26 (15H, s), 8.77 (IH, s) (2) 50% Formic acid (41 ml.) was added to a solution of ethyl 2-(2-tritylaminothiazol-4-yl)-2-propargyloxyiminoacetate (syn isomer, 8.2 g.) and tetrahydrofuran (41 ml.), and stirred at 60°C for an hour. The resultant solution was concentrated to a half of initial volume under reduced pressure, and the precipitates were collected by filtration and washed with diisopropyl ether. The filtrate and washing solution were combined together and concentrated in vacuo. The residue was added to ethyl acetate (200 ml.) under stirring. The insoluble substance was collected by filtration, and washed 94 \ 4 6674 with diethyl ether to give ethyl 2-(2-aminothiazol-4-yl)-2-propargyloxyiminoacetatc (syn isomer, 0.3 g.). The filtrate and ethyl acetate washing solution were combined together, washed with a saturated aqueous solution of sodium bicarbonate 5 and a saturated aqueous solution of sodium chloride twice in turn, and dried over magnesium sulfate. The solution was treated with activated charcoal and concentrated in vacuo. The residue was dried in vacuo after adding benzene. The residue was subjected to column chromatography on silica gel with benzene and ethyl acetate in turn. The eluate was concentrated in vacuo, and the residue was triturated with diisopropyl ether. The precipitates were collected by filtration, washed with diisopropyl ether to give the same compound as mentioned above (syn isom.er, 2.658 g.). 15 The I.R. spectrum and N.M.R. spectrum are the same as those of the compound obtained in Example I -(3). ?5 46674 Example N Sodium bicarbonate (0.84 g.) was added to a suspension of 2-(2-formamidothiazol-4-yl)oxalic acid (2 g.) in water (120 ml.) to prepare a solution. Ethyl 2-aminoxyacetate hydrochloride (4.56 g.) was added to the solution and stirred at room,temperature for 3 hours while adjusting to pH 6, with sodium ' bicarbonate. The resultant solution was adjusted to pH 1.5 with hydrochloric acid, salted out and extracted with ethyl acetate three times. The extract was dried over magnesium sulfate and concentrated in vacuo. The residue was pulverized with diethyl ether, and the precipitates were collected by filtration and dried to give 2-(2-formamidothiazol-4-yl)-2-ethoxycarbonyImethoxyiminoacetic acid (syn isomer, 1.44 g.), mp 112°C (dec.).

I.R. v SfJ?1 : 3150, 1740, 1670, 1550 cm'1 utax N.M.R. 6 (DMSO-dg, ppm) : 1.23 (3H, t, J=7Hz), 4.16 (2H, q, J=7Hz), 4.77 (2H, s), 7.56 (IH, s), 8.54 (IH, 96 10 20 25 46674 Example 0 (1) Ethyl 2-hydroxyimino-3-oxobutyrate (syn isomer, 60 g.),. l-bromo-2-chloroethane (54.1 g.), potassium carbonate (78 g.) and N,N-dimethylformamide (200 ml.) were treated in a similar manner to that of Example F-fl) to give ethyl 2-(2-chloro2thoxyimino)-3-oxobutyrate (syn isomer, 83.6 g.), oil.

I.R. v Fllm : 1740, 1680, 1430 cm"1 max .

N.M.R. 6 (CCJ,4, ppm) : 1.34 (3H, t, J=7Hz) , 2.34 (3H, s), 3.72 (2H, t, J=6Hz) , 4.28 (2H, q, J=7Hz), 4.46 (2H, t, J=6Hz) (2) Ethyl 2-(2-chloroethoxyimino)-3-oxobutyrate (syn isomer, 83.6 g.), sulfury chloride (52.4 g.) and acetic acid (83.6 ml.) were treated in a similar manner 15 to that of Example F-(2) to give Ethyl 2-(2- chloroethoxyimino)-3-oxo-4-chlorobutyrate (syn isomer, 68 g.), oil.

I.R. v j^lm : 1740 , 1720 cm"1 N.M.R. 6 (CCJl4, ppm) : 1.32 (3H, t, J=7Hz), 3.70 (2H, t, J=6Hz), 4.29 (2H, q, J=7Hz), 4.47 (2H, s) , 4.48 (2H, t, J=6Hz) (3) Ethyl 2-(2-chloroethoxyimino)-3-oxo-4-chlorobutyrate (syn isomer, 68 g.), thiourea (20.2 g.) , sodium acetate trihydrate (36.2 g.), ethanol (270 ml.) and water (170 ml.) were treated in a similar manner to that of Example F-(3) to give ethyl 2-(2-aminothiazol-4-yl)-2-(2-chloroethoxyimino)acetate (syn isomer, 33.7 g.), mp 126 to 128°C. 97 46674 I.R. v Nu3o1 : 3440, 3260, 3140, 1725, max ' 1620, 1540 cm"1 N.M.R. 6 (DMSO-dg, ppm) : 1.30 (3h, t, J=7Hz) 3.78 (2H, t, J=6Hz), 4.1-4.6 (4H, m) , 6.96 (IH, s), 7.27 (2H, s) (4) Ethyl 2-(2-aminothiazol-4-yl)-2-(2-chloroethoxyimi.no)acetate (syn isomer, 30.5 g.) , IN aqueous solution of sodium hydroxide (220 ml.), methanol (110 ml.) and tetrahydrofuran (140 ml.) were treated in a similar manner to that of Example F-(4) to give 2-(2-amiriothiazol-4-yl)-2-(2-chloroethoxyimino) acetic acid (syn isomer, 23.4 g.), mp 201°C (dec.). 1 .R. J[!go1 : 3210, 3100, 1640, 1620, 1580 cm"1 N.M.R.

I.R. v Nu3o1 . 3200, 1700, 1600, 1560 cm"1 max ' ' N.M.R. « (DMS0-d6, ppm) : 4.83 (2H, q, J=8.5Hz), 7.65 (IH, s), 8.58 (IH, s), 12.60 (IH, broad s) Example Q 2-(2-Formamidothiazol-4-yl)oxalic acid (10 g.), sodium bicarbonate (4.2 g.) and tert-butyl 2-aminooxyacetate 25 99 46674 (8.1 g.) were treated in a similar manner to that of Example N tp give an;oil, The oil was triturated with n-hexane and the precipitates were collected by filtration and dried to give 2-(2-formamidothiazol-4-yl)-2-tert-butoxycarbonylmethoxyiminoacetic acid (syn isomer, 11.3 g.), mp 117°C (dec.). 1 .R. v JJaj01 : 3180, 3140, 1750, 1690, 1630 cm"1 N.M.R. 6 (DMSO-dg, ppm) : 1.46 (9H, s), 4.66 (2H, s), 7.56 (IH, s), 8.56 (IH, s), 12.67 (IH, broad s) 100 46674 Example R (1) Ethyl 2-hydroxyimino-5-oxobutyrate (syn isomer, lOO g.), N,N-dimethylformamide (300 ml.), potassium carbonate (130 g.) and braiooctane (121 g.) were treated in a similar manner to that of Example F (1) to give ethyl 2-n-octyloxyimino-3-oxobutyrate (syn isomer, 165.5 g.), oil.

•I.R.ufllm : 1745, 1695, 1470 cm"1 max N.M.R.6(CC14, ppm) : 0.6~2.1 (18H, m), 2.35 (3H, s), 4.0^4.6 (4H, m) (2) Ethyl 2-n-octyloxyimino-3-oxobutyrate (syn isomer, 165.5 g.), sulfuryl chloride (84.7 g.) and acetic acid (165 ml.) were treated in a similar manner to that of Example F-(2) to give ethyl 2-n-OGtyloxyimino-4-chloro-3-oxobutyrate (syn isomer, 169.6 g.),oil. film , I.R.U : 1745, 1710, 1465 cm max N.M.R <5 (CC14, ppm) : 0.6 2.1 (18H,m), 4.0^4.6 (4H, m) , 4,48 (2H, s), (3) Ethyl 2-n-OGtyloxyimino-4-chloro-3-oxobutyrate (syn isomer, 169.6 g), thiourea (42.3 g.), sodium acetate trihydrate (75.5 g.), water (420 mljand ethanol (1020 ml.) were treated in a similar manner to that of Example F-(3) to give ethyl 2-(2-aminothiazol-4-yl)-2-n-octyloxyimino-acetate (syn isomer, 65 g.), mp. 77 to 78°C; Nujol I.R. U : 3470, 3250, 3125, 1735, max . 1545, 1465 cm"1 4 667 4 10 20 25 30 N.M.R. 6 (DMSO-dg, ppm) : 0.81 (3H, t, J=6Hz), 0.6~1.9 (15H, m), 4.07 (2H, t, J=6Hz), 4.28 (2H, q, J=7Hz), 6.86 (1H, s), 7.02 (2H, broad s) (4) Ethyl 2-(2-aminothiazol-4-yl)-2-n-octyloxy-iminoacetate (syn isomer., 64 g.), 2N-agueous solution of sodium hydroxide (196 ml.), methanol (196 ml.) and tetrahydrofuran (300 ml.) were treated in similar manner to that of Example F-(4) to give 2-(2-aminothiazol-4-yl)-2-n-octyloxyiminoacetic acid (syn isomer, 52.5 g.), mp. j 146°C (dec).

Nujol n I.R.U : 3170, 1635, 1565, 1460 cm"1 max 15 N.M.R. 6(DMS0-dg, ppm) : 0.86 (3H, t, J=6Hz), 0;6-^1.9 (12H, m) , 4.06 (2H, t, J=6Hz) , . 6.81 (IH, s), 7.22 (2H, s) (5) 2-(2-Aminothiazol-4-yl)-2-n-octyloxyiminoacetic acid (syn isomer, 20 g.), acetic anhydride (27.3 g.) and formic acid (12.'3 g.) were treated in a similar manner to that of Example F-(5) to give 2-(2-formamidothiazol-4-yl)-2-n-octyloxyiminoacetic acid (syn isomer, 21.3 g.), mp. 122°C (dec).

Nujor I.R. u : 3350, 3150, 3050, 1700, max , 1675, 1560 cm N.M.R. 6 (DMSO-dg, ppm) : 0.6^2.0 (15H, m), 4.16 {2H, t, J=6Hz), 7,56 (1H, s), 6.57 (IH, s), 12.67 (IH, s) ' 02 46674 Example 1 (l) N,N-Dimcthylformamide (0.16 g.) and phosphorous oxychloride (0.34 g.) were mixed to prepare Vilsmeier reagent in a usual manner, and the resultant Vilsmeier 5 reagent was suspended in dry ethyl acetate. To the sus pension was added 2-(2-formamido-4-thiazolyl)-2-methoxyiminoacetic acid (syn isomer» 0.46 g.) under ice-cooling with stirring, and then the solution was stirred at the same temperature for 30 minutes to prepare the activated 10 acid solution. p-Nitrobenzyl 7-amino-3-chloro-3- cephem-4-carboxylate hydrochloride (0.81 g.) was dissolved, in a solution of trimethylsilylacetamide (2.10 g.) in ethyl acetate (200 ml.). To the solution was added the activated acid solution obtained above all at once at -20°C, and ,c the solution was stirred at -20~'-5oC for 1.5 hours. id .

After water and ethyl acetate (100 ml.) were added to the resultant solution at -20°C, the insoluble product was separated by filtration, washed with water and acetone in turn and then dried to give p-nitrobenzyl 7-{2-(2-2q formamido-4-thiazolyl)-2-methoxyiminoacetamido}-3-chloro-3-cephem-4-carboxylate (syn isomer, 0.6 g.).

After ethyl acetate was removed from the above filtrate, the aqueous layer was extracted with ethyl acetate (50 ml.) twice. The ethyl acetate layer and the extract were com-25 bined together, washed with 101 hydrochloric acid, a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium .chloride in turn and then dried over magnesium sulfate. After removing ethyl acetate from the solution, diethyl ether was added to the residue. 46674 The insoluble product was collected by filtration to i give the same object compound (0.25 g.)> m.p. 226 to 228°C (dec.), Total yield 0.85 g. 1.R. v JJaj01 : 3250 , 1780, 1720, 1685, 1645, 1605, 1550, 1520 cm"1 N.M.R. 6ppm (DMSO-d6) : 3.45 (2H, broads), 3.93 (3H, s), 5.35 (IH, d, J=5Hz), '5.50 (2H, s), 5.95 (IH, dd, J=5,8Hz), 7.43 (IH, s), 7.72 (2H, d, J=9Hz), ,8.28 (2H, d, J=9Hz), 8.55 (IH, s) , 9.80 (IH, d, J=8Hz) (2) p-Nitrobenzyl 7-{2-(2-formamido-4-thiazolyl)- 2-me thoxyiminoacetamido}-3-chloro-3-cephem-4-carboxylate (syn isomer, 0.8 g.) vae dissolved in a mixed solution of methanol (30 ml.) and tetrahydrofuran (60 ml.). After adding 101 palladium carbon (0.4 g.) to the solution, the mixture was subjected to catalytic reduction at room temperature under atmospheric pressure. The catalyst was filtered off, and the filtrate was concentrated under; reduced pressure. Water (30 ml.) was added to the residue and the mixture was adjusted to pH 7.5 with an aqueous solution of sodium bicarbonate.

After removing the insoluble substance from the mixture by filtration, the filtrate was washed with ethyl acetate (50 ml.). Ethyl acetate (70 ml.) was added to the solution, and the mixture was adjusted to pH 1.5 with 10% hydrochloric acid and then shaked sufficiently. After the ethyl acetate layer was removed, the aqueous layer was 46674 10 15 extracted with ethyl acetate (30 ml.) twice. The ethyl acetate layer and the extracts were combined together, washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and then concentrated under reduced pressure to give 7-{2-(2-formamido-4-thiazolyl)-2-methoxyiminoacetamido} -3-chloro-7,-cephem-4-carboxy lie acid (syn isomer 0.48 g.), m.p. 165 to 174°C (dec.). '80, 1730, 1690, 1660, 1550 cm" N.M.R. S (DMSO-d,) : 3.57 (2H, broad s), ppm 6 3.91 (3H, s), 5.30 (IH, d, J=5Hz), 5.88 (IH, dd, J=5, 8Hz) , 7.44 (IH, s), 8.52 (IH, s), 9.78 (IH, d, J=8Hz), 12.60 (IH, s) I.A., v ^"i°l : 3250 , 17J max 3 -1 20 25 (3) 7-(2-(2-Formamido-4-thiazolyl)-2-methoxyimino- acetamido)-3-chloro-3-cephem-4-carboxylic acid (syn isomer, 0;4 g.) was suspended in methanol (15 ml.). After adding conc-hydrochloric acid (0.16 g.) to the suspension, the mixture was stirred at room temperature for 2.5 hours. Methanol was distilled off from the resultant mixture under reduced pressure, and the residue was dissolved in water (15 ml.). The solution was washed with ethyl acetate (30 ml.) and dichloromethane (30 ml.) in turn. To the acqueous layer was introduced nitrogen gas to remove the remaining organic solvent completely, and the solution was lyophilized to give 7-{2-(2-amino-4-thiazolyl) -2-methoxyiminoacetamido}-3-chloro-3-cephem-4-carboxylic acid hydrochloride (syn isomer 0.35 g.), 105 4 6 674 . m.p. 170 to 180°C (dec.j : 3300, 1780, 1730, 1670, 1630, 1545 cm"1 5 N.M.R. 6 ppm (DMS°- IC6 46674 Ethyl acetate (50 ml.) and water (100 ml.) were added to the resultant solution and the ethyl acetate layer was separated. The aqueous layer was extracted withtethyl acetatc (50 ml.) twicc. The extracts were combined with the ethyl acetate 5 layer, washed with a saturated aqueous solution of sodium bicarbonate three times and a saturated aqueous solution of sodium chloride thcree timers in tui*n~, dried over magnesium sulfate, treated with activated charcoal and then concentrated under reduced pressure. After washing the concentrate with n-hexane (50 ml.), n-hexane (50 ml.) and diethylether (25 ml.) were added to the residue and allowed to stand in a refrigerator overnight. The precipitating powder was collected by filtration, washed with n-hexane and dried to give a mixture (1.0 g.) of n-hexanoyloxymethyl 7-[2-(2-amino-4-thiazolyl)-2-. methoxyiminoacetamido]-3-chloro-3-cephem-4-carboxylate (syn- isomer) and n-hexanoyloxymethyl 7-[2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido]-3-chl0T0-2-cephem-4-carb0xylate (syn-isomcr.) (5) Thus obtained mixture (1.0 g.) was added to methylene chloride (10 ml.) To the solution were added acetic acid (7 ml.), a solution of sodium tungstate (Na2W04;2^0) (20 mg.) in water (0.5 ml.)j methylene chloride (5 ml.) and 35% hydrogen peroxide (180 mg.), and then stirred under ice-cooling for 4 hours. Ice-water was added to the resultant solution and / extracted with methylene' chloride. The extract was washed with 25 water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was pulverized with diethyl ether (20 ml.), washed with diethyl ether *(10 ml.) twice and dried. The product was purified with column chromatography on silica 30 Sel (eluent : ethyl acetate) to give n-hexanoyloxymethyl 7-[2- 107 (2-amino-4-thiazolyl)-2-methoxyiminoacetamido]-3-chloro-3-cephem-4-carboxylate-l-oxide (syn-isomer : 600 mg.) I.R. maxPl : 3300» 1790» 1760» 1680» 1630» 1540» 1380 cm"1 N.M.R. 6ppm (DMSO-dg) : 0.67 - 2.5 (11H, m), 3.90 (3H, s), 4.20 (2H, broad s), i 5.17 (IH, d), 5.83 - 6.17 (3H, m), 6.88 (IH, s), 9.17 (1H, d) (6) Phosphorus trichloride (210 mgO was added to a solution of n-hexanoyloxymethyl 7-[2-(2-amino-4-thiazolyl)- ; 2-methoxyiminoacetamido]-3-chloro-3-cephem-4-carboxylate-1- i oxide (syn-isomer : 570 mg.) in dry dimethylformamide (10 ml.) at -30°C, and stirred at -20 to -30°C for 50 minutes. 10$ Aqueous solution (50 ml.) of sodium chloride was added to the resultant solution, adjusted to pH 8.0 with a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, and then concentrated under reduced pressure. The residue (560 mg.) was purified with column chromatography on j silica gel (20 g.) (elufint:ethyl acetate), and the resultant i residue (180 mg.) was pulverized with n-hexane (10 ml.) and diethyl ether (5 ml.) to give n-hexanoyloxymethyl 7-[2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido]-3-chloro-3-cephem-4-carboxylate (syn-isomer : 150 mg.) 108 I.R. vNuj01 4667 4 max * 3^00 (broad), 1780 (broad), 1760 (shoulder), 1670, 1620, 1530 cm"1 i N.M.R. 6ppm (CDa3) : 0.67 - 2.5 (11H, m) , 3.67 (2H, q) , 4.00 (311, s), 5.17 (IH, d), 5; 90 (IH, s) , 6.00 (1H, m), 6.77 (IH, s),7.83 (IH, d) Example 2 2-{2-(2,2,2-Trifluoroacetamido)-4-thiazolyl}-2-methoxyiminoacetic acid (syn isomer, 0.65 g.) was added at 0°C to Vilsmeier reagent which had been prepared from dimethylformamide and phosphorus oxychloride in ethyl acetate (10 ml.), and the mixture was stirred at the same temperature for 40 minutes to prepare the activated acid solution. The activated acid solution was added dropwise to a solution of 7-amino-2,3-dimethyl-3-cephem-4-carboxyric acid (0.5 g.) and trimcthylsily]acetamide (1.73 g.) in ethyl acetate (30 ml.) at -20°C, and the mixture was stirred at the same temperature for 40 minutes. To the resultant mixture was t added water (10 ml.), and the ethyl acetate layer was separated from the mixture and washed with water. Water (30 ml.) was added to the solution and' the mixture was adjusted to pH 7.5 with sodium bicarbonate under ice-cooling. After shaking the mixture, the aqueous layer was separated. Ethyl acetate (50 ml.) was added to the aqueous solution, and the mixture was adjusted to pH 2 with dilute hydrochloric acid with stirring, and the ethyl acetate layer was separated, washed with water and a saturated aqueous solution of sodium chloride in turn, treated with activated charcoal, dried 46674 lo over magnesium sulfate and then concentrated under reduced 1 j pressure. The residue was pulverized with diisopropyl ether to give 7-[2-(2-(2,2,2-1rifluoroacetamido)-4-thiazolyl}-2-methoxyiminoacetamido]-2,3-dimethyl-3-cephem-4-carboxylic acid (syn isomer, 0.9 g.). 1.R. v mai01 : 3250' 1780 , 1725, 1680 » 1650 cn>1 N.M.R. 6ppm (DMSO-dg) : 1.43 (3H, d, J=8Hz), 1,92 (IH, s), 3.82 (3H, s), 3.98 (IH, q, J=8Hz), 5.18 (IH, d, ; J-6Hz) , 5.73 (IH, AB-q, J=6Hz), 7.43 (IH, s), 9.63 (IH, d, J=8Hz) ' (2) 7- [2-{2,- (2,2,2-Trifluoroacetamido)-4-thiazolyl}- 15 "2 -methoxyiminoacetamido]-2,3-dimethyl-3-cephem-4-carboxylic acid (syn isomer, 0.86 g.) wae die- l * . solved in an aqueous solution (9 ml.) containing sodium acetate trihydrate (2.3 g.), and the solution was stirred at room temperature for 19 hours. After removing the 20 insoluble substance from the resultant mixture by filtration, the filtrate was adjusted to around pH 2.5 with 10% hydrochloric acid under ice-cooling. The precipitates were collected by filtration, washed with water and dried to give 7-(2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido}-25 2,3-dimethyl-3-cephem-4-carboxylic acid (syn isomer, 0.16 g.).

I,R* v max01 : 3320» 3200, 1770 (shoulder), 1670, 1630 cm"1 30 N.M.R. 6ppm (DMS0-d6) : 1.44 (3H, d, J«7Hz), ; 1.98 (3H, s), 3.57 (IH, q, J«7Hz), 3.82 (3H, s), 5.18 (IH, d, J-5Hz), 5.73 (IH, dd, J»5, 8Hz), 6.76 (IH, s), 9.63 (IH, d, J*8iiz) HO 4 6 6 7 4 .Example 3 (1) A mixture of 2-{2-(2,2,2-trifluoroacetamido)-4- thiazolyl }-2-iuethoxyinrinoacetic acid (syn isomer, 0.8 g.), dimethylformamide (0.20 g.), phosphorus oxychloride (0.41 g. and ethyl acetate (10 nil.) was stirred for 30 minutes under ice-cooling to prepare the activated acid solution in a similar manner to that of Example2-(1).On the other hand, a solution of 7-amino-3-methoxy-3-cephem-4-carboxylic acid hydrochloride (0.C g.) and trimethylsilylacetamide (3 g.) in ethyl acetate (15 ml.) was stirred at 40°C for 3 hours. To the solution was added dropwise the activated acid solution at -10 to -20°C in 2 minutes, and the mixture was stirred at the same temperature for 1.5 hours. After water (10 ml.) was added to the resultant mixture, the ethyl acetate layer was separated and allowed to stand. The precipitates were collected by filtration to give 7-[2 -{2 -(2,2,2-trifluoroacetamido)-4-thiazolyl}-2-methoxyiminoacetamido] -3-methoxy-3-cephem-4-carboxylic acid (syn isomer, 0.3 g.). The aqueous layer, which was separated from the ethyl acetate layer, was extracted with ethyl acetate, and the extract was combined with the mother liquor obtained above. The ethyl acetate solution was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was washed with diethyl ether to give the same object compound (0.25 g.), Total .yield 0.55 g. : 3230, 1770, 1715, 1650, 1580 cm"1 10 v» 46674 N.M.R. 6 (DMSO-dfi) : 3.62 (2H, AB-q, J=16Hz), 3.78 (3H, s) , 3.93 (3H, s) , 5.17 (IH, d, J=4Hz), 5.54 (1H, dd, J=8, 4Hz), 7.60 (IH, s) , 9.69 (1H," d, J=8Hz) (2) A solution of 7-[2-{2-(2,2,2-trifluoroacetamido)- 4-thiazolyl)^2-methoxyiminoacetamido]-3-methoxy-3-cephem-4-carboxylic acid (syn isomer, 0.55 g.), and Bodium acetate trihydrate (1,76 g.) in ethyl acetate (3 ml.), tetrahydrofuran (3 ml.) and water (5.5 ml.) was stirred at room temperature overnight. The aqueous layer was separated from the resultant mixture,!'; : ' ' washed with dichloromethane, and then evaporated under 7 reduced pressure to remove the organic solvent. The aqueous solution was adjusted to pH 4.2 under ice-cooling, and subjected to column chromatography on Diaion HP-20 resin (Trade mark : manufactured by Mitsubishi Chemical Industries Ltd., 15 ml.). After washing the column with water, the object compound was eluted with 20% aqueous isopropyl alcohol. The eluate was concentrated under reduced pressurejmd the residue was lyophilized to give 7- {2- (2-amino-4-thiazolyl)-2-methoxyiminoacetamido}-3- ; methoxy-3-cephem-4-carboxylic acid (syn isomer 0.4 g.), m.p. 185 to 190°C (dec.). 25 I.R. v : 3300, 1770, 1660, 1630, 1540 cm"1 N.M.R. 6ppm (DMSO-dg) : 3.60 (2H, broad s), 3.75 (3H, s), 3.83 (3H, s), 5.12 (IH, d, J=4Hz), 5.55 (IH, dd, J-4,8Hz), 6.82 (IH, s), 9.52 (IH, d, J*8Hz) 30 15 20 r 1 0 Example 4 4 66 7 4 (l) To a suspension of p-nitrobenzyl 7-phenylacetamido- 3-cephem-4-carboxylate (10.50 g.) in dry dichloromethane (100 ml.) was added dry pyridine (2.14 g.). Phosphorus 5 pentachloride (5.50 g.) was added to the solution at -10°C, and the mixture was stirred at -5°C for 45 minutes and further at 10°C for an hour. After adding methanol (520 g.) to the resultant mixture, the mixture was stirred at -20°C for 1.5 hours. The precipitates were collected by filtration, washed with dichloromethane (120 ml.) and diethyl ether (130 ml.) in turn, and then dried to give p-nitrobenzyl 7-amino-3-cephem-4-carboxylate (7.90 g.), m.p. 182°C (dec.). 15 I-R- v max01 : 1790» 173d> 1638> 1600 cm 1 N.M.R. 6 (DMSO-d,) : 3.78 (2H, d, J=4Hz), ppm o 5.27 (2H, dd, J=5Hz), 5.44 (2H, s), 6.78 (IH, t, J=4Hz), 7.72 (2H, d, 1 i J-9Hz), 8.26 (2H, d, J=9Hz) fi3 46674 10 (2 ) Vilsmeier reagent prepared from dimethylformamide (0.43 g.) and phosphorus oxychloride (0.92 g.) was suspended in'dry ethyl acetate (10 ml.). To the suspension was added 2-(2-formamido-4-thiazolyl)-2-methoxyimino acetic acid (syn isomer, 1.15 g.) under ice-cooling with stirring, and the mixture was stirred at the same temperature for 30 minutes to prepare the activated acid solution. On the other hand, p-nitrobenzyl 7-amino-3-cephem-4-carboxylate hydrochloride (1.79 g.) and trimethylsilylacetamide (5.0 g.) were dissolved in ethyl acetate (40 ml.). To the solution was added the activated acidsolution at -20°C all at once, j and the mixture was stirred at the same temperature for 2.5 hours. Water (60 ml.) and ethyl acetate (200 ml.) were added to the resultant solution, and the ethyl acetate layer was 15 separated, washed with 10% hydrochloric acid (60 ml.), a saturated aqueous solution of sodium bicarbonate (60 ml.) and an aqueous solution of sodium chloride (50 ml.) in turn, dried over magnesium sulfate, treated with activated charcoal, and then evaporated under reduced pressure. Diethyl ether was added to the residue, and the precipitates were collected 20 by filtration to give p-nitrobenzyl 7-(2-(2-formamido-4-thiazolyl)-2-methoxyimino-acetamido}-3-cephem-4-carboxylate (syn isomer, 1.30 g.), m.p. 210 to 212°C (dec.). 25 I.R. v max01 : 3240» 1780» 1730> 1690' 1655 1605, 1550, 1520 cm"1 N.M.R. 6ppm (DMSO-dg) ': 3.65 (2H, broad s), 3.90 (3H, s), 5.20 (-1H, d, J»5Hz), 5.43 (2H, s), 5.95 (IH, q, J«5,8Hz), 30 114 6.68 (1H, t, J=4Hz), 7.42 (IH, s) , 7.72 (2H, d, J=9Hz), 8.28 (2H, d, J=9Hz), 8.46 (IH, s), 9.72 (IH, d, J=8Hz) (3) To a solution of p-nitrobenzyl 7-{2-(2-formamido-4- thiazolyl)-2-methoxyiminoacetamido}<-3-cephem-4-carboxylate (syn isomer, 1.25 g.) in methanol (40 ml.) and tetrahydrofuran (50 ml.) was added lOt palladium carbon (0.65 g.), and the mixture was subjected to catalytic reduction at room temperature under atmospheric pressure for 3.5 hours.- After removing the catalyst from the reaction mixture, the filtrate was concentrated under reduced pressure. Water (80 ml.) was added to the residue, and the mixture was adjusted to pH 7.5 with an aqueous solution of sodium bicarbonate, and then the insoluble substance was filtered off. The filtrate was washed with ethyl acetate (50 ml.), and then ethyl acetate (100 ml.) was added to the solution. After adjusting to pH 1.5 with 10% hydrochloric acid, the ethyl acetate layer was separated. The remaining aqueous layer was extracted with ethyl acetate (80 ml.) twice, and the extracts were combined with the ethyl acetate layer obtained above, washed with an aqueous solution of sodium chloride, dried over magnesium sulfate, and then concentrated under reduced pressure to give 7-{2-(2-formamido-4-thiazolyl)-2-methoxyiminoacetamido}- 3-cephem-4-carboxylic acid (syn isomer, 0.60 g.), m.p. 176 to 183°C (dec.). 466*4 ~ : I.R. ,v max01: 3250' 1780' 1690» 1660» 1550 cm'1 N.M.R. 5ppm (DMSO-d6) : 3.63 (2H, d, J=4Hz), 3.93 (3H, S), 5.10 (IH, d, J=5Hz), 5.90 (IH, q, J=5,8Hz), 6.53 (1H, t, J=4Hz), 7.47 (IH, s), 8.S7 (IH, s), 9.70 (1H, d, J=8Hz), 12.63 (1H, s) (4) 7-(2-(2-Formamido-4-thiazolyl)-2-methoxyiminoacet- aniido}-3-cephem-4-carboxylic acid (syn isomer, 95 mg.) was suspended in methanol (4 ml.).

To the suspension was added conc. hydrochloric acid (110 mg.) and the solution was stirred at room temperature for 4 hours. After distilling methanol under reduced pressure, the residue was dissolved in water (30 ml.) and the aqueous solution was washed with ethyl acetate (10 ml.) and dichloromethane (15 ml.) in turn. Nitrogen gas was introduced into the aqueous solution to exclude the remaining organic solvent, and the aqueous solution was lyophilized to give 7- {2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido}-3-cephem-4-carboxylic acid hydrochloride (syn isomer, 83 mg.), m.p. 180 to 190°C (dec.). 1 .R. v jj^01 : 3300, 1770, 1710, 1660, 1630 cm"1 N.M.R. 6ppm (DMSO-dg) : 3.64 (2H, broad s), 3.95 (3H, s), 5.14 (IH, d, Jc5Hz), 5.82 (IH, t, J=4Hz), 6.95 (IH, s), 9.80 (IH, d, J*8Hz) 116 46674 (5) The solution of 7--[2- (2-formamido-4-thiazolyl)-2- methoxyiminoacetamido\-3-cephem-4-carboxylic acid (syn ' I isomer 10.8 g.), conc. hydrochloric acid (11 g.) and methanol (350 ml.) was stirred at room temperature for 4 hours. After concentrating the resultant solution under 5 rerluced pressure? ethyl acetate was added to the residue. The solution was adjusted to pH 8.0 with a saturated aqueous solution of sodium bicarbonate and the aqueous layer was separated and washed with diethyl ether.

After nitrogen gas was bubbled in the aqueous solution, the aqueous solution was adjusted to pH 4.0 with 10% hydrochloric acid. The precipitates were collected by filtration and washed with water to give 7-{2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido}-3-cephem-4-carboxylic acid (syn isomer, 8.2 g.), nt.p.> 290°C.

IR i^max01 : 3470' 3280, 3200, 1780, 1695, 1655, 1622 cm"1 J ppm (DMSO-dg) : 3.60 (2H, broad s), 3.84 (3H, s), 5.12 (1H, dd, J=5Hz), 5.84 (IH, dd, Jo5,8Hz), 6.52 (1H» broad t) 6.76 (IH, s), 7.26 (2H, broad s), 9.65 (IH, d, J=8Hz) 15 20 NMR " 1 7 4667 4 (6) Sodium bicarbonate (1.04 g.) was added to a solution of 7-[2-(2-amino-4-thiazolyl)-2-methoxyirainoacetamido]-3-cephem-4-carboxylic acid hydrochloride (syn isomer, 2.6 g.) in water , (100 ml.) under ice-cooling and stirred at room temperature. 5 The resultant solution was lyophilized to give sodium 7-[ 2-(2-amino-4-thiazolyl) -2-methoxyirninoacetamido]-3-cephem-4-carboxylate (syn isomer).

I.R. IJ ^0l : 3100, 1760, 1650, 1590, 1530 cm"1 10 max N.M.R. § (D20, ppm) 3.60, (2H, broad q), 4.00 (3H, s), 5.22 (1H, d) , 5.88 (1H, d) , 6.35 (IK, q) , 7.03 (III, s) (7) The product obtained above was dissolved in dry N,N-dimethylformamide (20 ml.). To the solution was dropwise 15 added a solution of iodomethyl n-hexanoate (1.33 g.) and dry W,N-dimethylformamido (5 ml.) at -40°C over 5 minutes, and |i then stirred at the same temperature for 40 minutes and then' : .' • ii under ice-cooling for 45 minutes. The resultant solution was added to a mixed solution of ethyl acetate (60 ml.) and 2o water (125 ml.). The ethyl acetate layer was separated, washed with a saturated sodium bicarbonate aqueous solution and a staturated sodium chloride aqueous solution in turn dried over magnesium sulfate, and then treated with an activated charcoal. i After removing ethyl acetate from the solution, the residue w;as i 25 triturated with diethyl ether to give n-hexanoyloxymethyl 7- : (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -3-cephem-4-j carboxylate (syn iaomer, 750 mg.) j I,]<- ^ : 3170' 1780' 1750 (shoulder) , 1670, 1630, 1530 cm"1 30 N.M.R. £ (CDC13, ppm) 0.68-1.84 (9H, m) , 2.20-2.48 (2H, t) , : 3.20-3.80 (2H, m), 4.02 (3H, s), 5.04 (IH, d), 5.60-6.20 (3H, m), 6.62 (1H, q), 6.80 (IH, s), 7.72 (IH, d) M8 46674 (8) p-Nitrobcnzyl 7-[2-(2-formamido-4-thiazolyl)-2- methoxyiminoacetamido]-3-cephem-4-carboxylate (syn-isomer: 1.1 g.) was suspended in a mixture of ethanol (10 ml.) and water (15 ml.) IN Aqueous solution of potassium hydroxide g (6 ml.) was added dropwise to the suspension at 5 to 7°C over 10 minutes and stirre4 for 10 minutes- The resultant solution was adjusted to pH 7.5 with 10% hydrochloric acid, washed with ethyl acetate and adjusted to pH 2.5 with 101 hydrochloric acid. The precipitating crystals were collected by filtration 10 to give the mixture of 7-[2-(2-formamido-4-thiazolyl)-2- mcthoxyiminoacetami do] - 3-cephein-4- carboxy lie acid (syn- isomer : 0.32 g.) rind 7-(2-(2-amino-4-thiazolyl) - 2-/acetamido/ methoxyiinin I.R. v : 3350, 1760, 1670, 1590, 1535, 1465cm"1 N.M.R. 6 (D20, ppm) : 3.51 (IH, d, J=5Hz), 3.59 (IH, d, J«3Hz), 3.97 (3H, s), 5.15 (IH, d, J=5Hz), 5.82 (IH, d, J=5Hz) , 6.33 (IH, dd, J=5Hz, 3Hz) , 6.95 (IH, s) (11) 7-[2-(2-Aminothiazol-4-yl)-2-methoxyiminoacetamido] 3-cephem-4-carboxylic acid (syn isomer, 1.15 g.) was added to a suspension of magnesium hydroxide (0.088 g.) in water (100 ml.), and the mixture^was stirred at 70°C for 30 minutes to give a solution. After the resultant solution was filtered, the filtrate was lyophilized to give magnesium 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]- 3-cephem-4-carboxylate (syn isomer, 1.1 g.).

I.R. V max01 : 3350» 17*°> 1660» 1610» 1530, 1460cm"1 20 4 6674 N.M.R. 6 ppm) : 3.53 (IH, d, J=5Hz), 3.59 (IH, d, J=3Hz), 3.96 (3H, s) , ■ 5.16 (IH, d, J=5Hz), 5.84 (IH, d, ! J=5Hz), 6.32 (IH, dd, J=SHz, 3Hz), 7.98 (IH, s) 5 (12) 7- [2-(2-Aminothiazol-4-yl)-2-methoxyiminoacetamido]- 3-cephem-4-carboxylic acid (syn isomer, 1.15 g.) was added to a solution of arpinine (0.52 3 g.) in water (50 ml.), and the solution was stirred at room temperature l0 for 10 minutes.

After the resultant mixture was filtered, the filtrate was lyophilized to give an arginine salt of 7-[2-(2-amin o th i a zo 1 - 4 - y 1) - 2 - me thoxy imin o ace t ami do ] - 3 - cephem - 4-carboxylic acid (syn isomer, 1.35 g.). 15 I.R. v JJgj01 : 3350, 3150, 1770 1650 (broad), 1580, 1530, 1460cm"1 N.M.R. 6 (D20, ppm) : 1.4 - 2.1 (4H, m), 3.22 (2H, t, J=6Hz), 3.55 (IH, d, 20 J=6Hz) , 3.65 (IH, d, J=3Hz) , 3.82 (IH, d, J=6Hz), 3.97 (3H, s), 5.18 (IH, d, J=5Hz), 5.85 (IH, d, J°5Hz) , 6.33 (IH, dd, J=6Hzj 3Hz) , 7.00 (IH, s) 25 (13) Sodium 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate (syn isomer, 1.21 g.) was added to a solution of lysine hydrochloride (0.55 g.) in water (12 ml.)- - 121 4 6 6 7 4 The solution was lyophilized to give a lysine salt of 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer, 1.6 g.). 1 .R. v : 3350, 3150, 1770, 1600(broad) . 1530,- 1460cm"1 N.M.R. 6.(D2G, ppm) : 1.3 - 2.1 (6H, m), 3.03 (2H, t, J = 7H z ) , 3.54 (IH, d, J=5Hz) , 3.64 (IH, d, J=3Hz), 3.80 (IH, d, J=6Hz), 3.97 (3H, s), 5.17 (IH, d, • J = 5Hz) , 5.84 (IH, d, J=5Hz), 6,32 (IH, dd, J=5Hz, 3Hz) , 6.99 (IH, s) (14) 20% Aqueous solution of sodium hydroxide was added to a suspension of 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer, 15 g.) in a mixture of ethanol (8 ml.) and water (8 ml.) at room temperature to make a solution of pH 7.5. After filtration and washing, the filtrate and washings were combined (which /to/ contained 18.3 ml., of water) and added dropwise/ethanol (46 ml.) at 20 to 25°C under stirring and stirred at the same temperature for 30 minutes. Ethanol (28 ml.) was added dropwise to the mixture over 30 minutes, and stirred at the same temperature for 2 hours. The precipitates were collected by filtration, washed with ethanol (20 ml.) and dried in vacuo at room temperature to give plates of sodium 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate dihydrate (syn isoiuei-, 13.5 g.), mp 260°C (dec.). 122 I,R* v max01 : 3430, 3250, 1760 (shoulder), 1745, ;1650, 1630 (shoulder), 1590, 1540 cm"1 (15) Sodium 7-[2-(2-aminothiazol-4-yl)-2- methoxyiminoacetamido]- 3-cephem-4-carboxylate (syn isomer, 15 g.) was dissolved in water (13 ml.) at 35 to 45°C under stirring. Warmed ethanol (52 ml., 30°C) was added dropwise to the stirred solution, and stirred at the same temperature for 5 minutes and then at room temperature for 2 hours. The precipitates were collected by filtration, washed with ethanol and dried under reduced pressure to give plates of sodium 7-[2-(2- aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate dihydrate (syn isomer, 13.45 g.). (16) 4N Aqueous solution of sodium hydroxide was carefully added dropwise to a stirred suspension of 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]- 3-cephem-4-carboxylic acid (syn isomer, 52 g.) in water (100 ml.) below 5°G to make a solution of pH 7.0 to 7.5. After filtration and washing, the combined filtrate and the washings (200 ml.) was added dropwise to ethanol (2 £,.) under stirring over 30 minutes, and stirred at room temperature for 15 minutes and then at 5 to 10°C for an hour. The precipitates were collected by filtration, washed with ethanol (200 ml.) and dried in vacuo at 30°C to give amorphous sodium 7-[2- (2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem- 4-carboxylate (syn isomer, 46.3 g.).

I,R* V max01 : 3400' 3300, 3170, 1750, 1650, 1580 cm 1 1?3 4667 4 (17) ^ suspension of sodium 7-[2-(2-aminothiazol-4-yl) 2-methoxyiminoacetamido]-3-cephem-4-carboxylate (syn ■ , i .■ ■ ■ ■ ■ i I ■ . ' isomer, 10 g.) in methanol (250 ml.) was treated with a supersonic apparatus to make a clear solution. The solution was allowed to stand at room temperature, and then stirred at the same temperature for 3 hours. The precipitates were collected by filtration and washed with methanol to give amorphous sodium 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]- 3-cephem-4-carboxylate (syn isomer) (10) The crystals obtained in the above Example 4-(i4) were dried over P2°5 in vacuo for one day at room temperature to give another plates of sodium 7-[2-(2-/—4—yl/ aminothiazolfl-2-methoxyiminoacetamido]-3-cephem-4-carboxylate (syn isomer). 124 466 Hxample 5 (l) Vilsmeier reagent prepared from dimethylformamide (0.22 g.) and phosphorus oxychloride (0.46 g.) was suspended in dry ethyl acetate (20 ml.). 2-(2-Formamido-4-thiazolyl)-2-methoxyiminoacetic acid (anti isomer, 0.62 g.) was added to the suspension under ice-cooling with stirring, and the mixture was stirred at the same temperature for 30 minutes to prepare the activated acidsolution. The solution was added all at once to a solution of p-nitrobenzyl 7-amino-3-chloro-3-cephem-4-carboxylate (1 g.) and trimethylsilylacetamide (2.58 g.) ii> ethyl acetate (20 ml.) at -20°C with stirring, and the mixed solution was stirred at -10 to -20°C for 1.5 hours. To the resultant solution was added water (20 ml.), and the solution was stirred at -20°C. After separating the ethyl acetate layer, the aqueous layer was extracted with ethyl acetate (20 ml.). The ethyl acetate layer and the extract were combined together, washed with 10% hydrochloric acid (20 ml.) twice, water (20 ml.) once, a 5% aqueous solution of sodium bicarbonate (20 nil.) three times, and an aqueous solution of sodium chloride (20 ml.) once in turn, dried, and then concentrated under reduced pressure. The residue was washed with diethyl ether (50 ml.) to give p-nitTobenzyl 7-{2-(2-formamido-4-thiazolyl)-2-methoxyiminoacetamido} — 3-chloro-3-c.ephem-4-carboxylate (anti isomer, 1.27 g.), m.p. 135 to 145°C. (dec.).

I-R- v SI01 •' 3150 to 3300 (broad), 1780, 1730, nioA 1670 to 1690 (broad) cm 125 46674 6 ppm (DMS°-d6) : 3*83 (2H' AB"q' J=17Hz)» 3.97 (3H, s), 5.23 (1H, d, J=5Hz), 5.41 (2H, s), 5.9 (IH, dd J=5,8Hz), 7.62 (211, d, J-8Hz), 8.0 (IH, s) 8.2 (211, d, J=8Hz) , 8.42 (IH, s), I ' 9.55 (IH, d, J=8Hz), 12.43 (IH, s) (2) 10% Palladium carbon (0.6 g.) was added to a solution of p-nitrobenzyl 7-{2-(2-formamido-4-thiazolyl),-2-methoxyiminoacetamido}-3-chloro-3-cephem-4-carboxylate l0 (anti isomer, 1.16 g.) in methanol (20 ml.) and tetrahydrofuran (40 ml.), and the mixture was subjected to catalytic reduction at room temperature under atmospheric pressure for 5 hours.

After removing the catalyst from the reaction mixture, the 15 filtrate was concentrated under reduced pressure. Water (30 ml.) and ethyl acetate (60 ml.) were added to the residue, and the mixture was adjusted to pH 7.5 with an aqueous solution of sodium bicarbonate and shaked sufficiently. The aqueous layer was separated and ethyl acetate (90 ml.) 20 was added to the aqueous solution. The aqueous layer was adjusted to pH 2.5 with 10% hydrochloric acid with stirring under ice-cooling, and the ethyl acetate layer was separated. The remaining aqueous layer was extracted with ethyl acetate (30 ml.), and the extract and the ethyl acetate layer were 25 combined together, washed with an aqueous solution of sodium chloride, dried and then concentrated under reduced pressure. The residue was washed with diisopropyl ether to give 7-{2-(2-formamido-4-thiazolyl)-2-methoxyiminoacetamido}-3-chloro- N.M.R. 5 126 46674 25 S-cephem-4-carboxylic acid (anti isomer, 0.47 g.). The compound was colored at 210°C and decomposed at above than 250cC. 5 I.R. v max°1; 3250> 1780' 1720 (sh°ulder), 1670 to 1690 cm"1 N.M.R. 6ppin (DMS0-d6) : 3.8 (2H, AB-q, J=17Hz), 4.0 (3H, s), 5.21 (IH, d, J=5Hz), 10 5.83 (IH, dd, J=5,8Hz) , 8.05 (IH, s), 8.47 (IH, s), 9.55 (IH, d, J=8Hz), 12.55 (IH, broad s) (3) 7- {2- (2-Formamido-4-thiazolyl)-2-methoxyimino- acetamido}-3-chloro-3-cephem-4-carboxylic acid (anti isomer, 15 0.4 g.) was suspended in methanol (15 ml.). Cone, hydrochloric acid (0.16 g.) was added to the suspension and the mixture was stirred at room temperature for 5 hours. The precipitates were collected by filtration, washed with a mixed solvent of methanol and diethyl ether 2o (!•!)» and dried to give 7-(2-(2-amino-4-thiazolyl)-2- methoxyiminoacetamido} -3-chloro-3-cephem-4-carboxylic acid hydrochloride (anti isomer, 0.31 g.), m.p. above than 250°C. 30 I*R* v Ho!01 : 3250, 3200, 1788, 1720, 1680, JUaA 1640 cm"1 N.M.R. 6ppm (DMSO-dg) : 3.81 (2H, AB-q, J=17Hz), 4.08 (3H, s), 5.22 (IH, d, J=5Hz), 5.7 (IH, dd, J=5,8 Hz), 7.59 (IH, s), 9.5 (IH, d", J=8Hz) 12? 4667 4 Example 6 (l) A solution of Vilsmeier reagent was prepared from dry dimethylformamide (0.39 g.), dry ethyl acetate (1.2 ml.) and phosphorus oxychloride (0.84 g.) in a usual manner. 5 To the solution was added a solution of 2-(1,2,3-thiadiazol- 4-yl)-2-methoxyiminoacetic acid (syn isomer, 0.93 g.) in ethyl acetate (10 ml.) at -15°C to prepare the activated acid solution. On the other hand, a p-nitrobenzyl 7-amino-3-cephem -4-carboxylate (1.5 g.), trimethylsilyl-acetamide (4.6 g.) and bis(trimethylsilyl)acetamide (1 ml.) in dry ethyl acetate (50 ml.) was stirred at 45°C for 5 hours to give a solution. To the solution was added all at once the activated acid solution obtained above at » -10°C with stirring, and the mixed solution was stirred at -5cC for 1.5 hours. Water was added to the reaction mixture, and the insoluble product was separated by filtration, washed with ethyl acetate and water in turn, and then dried to give pale yellow powder of p-nitrobenzyl 7-{2-(1,2,3-thiadiazol-4-yl)-2-methoxyiminoacetamido}-3-cephem-4-carboxylate (syn isomer, 1.9 g.), m.p. 243 to 245°C (dec.).

I.R. v j^01 : 3250, 1782, 1725, 1655, 1630, 1600, 1520, 1345 cm'1 N.M.R. « (DMS0-d6) : 3.69 (2H, AB-q, J-14Hz), 4.00 (3H, s), 5.24 (IH, d, J=5Hz), 5.46 (2H, s), 6.00 (IH, dd, J=5,8Hz), 6.68 (IH, t, J=4Hz), 7.7 to 8.4 (4H, 3Q m), 9.44 (IH, s), 9.88 (IH, d, J=8Hz) 15 20 25 128 46674 (2) 10% Palladium carbon (0.85 g.) was added to a solution of p-nitrobenzyl 7-(2-(1,2,3-thiadiazol-4-yl)-2-; methoxyiminoacetamido}-3-cephem-4-carboxylate (syn Isomer, 1.65 g.l in methanol (70 ml.) and 5 tetrahydrofuran (90 ml.), and the mixture was subjected to catalytic reduction at room temperature under atmospheric pressure for 3.5 hours. After removing the catalyst from the reaction mixture by filtration, the filtrate was concentrated under reduced pressure. Water was added to l0 the residue, and the mixture was adjusted to pH 7 to 8 with sodium bicarbonate, washed with ethyl acetate, adjusted to pH 1.5 with 10% hydrochloric acid, and then extracted with ethyl acetate. The extract was washed with a saturated * aqueous solution of sodium chloride, dried over magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure, and the residue was pulverized with diethyl ether. The precipitates were collected by filtration and the dried to give yellow powder of 7-{2-(1,2,3-thiadiazol-4-yl)-2-methoxyiminoacetamido}-3-cephem-4-carboxylic acid (syn isomer, 0.3 g.), m.p. 200 to 210°C (dec.).

I.R. v JJax01 : 3250' 2550 t0 2600' 1785» 1715' 1655, 1630, 1600 cm"1 N.M.R. 6 " (DMSO-d6) : 3.58 (2H, AB-q, J=14Hz), 4.00 (3H, s), 5.15 (IH, d, J=5Hz), 5.90 (IH, dd, J=5,8Hz), 6.52 (IH, t, J=5Hz), 9.38 (IH, s), 9.84 (IH, d, J=8Hz) 20 25 1?9 4 6 674 U Example ? 7-Amino-3-cephem-4-carboxylic acid (1.7 g.) and sodium bicarbonate (2.84 g.) were dissolved in a mixture of water (35 ml.) and acetone (35 ml.). On the other hand, g pliosporus oxychloride (1.95 ml.) was added dropwise to a suspension of 2-(2-amino-4-thiazolyl)-2-methoxyiminoacetic acid (syn-isomer: 3.42 g.) in dry ethyl acetate (34 ml.) over 10 minutes at 0 to 6°C, and the mixture was stirred at the same temperature for 30 minutes. To the solution was added dropwise a solution of trimethylsilylacetamide (2.39 g.) in ethyl acetate (5 ml.) at 0 to 6°C over 20 minutes, and the mixture was stirred for 20 minutes. After phosphorus oxychloride (1.95 ml.) was added dropwise to the mixture at the above temperature over 10 minutes, the mixture obtained thus was stirred for 30 minutes. And further, dimethylformamide (1.29 ml.) was added dropwise to the mixture over 10 minutes at the same temperature and stirred for one hour to give a clear solution. The solution was added dropwise to the solution of 7-amino-3-cephem-4-carboxylic acid at -5 to 5°C, over 30 minutes, at pH 6.5 to 7.5, and the react-20, i°n mixture was stirred for one hour at the same temperature. Ethyl acetate (200 ml.) was added to the resultant solution, and the aqueous layer was separated, washed with methylene chloTide, bubbled with nitrogen gas and adjusted to pH 4 with acetic acid. The solution was subjected to column chromatio-22 gTaphy on macToporous, non-ionic adsorption resin "Diaion HP-20" (Trade mark: manufactured by Mitsubishi Chemical Industries Ltd.) and eluted with 20% aqueous solution of iso-propyl alcohol. The eluate was concentrated under reduced pressure and lyophilized to give 7-[2-(2-amino-4-thiazolyl)-2-30 raethoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn-isomer: 4 667 4 • ■ ' 1 2.0 g.) The product was identified with the authentic sample by IR and NMR spectrum.

Example 8 ' ■ (l) Phosphorus oxychloride (1.2 g.) was added all at 5 once to a suspension of 2-(2-amino-4-thiazolyl)-2- methoxyiminoacetic acid (syn-isomer: 1.23 g.) in ethyl acetate (12 ml.) at 5°C and stirred at 4 to 6°C for 30 minutes. Trimctiiylsilylacetamide (1.0 g.) was added to the solution and stirred at 4 to 6°C for 30 minutes. Phosphorus oxychloride (1.2 g.) was added ag'^in to the solution and stirred for 15 minutest jAnd furtherJ dimethylformamide (0.5 g.) was added all at $)rice to the solution at 4 to 6°C and stirred for 40 j minutes to give a clear solution. On the other hand, p-nitrobenzyl 7-amino-3-cephem-4-carboxylate hydrochloride 15 (1.9 g.) was added to a mixture of tetrahydrofuran (30 ml.) and acetone (10 ml.), and an aqueous solution (20 ml.) of sodium bicarbonate (0.6 g.) was added to the mixture. To the solution was added dropwise the solution obtained above at 0 to 5°C, pH 8.0. After stirring the mixture at -2 to 2°C, at 2Q pH 8.0 for 30 minutes, the insoluble substance was filtered out. The filtrate was extracted with ethyl acetate, and the extract was washed with a saturated aqueous solution of sodium chloridc, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was pulverized with di-25 isopropyl ether to give p-nitrobenzyl 7-[2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate (syn-isomer: 1.6 g.) i.R. « : 3300, 1780, 1730, 1670, 1520 cm"1 30 31 4667 4 N.M.R. 6ppm (DMSO-d6) : 3.60 (2H, m) , 3.81 (3H, s), S.12 (1H, d, J=5Hz) ; 5.85 (1H, dd, J=5Hz, 10Hz) , 6.64 (IH, m), 6.70 (III, s), 7.20 (2H, s), 7.65 (2H, d, J=10Hz), 8.19 (2H, d, J=10Hz), 9.60 (IH, d,•J=10Hz) (2) p-Nitrobenzyl 7-[2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido] 3-cephem-4-carboxylate (syn-isomer : 7.8 g.) was suspended in a mixture of ethanol (60 ml.) and water (60 ml.) IN ^ Aqueous solution of potassium hydroxide (45 ml.) was added dropwise to the stirred suspension under ice-cooling over , 10 minutes and stirred at 5°C for 15 minutes. The resultant solution was adjusted to pH 7.0 with conc. hydrochloric acid, washed with ethyl acetate and the concentrated under reduced pressure to half of its initial volume. The concentrated solution was adjusted to pH 5.0 and subjected to column chromatography on macroporous, non-ionic adsorption resin "Diaion HP-20" (Trade mark; manufactured by•Mitsubishi Chemical Industries Ltd.; 80 ml.), and eluted with 5% aqueous solution of isopropyl alcohol. The fractions containing the object compound were collected and adjusted to pH 3.2 with 101 hydrochloric acid. The precipitating crystals were collected by filtration, and dried to give 7-[2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn-25 isomer : 2.3 g.) 15 20 1 -7- 1 1 DL 46674 Example,9 I i p-Nitrobenzyl' 7-amino-3-cephem-4-carboxylate (3.4 g.) was suspended in tetrahydrofuran (60 ml.) and an aqueous solution (20 ml.) of sodium bicarbonate (1.2 g.) was added to the suspension. IN Aqueous sodium hydroxide (30 ml.) was 5 , added dropwise to the solution at 3 to 4°C and stirred for 20 minutes. The resultant solution was adjusted to pH 7.0 with 101 hydrochloric acid and. concentrated under reduced pressure.

The insoluble substance was filtered out and the filtrate was j washed with ethyl acetate. Acetone (30 ml.) was added to the 10 ' filtrate and cooled to -5°C. A solution prepared from phosphorus oxychloride, dimethylformamide, trimethylsilylacetamide and 2-(2-amino-4-thiazolyl)-2-methoxyiminoacetic acid (syn-isomer : 2.2 g.) in a similar manner to Example 7 was added 15 to the solution obtained above at -5 to 0°C, at pH 7.5 to 8.5. The mixture was stirred at 3 to 7°C, at pH 7.5 to 8.5 for 2 hours, and the insoluble substance was filtered out. The aqueous layer was separated from the filtrate, washed with ethyl acetate and adjusted to pH 3.0 to give 7-[2-(2-amino-2P 4-thiazolyl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn-isomer : 1.1 g.) 133 4 6 6 7 4 Example 10 , (1) Phosphoryl chloride (1.764 g.) was added to a suspension of 2-(2-amirio-4-thiazolyl)-2-ethoxyiminoacetic acid (syn isomer, 1.0 g.) in tetrahydrofuran (10 ml.) below 5°C and stirred at the same temperature for 20 minutes. To the solution were added trimethylsilylacetamide (0.4 g.) and N,N-dimethylformamide (0.4 g.), and the solution was stirred below 5°C for 40 minutes(Solution A]. On the other hand,,trimethylsilylacetamide (3.5 g.) was added to a suspension of 4-nitrobenzyl 7-amino-3-cephem-4-carboxylate (1.5 g.) in tetrahydrofuran (15 ml.), and stirred at room temperature for 1.5 hours. To the solution was added all at once the above Solution A at -20°C, and the solution was stirred at -5 to 0°C for an hour. Water 134 46674 (20 ml.) was added to the resultant solution at -20°C, and the solution was adjusted to pH 7.5 with an aqueous solution of sodium bicarbonate.

Tetrahydrofuran C70 ml.) and a saturated aqueous solution ^ of sodium chloride (50 ml.) were added to the solution, ;and the solution was shaken sufficiently. The aqueous layer was separated and extracted with tetrahydrofuran. The tetrahydrofuran layer and extract were combined and washed with a saturated aqueous solution of sodium chloride, lo The solution was dried over magnesium sulfate and concentrated under reduced pressure. The residue was itriturated with diisopropyl ether to give 4-nitrobenzyl i i 17- [2-(2-amino-4-thiazolyl)-2-ethoxyiminoacetamido]-3- i cephem-4-carboxylate (syn isomer, 2.5 g.). [j 15 I. R*v max°1 : 3330' 1780» 1730' 1680» 1640' 1610 cm"1 N.M.R. 6ppm(DMSO-d6) : 1.17 (3H, t, J=7Hz), 3.50 (2H, m), 4.05 (2H, q, J=7Hz), 20 5.10 (IH, d, J=5Hz), 5.85 (IH, dd, J=5Hz, 8Hz), 6.67 (IH, s), 7.17 (2H, m), 7.63 (2H, d, J=8Hz), 8.18 (2H, d, J=8Hz), 10.13 (1H, d, J-8Hz). 25 (2) Palladium on carbon (1.0 g.) moistened with water (3 ml.) was added to a solution of 4-nitrobenzyl 7-[2-(2-amino-4-thiazolyl) - 2-ethoxyiminoacetamido]-3-cephem-4-carboxylate (syn isomer, 2.3 g.) in a mixture of tetrahydrofuran (30 ml.), methanol (15 ml.) and acetic acid 3Q (0.3 ml.), and the suspension was subjected to catalytic 1 4 667 4 reduction at room temperature under ordinary pressure for 2 hours. After removing the catalyst from the resultant mixture by filtration, the filtratej w,as 1 concentrated , , und^r rcduced pressure. Ethyl acetate was added to the residue, and the solution was adjusted to pH 7.5 with an aqueous solution of sodium bicarbonate. After removing the insoluble substance by filtration, the aqueous solution was separated, washed with ethyl acetate, adjusted to pH 5.5 and then treated with activated charcoal. The aqueous solution was adjusted to pH 3.2, and the precipitates were collected by filtration and dried to give 7-[2-(2-amino- 4 —thiazolyl) 2-ethoxyiminoacetamido] - 3-cephem-4-carboxylic acid (syn isomer, 0.6 g.).

I-R- v!!oi01 • 3500, 3300, 3200, 1785, 1625, lUOA 16Q0 cm'1 N.M.R. 6ppm(DMSO-d6): 1.20 (3H, t, J=7Hz), 3.57 (2H, m), 4.08 (2H, q, J=7Hz), 5.08 (IH, d, J-SHz), 5.83 (IH, dd, J=5Hz, 8Hz) , 6.47 (IH, m), 6.73(1H, s) , 7.20(2H, iji) , 9.58 (IH, d, J=8Hz) 15 20 Example 11 (1) Triethylamine (2.37 g.)> dimethylaniline (7.12 g.) and trimethylsilyl chloride (3.93 g.) were added to a stirred suspension of 4-nitrobenzyl 7-(2-phenylacetamido)-3-hydToxy-3-cephem-4-carboxylate (10 g.) in methylene chloride ! 156 46674 (200 ml.) in turn, and the solution was stirred at I room temperature for an hour. Phosphorus pentachloride (4.88 g.) was added to the solution at -30 to -25°C and stirred at -25 to -20°C for 3 hours. Methanol (42 ml.) was added to the solution at -25 to -20°C, and stirred for an hour. To the solution was added water (35 ml.) i at -25 to -20°C, and the solution was stirred at room temperature. The precipitates were^ collected by filtration, washed with methylene chloride and diethyl ether in turn, and dried to give 4-nitrobenzyl 7-amino-3-hydroxy-3-cephem-4-cnrboxylate (5.2 g.), mp 148°C (dec.). 1.R. v max01 : 3440» 3300» 1760' 1740 cm 1 N.M.R. 6ppm (DMSO-d6) : 2.8 - 3.7 (2H, m), 4.90 (IH, t, J=4Hz), 5.29 (IH, d, J*4Hz), 5.38 (2H-, s), 7.71 (2H, d, J-8Hz), 8.26 (2H, d, J=8Hz). (2) Phosphoryl chloride (2.87 g.) was dropwise added to a solution of N,N-dimethylformamide (1.37 g.) in ethyl acetate (10 ml.) at 5 to 10°C. Ethyl acetate (40 ml.) was added to the solution, and stirred under ice cooling for 40 minutes. To the solution was added 2-(2-formamido-4-thiazolyl)-2-methoxyiminoacetic acid (syn isomer, 3.58 g.), and the solution was stirred at 0 to 5°C for 40 minutes. The resultant solution was added all at once to a mixture of 4-nitrobenzyl 7-amino-3-hydroxy-3-ccphcm-4-carboxylate (5 e«), ethyl acetate (50 ml.), trimetihylsilylacetmnide (14.3 g.) and bis{trimethylsilyl)acetamide (5.8 g.) at -15°C, and stirred at -20 to -15°C for 1.2 hours. 137 15 i 4 6 674 Water (50 ml.) was added to the resultant solution at -25 to -20°C, and stirred until the temperature rise 5°C. The aqueous layer was separated and extracted with ethyl acetate. The ethyl acetate layer and 5 extract were combined, washed with a saturated aqueous solution of sodium chloride and' dried over magnesium sulfate. After the solution was concentrated to a volume of 50 ml. under reduced pressure, the precipitates were collected by filtration and washed with ethyl acetate to 10 give 4-nitrobenzyl 7- [2- (2-formamido-4-thiazolyl)-2- rnethoxyiminoacetamido]-3-hydroxy-3-cephem-4-carboxylate (syn isomer, 3.5 g.), mp 163°C (dec.).

I.R. v ^ol : 3210, 3160, 3050, 1780, 15 1665 cm"1 N.M.R. 6ppm (DMSO-dg): 3.0 - 4.2 (2H, m), 3.95 (3H, s), 5.28 (IH, d, J=4Hz), 5.41 (2H, s) 5.64 (IH, dd, J=4Hz, 9Hz), 7.49 (IH, s) 7.67 (2H, d, J=8Hz), 8.21 (2H, d, J=8Hz), 20 8.50 (IH, t, J=9Hz). 158 (3) A solution of the compound obtained above (1 g.) in methanol (15 ml..), tetrahydrofuran (5 ml.) and conc. hydrochloric acid (0.72 g.) was stirred at room temperature for an hour. Diethyl ether (100ml.) was added to the resultant solution gnd then triturated. The crystals were collected by filtration to give 4-nitrobenzyl 7-[2—(2—aminothiazol—4—yl)—2-methoxyiminoacetamido ]-3-hydroxy-3-cephem-4-carboxylate hydrochloride (syn isomer, 0.65 g.).

I-*« : 3180, 1780, 1680, 1670, 1640 cm"1 N.M.R. £ ppm (DMSO-dg) : 3.2 - 4.0 (2H, m), 3.97 (3H, s), 5.27 (IH, d, J=4Hz), 5.41 (2H, s), 5.60-(IH, dd, J=4Hz, 8Hz), 7.10 (IH, s), 7.66 (2H, d, Jjfe9Hz), 8.25 (2H, d, J=9Hz), 9.73 (IH, d, /=8Hz) Example 12 (1) Phosphoryl chloride (1.76 g.) and trimethylsilylacetamide (0.4 g.) were added to a stirred suspension of 2-(2-amino-4-thiazolyl)-2-ethoxyiminoacetic acid (syn isomer, 1.0 g) in tetrahydrofuran (10 ml.) below 5*C, and stirred at the same temperature for 30 minutes. N,N-Dimethylformamide (0.4 g.) was added to the solution and stirred below 5°C for :20 minutes [Solution.A]. Trimethylsilylacetamide (4.8 g.) was added to a stirred suspension of 4-nitrobenzyl 7-amino-3-chloro-3-cephem-4-carboxylate hydrochloride (1.9 g.) in tetrahydrofuran (15 ml.), and the solution was stirred at room temperature for an hour. To the solution was added the above Solution A all at once at -20°C, and the solution 159 4 667 4 was stirred at 0°C for an hour. Water (50 ml.) was added to the resultant solution at -20°C, and adjusted to pH 8.0 with an aqueous solution of sodium bicarbonate. Tetrahydrofuran (50 ml.) and a saturated aqueous solution of sodium chloride (50 ml.) were added to the solution. The organic layer was separated, .washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. After concentrating the solution under reduced pressure, the residue was triturated with diisopropyl ether and the precipitates were collected by filtration to give 4-nitrobenzyl 7-[2-(2-amino-4-thiazolyl)-2-ethoxyiminoacetamido] -3-chloro-3-cephem-4-carboxylate (syn isomer, 2.0 g.).

I. R. v ^ax01: 3200' 1780, 1730' 1670 c™~1 N.M.R. £ppm (DMS0-d6): 1.23 (3H, t, J=7Hz), 3.96 (2H, s), 4.13 (2H, q, J=7Hz), 5.31 (1H, d, J=5Hz), 5.88 (IH, dd, J=5Hz, 8Hz), 6.77 (IH, s), 7.67 (2H, d, J=8Hz), 8.25 (2H, d, J=8Hz), 10.30 (IH, d, J=8Hz). (2) A suspension of palladium on carbon (0.8 g.) in water (5 ml.) was added to a mixture of 4-nitrobenzyl 7-[2-(2-amino-4-thiazolyl)-2-ethoxyiminoacetamido]-3-chloro-3-cephem-4-carboxylate (syn isomer, 2.0 g.), acetic acid (0.6 ml.) and tetrahydrofuran' (60 ml.), and the suspension was subjected to catalytic reduction under ordinary pressure at room temperature for 3 hours. 140 46674 10 15 20 After removing the.catalyst by filtration, the filtrate was concentrated under reduced pressure. After adding ethyl acctule (.SO ml.) to the residue, the solution was adjusted to pll 7.5 with an aqueous solution of sodium bicarbonate, and the insoluble substance was filtered out. The aqeuous layer was separated and adjusted to pH 6.0 with 10% hydrochloric acid, and then the organic solvent was removed under reduced pressure. The aqueous solution was subjected to column chromatography on macroporous, nonionic adsorption resin "Diaion HP-20" (Trademark, manufactured by Mitsubishi Chemical Industries Ltd.) (30 ml.). The column was washed' with water and eluted with 5% aqueous isopropyl alcohol. The eluate was lyophilized to give sodium 7-[2-(2-amino-4-thiazolyl)-2-ethoxyiminoacetamido]-3-chloro-3-cephem-4-carboxylate (syn isomer, 0.3 g.).

I. R. v Nu3o1 : 3350 3200, 1770, 1675, 1620 cm'1 max » » » » N.M.R. <5 ppm (D20) : 1.33 (3H, t, J=7Hz), 3.76 (2H, q, J=18Hz, 30Hz), 4.30 (2H, q, J=7Hz), 5.33 (IH, d, J=5Hz), 5.83 (IH, d, J=5Hz), 7.06 (III, s). 141 466 7 4 • Example 13 I (1) Phosphoryl chloride (4.6 g.), trimethylsilylacetamide (0.95' g.) and N,N-dimethyl.f ormamide (1.2 g.) were added to a stirred suspension of 2-(2-amino-4-thiazolyl)-2-isopropoxyiminoacetic acid (syn isomer, 2.8 g.) in tetrahydrofuran (25 ml.) below 5°C for 30 minutes [Solution A]. On the other hand, trimethylsilylacetamide (10.5 g.) was added to a suspension of 4-nitro- i benzyl 7-amino-3-cephem-4-carboxylate (3.9 g.) in tetrahydrofuran (50 ml.), and stirred at room temperature for 1.5 hours.

To the solution was added the above solution A at -20°C all at once, and the solution was stirred at -5 to 0°C for 40 minutes. Water (70 ml.) and tetrahydrofuran (100 ml.) were added to the resultant solution at -20°G. The solution was adjusted to pH 7.5 with an aqueous solution of sodium bicarbonate and stirred for / an hour. After a saturated aqueous solution of sodium chloride (200 ml.) was added, the organic layer was separated. The remaining aqueous layer was extracted with tetrahydrofuran, and the extract and the above organic layer were combined, washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was triturated with diisopropyl ether and the precipitates were collected by filtration to give 4-nitrobenzyl 7- [2-(2-amino-4-thiazolyl)-2-isopropoxyiminoacetamido]-3-cephem-4-carboxylate (syn isomer, 6.0 g.). : 3320, 3270, 1775, 1730, 1670, 1630 cm"1 max N.M.R. j ppm (DMSO-dg) : 1.17 (6H, d, J=6Hz), 3.63 (2H, m), 4.33 (IH, q, J=6Hz), 5-17 (IH, d, J=5Hz), 5.42 (2H, s) , 5.92 (lH, dd, J=5Hz, 8Hz), 6.67 (IH, m) , 142 4 6 6 7 4 6.70 (1H, s), 7.22 (2H, m), 7.70 (2H, d, J=8Hz), ^ 8.25 (2H, d, J=8Hz), 10.13 (1H, d, J=8Hz) (2) Acetic acid <1 ml.) and a suspension of 10% palladium on carbon (2.0 g.) in water (8 ml) were added to a solution of 4-nitrobenzyl 7-[2-(2-amino-4-thiazolyl)-2-isopropoxyimino-acetamido]-3-cephem-4-carboxylate (syn isomer, 5.0 g.) in tetrahydrofuran (150 ml.), and the suspension was subjected to catalytic reduction at room temperature under ordinary pressure. After removing the catalyst by filtration, the 10 filtrate was concentrated under reduced pressure. Ethylacetate (80 ml.) was added to the residue, and adjusted to pH 7.5 with an aqueous solution of sodium bicarbonate. The organic layer was separated and extracted with an aqueous solution of sodium bicarbonate. The extract and the aqueous layer obtained 15 above were combined, adjusted to pH 3.0 with conc. hydrochloric acid and extracted with tetrahydrofuran. The extract was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated under reduced pressure. 2o The precipitating crystalls were collected by filtration and dried to give 7-[2-(2-amino-4-thiazolyl)-2-isopropoxyimino-acetamido]-3-cephem-4-carboxylic acid (syn isomer, 0.8 g.). ■ 3320. 1780, 1670, 1635 cm"1 25 max N.M.R. J ppm (DMSO-dg) : 1.20 (6H, d, J=6Hz), 3.55 (2H, m), ' 4.30 (IH, q, J=6Hz), 5.08 (IH, d, J=5Hz), 5.82 (III, dd, J=5Hz, 8Hz) , 6.45 (IH, m) , 6.68 (IH, s) , 7.10 (211, m) , 10.08 (111, d, J=8Hz) 145 Example 14 (1) Phosphoryl chloride (4.6 g.), trimethylsilylacetamide (0.95 g.) and N,N-diraethylforniamide (1.2 g.) were added to a stirred suspension of 2-(2-amino-4-thiazolyl)-2-propoxyimino-acetic acid (syn isomer, 2.8 g.) in tetrahydrofuran (25 ml.) below 5°C, and stirred for 20 minutes. The solution was dropwise added to a suspension of 4-nitrobenzyl 7-amino-3-cephem-4-carboxylate (3.9 g.) in a mixture of tetrahydrofuran (20 ml.), water (20 ml.) and acetone (20 ml.) at -5 to 5°C while keeping the pH value at 6.9 to 7.1 with 20% aqueous solution of sodium carbonate. The solution was stirred at -5 to 5°C for 30 minutes and further at 10°C for an hour, and adjusted to pH 7.5. After tetrahydrofuran (100 ml.) and a saturated aqueous solution of sodium chloride (200 ml.) were added to the resultant solution, the insoluble substance was filtered out. The organic layer was separated from the filtrate, washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was triturated with diisopropyl ether and the precipitates were collected by filtration to give 4-nitrobenzyl 7- 12- (2-amino-4-thiazolyl) -2-propoxyiminoacetamido] -3-cephem-^ 4-carboxylate (syn isomer, 5.8 g.).

I,R,^max01 : 3300, 1780' 1730, 1670, 1640 cm"1 N.M.R. J ppm (DMSO-dg) : 0.93 (3H, t, J=6Hz), 1.70 (2H, m), 3.70 (2H, m), 4.08 (2H, t, J=6Hz), 4.5 (2H, m) , 5.23 (IH, d, J=5Hz), 5.50 (2H, s), 5.97 (IH, dd, J=5Hz, 8Hz) , 6.73 (III, m) , 6.80 (IH, s) , 7.75 (211, d, J=9Hz) , 8.30 (2H, d, J=9Hz), 9.65 (111, d, J=8Hz) . (2) 4-Nitrobenzyl 7-[2-(2-amino-4-thiazolyl)-2-propoxyiminoacetamido] -3-cephem-4-carboxylate (syn isomer, 5.0 g.) was 46674 treated in a similar manner to that of Example 13-(2) to give ! 7- [2- (2-amino-4-thiazoly.l) -2^propoxyiminoacetamido) -3-cephem-4-carhoxylic acid I.R. v JJax— 3240, 3050, 1780, 1730, 1695, 1660 cm"1 N.M.R. 6(DMSO-dg, ppm) : 0.92 (3H, t, J=7Hz), 0.8—2.2 (4H, m), 3.67 (2H, d, J=4Hz), 4.16 (2H, t, J=7Hz) , 5.23 (IH, d, J=5Hz), 5.46 (2H, s), 5.99 (IH, dd, J=SHz, 8Hz), 6.71 (IH, t ; J=5Hz), 7.43 (IH, s) , - 7 46 25 30 10 46674 7.76 (2H, d, J=9IIz), 8.30 (2H, d, t J=9Hz), 8.58 CI", s), 9.72 (IH, d, J=8Hz), 12.66 (1H, s) (2) A mixture of 4-nitrobenzyl 7-[2-(2-formamidothiazol-4-yl)-2-n-butoxyiminoacetamido]-3-cephem-4-carboxylate (syn isomer, 34.5 g.), tetrahydrofuran (345 ml.), 10% palladium carbon (14 g.), methanol (140 ml.), acetic acid (2.5 ml.) and water (50 ml.) was subjected to catalytic reduction under ordinary pressure at room temperature for 3 hours. The resultant mixture was filtered, and washed with tetrahydrofuran. The filtrate was concentrated in vacuo, and the residue was dissolved in a mixture of ethyl acetate and an aqueous solution of sodium bicarbonate. The insoluble substance was removed by filtration. After the ethyl acetate layer was separated and extracted with an aqueous solution of sodium bicarbonate, the aqueous layer and the aqueous extract were combined.

After the aqueous solution was washed with ethyl acetate and diethyl ether in turn, the solution was adjusted to pH 2.0 with 10% hydrochloric acid and stirred for 30 minutes. The 2o precipitates were collected by filtration, washed with water and dried over magnesium sulfate to give 7-[2-(2-formamidothiazol-4-yl)-2-butoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer, 18.3 g.). 25 I.R. v Jjgj.01: 3330, 3040, 1780, 1725, 1695, 1655 cm"1 N.M.R. 6(DMSO-d6, ppm) : 0.90 (3H, t, J=7Hz), 1.1-1.9 (4H, m), 3.58 (2H, d, J=5Hz), 4.12 (2H, t, J= 7Hz), 5.13 (IH, d, J=5Hz), 5.86 (IH, dd, J=5Hz, 8Hz), 6.46 (IH, t, J=4Hz), 7.40 (IH, s), 15 30 -U? 4 6 6 7 4 ; 8.50 cm, s), 9.63 (1H, d, J=0Hz), ' 12.57 (1H, broad s) (3) A mixture of 7-[2-(2-formamidothiazol-4-yl)-2-n-butoxyiminoacetamido] - 3-cephem- 4- carboxylic acid (syn isomer, 12.7 g.), cone, hydrochloric acid (9.6 ml.), methanol (9.5 ml.) and tetrahydrofuran (9.5 ml.) was stirred at room temperature for 3 hours. The resultant solution was concentrated in vacuo, and the residue was suspended in water. The suspension was adjusted to pH 3.5 with sodium bicarbonate under ice cooling, and stirred at same temperature for 30 minutes. The precipitates were collected by filtration and dried over magnesium sulfate to give the powder (10 g.). The powder was suspended in water (300 ml.) and adjusted to pH 7.0 with sodium bicarbonate. The solution was adjusted to pH 6.0 with 10% hydrochloric acid and subjected to column chromatography on nonionic adsorption resin (Diaion HP-20 : trademark, manufactured by Mitsubishi Chemical Industries Ltd.) (300 ml.) with 10% aqueous solution of isopropyl alcohol. The eluate was adjusted to pH 3.5 with 10% hydrochloric acid under ice cooling, and the precipitates were collected by filtration, washed with water and dried to give 7-[2-(2-aminothiazol-4-yl)-2-n-butoxyimino-acetamido]-3-cephem-4-carboxylic acid (syn isomer, 7.2 g.). I.R. v jjjjj01 : 3320, 1775, 1660 cm"1 N.M.R. <5 (DMSO-d6, ppm) : 0.88 (3H, t, J=7Hz), 1.1^1.9 (4H, m), 3.58 (2H, broad s), 4.05 (2H, t, J=7Hz), 5.08 (IH, d, J=5Hz), 5.80 (IH, dd, J=5Hz, 8Hz), 6.44 (IH, braod s), 7.18 (2H, s), 9.51 (IH, d, J=8Hz) 148 46674 Example 16 ' (1) 2 - (2-Formataidothiazol-4-yl)-2-iso-butoxyiminoacetic acid (syn isomer, 6.48 g.), N,N-dimethylformamide (2.10 g.)» phosphoryl chloride (4.40 g.), tetrahydrofuran (110 ml.), 4-nitrobenzyl 7-amino-3-cephem-4-carboxyIate (8.23 g.), acetone (16 ml.) and water (16 ml.) were treated in a similar manner to that of Example 15*(1) to give 4-nitrobenzyl 7-[2-(2-form- amidothiazol-4-yl)-2-iso-butoxyiminoacetamido]- 3-cephem-4- carboxylate (syn isomer, 12.8 g.). 10 I.R. v Nu)01 : 3240, 3050, 1780, 1720> 1700, max ' ' 1655 cm"1 N.M.R. 6(DMSO-d6, ppm) : 0.92 (6H, d, J=7Hz), 1.7^2.2 (IH, m), 3.67 (2H, broad s), 3.91 (2H, d, J=7Hz), 5.21 (IH, d, J=5Hz), 5.95 (IH, dd, J=5Hz, 9Hz), 6.67 (IH, t f J=4Hz), 7.37 (IH, s), 7.72 (2H, d, J-8Hz), 8.24 (2H, d, J=8Hz), 8.52 (IH, s), 20 9.68 (IH, d, J=9Hz), 12.58 (IH, broad s) (2) 4-Nitrobenzyl 7-[2-(2-formamidothiazol-4-yl)-2-iso-butoxyiminoacetamido] -3-cephem-4-carboxylate (syn isomer, 25 14.2 g.), 10% palladium carbon (5.7 g.), methanol (57 ml.)» tetrahydrofuran (142 ml.), acetic acid (1 ml.) and water (10 ml.) were treated in a similar manner to that of Example 15-(2) to give 7- [2-(2-formamidothiazol-4-yl)-2-iso-butoxyiminoacetamido] -3-cephem-4-carboxylic acid (syn isomer, 4.25 g.).

I.R. v Uax°1: 3260» l790' 1725» 1670 cml 30 149 4 6674 v— N.M.R. 6{DMS0-d6, ppm) : 0.92 (6H, d, J=6Hz), 1.6*2.3 (IH, m), 3.61 (2H, d, J=4Hz), 3.91 (2H, d, J=6Hz), 5.14 (IH, d, J=5Hz), 5.88 (IH, dd, J=5Hz, 8Hz), 6.50 (IH, t, J=5Hz), 7.40 (IH, s) , | 5 8.56 (IH, s), 9.64 (IH, d, J=8Hz) (3) 7-[2-(2-formamidothiazol-4-yl)-2-iso-butoxyiminoacet- i amido]-3-cephem-4-carboxylic acid (syn isomer, 4.1 g.), conc. hydrochloric ^acid (3.65 g.) and methanol (61.5 ml.) were treated in a similar manner to that of Example 15*(3) to give 10 7-[2-(2-aminothiazol-4-yl)-2-iso-butoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer, 2.4 g.). 1.R. v max01 : 3330' 1780' 1665' 1630» 1545 cm N.M.R. 6(DMSO-d,, ppm) : 0.89 (6H, d, J=7Hz), 15 ° 1.6*2.2 (1H, m), 3.58 (2H> broad s), 3.84 (2H, d, J=7Hz>, 5.10 (IH, d, J=5Hz), 5.82 (IH, dd, J=5Hz, 9Hz), 6.46 (IH, braod s), 6.68 (IH, s), 7.20 (2H, s), 9.53 (IH, d, J=9Hz) 20 Example 17 (1) 2-(2-Formamidothiazol-4-yl)-2-c)^clohexyloxyiminoacetic acid (syn isomer, 0.9 g.), N,N-dimethylformamide (266 mg.), ph'osphoryl chloride (55 7 mg.), tetrahydrofuran (20 ml.), j i 25 4-nitrqbenzyl 7-amino-3-cephem-4-carboxylate (1.05 g.), acetone (3 ml.) and water (3 ml.) were treated in a similar manner to that of Example 15-(1) to give 4-nitrobenzyl 7-[2-(2-formamidothiazol-4-yl)-2-cyclohexyloxyiminoacetamido]-3-cephem-4-carboxylate (syn isomer, 1.69 g.). 30 I.R. v *j"Jo1 : 3260, 3170,3070 , 1785, 172S, 1700, JTlaA. 1655 cm"1 isn 4 6 6 7 1 10 20 25 N.M.Ri 6 (l)MS0-d6, ppm) : 0.8*2.2 (1011, m) , 3.66 (2H, broad s), 4.10 (IH, m), 5.16 (IH, d, J=5Hz), 5.42 (2H, s), 5.95 (IH, dd, J=5Hz, 9Hz) , 6.66 (IH, broad s), 7.37 (1H, s), 7.70 (2H, df'J=8Hz), 8.22 (2H, d, J= 8Hz), 8.50 (IH, s), \ , 9.63 (1H, d, J=9Hz), 12.60 (IH, broad s) (2) 4-Nitrobenzyl 7-[2-(2-formamidothiazol-4-yl)-2-cyclo-hexyloxyiminoacetamido]-3-cephem-4-carboxylate (syn isomer, 2.0 g,), 10% palladium carbon (0.8 g.), methanol (8 ml.), tetrahydrofuran (20 ml.), acetic acid (0.14 ml.) and water (1.4 ml.) were treated in a similar manner to that of Example l5-(2) to give 7-[2-(2-formamidothiazol-4-yl)-2-cyclohexyloxyimino- 25 acetamido]-3-cephem-4-carboxylic acid (syn isomer, 0.77 g.).

I.R. v NujQl : 3275, 3070, 1780, .1675 cm"1 max ' ' N.M.R. 6(DMS0-d6, ppm) : 0.8*2.2 (10H, m), 3.62 (2H, broad s), 4.12 (IH, m), 5.13 (IH, d, J=5Hz), 5.87 (IH, dd, J=5Hz, 9Hz), 6.47 (IH, broad s), 7.37 (IH, s), 8.50 (IH, s), 9.58 (IH, d, J=9Hz), 12.61 (IH, broad s) (3) 7-[2-(2-Formamidothiazol-4-yl)-2-cyclohexyloxyimino-acetamido]-3-cephem-4-carboxylic acid (syn isomer, 0.72 g.), methanol (10.8 ml.) and conc. hydrochloric acid (0.61 g.) were treated in a similar manner to that of Example l5-(3) to 30 give 7-[2-(2-aminothiazol-4-yl)-2-cyclohexyloxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer, 0.28 g.). 151 4 667 4 ^ I.R. ; 3350' 1775» 1665» 1620,1540 cm"1 N.M.R. 6(DMSO-d6, ppm) : 0.8*2.2 (10H, m), 3.60 (2H, broad s), 4.04 (IH, m), 5.09 (IH, 5 d, J=5Hz), 5.83 (IH, dd, J=5Hz, 9Hz), 6.45 (IH, t, J=4Hz), 6.67 (IH, s), 7.19 (2H, s), 9.48 (IH, d, J=9Hz) Example 18 Phosphoryl chloride (0.84 g.) was added dropwise to a stirred suspension of 2-(2-aminothiazol-4-yl)-2-allyloxyimino-acetic acid (syn isomer, 1.0 g.), tetrahydrofuran (10 ml.) and water (0.05 ml.) at 5°C, and stirred at the same temperature for 20 minutes. Trimethylsilylacetamide (0.66 g.), phosphoryl 15 chloride (0.84 g.) and N,N-dimethylformamide (0.45 g.) were added to a solution, and stirred at 5°C for an hour to prepare the activated acid solution. On the other hand, trimethylsilylacetamide (4.0 g.) was added to a suspension of 7-amino-3-cephem-4-carboxylic acid (0.88 g.) in tetrahydrofuran (10 ml.) 2o 40°C, and stirred for 30 minutes. To the solution was added all at once the activated acidsolution obtained above at -20°C, and stirred at 0°C for an hour. After water (20 ml.) was added to the resultant solution at -20°C, the solution was adjusted to pH 7.5 with an aqueous solution of sodium 25 bicarbonate. Ethyl acetate was added to the solution, and the aqueous layer was separeted. The solution was washed with ethyl acetate and diisopropyl ether in turn, adjusted to pH 5.0 and treated with activated charcoal. After the solution was adjusted to pH 3.0, the precipitates Were collected by filtration, 30 washed with water and dried over phosphorus pentoxide to give 7-[2-(2-aminothiazol-4-yl)-2-allyloxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer, 0.8 g.).

I-R. v jJaj01 : 3300, 1780, 1660, 1630 cm"1 35 .'52 46674 i 1 s-- ! N.M.rJ 6(DMSO-d6> ppm) : 3.67 (2H, d, J=4Hz), 4.67: (2H, m), 5.17 (IH, d, J=5Hz), 5.25 (111, in), 5.50 (111, m), 5.9.(1 (1H, dd, J=5IIz, 8Hz) , 6.03 (IH, m), 6.55 (IH, m), 6.80 (IH. si, 5 7.50 (211, m), 9.68 (IH, d, J=8Hz) Example 19 Phosphoryl chloride (1.4 g.) was added dropwise to a suspension of 2-(2-aminothiazol-4-yl)-2-propargyloxyiminoacetic 10 acid (syn. isomer, 1.7 g.) in tetrahydrofuran (15 ml.) below 7°C, and stirred at the same temperature for 10 minutes.

Phosphoryl chloride (1.4 g.), trimethylsilylacetamide (1.3 g.) and N,N-dimethylformamide (0.76 g.) were added to a solution, and stirred for 20 minutes to prepare the activated acidsolution. 15 On the other hand, trimethylsilylacetamide (7.8 g.) was added to a suspension of 7-amino-3-.cephem-4-carboxylic acid (1.5 g.) in tetrahydrofuran (20 ml.), and stirred at 40°C for 30 minutes. To the solution was added all at once the activated acid solution obtained above at -20°C, and stirred for 30 minutes at 0°C. 20 After: adding water (20 ml.) to the resultant solution at -20°C, the solution was adjusted to pH 7.5 with an aqueous solution of sodium bicarbonate. The aqueous layer was separated, washed with ethyl acetate and diisopropyl ether in turn, and treated with activated charcoal at pH 5.5. The solution was 25 adjusted to pH 3.0, and the precipitates were collected by filtration and dried over phosphorus pentoxide under reduced pressure to give 7-[2-(2-aminothiazol-4-yl)-2-propargyloxy-iminoacetamido]-3-cephem-4-carboxylic acid (syn isomer, 1.47 g.).

I,R* v max01 : 3500' 3300' 1780» 1720' 1660' 1630 cm"1 30 j3 4007 4 10 15 20 30 N.M.R. 6(I)MSO-d6, ppm) : 3.48 (III, in), 3.67 (211, m) , 4.80 (.211, d, J"211z), S.17 (IH, d, J=5Hz), 5.88 (IH, dd, J=5Hz, 8Hz) , 6.55 (1H, in), 6.85 (IH, s) , 7.33 (211, in), 9.73 (111, d, J=8Hz) Example 20 (1) N,N-Dimethylformamide (3 drops) was added to a suspension of 2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetic acid (syn /in thionyl chloride (230 ml.)/ isomer, 23 g.)/ and stirred at 60°C for 5 minutes. After concentrating the solution in vacuo, benzene was added to the residue. The presipitates were collectcd by filtration, Washed with benzene (30 ml.) three times and diethyl ether in turn to give 2-(2-formamidothiazol-4-yl)-2-methoxyi.ininoacetyl chloride (anti isomer, 18 g.). On the other hand, trimethylsilylacetamide (46 g.) was added to a suspension of 4-nitrobenzyl 7-amino-3-cephem-4-carboxylate (16.8 g.) in methylene chloride (ICS ml.), and stirred at 40°C for an hour. To the suspension was gradually added 2-(2-formainidothiazol-4-yl) -2-methoxyimino-acetyl chloride (anti isomer, 13.6 g.) at -5 to 0°C, and stirred at the same temperature for an hour. Water (150 ml.) was added to the resultant solution and stirred for 15 minutes. The recipitates were collected by filtration, washed with water and dried over phosphorus pentoxide under reduced pressure to 25 give 4-nitrobenzyl 7-[2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetamido] - 3- cephem-4-carboxylate (anti isomer, 25.7 g.).

I.R. . v mak01 : 3300 (broad), 1780, 1730, 1680, 1520 cm"1 N.M.R. 6(DMS0-dg, ppm) : 3.70 (2H, broad s), 4.07 (3H, s), 5.19 (IH, d, J=5Hz), 9.57 (lH, d, J=8Hz),6.00 (]H, dd, J=5Hz, 8Hz) , 5.30 (2H, c), 4 6 6 7 4 6.70 (111, t, .JMllz) , 7.71 , 8.25 (411, A2B2, .I=9Hz) , 8.07 (1H, s), 8.50 (IH, s), 12.55 (111, broad s) (2) A suspension of 4-nitrobenzyl 7-[2-(2-formamidothiazol-4-yl)- 2-ihethoxyiminoacetamiclo] -3-cephem-4-carboxylate (anti isomer, 4.2 g.), 10% palladium carbon (1.7 g.), acetic acid (0.63ml.), water (6.3 ml.), methanol (42 ml.), and tetrahydrofuran (84 ml.) was subjected to catalytic reduction in a hydrogen atmosphere dt room temperature for 2 hours. After removing the catalyst'by filtration, the filtrate was concentrated to a volume of about 15 ml. under reduced pressure. Water (30 ml.) and ethyl acetate (50 ml.) were added to the concentrated i . solution, and the solution was adjusted to pH 8.0 with sodium bicarbonate under stirring. The insoluble substance was ! removed by filtration, and the aqueous layer was separated ank | washed with ethyl acetate (50. ml.). The solution was treated with activated charcoal, and adjusted to pH 2.2 with 10% hydrochloric acid under ice cooling. The precipitates were collected by filtration and washed with water to give ■ 7-[2-(2-formamidothiazol-4-yl) - 2-methoxyiminoacetamido]- 3-cephem-4-£arboxylic acid (anti isomer, 2.52 g.).

I,R* V max01 : 3300 (broad)» 1780» 1680, 1670, ; 1550 cm'1 ; N.M.R. 6(DMSO-d6, ppm) : 3.63 (2H, broad s), J 4.08 (3H, s), 5.15 (1H, d, J-5Hz);,-5.87 (IH, dd, J=5Hz, 8Hz), 6.55 (IH, t, J=4Mz), 8,09 (IH, s), 8.52 (IH, s), 9.46 (IH, d, J=8Hz) (3) A suspension of 7-[2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetamido]-3-ccphem-4-carboxylic acid (anti isomer, 4 6 6 7 4 /2,;5 g.), conc..•.•hydrochloric acid (2.5 ml.) and'methanol (38 ml.) was stirred at room temperature for two hours. After treating the resultant solution with activated charcoal, the sbliition was conccntratcd in vacuo. The residue was crystallized out with diisopropyl ether (100 ml.), and the precipitates were collected by filtration, and washed with diisopropyl ether (30 ml.) to give 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido] -3-cephem-4icarboxylic acid hydrochloride (anti isomer, 2.1 g.). The prystals were added to water (20 ml.) and adjusted to pH 6.0 with sodium bicarbonate. The solution was subjected to column chromatography on nonionic adsorption resin "Diaion HP-20''1 [Trademark: manufactured by Mitsubishi / Chemical Industries Ltd.] (75/ml.) with 10% diisopropyl ether.

I The eluate was adjusted to pH 3.5 with 10% hydrochloric acid,; and the precipitates were collected by filtration and dried to give 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3- cephem-4-carboxylic acid (anti isom«r, 0.7 g.). ! 1 •R. v : ^3400*3200 (broad), 1770, 1680, 1640, 1520 cm"1 N.M.R. 6(DMSO-d6, ppm) : 3.60 (2H, d, J=5Hz), 4.00 (3H, s), 5.10 (IH, d, J=5Hz), 5.82 (IH, dd, J=5Hz, 8Hz), 6.48 (IH, t, J=4Hz), 7.13 (2H, broad), 7.47 (IH, s), 9.42 (IH, d) Example 21 (1) The Vilsmeier reagent was prepared from N,N-dimethyli4-formamide (0.4 g.) and phosphoryl chloride (0.86 g.) in a usual manner. After the reagent was suspended in ethyl acetate (10 ml.), 2-(2-formamidothiazol-4-yl)-2-n-prOp«xyiminoacetic acid (syn isomer, 1.3 g.) was added to the stifred suspension 156 4 6 674 under ice cooling and stirred at the same temperature for 30 minute. The solution was added to a solution of 4-nitrobenzyl 7-amino-3-chloro-3-cephem-4-carboxylate hydrochloride (2.0 g,)> trimcthyisilylacetamide (5.2 g.) and ethyl acetate (40 ml.) at -25°C, and stirred at -20 to -10°C for 1.5 hours. After adding water into the resultant solution, the solution was extracted with ethyl acetate (60 ml.). The aqueous layer was extracted with ethyl acetate (50 mL). The extracts were combined together, washed with a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride in turn, and dried over magnesium sulfate-The solution was concentrated in vacuo, and the residue was triturated with diethyl ether. The precipitates were J collected by filtratation, washed and dried to give 4-nitrobeiuyl 7-(2-(2-formamidothiazol-4-yl)-2-n-propoxyiminoacetamido]-3-chloro 3-cephem-4-carboxylate (syn i.somer, 2.55 g.)» I.R. v 3250*3150, 1780, 1730, 1690, 1660, 1610, 1550, 1520 cm"1 N.M.R. 6(DMSO-d6, ppm) : 0.87 (3H, t, J=7Hz), 1.63 (IH, m), 3.88 (2H, q, J=17Hz), 3.97 (2H, q, J=7Hz), 5.30 (IH, d, J=5Hz), 5.40 (2H, s), 5.92 (IH, dd, J=5Hz, 8ttz), 7.33 (IH, s), ; 7.65 (2H, d, J=9Hz), 8.20 (2H, d, J«9Hz), 8.47 (IH, s), 9.70 (IH, d, J=8Hz), 12.40 (IH, s) (2) A suspension of 4-nitrobenzyl 7-[2-(2-formamidothiazol- 4-yl)-2-n-propoxyiminoacetamido]-3-chloro-3-cephem-4-carboxylate (syn isomer, 2.4 g.), 10% palladium carbon (1.0 g.), methanol (24 ml.), water (3.6 ml.) and tetrahydrofuran (48 ml.) was 4 6 6 7 4 ( subjected to catalytic reduction under ordinary pressure at room temperature. After removing insoluble substance by filtration, the filtrate was concentrated in vacuo. Water and ethyl acctate were added to the residue, and adjusted to pH 8 with a saturated aqu^o^fe solution of sodium bicarbonate. The insoluble substance was removed by filtration, and the aqueous layer was separated. Ethyl acetate was added to the solution, adjusted to pH 2.0 with hydrochloric acid and extracted with ethyl acetate. The ethyl acetate solution and extract were combined together, 10 washed with a saturated aqueous solution of sodium chloride / and dried over magnesium sulfate. ' The solution was concentrated in vacuo, and the residue was triturated with diethyl ether and collected by filtration to give 7-[2-(2-formamidothiazol-4-yl)-2-n-propoxyiminoacetamido]- 3-chloro-3-cephem-4-carboxylie 15 acid (syn isomer, 1.6 g.). 1.R. v max01 : 3300*3150, 1780, 1720, 1685, 1650, 1540 cm"1 N.M.R. 6(DMSO-dg, ppm) : 0.93 (3H, t, J=7Hz), 1.72 (IH, m), 3.88 (2H, q, J=18Hz), 4.08 (2H, q, J=7Hz), 5.33 (IH, d, J=5Hz), 5.92 (IH, dd, J=5Hz, 8Hz), 7.43 (IH, s), 8.57 (IH, s), 9.73 (IH, d, J=8Hz) (3) A suspension of 7-[2-(2-formamidothiazol-4-yl)-2-n-propoxyiminoacetamido] -3-chloro-3-cephem-4-carboxylic acid (syn isomer, 1.5 g.), conc. hydrochloric acid (0.7 ml.) and methanol (30 ml.) was stirred at room temperature for 1.5 hours. After removing methanol from the resultant solution in.vacuo, water (30 ml.) was added to the residue. After the solution 20 25 30 4 6 6 7 4 sodium bicarbonate, the insoluble substance was removed by filtration. The filtrate was adjusted to pH 3 with 10% hydrochloric acid. The precipitates were collected by filtration and dried over phosphorus pentoxide to give 7-[2-(2-aminothiazol-5 4-yl)-2-n-propoxyiminoacetamido]- 3- chloro-3-cephem-4-carboxylic acid (syn isomer, 0.6 g.).

I.R. v ^0l : 3300, 1780, 1670, 1630, 1530 cm"1 N.M.R. 6(DMSO-dg, ppm) : 0.92 (3H, t, J=7Hz), 1.67 (IH, m), 3.70 (2H, q, J=18Hz), 4.00 (211, q, J=7Hz), 5.25 (IH, d, J-5Hz), 5.83 (IH, dd, J=5Hz, 8Hz), 6.75 (IH, s), 9.63 (IH, d, J=8Hz) Example 22 15 : 2-(2-Aminothiazol-4-yl)-2-n-hexyloxyiminoacetic acid (syn isomer* 3 g*), water (0.15 g.), phosphoryl chloride (3.8 g.) , trimethylsily-acetainide (10.7 g.), N,N-dimethylformamide (1.0 g,), tetrahydrofuran (50 ml.) and 7-atnino-3-cephem-4-carboxylic acid (2.0 g.) were treated 2o in a 8imilar manner to that of Examplel8 to give 7-[2-(2-aminothiazol-4-yl)-2-n-hexyloxyiminoacetamidol-3-cephem-4-carboxylic acid (syn isomer, 1.1 g.).

I.R. 3250, 1760, 1640, 1600 cm-1 N.M.R. 6 (DMS0-dg, ppm) ; 1.88 (3H, m), 1.1^1.9 (8H, m), 3.60 (2H, m), 4.06 (2H, t, J=6Hz), 5.10 (IH, d, J=5Hz), 5.82 (IH, dd, J= 5Hz, 8Hz), 6.46 (IH, m), 6.70 (IH, s), 7.26 (2H, m), 9.56 (IH, d, J«8Hz) 25 159 4 6 6 7 4 Example 23 2-(2-formamidothiazol-4-yl)- 2-propargyloxyiminoacetic acid (syn isomer, 0.506 g.), N,N-dimethylformamide (0.161 g.), phosphoryl chloride (0.337 g.) and ethyl acetate (7.9 ml.) were treated in a similar manner to that of Example 1^7^to^give the activated acid solution.

On the other hand, trimethylsilylacetamide (1.85 g.) and bis(trimethylsilyl)acetamide (1.60 g.) were added to a suspension of 4-nitrobenzyl 7-amino-3-hydroxy-3-cephem-4-carboxylate (0.703 g.) in ethyl acetate (10 ml.) and stirred at room temperature for an hour.

To the solution was added the activated acid solution obtained above at -10°C all at once, and stirred at the same temperature for an hour. Water (20 ml.) and ethyl acetate (20 ml.) were added to the solution. The organic layer was separated, washed with a saturated aqueous solution of sodium bicarbonate (8 ml.) and an aqueous solution of sodium chloride (15 ml.), and dried over magnesium sulfate.

After the solution was concentrated in vacuo, the residue was pulverized with diethyl ether and the precipitates were/ collected by filtration to give 4-nitrobenzyl 7-[2-(2-formamidothiazol-4-yl)-2-propargyloxyiminoacetamido]-3-hydroxy-3-ccphem-4-carboxylate (syn isomer, 0.71 g.).

I. R. v 3270, 1770, 1740, 1670 cm"1 N.M.R. 6 (DMSO-dg , ppm) : 3.39 (IH, m), 3.63 (2H, broad s), 4.90 (2H, broad s), 5.23 - 5.90 (4H, m), 7.57 (IH, s), 4667 4 10 15 20 25 30 7.83 (2H, d, J=9Hz), 8.40 (2H, d, j=9Hz), 8.67 (1H, s), 9.80 (IH, d, J=8Hz), 12.83 (IH, broad s) Example 24 : 2-(2-Formamidothiazol-4-yi)-2-propoxyiminoacetic acid (syn isomer, 0.515 g.), N,N-dimethylformamide (0,il61 g.), phosphoryl chloride (0.337 g.) and ethyl acetate (7.9 ml.) were treated in a similar manner to / /-(l)/ that of Example 15 / to give the activated acid solution, On the other hand, trimethylsilylacetamide (1.85 g.) :and bis(trimethylsilyl)acetamide (1.60 g.) were added t to a suspension of 4-nitrobenzyl 7-amino-3-hydroxy- i ' 1 • ; I : - 3-cephem-4-carboxylate (0.703 g^f) in ethyl acetate (10 ml.), and stirred at room temperature for an hour, s To the solution was added the activated acid solution obtained above at -10°C all at/oncfe, and stirred at the same temperature for an ho(tr. To the resultant : I solution were added water (20(ml.) and ethyl acetate (20 ml.). The organic layer was separated, washed with a saturated aqueous solution of sodium bicarbonate (8 ml.) and water (14 ml.) and dried over magnesium sulfate. After the solution was concentrated in vacuo, ■ i . the residue was pulverized with diethyl ether, and the precipitates were collected by filtration to give 4-nitrobenzyl 7-[2-(2-formamidothiazol-4-yl)- 2-propoxyiminoacetamido]-3-hydroxy-3-cephem-4-carboxylate (syn isomer, 0.75 g.).

I.R. v Nujol . 3250 1?65 1?40 167Q cm max ' ' -1 N.MiR. 6 (DMS0-d6, ppm):0.90 (3H, t, J=8Hz), 1.67 (2H, m), 3.40 (2H, AB-q, J=2flHz), 4.08 (2H, q, J«8Hz) , 1.6 1 S.03 - 5.83 (4H, m) , 7.40 (IH, s), , 7.70 (2H, d, J=9Hz) , 8.27 (211, d, J=9Hz) , 8.53 (IH, s), 9.50 (IH, d, J=8Hz) , 12.60 (IH, broad s) I-x ample 25 2-(2-Formamidothiazol-4-yl)- 2-isobutoxyiminoacetic acid (syn isomer, 0.54g.), N,N-dimethylformamide (0.16 g.), phosphoryl chloride (0.34 g.) and ethyl acetate (10 ml.) were treated in a similar manner to that of Example 1^/to^give the activated acid solution. On the other hand, trimethylsilylacetamide (1.85 g.) and bis(trimethylsilyl)acetamide (1.62 g.) were added to a suspension of 4-nitrobenzyl 7-amino-3-hydroxy-3-cephem-4-carboxylate (0.7 g.) in ethyl acetate (10 ml.) and stirred at 40°C for 30 minutes. The activated acid solution obtained above was added to the solution at -20°C. all at once, and stirred at the same temperature for an hour. Water (10 ml.) was added to the resultant solution, and the organic layer was separated, washed with water, an aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride, and then dried. After the solution was concentrated in vacuo, the residue was pulverized with diisopropyl ether. The precipitates were collected by filtration, washed with diisopropyl ether and dried to give 4-nitrobenzyl 7-[2-(2-formamidothiazol-4-yl)-2 -isobutoxyiminoacetamido] - 3-hydro.xy- 3-cephem-4-carboxylate (syn isomer, 1.09 g.). 162 4 6 6 7 4 1 . R. v : 3250, 3050, 1750, 1650, 1610 cm"1 N.M.R. 6 (DMSO-dg, ppm) : 0.97 (6H, d, J=6Hz), 2.0 (IH, m), 3.60 (2H, AB-q, J=18Hz), 3.95 (2H, d, J=6Hz), 5.1 - 5.8 (4H, m), 7.53 (IH, s), 7.63 (2H, d, J=8Hz) , 8.18 (2H, d, J=8Hz), 8.58 (IH, s), . 9.4.7 (IH, d, J=9Hz), 12.77 (IH, broad s) Example 26 N,N-Dimethylformamide (0.114 g.), phosphoryl chloride (0.240 g.) and ethyl acetate (0.5 ml.) were reacted in a conventional manner to give a Vilsmeier reagent. Ethyl acetate (5 ml.) and 2-(2-formamido-thiazol-4-yl)-2-ethoxyiminoacetic acid (syn isomer, 0.35 g.) were added at the same temperature for 30 minutes to give the activated acid solution.

On the other hand, trimethylsilylacetamide (1.31 g.) and bis(trimethylsilyl)acetamide (1.14 g.) were added to a suspension of 4-nitrobenzyl 7-amino-3-hydroxy-3-cephem-4-carboxylate (0.50 g.) in ethyl acetate (7.5 ml.) and stirred at room temperature for an hour. To the solution was added the activated acid solution obtained above all at once at -10°C, and stirred at the same temperature for 30 minutes. Water (15 ml.) and ethyl acetate (15 ml.) were added to the resultant solution. The organic layer was separated, washed with a saturated aqueous solution of sodium bicarbonate (15 ml.) and water (10 ml.), dried over magnesium sulfate and concentrated in vacuo. The residue was pulverized with diethyl ether and the precipitates were 163 4 667 4 collected by filtration to give 4-nitrobenzyl 7- [2-(2-formamidothiazol-4-yl)-2-ethoxyiminoacetamido]-3-hydroxy-3-cephem-4-carboxylate (syn isomer, 0.634 g.). * 1 LR. v JJax01 : 3220' 1760' 1740, 1670cm"1 N.M.R. 6 (DMSO-dg, ppm) : 1.24 (3H, t, J=»8Hz) , 3.36 (2H, AB-q, J»20Hz) , 4.15' (2H, q, J=8Hz), 5.10 - 5.60 (4H, m)., 7.37 (IH, s), 7.65 (2H, d, J=9Hz) , 8.22 (2H, d, J=9Hz), 8.48 (IH, s) , 9.52 (IH, d, J=8Hz), 12.58 (IH, broad s) 46674 Example 27 (1) 2-(2-Formamidothiazpl-4-yl)-2-pentyloxyiminoacetic acid (syn isomer, 4.14 g.)» 4-nitrobenzyl 7-amino^-3-cephSm-4-carboxylate (4.5 g.)» N,N-dimethylformamide (1.41 g.), phosphoryl chloride (2.96 g.)» tetrahydrofuran (72 ml.), acetone (15 ml.) and water (15 ml.) were treated in a similar manner to that of Example 15 -(1) to give 4-nitrobenzyl 7- [2-(2-formamidothiazol-4-yl)-2-pentyloxyiminoacetamido]- 3-cephem-4-carboxylate (syn isomer, 8.1 g.).

I. R. v 3240' 3050> 1780' 1730' 1655 cm"1 N.M.R. 6 (DMSO-d6, ppm) : 0.6 - 2.0 (9H, m), 3.66 (2H, s), 4.10 (2H, t, J=6Hz), 5.19 (1H, d, J=5Hz), 5.42 (2H, s), 5.95 (IH, dd, J=5Hz, 8Hz), 6.16 (IH, broad s) , 7.38 (IH, s), 7.72 (2H, d, J=9Hz), 8.26 (2H, d, J=9Hz), 8.54 (IH, s), 9.69 (IH, d, J=8Hz), 12.69 (IH, broad s) (2) 4-Nitrobenzyl 7-[2-(2-formamidothiazol-4-yl)-2-pentyloxyiminoacetamido]-3-cephem-4-carboxylate (syn isomer , 8 g.), 10% palladium carboji (3.6 g.), methanol (36 ml.), tetrahydrofuran (90 ml.), acetic acid (0.63 g.) and water (6.3 ml.) were treated in a similar manner to that of Example 15 -(2) to give 7-[2-formamidothiazol-4-yl)-2-pentyloxyiminoacetamido]- 3-cephem-4-carboxylic acid (syn isomer, 3.4 g.). 1 .R. v Jnaj01 : 3275, 3075, 1795, 1700, 1660, 1630 cm"1 466"? 4 N.M.R. 6. (DMSO-dg, ppm) : 0.6 - 2.0 (9H, m) 3.60 (2H, d, J=4Hz) , 4.12 (2H, t, J=6Hz), 5.14 (IH, d, J=5Hz), 5.87 (IH, dd, J=5Hz, 9Hz), 6.49 (IH, t, J=3Hz), 7.40 (IH, s), 8.53 (IH, s 9.64 (1H, d, J=9Hz), 12.68 (IH, s) (3) 7-[2-(2-Formamidothiazol-4-yl) -2- pentyloxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer, 3.3 g.), conc.hydrochloric acid (2.80 g.), tetrahydrofuran (20 ml.) and methanol( 50 ml.) were treated in a similar manner to that of Example 15-(3) to give 7-[2-(2-aminothiazol-4-yl)-2-pentyloxyimino-acetamido]-3-cephem-4-carboxylic acid (syn isomeT, 2.3 g.) 1 .R. v . : 3300, 1775, 1650, 1540cm"1 N.M.R. 5 (DMSO-dg, ppm) : 0.6-2.0 (9H, m) , 3.56 (2H, d, J=2Hz), 4.03 (2H, t, J=6Hz), 5.08 (IH, d, J=5Hz) , 5.81 (IH, dd, J=5Hz, 8Hz) , 6.46 (l^H, t, J=4Hz) , 6.69 (IH, s), 7.20 (2H, s), 9.15 (IH, d, J=8Hz) Example 28 (1) Triethylamine (3.41 g.), N,N-dimethylphenylamine (10.3 g.) and trimethylchlorosilan (5.64 g.) were added to a stirred solution of 7-phenylacetamido-3-tosyloxy-3^cephem-4-carboxylic acid (15 g.) in methylene chloride (150 ml.) at room temperature in turn, and the solution was stirred at room temperature for an hour.

Phosphorus pentachloride (7.03 g.) was added to the solution at -35°C, and stirred at -25 to -20°C for 1.5 hatf.fs> .Methanol (61 ml v.)^ was added to the"1 solution and stirred at the same temperature for 40 minutes. To the resultant solution was added water (50 ml.) at -20 to -10°C. The organic layer was separated and washed with water twice. The aqueous layer and ,the washings were combined, and washed with methylene chloride twice and diethyl ether in turn.

After the solution was adjusted to pH 4.7 with 10% aqueous sodium hydroxide under cooling, the precipitates were collected by filtration, washed with water, acetone and diethyl ether in turn, and then dried over phosphorus pentoxide to give 7-amino-3-tosyloxy-3-cephem-4-carboxylic acid (5.01 g.), mp j 172°C (dec.). | I-R- v !!oj01 = 3210, 1800, 1653, 1620cm"1 I max ' N.M.R. 6 (D20+NaHC03, ppm): 2.45 (3H, s) , 3.51 (2H, q, J=18Hz), 5.08 (IH, d, J=5Hz) , 5.51 (IH, d, J=5Hz), 7.48 (2H, d, J=9Hz), 7.84 (2H, d, J«9Hz) 1 (2) 2-(2-Aminothiazol-4-yl)- 2-methoxyiminoacetic acid (syn isomer0.76 g.), N,N-dimethylformamide (0.33 g.), phosphoryl chloride (1.46 g.), trimethylsilylacetamide (0.5 g.) and ethyl acetate (10 ml.) were treated to give the activated-acid solution in a conventional manner.

On the other hand, trimethylsilylacetamide (2.7 g.) was added to a suspension of 7-amino-3-tosyloxy-3-cephem-4-carboxylic acid (1.0 g.) in ethyl .acetate (15 ml.) and stirred at room temperature. 767 4 6 67 4 To the solution was added the activated acid solution obtained above at -15°C all at once, and stirred at -5 - 5°C for an hour. After the resultant solution was chilled to -20°C, water (30 ml.) was added to the chilled solution and adjusted to pH 6.5 with an aqueous solution of sodium bicarbonate. The insoluble substance was removed by filtration. The aqueous layer was separated and adjusted to pH 3.0 with hydrochloric acid. The precipitates were collected by filtration and dried to give 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-tosyloxy-3-cephem-4-carboxylic acid (syn isomer, 1.0 g.).

I.R. v : 3350, 1780, 1670, 1630cm"1 i N.M.R. 6 (DMSO-dg, ppm) : 2.17 (3H, s), 5 3.71 (2H, m), 3.92 (3H, s), 5.32 (IH, d, J=5Hz), 5.87 (IH, dd, J=5Hz, 8Hz), 6.82 (IH, s), 7.50 (2H, d, J=8Hz), 7.92 (2H, d, J=8Hz), 9.73 (IH, d,.J=8Hz) 168 46674 Example 29 (1) 2-(2-Formamidothiazol-4-yl)-2-ethoxycarbonylmethoxyiminoacetic acid (syn isomer, 1.35 g.), 4-nitrobenzyl 7-amino-3-cephem-4-carboxylate (1.54 g.), N,N-dimethylformamide (393 mg.) , phosphoryl chloride (825 mg.), tetrahydrofuran (21.2 ml.) , acetone (3.9 ml.) and water (3.9 ml.) were treated in a similar manner to that of Example 15 - (1) to give 4-nitrobenzyl 7-[2-(2-formamidothiazol-4-yl)- 2- 1Cj ethoxycarbonylmethoxyiminoacetamido] - 3-cephem-4-carboxylate (syn isomer 2.5 2 g.). l- R* v!Ioi01 : 3250» 1790, 1730, 1690, UlaA 15 1640 cm 1 N.M.R. 6(DMSO-d6, ppm):1.23 (3H, t, J=7Hz), 3.66 (2H, s), 4.13 (2H, q, J=7Hz), 4.74 (2H, s), 5.22 (IH, d, J=5Hz), .5.42 (2H, s), 5.98 (IH, dd, J=5Hz, 9Hz), 6.49 (IH, broad s), 7.43 (IH, s), 20 7.71 (2H, d, J=9Hz), 8.23 (2H, d, J=9Hz), 8.52 (IH, s), 9.68 (IH, d, J-9Hz), 12.66 (IH, s) (2) 4-Nitrobenzyl 7-[2-(2-formamidothiazol-4-yl)-2-25 ethoxycarbonylmethoxyiminoacetamido]-3-cephem-4- carboxylate (syn isomer, 2.52 g.), 10% palladium carbon (1*3 g.), ethanol (13 ml.), tetrahydrofuran (25 ml.), acetic acid (0.22 ml.) and wateT (2.2 ml.) were treated in a similar manner to that of Example 15-(2) to give 30 7- [2-(2-formamidothiazol-4-yl)- 2-ethoxycarbonylmethoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer, 0.4 g.). 169 4 6 6 7 4 Example 32 (1) A solution of 2-(2-formamidothiazol-4-yl)- 2-(tert-butoxycarbonylmethoxyimino)acetic acid (syn isomer, 3.2 g.), N,N-dimethylformamide (0.852 g.) and 5 phosphoryl chloride (1.79 g.) in ethyl acetate (34 ml.) i and a solution of 7-amino-3-cephem-4-carboxylic acid (1.95 g.) and bis(trimethylsilyl)acetamide (9.9 g.) in ethyl acetate (19.5 ml.) were treated in a similar j ■manner to that of Example 15-(1) to give 7- [2-(2-10 formamidothiazol-4-yl)-2-(tert-butoxycarbonylmethoxyimino) acetamido]-3-cephem-4-carboxylic acid (syn isomer, 2.9 ;g.) I.R. v Nujol . 326Q 31g0j 306Q 17g5 max ' , ■ 1730, 1690, 1640 cm"1 j j N.M.R. 6 (DMSO-dg, ppm) : 1.44 (9H, s) , 3.63 (2H, s), 4.62 (2H, s), 5.12 (IH, d, J=5Hz), 5.87 (1H, dd, ; J=5Hz, 9Hz) , 6.48 (IH, broad s), 7.42 (IH, s), 8.50 (IH, s), 9.57 (IH, d, J=9Hz), 12.62 (IH, broad s) A mixture of 7-[2-(2-formamidothiazol-4-yl)-2- (tert-butoxycarbonylmethoxyimino) acetamido] - 3-cephem|-4-cirboxylic acid (syn isomer, 2.8 g.), anisole (2.8 ml.) and trifluoroacetic acid (11.2 ml.) was stirred at room temperature for an hour. Ethyl acetate and water wete added to the resultant solution and adjusted to i ; I ; pH | 7. 0 with sodium bicarbonate. The aqueous layer was! separated, and the ethyl acetate layer was extracted ! with water. ;The aqueous extracts were combined, 15 20 (2) >♦6674 washed with ethyl acetate and diethyl ether in turn, and then adjusted to pH 2.0 with 10% hydrochloric acid under ice cooling. The precipitates were collected by filtration, washed with water and dried to give 7-[2-(2-formamidothiazol-4-yl)-2-carboxymethoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer, 1.43 g.).

I.R. v Nu3o1 : 3270, 3120, 3070, 1760, max ' ' 1720, 1690, 1660, 1620 cm"1 N.M.R. 6 (DMSO-d6, ppm) : 3.60 (2H, s), 4.63 (2H, s), 5.11 (IH, d, J=5Hz), 5.88 (IH, dd, J=5Hz, 9Hz), 6.48 (IH, t, J=4Hz), 7.44 (IH, s), 8.52 (IH, s), 9.59 (IH, d, J=9Hz), 12.64 (IH, broad s) (3) A mixture of 7-[2-(2-formamidothiazol-4-yl)-2- carboxymethoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer, 1.35 g.), conc. hydrochloric acid (3.926 g.), methanol (20 ml.), water (10 ml.) and tetrahydrofuran (40 ml.) was stirred at 30°C for 6 hours. The resultant solution was concentrated in vacuo in order to evaporate the methanol, and the aqueous solution obtained was adjusted to pH 4.2 with 10% aqueous solution of sodium hydroxide. The solution was adjusted to pH 3.0 with 10% hydrochloric acid. The precipitates were collected by filtration and dried to give 7-[2-(2-aminothiazol-4-yl)-2-carboxymethoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer, 0.8 g.). 175 v !^01 : 3300 (broad), 3200 (broad), 1775, 1670, 1635 cm"1 N.M.R. 6(DMSO-d6, ppm) : 3.64 (2H, s), 4.64 (2H, s), 5.13 (IH, d, J=5Hz), 5.86 (IH, dd, J=5Hz, 7Hz), 6-4? (IH, t, J=4Hz) , 6.82 (IH, s), 7.33 (2H, s), 9.57 (IH, d, J=9Hz) Example 33 (1) A solution of 2-(2-formamidothiazol-4-yl)-2- (2,2,2-trifluoroethoxyimino)acetic acid (syn isomer, 0.9 g.), N,N-dimethylformamide (0.24 g.) and phosphoryl chloride (0.S g.) in ethyl acetate (10 ml.) and a solution of 4-nitrobenzyl 7-amino-3-chloro-3-cephem-4-cafboxylate hydrochloride (1.2 3 g.) and trimethylsilylacetamide (2.8 g.) in ethyl acetate (20 ml.) were treated in a similar manner to that of Example 21-(1) to give 4-nitrobeftzyl 7-[2-(2-formamidothiazol-4-yl)-2-(2,2,2-trifluoroethoxyimino) acetamido]-3-chloro-3-cephem-4-carboxylate (syn isoiher, 1.9 g.).

N.M.R.

I,R* v max01 : 3250' 1790' 1740' 1700' 1660, 1610, 1530 cm"1 max (2) A suspension O'f !4-nitrobenzyl 7- [2- (2- formamidothiazol-4-yl)-2 - (2,2,2-trifluoroethoxyimino)- ! acetamido]-3-chloro-3-cephem-4-carboxylate (syn isomer, 1.8 g.) and 10% palladium carbon (0.9 g.) in methanol (20 ml.) and tetrahydrofuran (20 ml.) was treated in a similar manner to that of Example 21-(2) to give 7- [2-(2-formamidothiazol-4-yl)-2-(2,2,2-t rifluoroethoxyimino)acetamido]-3-chloro-3-cephem-4-carboxylic acid (syn isomer, 1.0 g.).

I.R. v ^0l : 3250, 1780, 1690, 1655, 1530 cm"1 N.M.R. .6 (DMSO-dg, ppm) : 3.86 (2H, q, J=17Hz), 4.80 (2H, q, J=8.5Hz), 5.33 (1H, d, J=5Hz) , 5.92 (IH, dd, J=5Hz, 8Hz) , 7.53 (IH, s), 8.53 (IH, s), 9.93 (IH, d, J=8Hz), 12.70 (IH, broad s) (3) 7-[2-(2-Formamidothiazol-4-yl)-2-(2,2,2-trifluoroethoxyimino)acetamido]-3-chloro-3-cephem-4-carboxylic acid (syn isomer, 0.7 g.), conc.hydrochloric acid (0.43 ml.) and methanol (16 ml.) were treated in a similar manner to that of Example 21-(3) to give 7-[2-(2-aminothiazol-4-yl)- 2-(2,2,2-trifluoroethoxyimino)-acetamido]-3-chloro-3-cephem-4-carboxylic acid (syn isomer, 0.65 g.) I,R* v max01 : 3320' 3150' 1775' 1720' 1660, 1645, 1600, 1545 cm"1 N.M.R. 6(DMSO-d6, ppm) : 3.87 (2H, q, J=18Hz), 4.80 (2H, q, J=8.5Hz), 5.30 (1H, d, J=5H 177 5.83 (IH, dd, J=5Hz, 8Hz), 17.05 (1H, s), 10.00 (IH, d, J=8Hz) .Example 34 (!) A solution of 2-(2 - formamidothiazol-4-yl) - 5 2-butoxyiminoacetic acid (syn isomer, 1.5 g.), N,N- dimethylformamide (440 mg.) and phosphoryl chloride ! (920 mg.) in ethyl acetate (12 ml.) and a solution of 4-mitrobenzyl 7-amino-3-chloro-3-cephem-4-carboxylate (2.03 g.), trimethylsilylacetamide (7 g.) and 10 bis(trimethylsilyl)acetamide (2 ml.) in ethyl acetate (25 ml.) were treated in a similar manner to that of Example 21-(1) to give 4-nitrobenzyl 7- [2- (2-formamidothiazol-4-yl)-2-butoxyiminoacetamido]- 3-chloro-3-cephem-4:carboxylate (syn isomer, 2.8 g.), yellow powder.

I.R. v N^01 : 3200-3250, 1780, 1730, 1690, max 1655, 1605, 1530, 1350 cm"1 20 N.M.R. 6 (DMS0-d6, ppm) : 0.90 (3H, m), 1.2-1.6 (4H, m), 3.88 (2H, AB-q, J=19Hz), 4.0-4.2 (2H, m), 5.32 (IH, : d, J=4Hz) , 5.44 (2H, s), 5.92 (IH, d-d, ' J=4Hz, 8Hz) , 7.36 (IH, s) , 7.68 (2H,j d, J=8Hz) , 8.22 (2H, d, J=8Hz), 8.50 (IH, s), 9.72 (IH, d, J=8Hz), 12.56 (Hi, s) (2) A mixture of 4-nitrobenzyl 7- [2- (2-formamidothiazol-4-yl)-2-butoxyiminoacetamido]-3-30 chloro-3-cephem-4-carboxylate (syn isomer, 2.7 g.), 25 "1 7 0 10% palladium carbon (1.3 g.), water (4 ml.), i i ajcetic acid (0.4 ml.), methanol (27 ml.) and tetrahydrofuran (54 ml.) was treated in a similar . manner to that of Example 21-(2) to give 7-[2-formainidothiazol-4-yl) -2-butoxyiminoacetamido] -3-chloro-3-cephem-4-carboxylic acid (syn isomer, 1.4 g.), pale yellow powder.

I,R* v mal01 : 3250' 2400-2600, 1780, 1700, 1690, 1650, 1610 cm"1 N.M.R. 6 (DMSO-dg, ppm) : 0.90 (3H, m), 1.2-1.70 (4H, m), 3.88 (2H, ABq, J=19Hz) , 4.0-4.25 (2H, m), 5.32 (IH, d, J=5Hz) , 5.90 (lH,d,d, J=5Hz, 9Hz) , 7.42 (IH, s), 8.50 (IH, s), 9.73 (1H, d, J=8Hz), 12.60 (IH, s) (3) A mixture of 7-[2-(2-formamidothiazol-4-yl)-2-butoxyiminoacetamido]-3Jchloro-3-cephem-4-carboxylic acid (syn isomer, 1.3 g.), cone, hydrochloric acid (1.3 ml.) and methanol (20 ml.) was treated in a similar manner to that of Example 21-(3) to give 7- [2- (2-aminothiazol-4-yl)-2-butoxyiminoacetamido]-3-chloro-3-cephem-4-carboxylic acid (syn isomer, 1.2 g,), pale yellow powder.

I-R- v : 3300, 2500-2600, 1785, IllaA 1730, 1655, 1630 cm"1 4 a 67 4 " N.M.R. 6 (DMSO-|d6> ppm) : 0.90 (3H, m) , 1.2-1.75 (4H, m), 3.88 (2H, AB-q, . 1 J=19Hz), 5.17 (2H, m), 5.33 (IH, d, J=5Hz), 5.83 (1H, d,d, J=5Hz, 8Hz), 6.93 (IH, s), 9.50 (2H, broad s), 9.85 (IH, d, J=8Hz) Example 35 (1) A solution of 2-(2-formamidothiazol-4-yl)-2- butoxyiminoacetic acid (syn isomer, 1.09 g.), N,N-dilftethylformamide (322 mg.) and phosphoryl chloride (675 mg .) in ethyl acetate (9.2 ml.) and a solution of 4-nitrobenzyl 7-amino-3-methoxy-3-cephem-4-carboxylate hydrochloride (1.5 g.), trimethylsilylacetamide (5 g.) and bis(trimethylsilyl)acetamide (2 ml.) in ethyl acetate (30 ml.) were treated in a similar manner to that of Example 3-(1) to give 4-nitrobenzyl 7-[2-(2-formamidothiazol-4-yl)-2-butoxyiminoacetamido]- 3-methoxy^-3-cephem-4-carboxylate (syn isomer,1.8 g.). 1 .R. v ^jo1 : 3300, 3220, 1770, 1715, 1690, 1650, 1610, 1540, 1350 cm"1 N.M.R. 6 (DMSO-dg, ppm) : 0.90 (3H, m), 1.2-1.7 (4H, m), 3.72 (2H, broad s), 3.96 (3H, s), 4.10 (2H, m), 5.22 (IH, d, J=4Hz), 5.32 (2H, s), 5.75 (IH, d,d, J=4Hz, 8Hz) , 7.43 (IH, s) , 7.64 (2H, d, J=9Hz), 8.20 (2H, d, J=9Hz), 8^48 (IH, s), 9.56 (IH, d, J=8Hz) , 12.59 (IH, s) i fifl 46674 (2) A mixture of 4-nitrobenzyl 7-[2-(2-formamidothiazol-4-yl)- 2-butoxyiminoacetamido]-3-methoxy-3-cephem-4-carboxylate (syn isomer, 1.7 g.), 10% palladium carbon. (1 g.), water (3 ml.), acetic 5 acid (0.3 ml.), methanol (20 ml.) and tetrahydrofuran (35 ml.) was treated in a similar manner to that of Example 15-(2) to give 7-[2-(2-formamidothiazol-4-yl)-2-butoxyiminoacetamido]-3-methoxy-3-cephem-4-carboxylic acid (syn isomer, 1 g.), yellow powder.

I.R. v jjjjj01 : 3200-3250, 2600, 1775, 1700, 1690, 1650 cm'1 N.M.R. 6 (DMSO-d^, ppm) : 1.0 (3H, m), 1.2-1.75 (4H, m), 3.67 (2H, broad s), 3.86 (3H, s), 4.0-4.3 (2H, m), 5.23 (IH, d, J=4Hz), 5.68 (1H, d,d, J=4Hz, 8Hz) , 7.50 (IH, s), 8.58 (IH, s), 9.63 (IH, d, J=8Hz) A mixture of 7-[2-(2-formamidothiazol-4-yl)-2-butoxyiminoacetamido]-3-methoxy-3-cephem-4-carboxylic acid (syn isomer, 0.9 g.), conc. hydrochloric acid (0.8 ml.) and methanol (13.5 ml.) was treated in a similar manner to that of Example 15-(3) to give 7- [2- (2-aminothiazol-4-yl)-2-butoxyiminoacetamido]-3-methoxy-3-cephem-4-carboxylic acid (syn isomer, 0.4 g.), yellowish white powder.

I-R* V max°l : 3200-3300, 2600, 1770, 1705, 1670, 1620 cm'1 10 15 20 (3) 191 • , N.M.R. 6 (DMSO-d6, ppm) : 0.90 (3H, m) , 1.2-1.65 (4H, m), 3.60 (2H, s), . • ' 3.96 (3H, s), 4.0-4.16 (2H, m) , ' 1 \o' 5.12 (IH, d, J=4Hz) , 5.55 (IH, . d,d, J=4Hz, 8Hz), 6.80 (1H, s) , 7.2-7.6 (2H, broad s), 9.50 (IH, d, J=8Hz) 182 46674 Example 36 (1) 4-Nitrobenzyl 7-amino-3-cephem-4-carboxylate (5 g.) was dissolved in a solution of triinethylsilylacetamide (13.8 g.) and bis(trimethylsilyl)acetamide (10 ml.) in dry ethyl acetate (50 ml.) and stirred at 45°C for 1.5 hours. A solution of D bromine (2.88 g.) in methylene chloride (7 ml.) was added dropwise to a solution of diketene (1.5 g.) in methylene chloride (7 ml.) at -40°C over 20 minutes and stirred at -30*C for 1 hour. The solution obtained thus was added to dropwise 10 to the above solution of 4-nitrobenzyl 7-amino-3-cephem-4-carboxylate under cooling at -15°C and then stirred at the same temperature for 30 minutes. Water (50 ml.) was added to the resultant solution and extracted with ethyl acetate. The ethyl acetate extract was washed with water, dried over 15 magnesium sulfate and concentrated under reduced pressure to give oily 4-nitrobenzyl 7-[2-(2-bromoacetyl)acetamido]-3-cephem-4-carboxylate (6.15 g.) 1780, 1740, 1630 cm-1 20 N.M.R. 6ppm (DMSO-dg) : 3.62 (2H, broad ;, 4.37 (2H, s), 5.08 (IH, d, J=5Hz), 5.40; (2H, s) , 5.77 - 6.05 (m) , I 163 4667 4 6.67 (IH, t, J=5Hz), 7.68, 8.04 (4H, m, J=9IIz), 9.07 (IH, d, J=8Hz) (2) 4-Nitrobenzyl 7-[2-(2-bromoacetyl)acetamido]-3-cephem-4-carboxylate (8.40 g.) was suspended in a mixture of tetrahydrofuran (150 ml.) and water (30 ml.) To the suspension were added acetic acid (50 ml.) and a solution of sodium nitrite (1.20 g.) in water (15 ml.) under ice-cooling, and stirred at 20 to 22°C for 1.5 hours. The resultant solution was poured into ice-water (300 ml.) and stirred for 20 minutes. The precipitating substance was collected by filtration, washed with water, dried and then recrystallized from ethyl acetate to give 4-nitrobenzyl 7-[2-(2-bromoacetyl)-2-hydroxyiminoacetamido]-3-cephem-4-carboxylate (syn-isomer : 3.1 g.), mp 153 to 162°C.

I,R* V mai01 : 3250» 17'80> 1720» 1705» 1650» 1610» 1600 (shoulder), 1550, 1520 cm"1 N.M.R. <5ppm (DMS0-dfJ : 3.67 (2H, d, J=4Hz), 4.63 (1.5H, a), 4.88 (0.5H, s), 5.18 (IH, d, J=5Hz), 5.45 (2H, b), 5.93 (IH, dd, J=5Hz, 8Hz), 6.72 (IH, t, J=4Hz), 7.73 (2H, d, J=9Hz) , 8.28 (2H, d, J=9Hz) , 9.38 (IH, d, J=8Hz), 11.27 (IH, s) (3) A solution of diazomethane in diethyl ether was added little by little to a solution of 4-nitrobenzyl 7- [2-(?.-bromoacctyl) - 2- hydroxyiminoacetamido) -3-cephem-4-carboxylate (0.9 g.) in tetrahydrofuran (30 ml.) under ice-cooling until the reaction terminated, and then acetic acid 164 15 20 4 6 674 was added to the resultant solution to decompose excess diazomcthane. The resultant solution was concentrated under reduced pressure to give the foamy product of 4-nitrobenzyl 7- [2- (2-bromoacety])- 2-methoxyiminoacetamido] -3-cephem-4-5 carboxylate (syn-isomer : 0.9 g.) (4) Thiourea (0.14 g.) was added to a solution of 4- nitrobenzyl 7-[2-(2-bromoacety])-2-methoxyiminoacetamido)-3-cephem-4-carboxylate (syn-isomer : 0.8 g.) in ethanol (20 ml.) and water (5 ml.), and stirred at room temperature for 3.5 10 hours. The resultant solution was concentrated under reduced pressure, and to the residue were added water and ethyl acetate. The ethyl acetate layer was separated, washed with water, dried over magnesium sulfate and concentrated under reduced pressure to give the crude product (0.6 g.) 15 The product was purified by column chromatography on silica gel (eluent : benzene and ethyl acetate (8:2) ) to give 4-nitrobenzyl 7-[2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamidoJ-3-cephem-4-carboxylate (syn-isomer : 0.21 g.), mp 165 to 170°C (dec.) 20 I.R. v : 3350-3200, 1770, 1720, 1665, 1615, 1515 cm"1 N.M.R. 6ppm (DMSO-dg) : 3.60 (2H, broad s), 25 3.81 (3H, s), 5.12 (IH, d, J=5Hz), 5.36 (2H, s), 5.83 (IH, dd, J=5Hz, 8Hz), 6.64 (IH, t, J=4Hz), 6.70 (IH, s), 7.20 (2H, s), 7.65 (2H, d, J=9Hz.), 8.19 (2H, d, J=9Hz), 9.60 (IH, d, J=8Hz) 1 85 46674 Example 37 (1) A solution of bromine (4 3.0 g.) in methylene chloride (30 ml.) was dropwise added to a solution of diketene (22.6 g.) in methylene chloride (30 ml.) at -30°C over 35 minutes, and stirred at the same temperature for 30 minutes. The solution was dropwise added to a stirred solution of 4-nitrobenzyl 7-umino-3-cephem-4-carboxylate (75.1 g.) and bis(trimethylsilyl)acetamide (68.4 g,) in tetrahydrofuran (1.5 J£) at -15°C over 10 minutes, and the solution was stirred at the same temperature for 50 minutes. Water (35 ml.) and an aqueous solution (35 ml.) of sodium nitrite (18.6 g.) were added to the resultant solution while keeping at pH 2.0, arid the solution was stirred at 10 to 15°C for 15 minutes. After the solution was adjusted to pH 4.5 with a saturated aqueous solution of sodium bicarbonate, an aqueous solution (150 ml.) of thiourea (17.1 g.) was added to the solution, adjusted to pH 6.0 with a saturated aqueous solution of sodium bicarbonate, and stirred for 20 minutes. The organic layer was separated and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (1.5 £.) , and washed with water three times. The solution was dried over magnesium sulfate, treated with activated charcoal and concentrated under reduced pressure.

After the residue was triturated with diethyl ether (200 ml.), the precipitates were collected by decantation and washed with ether acetate (300 ml.), a mixture of tetrahydrofuran (500 ml.) and ethyl acetate (1 £) at 60°C and then with ethyl acetate (100 ml.) three times, and dried to give 4-nitrobenzyl 7- (2- (2-amino74-tliiazolyl) -2-hydroxyiininoacetamido] -3-cephem-4-carboxylate (syn isomer, 55.5 g.). 1 a 6 46674 I,R* V max01 : 1760' 1710> 1660,1630 cm"1 N.M.R. 6ppm (DMSO-dg) : 3.60 (2H, d, J=5Hz), 5.12 (IH, d, J=5Hz), 5.39(2H, s), 5.88 (IH, dd, J=8Hz, 5Hz), 6.63 (IH, s), 6.53 - 6,77 (IH, m), 7.08 (2H, broad s), 7.68 (2H, d, J=9Hz), 8.22 (2H, d, J=9Hz), 9.47 (1H-, d, J=8Hz), 11.33 (IH, s) 187 4 667 4 (.2) 101 Palladium carbon (0.35 g.) was added to a solut ion of 4-nitrobenzyl 7-[2-(2-amino-4.-thiazolyl)-2-hydroxyiininoacetamido]-3-cepheni-4-carboxylate (syn-isomer : 0.7 g.) in methanol (70 ml.), and the mixture was subjected to catalytic reduction at room temperature under atmospheric pressure for 1.5 hours. The resultant mixture was filtered, and the filtrate was concentrated under reduced pressure.

To the residue was added an aqueous solution of sodium bicarbonate and the insoluble substance was filtered out. 10 The filtrate was washed with ethyl acetate and methylene chloride in turn, bubbled with nitrogen gas and then lyophilized. The residue was dissolved in water (30 ml.) and adjusted to pH 3.8 with 101 hydrochloric acid. The solution was subjected to column chromatography on macroporous, non-15 ionic adsorption resin "Diaion HP-20" (Trade mark; manufactured by Mitsubishi Chemical Industries Ltd., 20 ml.), washed with water, and then eluted with 40% aqueous acetone. After acetone was removed from the eluate under reduced pressure, the residue was lyophilized'to give 7-[2-(2-amino-4-thiazolyl)-2-2o hydroxyiminoacetamido]-3-cephem-4-carboxylic acid (syn-isomer: 0.25 g.) I.R. vmax01 : 3550 to 3200' 1770, 1670' 1630 cm l 25 N.M.R. 6ppm (DMS0-d&) : 3.60 (2H, broad s), 5.10 (IH, d, J=5Hz), 5.83 (IH, dd, J=5Hz, 8llz) , 6.47 (IH, t, J=4Hz) , 6.67 (IH, s) , 9.47 (IH, d, J= 8Hz) 188 Example 38 (1) Thiourea (0.18 g.) was added to a suspension of 4-nitrobenzyl 7-[2-(2-bromoacetyl)-2-hydroxyiminoacetamido]-3-cephem-4-carboxylate (syn-isomer : 1.05 g.) in ethanol ( 25 ml.), tetrahydrofuran (25 ml.) and water (5 ml.), and stirTed at room temperature for 4 hours. The resultant solution was concentrated under reduced pressure and cooled. The residue was crystallized by treating with a mixture of tetrahydrofuran and ethyl acetate, and collected by filtration to 10 give 4-nitrobenzyl 7-[2-(2-amino-4-thiazolyl)-2-hydroxyiirtino-acetamido]-3-cephem-4-carboxylate (syn-isomer : 0.95 g.), colorless crystals, mp 172 to 175*C (dec.) 1.R. v : 3350 - 3200, 1770, 1725, 1670, 15 . 1625, 1S20 cm"1 N.M.R. 6ppm (DMS0-d6) : 3.68 (2H, d, J=4Hz), 5.20 (IH, d, J=5Hz), 5.43 (2H, s), 5.90 (IH, dd, J«8Hz, 5Hz) , 6.70 (IH, t, J»4Hz), 6.88 (IH, s), 7.70 (2H, d, J=9Hz), 20 8.23 (211, d, J-9Hz), 9.68 (IH, d, J=8Hz) (2) A solution ?f diazomethane in diethyl ether was added little by little to a solution of 4-nitrobenzyl 7- [2-(2-amino-4-thiazolyl)-2-hydroxyiminoacetamido]-3-cephem-4- 25 carboxylate (syn-isomer : 0.3 g.) in methanol (30 ml.) until the reaction terminated. The resultant solution was concentrated under reduced pressure, and the residue was pulverized with diethyl ether, collected by filtration and dried to give 4-nitrobenzyl 7-[2-(2-amino-4-thiazolyl)-2-30 methoxyiminoacetamido]-3-cephem-4-carboxylate (syn-isomer : 0.26 g.) 189 46674 Hhis product was identified with the authentic sample.

Example 39 7-Amino-3-cephem-4-carboxylic acid (2.54 g.) was dissolved in a solution of trimethylsilylacetamide (11.7 g.) j. and bis (trimethylsi lyl) acetamide (15 ml.) in dried ethyl acetate (50 ml.) A solution of bromine (2.43 g.) in dried methylene chloride (10 ml.) was added dropwise to a solution of diketene (1.28 g.) in dried methylene chloride (25 ml.) at -30°C over 10 minutes and stirred at the same temperature 10 for 1.5 hours. The solution was added to the above solution containing 7-amino-3-cephem-4-carboxylic acid at -15°C over 10 minutes, and stirred at -15 to -10°C for 1.5 hours.

Water (50 ml.) was added to the resultant solution. The ethyl acetate layer was separated, and extracted with aqueous 15 solution of sodium bicarbonate. The aqueous extract was adjusted to pH 2.0 with 10% hydrochloric acid and extracted with ethyl acetate. The ethyl acetate extract was washed with water, dried over magnesium sulfate and concentrated under reduced pressure to give 7-[2-(2-bromoacetyl)acetamido]-3-2o cephem-4-carboxylic acid (2.82 g.) LR. v : 1760, 1660 cm"1 N.M.R. 6ppm (DMS0-d6) : 3.58 (2H, d, J=4Hz), 3.65 (2H, s), 4.40 (2H, s), 5.06 (IH, d, J=5Hz), 25 5.73 (IH, dd, J=8Hz, 5Hz) , 6.50 (IH, t, J=4Hz), 9.08 (IH, d, J=8Hz) 190 4 6 6 7 4 Example 40 The following compounds wore prepared in a similar manner to that of Example 36. (1) 4-Nitrobenzyl 7-[2-(2-aminothiazol-4-yl)-2-ethoxyimino-acetamido]-3-cephem-4carboxylate (syn isomer) (2) 4-Nitrobensyl 7-'[2-(2-axninothiazol-4-yl)-2-propoxyiniino^ acetamido]-3-cephem-4-carboxylate (syn isomer) (3) 4-Nitrobenzyl 7-[2-(2-aminothiazol-4-yl)-2-isopropoxy-> iminoacetamido]-3-cephem-4-carboxylate (syn isomer) Example 41 The following compounds were prepared in a similar manner to that of Example 38 - (2). (1) 4-Nitrobenzyl 7-[2-(2-aminothiazol*"1-yl)-2-ethoxyimino-acetamidol-3-cephem-4-carboxylate (syn isomer) (2) 4-Nitrobenzyl 7-[2-(2-aminothiazol-4~yl)~2-propoxyimino~ acetamido)-3-cephem-4-carboxylate (syn isomer) (3) 4-Nitrobenzyl 7-[2-(2-aminothiazol-4-yl)-2-isopropoxyimino-acetamido]-3-cephem-4-carboxylate (ayn ioomer) 4 0 6 7 4 v—Example 42 (1) Sodium boron hydride (160 mg.) was added to a suspension of 4-nitrobenzyl 7-[2-(2-formamido-4-thiazolyl)-2-methoxyimi noacetamido)-3-hydroxy-3-cephem-4-carbokylate ^ (syn isomer, 1 g.) in tetrahydrofuran (10 ml.)» acetic acid (3 ml.) and water (1 ml.) at 0°C over 10 minutes, and stirred at 0 to 3°C for S5 minutes. After water was added to the resultant solution, the solution was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, a saturated aqueous 10 solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride in turn, and dried over magnesium sulfate. The solution was concentrated under reduced pressure, and the residue was pulverized with ^ diethyl ether to give 4-nitrobenzyl 7-[2-(2-formamido-4-thiazolyl)-2-methoxyimi noacetamido]- 3-hydroxycepham-4 -carboxylate (syn isomer, 0.77 g.), mp 172 to 175°C (dec.). 1. R. v jjljj01 : 3250, 1775, 1745, 1660 cm"1 N.M.R. 6ppm (DMSO-dg) : 2.76 (IH, dd, J=14 Hz, 3Hz), 3.17 (IH, dd, J=14Hz, 13Hz) , 3.92 (3H, s), 4.03 (IH, m) , 4.72 (IH, d, J=6Hz), 5.24 (IH, d, J=4Hz), 5.37 (2H, s), 5.56 (IH, dd, J--9Hz, 4Hz) , 6.07 (IH, d, 25 J=4Hz), 7.44 (IH, s), 7.72 (2H, d, J=8Hz), 8.27 (2H, d, J=8Hz), 8.54.(1H, s) , 9.67 (IH, d, J=9Hz). 192 4 6674 \ ' (2) Mesyl chloridc (0.406 g.) was dropwise added to a stirred mixture of 4-nitrobenzyl 7-[2-(2-formamido-4-thiazolyl)-2-methoxyiminoacetamido]-3-hydroxyceph^m-4-carboxylate (syn isomer, 1 g.), N,N-dimethylformamide (10 i ml.) and potassium carbonate (0.732 g.) at 0 to 5°C over 2 minutes, and the solution was stirred at room temperature for 2.5 hours. After ethyl acetate and water were added to the resultant solution, the solution was extracted with ethyl acetate. The remaining aqueous layer was extracted 10 again with ethyl acetate. The ethyl acetate extract solution was washed with a saturated aqueous solution of sodium chloride,dried over magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel (30 g.) and eluted with a mixture of chloroform and ethyl acetate. The eluate was concentrated under reduced pressure to give 4-nitrobenzyl 7-[2-(2-formamido-4-thiazolyl)-2-methoxyimino-a.c.etamido]-3-cephem-4-carboxylate (syn isomer, 0.12 g.), mp 224°C (dec.). 193 46674 Example 43 Phosphoryl chloride (704 mg.) was added dropwise to a solution of N,N-dimethylformamide (336 mg.) in ethyl acetate (8 ml.) below 5°C and stirred at the same temperature for 5 30 minutes. 2-(2-Formamidothiazol-4-yl)-2-methoxyiminoacetic acid (syn isomer, 1 g.) was added to the solution and stirred at 5 to 10°C for an hour. The solution was added dropwise to a solution of 7-amino-3-hydroxycepham-4-carboxylic acid (872 mg.) and trimethylsilylacetamide (1.05 g.) in ethyl 10 acetate (20 ml.) at -20°C over 5 minutes, and stirred at -20 to -25°C for an hour. Water (50 ml.) was added to the resultant solution and adjusted to pH 7.0 with sodium bicarbonate. The aqueous layer was separated, and the ethyl acetate layer was extracted again with water (10 ml.). 15 The aqueous extracts were combined, adjusted to pH 6 and absorbed on macroporous nbnionic adsorption resin Diaion HP-20 (50 ml., Trademark, manufactured by Mitsubishi Chemical Industries). The column was washed with water (50 ml.) and eluted with 30% aqueous isopropyl alcohol. The eluate 2o containing the object compound was adjusted to pH 6.5 and concentrated under reduced pressure. The residue was lyophilized to give sodium 7-[2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetamido]-3-hydroxycepham-4-carboxylate (syn isomer, 1.1 g.) 25 N.M.R. <5 (D20, ppm): 2.72 - 3.18 (2H, m) , 4.02 (3H, s) , 4.02 - 4.28 (IH, m), 4.54 (IH, d, J=4Hz), 5.28 (IH, d, J=4Hz), 5.53 (IH, d, J=4Hz), 7.50 (IH, s), 8.53 (IH, s) 194 ^ >46674 Example 44 j Thionyl chloride (0.42*3 g.) was dropwise added to a stirred solution of 4-nitrobenzyl 7-[2-(2-formamido-4-thiazolyl)-2-methoxyiminoacetamido]-3-hydroxy-3-cephem-4-carboxylate (syn isomer, .1 g.) in N,N-dimethylformamide (10 ml.) under ice cooling over 2 minutes, and the solution was stirred at room temperature for 1.1 hours. Ethyl acetate (40 ml.) and water (30 ml.) were added to the resultant solution and shaken sufficiently. The aqueous 10 layer was extracted with ethyl acetate, and the extract was combined with the ethyl acetate layer separated above.

The ethyl a:cetate solution was washed with a saturated aqueous solution of sodium chloride, dried over magnesium j 3. ■ V sulfate and then concentrated under reduced pressure. | 15 The residue was subjected to column chromatography on silica gel (30 g.) and eluted with chloroform and then a mixture of chloroform and ethyl acetate.(7:3). The latter eluate was concentrated under reduced pressure to give 4-nitrobenzyl 7-[2-(2-formamido-4-thiazolyl)-2-methoxyimino-2o acetamido] - 3-c'hloro-3-cephem-4-carboxylate (syn isomer, 0.2 g.), mp 216°C (dec.).

I,R* vmax01 : 3230 (shoulder), 3110, 3050, 1785, 1725, 1690, 1655 cm 1 25 N.M.R. 6 ppm (DMSQ-dg) : 3.93 (3H, s), 3.93 (2H, q, J=18Hz), 5.36 (IH, d* J-SHz), 5.50 (2H, s), 5.97 (IH, dd, J=5Hz, 9Hz), 7.45 (IH, z), 7.73 (2H, d, J=9Hz), 8.29 (2H, d, J=9Hz), 8.56 (IH, s), 9.78 (IH, d, J=9Hz). 195 Example 45 The following compound8 were prepared in a similar manner to that of Example 44. (1) 4-Nitrobenzyl 7-[2-(2-formamidothiazol-4-yl)-^2-propoxy-iminoacetamido]-3-chloro-3-cephem-4-carboxylate (syn Aiomer) (2) 4-Nitrobenzyl 7-[2-(2-formamidothiazol-4-yl)-2-(2,2,2-trifluoroethoxyimino)acetamido]-3-chloro-3-cephem-4-carboxylate (syn isomer) (3) 4-Nitrobenzyl 7-[2-(2~formamidothiazol-4-yl)-2-butoxyiminoacetamido]-3-chloro-3~cephera-4-carboxylate (syn isomer) 96 Example 4 6 ^'Fermentation:- 46674 Pre-culture medium: Trypticase soy broth (B3L) Main culture medium: glycerin 3 g ^ peptone 1 g corn stce;> .• quor 1 y . dry yeast 2 y sodium carbonate 0.1 g KH2P04 0.55 g NaoHP0.>12H-0 2.15 g 10 2 4 2 r (The above components were dissolved in water so as to become 100 ml in total, and the medium was adjusted to pH 7.2.) I A main culture broth (100 ml.) was placed in Sakaguchi-fl^sk (500 ml) and sterilized at 120°C for 20 minutes. Into this medium, there was inoculated a culture broth (1 ml.) tof each of microorganisms as given belcw, which were cultured at 30°C for 18 hours in a pre-culture medium, respectively, and then a shaking culture was Conducted.at 30°C. for 48 hours.

Reaction:- Into above cultured broth (1ml.), there was added the Substrate (0.1 y) as yiven below suspended in 0.1 M phosphate buffer (;MI 7.2, 1 ml.), and then the mixture was tihaked at 30°C for 48 hours. 25 Identification and assays- After the reaction, in order to identify the generated product the reaction mixture as obtained above was chromatographed 15 20 1" 7 f 10 46674 on Eastman chromatogram 6065 cellulose at room temperature. As a developping agent, there was used (A) the upper layer of a mixture of n-tutanol, othanol and water (4:1:5 by volume) and .(B) a mixture of n-propanol and water (7:3 by volume). Rf value was determined by index of antimicrobial activity against a sensitive strain of Escherichia coli ES 111, and as the result only one spot showing each of Product I and II was observed on the Eastman chromatogram 6065 cellulose without showing any spot of each of Substrate I and II. Rf value are shown in the following table. 15 20 Reaction Mixture (Product I) Reference (Substrate I) Reaction Mixture (Product II) Reference (Substrate II) Developping Solvent A 0 .85 0. 39 0. 90 0. 36 B 0. 90 0.60 0.92 0. 54 25 30 Note: Substrate I: 4-nitrobenzyl 7-[2-formamido-4-thiazolyl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate (syn isomer) Product I: 7-[2-(2-formamido~4-thiazolyl)-2-methoxyimino- acetamido]-3-cephem-4-carboxylic acid (syn isomer) Substrate II: 4-nitrobenzyl 7- [ 2-aniino-4-thiazolyl)-2- methoxyiminoacetamido]-3-cephem-4-carboxylate (syn isomer) Product II: 7-[2-(2-amino-4-thiazoly1)-2-methoxyimino- acetaniido i - 3-co| >h^m- 4-<-a rboxy 1 i c acid (syn isomer) 198 The product generated in the reaction mixture as obtained above was assayed by paper cjisk-platc method using a sensitive strain of Escherichia coli ES 111 (culture: 37°C, 16 hours) and the yield thereof was calculated. The results are shpwn gr in the following.

Microorganism used for enzymatic hydrolysis Yield («) Product I Product II Bacillus subtilis IAM 1069 75 60 II ) sphaericus IAM 1286 75 20 M subtilis IAM 1107 75 95 II subtilis IAM 1214 85 20 .Corynebacterium equi IAM 1038 95 95 Micrococcus varians IAM 1314 70 20 ; Flavobacterium rigens IAM 1238 85 90 Salmonella typhimurium IAM 1406 90 20 Staphylococcus epidermidis IAM 1296 90 95 Microbacterium flavum IAM 1642 90 95 The following are examples of pharmaceutical compositions 2o prepared in accordance with this invention and containing 7- [2-(2-araino-4-thiazolyl) -2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer, Compound A) as the active substance. 4 6674 \ Example 47. (lyophlized preparation for injection) Sodium salt of compound A (20 g. potency) was dissolved in water (200 ml.), and the solution (5 ml.) was filled in each 10 ml. vial.' These vials are frozen and dried in a vacuum (lyophilization). 5 Example 48. (suspension for injection) Compound A 2 5 g.

Methyl cellurose 0.5 g.

Methyl 4-oxobenzoate 0.J g. 10 Polysolvate 80 0.1 g.

Lidocaine hydrochloride 0.5 g.

Water for injection to make 100 rnl.

This aqueous suspension is suitable for intramuscular injection. 15 Example 49. (tablets for oral use) Compound A 500 mg.

Lactose 37 5.5 mg.

Hydroxypropylcellurose 2 mg.

Magnesium stearate 22.5 rag. 20 This mixture provides a tablet for oral use in the treatment of infectious deseases caused by pathogenic bacteria.

Example 50- (capsule for oral use) Compound A 50 0 mg.

Magnesium stearate 10 iiki .

This mixture provides capuuj c l or oral use i n t he treatment of infectious diseases caused by pathogenic bacteria. .. 200 466 F.xample 51 (1) A solution of 2-(2-formamidothiazol-4-yl)-2-n-hexyloxyiminoacetic'acid (syn isomer, 3.24 g.), N,N-dimethylformamide (0.951 g.), and phosphoryl chloride (2.00 g.) in ethyl acetate (20 ml.), and a solution of 4-nitrobenzyl 7-amino-3-chloro-3-cephem-4-carboxylate hydrochloride (4 g.) in a mixture of acetone (20 ml.), vfater (20 ml.) and tetrahydrofuran (40 ml.) were treated in a similar manner to that of Example 21-(1) to give 4-nitrobenzyl 7-[2-(2-formamidothiazol-4-yl)-2-n-hexyloxy-iminoacetamido]-3-chloro-3-cephem-4-carboxylate (syn isomer, 5.78 g.).

I.R. v max01 : 3240' 3200» 3050> 1780» 1730» 1695, 1660 cm"1 N.M.R. <5 (DMS0-d6, ppm) : 0.6^2.1 (11H, m) , J 3.96 (2H, q, J=19Hz), 4.15 (2H, t, J=6Hz) , 5.37 (IH, d, J=5Hz) , 5.50- (2H, s) , 5.97 (IH, d, d, J=5Hz, 8Hz) , 7.42 (IH, s), 7.72 (2H, d, J=9Hz) , 8.28 (2H, d, J=9Hz) , 8.54 (IH, s), 9.74 (IH, d, J=8Hz), 12.73 (IH, broad s) (2) A mixture of 4-nitrobenzyl 7-[2 -(2-formamidothiazol -4-yl)- 2-n-hexyloxyiminoacetamido]-3-chloro-3-cephem-4-carboxylate (syn isomer, 5.6 g.), acetic acid (0.4 ml.), 10% palladium carbon (2.24 g.), water (4 ml.), methanol (23 ml.) and tetrahydrofuran (56 ml.) was treated in a similar manner to that of Example 21-(2) to give 7-[2-(2-formamidothiazol-4-yl)- 2-n-hexy]oxyiminoacetamido]-3-chloro-3-ccphem-4-carboxylic acid (syn isomer, 2.5 g.). 4667 4 I.R. v : 3225, 1785, 1690, 1650 cm"1 N.M.R. 6 (DMSO-d^, ppm) : 0.6%2.0 (llll, m), 3.86 (2H, q, J=18Hz) , 4.13 (2H, t, J=6Hz), 5.30 (1H, d, J=5Hz), 5.88 (IH, d, d, J=5Hz, 8Hz), 7.41 (IH, s), 8.54 (IH, s) , 9.70 (IH, d, J=8Hz), 12.68 (IH, s) (3) A mixture of 7-[2-(2-formamidothiazol-4-yl)-2- n-hexyloxyiminoacetamido]-3-chloro-3-cephem-4-carboxylic acid (syn isomer, 2.4 g.), conc.hydrochloric acid (1.84 g.), methanol (36 ml.) and tetrahydrofuran (30 ml.) was stirred at 30°C for 2 hours. The resultant solution was concentrated in vacuo. Water (60 ml.) was added to the residue and the precipitates were collected by filtration, washed with water and dried over phosphorus pentoxide to give 7-[2-(2-aminothiazol-4-yl)- 2-n-hexyloxyiminoacetamido]- 3-chloro-3-ccphem-4-carboxylic acid (syn isomer, 1.86 g.).

I.R. v max01 : 3300' 1780> 1665» 1535 cml N.M.R. 6 (DMSO-dg, ppm) : 0.6^2.0 (11H, m) , 3.84 (211, q, J=18Hz), 4.08 (211, t, J=7Hz) , 5.28 (III, d, J = 5Hz) , 5.82 (IH, d, d, J=5Hz, 8Hz), 6.77 (Hi, s), 9.66 (IH, d, J=8Hz), 6.0^8.0 (2H, broad's) Example 5 2 (1) 2-(2-Formamidothiazol-4-yl)-2-propargyloxyimino- acetic acid (syn isomer, 1.27 g.), N,N-dimethylformamide (402 mg.), phosphoryl chloride (843 mg.) and ethyl acetate (11.2 ml.) were treated in a conventional manner to prepare an activated acid solution. On the other hand, a mixture of 7 - amino-3-methoxy-3-cephem-4'-carboxylic acid 202 4 6 674 hydrochloride (1. 33' g.) ,- trimethylsilylacetamide (4 g.), bis(trimethylsilyl)acetamide (2 ml.) and ethyl acetate (20 ml.) was stirred at 40 to 45°C for an hour. To the solution was added the activated acid solution obtained above all at once at -15°C, and then stirred at -5 to -10°C for 1.5 hours. Water (30 ml.) was added to the resultant solution, filtered and the organic layer was separated. The insoluble substance filtered out was dissolved in a saturated aqueous solution of sodium bicarbonate, and the solution was added to the organic layer. The solution was adjusted to pH 7.5 and the aqueous solution was separated, and then extracted with ethyl acetate at pH 2.0.

The extract was washed with water, dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo to give 7-[2-(2-formamidothiazol-4-yl) -2-propargyloxyiminoacetamido]-3-methoxy-3-cephem-4-carboxylic acid (syn isomer, 1.0 g.), yellow powder.

I.R. v : 3200^3300, 2500^2600, 2120, 1770, 1710, 1690, 1670 cm"1 N.M.R. 6 (DMSO-d6, ppm) : 3.50 (IH, m), 3.65 (2H, s), 3.82 (3H, s), 4.80 (2H, d, J= 2Hz) , 5.20 (IH, d, J = 4Hz), 5.62 (IH, ; d,d, J=4Hz, 8Hz) , 7.52 (lH, s), 8.55 (IH, s), 9.68 (IH, d, J=8Hz), 12.65 (IH, broad s) (2) A mixture of 7-[2-(2-formamidothiazol-4-yl)-2 -propargyloxyiminoacetamido]-3-methoxy-3-cephem-4-carboxylie acid (syn isomer, 0.9 g.), conc. hydrochloric acid (0.9 nil.) and methanol (13.5 ml.) was stirred at room temperature 2.03 46674 for 4 hours. After concentrating the resultant solution in vacuo at 35°C, the residue was dissolved in water and washed with ethyl acetate. The aqueous solution was adjusted to pH 7.0 with sodium bicarbonate and washed with ethyl acetate and diethyl ether. After removing the organic solvent by bubbling nitrogen gas, the solution was adjusted to pH 3.0 with 10% hydrochloric acid and stirred under ice cooling. The precipitates were collected by \ filtration, washed with water and dried to give 7-[2-(2- aminothiazol-4-yl)-2-propargyloxyiminoacetamido]-3- methoxy-3-cephem-4-carboxylic acid (syn isomer, 0.25 g.), whitish yellow powder.

I.R. v Nu3o1 : 3300, 2500*2600, 2120, 1775, max ' » » » 1710, 1670, 1620 cm"1 N.M.R. 6 (DMS0-d6, ppm) : 3.52 (IH, m), 3.82 (3H, s), 4.77. (211, d, J = 2Hz) , 5.17 (III, d, J = 4Hz) , 5.58 (1H, d,d, J=4Hz, 8Hz), 6.93 (IH, s), 7.1*7.3 (2H, broad s), 9.67 (III, d, J=8Hz) Example 53 (1) 2-(2-Formamidothiazol-4-yl)-2-propargyloxyimino- acetic acid (syn isomer, 1.27 g.), N,N-dimethylformamide (400 mg.), phosphoryl chloride (850 mg.) and ethyl acetate (11.2 ml.) were treated in a conventional manner to give the activated acid solution. The activated acid solution was added to a solution of 7-amino-3-chl oro-3-c.ephcni-4-carboxylic acid hydrochloride (2 g.), trimethylsilylacetamide (6 g.) and bis(trimethylsilyl)acetamide (3 ml.) in ethyl acetate (40 ml.) at -15°C all at once, and stirred 204 4 6 6 7 4 at -5 to -10°C for 1.5 hours. After adding water (30 ml.) to the resultant solution, the ethyl acetate layer was separated and extracted with a saturated aqueous solution of sodium bicarbonate. Ethyl acetate was added to the aqueous extract, adjusted to pH 2.0 with 10% hydrochloric acid. The ethyl acetate layer was separated, washed with water, dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo, and the residue was crystallized with a mixture of ethyl acetate and diisopropyl ether. The precipitates were collected by filtration and dried to give 7-[2-(2-formamidothiazol-4-yl)-2-propargyloxyiminoacetamido]-3-chloro-3-cephem-4-carboxylic acid (syn isomer, 1.5 g.), yellow powder.

I,R* V max01 ; 3250*3300, 2500*2600, 2120, 1780, 1725, 1690, 1670 cm"1 N.M.R. <5 (DMSO-d6, ppm) : 3.45 (IH, m) , 3.57 (2H, AB-q, J=20Hz), 4.77 (2H, d, J=2Hz), 5.28 (IH, d, J = 4Hz) , 5.'80 (IH, d,d, J=4Hz, 8Hz), 8.42 (IH, s), 8.52 (1H, s), 9.78 (Hi, d, J=8IIz) , 12.72 (IH, broad s) (2) A mixture of 7-[2-(2-formamidothiazol-4-yl)-2-propargyloxyiminoacetamido]-3-chloro-3-cephem-4-carboxylie acid (syn isomer, 1.4 g.), conc. hydrochloric acid (1.4 ml.) and methanol (20 ml.) was treated in a similar manner to that of Example 51-(2) to give 7-[2-(2-aminothiazol-4-yl)-2-propargyloxyiminoacetamido]-3-chloro-3-cephem-4-carboxylic acid (syn isomer, 0.7 g.), yellowish white powder.

I.R. v Nujo1 : 3350, 2500*2600, 2130, 1775, max ' tit 1710, 1670, 1630 cm"1 205 46674 N.M.R. 6 (DMSO-d6, ppm) : 4.38 (1.H, m), 4.48 (2H, AB-q, J=19Hz) , 4.72 (211, d, J=2Hz), 5.28 (III, d, J=4Hz) , 5.80 (IH, d,d, J=4Hz, 8Hz), 6.78 (IH, s), 9.73 (IH, d, J=8Hz) Example 54 Thiourea (11 mg.) and a solution of 7-[2-(2-bromoacetyl)- 2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer, 30 mg.) in ethanol (2 ml.) were treated in a similar manner to that of Example 36-(4) to give 7-[2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer). The product was identified with an authentic sample by thin layer chromatography.

Example 55 (1) A solution of 4-nitrobenzyl 7-amj.no-3-chloro-3- cephem-4-carboxylate hydrochloride (15.0 g.), bis(trimethylsilylacetamide (11.3 g.) and trimethylsilylacetamide (9.7 g.) in tetrahydrofuran (300 ml.), a solution of diketene j (3.41 ml.) in methylene chloride (4 ml.), a solution of bromine (2.27 ml.) in methylene chloride (4 ml.), a solution of sodium nitrite (3.1 g.) in water (20 ml.) and a solution of thiourea (4.0 g.) in water (40 ml.) were treated in a similar manner to that of Example 37-(1) to give 4-nitrobenzyl 7-[2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-chloro-3-cephem-4-carboxylate (syn isomer, 10.4 g.). 1.R. v : 3300, 3180, 1777, 1730 , 1670, 1603 cm 1 206 46674 10 N.M.R. &'(DMSO-d6, ppm) : 3.93 (21!, d, J = 5I!z) , 5.33 (IH, d, J=5Hz) , 5.49 (2H, s), .5.90 (IH, d,d, J=5Hz, 8.2Hz), 6.68 (IH, s), 7.14 (IH, broad s), 7.72 (2H, d, J=9.2Hz) , 8.27 (2H, d, J=9.2Hz), 9. 54 (III, d, J=8 . 2Hz) (2) 4-Nitrobenzyl 7-[2-(2-aminothiazol-4-yl)-2- hydroxyiminoacetamido]-3-chloro-3-cephem-4-carboxylate (syn isomer, 5.0 g.), 10% palladium carbon (3.0 g.), methanol (100 ml.), water (10 ml.) and tetrahydrofuran (150 ml.) were treated in a similar manner to that of Example 37-(2), to give 7-[2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-chloro-3-cephem-4-carboxylic acid (syn isomer, 1.28 g.). 15 I.R. v N"j°l : 3330, 1775, 1675, 1630 cm"1 max ' ' ' N.M.R. <5 (DMSO-dg, ppm) : 3.72 (2H, m) , 5.24 (IH, d, J=5Hz) , 5.80 (III, d,d, J=5.0Hz, 8.2Hz), 6.66 (IH, s), 9.50 (IH, d) 20 25 30 .207 667 4 Example 56 (1) A solution of 2-(2-formamidothiazol-4-yl)-2-n-octyloxyiminoacetic acid (syn isomer, 7.52 g.), phosphoryl chloride (5.4 g.) and N,N-dimethylformamide (2.58 g.) in tetrahydrofuran (16 ml.), which was prepared in a similar manner to that of Example 30-(1), and a solution of 7-amino-3-cephem-4-carboxylic acid (4 g.) in a mixture of acetone (20 ml.) water (20 ml.) and tetrahydrofuran (20 ml.) were treated in a similar manner to that of Example 30-(1) to give 7-[2-(2-formamidothiazol-4-yl)-2-n-octyloxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer, 8.1 g.) I.R. v Nu-io1 : 3280, 3200, 3060, 1795 , 1705 , max ' ' ' 1660, 1630 cm 1 N.M.R. 6 (DMS0-d6, ppm) : 0.6*2.1 (15H, m), 3.62 (211, d, J=4Hz) , 4.14 (2H, t, J=6Hz) , 5.16 (lfl, d, J=5Hz), 5.88 (1H, d,d, J=5Hz, 8Hz) , 6.51 (IH, t, J=4.Hz) , 7.42 (IH, s) , 8.54 (IH, s), 9.63 (IH, d, J=8Hz) , 12.66 (IH, s) (2) 7-[2-(2-Formamidothiazol-4-yl)-4-n-octyloxyimino-acetamido]-3-cephem-4-carboxylic acid (syn isomer, 8.0 g.), conc. hydrochloric acid (6.23 g.), tetrahydrofuran (15 ml.) and methanol (120 ml.) were treated in a similar manner to that of Example 21-(3) to give 7-[2-(2-aminothiazol-4-yl)-2-n-octyloxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer, 6.95 g.).

I.R. v Nujo1 : 3320 (shoulder), 1785, 1660, max ' * ' ' 1630, 1535 208 10 15 20 25 30 4 6 6 7 4 N.M.R. 6 (DMSO-dg, ppm) : 0.6*2,.0 (15H, m) , . • 3.62 (2H> broad.s), 4.07 (2H, t, : J=6Hz), 5.12 (1H, d, J=5Hz) , 5.83 (1H, . i ! ' d,d, J=5Hz, 9Hz), 6.48 (1H, broad s) , ! 6.72 (IH, s), 7.22 (2H, s), 9.53 (IH, I j d, J=9Hz) Example 57 . I I Zinc powder (4.5 g.) was added to a stirred solution of 7-£2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido7'- 3-cephem-4-carboxylic acid (syn isomer : 3 g.) in 90% formic acid (150 ml.) under ice cooling over 5 minutes, and stirred at the same temperature for 15 minutes. After the resultant solution was filtered and washed with formic acid, the filtrate and the washings were combined and concentrated under reduced pressure to a volume of about 20 ml. The concentrate was dissolved in water (150 ml.) and bubbled with hydrogen sulfide gas for 20 minutes under ice-cooling. The precipitating zinc sulfide was filtered off,"and the filtrate was treated with activated charcoal and lyophilized to give 7-/7- (2-amino-4-thiazolyl)glycinamido7-3-cephem-4-carboxylic ! o acid formate (2.9 g.), pale yellow powder, mp?2 40 C. i i .i I.R. U Nujol . 3330f 3200, 3100, 1770, 1690 cm"1 max N.M.R 6 (D2°: ppm) : 3.42 - 3.61 (2H, m), 5.03 5.16 (IH, m), 5.19 (IH, s), 5.60 (1/2 H, d, J=5Hz), 5.79 (1/2 H, d, J=5Hz), 6.36 - 6.50 (IH, m), 8. 32 (1H, s) Example 58 Thiourea (663 mg.), "sodium bicarbonate (732 mg.) 209 46674 and water (20 ml.) were added to a stirred solution of 7 -(4 - bromo - 3 - oxobutyramido) - 3 - cephem - 4 - carboxylic acid (2.11 g.) in tetrahydrofuran (20 ml.) under ice cooling and stirred at the same temperature for an hour. After the 5 resultant solution was adjusted to pH 4.0 with dilute hydrochloric acid, the precipitates were collected by filtration, washed with water and dried over phosphorus pentoxide under reduced pressure to give 7 - £T-\2 - amino - 4 - thiazolyl) acetamido? - 3 - cephem - 4 - carboxylic acid (1.01 g.). 10 I.R. u Nujol. 3550f 3330f 1750/ 1670, max , 1670, 1620 cm"1 N.M.R 6 (DMSO-d,.: ppm): 3.42(2H, s), 3.60 o (2H, d, J=4 Hz), 5.08 (IH, d, J=5 Hz), 5,77 (IH, dd, J=8 Hz), 6.30 (IH, s), 15 6.52 (IH, t, J=4 Hz), 8.87 (1H, d, J=8 Hz) Example 59 (1) Thiourea (1.13 g.), sodium bicarbonate (1.24 g) and water (20 ml.) were added to a solution of 4 - nitro-20 benzyl 7 - (4 - bromo - 3 - oxobutyramido) - 3 - cephem -4 - carboxylate (6.15 g.) in tetrahydrofuran (60 ml.), and stirred at room temperature for an hour. After concentrating the resultant solution under reduced pressure, the residue was extracted with ethylacetate. The extract was washed with 25 water, dried over magnesium sulfate and concentrated under reduced pressure. The oily residue was subjected to column chromatography on silica gel, and eluted with benzene, a mixture of benzene (1 part) and ethyl acetate (1 part) 210 46674 and then euhyl acetate in turn. The ethyl acetate fractions, were collected and concentrated under reduced pressure to give 4 - nitrobenzyl 7 -{ 2 - (2 - amino - 4 - thiazolyl)-acetamido } - 3 - cephe... 4 - carooxylate (1.5 g.) . 5 I.R.u Nu^01; 3350, 1780, 1740, 1680, 1610 cm"1 max N.M.R 6 (DMSO-dg, ppm ) : 3 . 40 (2H,broad s) , 3.68(2H,broad s), 5.12(lH,d, J=5 Hz), 5.43 (2H, s), 5.84(IH, dd, J=8Hz, 5 Hz),6.30(IH, s),6.70(IH,broad s), 7 . 72(2H,d,J=9Hz), 8.27(2H,d,J=9Hz), 8.93(lH,d,J=8Hz) (2) A solution of 4 - nitrobenzyl 7 - { 2 - (2 - 15 amino - 4 - thiazolyl)-acetamido }- 3 - cephem - 4 - carboxylate (1.4 g.)in a mixture of methanol (25ml.)and tetrahydrofuran (60 ml.)was added to a mixture of 10% palladium-on-carbon (1.7 g),glacial acetic acid(7 ml.)and methanol (20 ml) in an atmosphere of nitrogen. Hydrogen gas was introduced into 2q the mixture and shaken for 8.5 hours at room temperature.

After removing the insoluble substance by filtration, the filtrate was concentrated under reduced pressure. The residue was pulverized with diethyl ether, and the resultant substance was dissolved in an aqueous solution of sodium bicarbonate, 25 washed with ethyl acetate and diethyl ether in turn and then the remaining ether was removed by bubbling with nitrogen gas. The resultant solution was adjusted to pH. 4.5 with dilute hydrochloric - 211- acid, subjected to column chromatography on macroporous non-ionic adsorption resin "Diaion HP-20" (Trademark, manufactured by Mitsubishi Chemical Industries Ltd.), and eluted with 20% isopropyl alcohol. Isopropyl alcohol wias distilled off under reduced pressure and the remaining; solution was lyophilized to give 7 -/2 - (2 - amino - :4 -thiazolyl)acetamido7 - 3 - cephem - 4 - carboxylic acid (185 mg.).

I.R. o Nujol ; 3550f 3330/ 1750, 1670, 1620 max cm N.M.R 6 (DMSO-dg: ppm): 3.42(2H, s) , 3.60 (2H, d, J= 4 Hz), 5.08(IH, d, J=5 Hz) 5,77 (IH, dd, J=8 Hz, 5 Hz),|6.30 ] (IH, s), 6.52(lH,t,J=4 Hz), 8.87 (IH, d, J= Hz) i i Example 60 (1) 4 - Nitrobenzyl 7 - amino - 3 - cephem - 4 -carboxylate hydrochloride (9 g.), trimethylsilylacetamide (24.81 g.) and bis - (trimethylsilyl)acetamide (9 ml.) were added to dry ethyl acetate (100 ml.) and stirred! at 45°C for an hour. j On the other hand, phosphoryl chloride (8.4 ml.) was added dropwise to a stirred mixture of dimethylformamide (4.0 ml) and dry ethyl acetate (16.0 ml.) under ice cooling, and stirred for a while. To the solution were added ethyl acetate (240 ml) and 2 - (2 - formamido - 4 - thiazolyl) oxalic acid (5.35 g.) gradually at —3°C, and the mixture was stirred at the same temperature for 15 minutes. The Z' 2 j 46674 i i solution was added dropwise to the solution containing the cephalosporin compound prepared above at —15°C and stirred at the same temperature for 30 minutes. Water (50 ml) was ?4ded to the resultant solution, and the precipitates were 5 collected by filtration, washed with water and dried over phosphorus pentoxide under reduced pressure to give 4 - nitrobenzyl 7 - /T - (2 - formamido - 4 - thiazolyl)oxalylamino7 -3 - cephem - 4 - carboxylate (7.124 g.). The ethyl acetate layer was separated from the filtrate, washed with a saturated 10 aqueous solution of sodium chloride, dried over magnesium sulfate, and concentrated under reduced pressure to give the same object as above (1.03 g.). Total yield 8.154 g.

I. R. V) N.M.R. S 15 (2) A mixture of 4 - nitrobenzyl 7 - - (2 -20 formamido - 4 - thiazolyl) - oxalvlamino7 - 3 - cephem - 4 -carboxylate (3.0 g.), methanol (60 ml.) and tetrahydrofuran (80 ml.) was added to a mixture of 10% palladium-carbon (1.5 g.), acetic acid (10 ml.) and methanol (10 ml.) in an atmosphere of nitrogen gas, and then subjected to catalytic 25 reduction at room temperature under ordinary pressure for 4 hours. The resultant mixture was filtered, and the filtrate Nujol . 1775f 1725f 1650 cm-l max (DMSO-dg, 5 .4 2(2H , s), 5.90(1H, dd, J=5.2 Hz, 7.8 Hz), 6.66 (IH, t, J= 5.0 Hz), 7.67(2H, d, J=9 Hz), 8.22 (2H, d, J=9 Hz), 8.39(IH, s), 8.55 (IH, s), 9.87(IH, d, J=7.8 Hz) Z13 46674 was concentrated under reduced pressure. The precipitates were collected by filtration, washed with diisopropyl ether (50 ml.) and dried to give powder (1.34 g.), A mixture of water (100 ml.) and ethyl acetate (100 ml.) was added to 5 the powder adjusted to pH 6.0 with sodium bicarbonate and the aqueous layer was separated, washed with ethyl acetate and diethyl ether. The remaining ether was removed off by bubbling with nitrogen gas, and the aqueous solution was adjusted to pH 2.0 with 10% hydrochloric acid. The 10 resultant precipitates were collected by filtration and dried over phosphorus pentoxide to give 7 - - (2 - formamido - 4 - thiazolyl) - oxalylamino/ - 3 - cephem - 4 - carboxylic acid (0.47 g.). The above filtrate was concentrated under reduced pressure, and the residue was pulverized with a 15 mixture of diethyl ether and petroleum ether. The precipitates i were collected by filtration, washed with diethyl ether and petroleum ether and dried under reduced pressure to give the same objective compound (1.1 g.). Total yield 1.57 g.

I.R. u Nujol. 178Qj 167Q cm-l max 20 N.M.R. 6 (DMSO-dg): 3.63(2H, m, J=4 HZ), 5 .17 (IH, d, J=5. 2 Hz), 5.87 (IH, dd, J=5.2 Hz, 8.2 Hz), 6.53(1H, t, J=4 Hz), 8 . 42 (IH, s) , 8.59(lHj s) , 9.83 (IH, d, J=8.2 Hz) 25 (3) A mixture of conc. hydrochloric acid (2-.44 g.) and methanol (10 ml.) was added to a mixture of 7 - /2~- (2 -formamido - 4 - thiazolyl)-oxalylaminc^ - 3 - cephem - 4 - 214 carboxylic acid (2.44 g.) in methanol (40 ml.) under ice-cooling, stirred, at 20 to 22°C for 5 hours and filtered, The filtrate was concentrated under reduced pressure, and i water (100 ml) was added to the residue, adjusted to pH 6.5 with sodium bicarbonate with stirring and filtered. The filtrate was washed with ethyl acetate, and adjusted to pH 3.5 with 10% hydrochloric acid]. The resultant i precipitates were collected by filtration, washed with water and dried over phosphorus pentoxide under reduced pressure to give 7 - /Z~- (2 - amino - 4 - thiazolyl)oxalyl- amino7 - 3 - cephem - 4 - carboxylic acid (0.492 g.), The / filtrate and washings were sijfojected to column chromatography on macroporous, non-ionic adsorption resin "Diaion HP-20" I (Trademark, manufactured by Mitsubishi Chemical Industries Ltd), washed with water and eluted with 15% isopropyl alcohol. The isopropyl alcohol was distilled off under reduced pressure and the remaining solution was lyopholized to give the same object compound (1.561 g.). Total yield 2.053 g.

I.R u Nujol . i78o, 1668 cm"1 max N.M.R. 6 (D20): 3.57(2H, m) 5.17(lH, d, J= 4.8Uz), 5.78(IH, d, J=4.8 Hz), 6.33 (IH, m), 8.26(IH, s) .

Example 61 To a stirred solution of 7 - /T - (2 - amino - 4 -thiazolvl)oxalvlamin67 - 3 - cephem - 4 - carboxylic acid 2J5 46674 i (520 mg.) in methanol (15 ml.) was added sodium borohydride (100 mg.) under ice-cooling, and stirred at the same temperature for 3 hours. Methanol was distilled off under reduced pressure from the reaction mixture, and the residue 5 was dissolved in water (3 ml.) and adjusted to pH 3 with 6N - hydrochloric acid. The precipitates were collected by filtration, washed with water and dried over phosphorus pentoxide to give 7 -{ 2 - (2 - amino - 4 - thiazolyl) - 2 -hydroxyacetamido } - 3 - cephem - 4 - carboxylic acid (290 mg.).

I,R,umax°1: 1775, 1630 cm-1 N.M.R 6 (D20+DMS0-dg, ppm): 5.03(lH,s), 5.07 (lH,d, J=4.6Hz), 5.72 (IH, d, J=4.6 Hz), 6.49 (IH, m, J=3.2 Hz), 6.67 (IH, s).

Example 62 A solution of 1 -£2 - (2- amino - 4 - thiazolyl) glyoxylamido]7 ~ 3 - cephem - 4 - carboxylic acid hydrochloride (1.78 g.) in water (100 ml) was adjusted to pH 6.0 with sodium bicarbonate under ice cooling with stirring. :Sodium acetate (0.38 g.) and methoxylamine hydrochloride (1.37 g.) were added to the solution adjusted to pH 7.0 with sodium bicarbonate and then stirred at 48°C for an hour. The resultant solution was washed with ethyl acetate (200 ml) and diethyl ether (100 ml.) in turn, and then nitrogen gas was bubbled into the solution to remove diethyl ether. The aqueous solution was adjusted to pH 3.5 with 10% hydrochloric -216- 10 15 4 6674 acid under ice cooling with stirring. The precipitates were collected by filtration, washed with water and dried over phosphorus pentoxide under reduced pressure to give 7 - UL- (2 - amino - ■* - thiazolyl) - 2 - methoxyimino-5 aoetamldc7 - 3 - cephem - 4 - carboxylic acid (syn isomer, 120 mg.). The mother liquor was subjected to column chromatography on macroporus, nonionic adsorption resin Diaion "HP-20" (Trademark: manufactured by Mitsubishi Chemical Industries Ltd). and eluted with 40% aqueous 10 acetone. The eluate was concentrated under reduced pressure, lyophilized, and then dried over phosphorus pentoxide to i give the same object compound (950 mg.). Total yield 1070 mg.

I.R.u Nujol: 3460, 3290, 3150, 1780, 1655, max i 1623 cm N.M.R. 6 ppm (DMSO-dg): 3.60 (2H, broad s), 3.84 (3H, s), 5.12 (IH, d, J=5 Hz), 5.84 (IH, d, d, J=5 Hz, 8 Hz), 6.52 (IH, t), 6.76 (IH, s), 7.26 (2H, Broad s), 9.65 (IH, d, J=8 Hz). 15 20 -217- 46674 10

Claims (9)

1. CLAIMS:- 1. A compound of the formula: R1-A-C0NH~i (/T~ R4 ,av- R r5 wherein 5 R1 is thiadiazolyl, thiazolyl of the formula: R -u- in which R^ is amino or protected amino, or haloacetyl, A is methylene which may be substituted with amino, hydroxy or oxo, or a group of the formula: ! N .2 £—R' 2 in which R is hydrogen or an aliphatic hydrocarbon residue which may be substitute^ with halogen, carboxy or j esterified carboxy, 3 R is hydrogen or lower alkyl, 4 15 R is hydrogen, halogen, lower alkyl or a group of 7 7 the formula: —0—R in which R is hydrogen, lower alkyl or acyl R"* is carboxy or functionally modified carboxy, and the dotted line represents 3-cephem arid cepham nuclei, 20 inclusively, provided that 4 i) R is hydrogen, halogen or a group of the formula :—i 7 7 3 R in which R is as defined above, when R is hydrogen, -218- 4 6 6 7 4 15 20 4 3 ii) R is lower alkyl, when R is lower alkyl, 4 1 iii) R is hydrogen, when R is thiadiazolyl or thiazolyl group of the formula: in which R^ is amino or protected amino and A is methylene which may be substituted with amino, hydroxy or oxo, and iv) A is methylene or a group of the formula: II N 8 2 4 in which R is as defined above, R is hydrogen, halogen, *7 10 lower alkyl or a group of the formula:-—0—R in which R7 is lower alkyl and then the dotted line represents 3-cephem nucleus, when R is haloacetyl, pharmaceutically acceptable salts and pharmaceutically acceptable bioprecusor thereof.

2. The compound of the claim- 1, wherein R1 is thiadiazolyl or thiazolyl of the formula: in which R® is amino or protected amino, A is a group of the formula: I N b—r2 2 in which R is hydrogen or aliphatic hydrocarbon residue which may be substituted with halogen, carboxy or esterified carboxy.

3. The compound of the claim 2, wherein the dotted 25 line represents 3-cephem.

4. The compound of the claim 3, wherein R3 is hydrogen. -219- 67 4 4 The compound of the claim 4, wherein R is hydrogen. The compound of the claim 5, wherein R1 is thiadiazolyl or thiazolyl of the formula : ft ^ \\ 6 Rzjj "TT in which R is amino, lower alkanamido S or halo(lower)alkanamido, 2 A is a group of the formula: -jj!- in which R N i-R2 is hydrogen, alkyl which may be substituted with halogen, c,arboxy or lower alkoxycarbonyl, cycloalkyl, alkenyl or alkynyl, and R^ is carboxy or esterified carboxy. The compound of the claim 6, wherein R* is thiadiazolyl, A is a group of the formula: -jj!- S 2 2 0 in which R is alkyl. The compound of the claim 7, wherein 2 R is lower alkyl. The compound of the claim 8, which is 7-[2 - (l,2,3-thiadiazol-4-yl)-2-methoxyiminoacetkmido]-3-cephem-4-carboxylic acid (syn isomer). The compound of the claim 8, wherein R^ is substituted benzyloxycarbonyl. The compound of the claim 10, which is p-nitrobenzyl 7-[2-(1,2,3-thiadiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate. (syn isomer) 220 4 6 6 7 4 12. The compound of the ciaim 6, wherein 1 • gN —r\ R is thiazolyl of the formula : ■yr~ in which R^ is amino, lower alkanamido or halo(lower)-alkanamido. 13. The compound the claim 12, wherein 2 6 R is hydfogen or alkyl and R is amino or lower alkanamido. 14. The compound of the claim 13, wherein 6 ' 10 R is amino. 1

5. The compound of the claim 14, wherein 1 2 R is 2-aminothiazolyl, and R is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobuty] , 15 pentyl, hexyl, heptyl, or octyl. 1

6. The compound of the claim 15, wherein R1 is 2-aminothiazol-4-yl, and R"' is carboxy. 20 1

7. The compound of the claim 16, which is 7-[2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido] 3-cephem-4-carboxylic acid (syn isomer). 1

8. The compound of the claim 16, which is 25 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido] ■ 3-cephem-4-carboxylic acid (syn isomer). 1

9. The compound of the claim 16, which is 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]• 3-cephem-4-carboxylic acid (anti isomer). 2? I 46674 20. The compound of the claim 16, which is 7- [2- (2-aminothiazol-4-yl)-2-ethoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer). 5 21. The compound of the claim 16, which is 7-[2-(2-aminothiazol-4-yl)-2-propoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer). 22. The compound of the claim 16, which is 10 7- [2- (2 - amino tihiazol- 4-yl) - 2- i s op ropoxy imino ace tami do] 3-cephem-4-carboxylic acid (syn isomer). 1 t 23. The compound of the claim 16, which is 7- [2-(2-aminothiazol-4-yl)-2-butoxyiminoacetamido]-IS 3-cephem-4-carboxylic acid (syn isomer). 24. The compound of the claim 16, which is 7-[2-(2-aminothiazol-4-yl)- 2-isobutoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer). 20 25. The compound of the claim 16, which is 7-[2-(2-aminothiazol-4-yl)-2-pentyloxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer). 25 26. The compound of the claim 16, which is 7-[2-(2-aminothiazol-4-yl)-2-hexyloxyiminoacetamido]-3-cephem-4-carboxylic. acid (syn isomer) . 27. The compound of the claim 16, which is 30 7-[2-(2-aminothiazol-4-yl)- 2-octyloxyiminoacetamido]- 272 ■ 4 6 6 7 4 3-cephem-4-carboxylic acid (syn isomer). 28. The compound of the claim 16, wherein the pharmaceutically acceptable salt is sodium, 5 potassium, calcium, magnesium, lysine or arginine salt or the hydrochloride. 29. The compound of the claim 28, which is sodium 7-[2-(2-aminothiazol-4-yl)-2- 10 methoxyiminoacetamido]-3-cephem-4-carboxylate (syn isomer). 30. The compound of the claim 28, which is potassium, calcium, magnesium, lysine or arginine 15 salt of 7-[2-(2-aminothiazol-4-yl)-2- methoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer). 31. The compound of the claim 28, which is 20 7- [2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]- 3-cephem-4-carboxylic acid hydrochloride (syn isomer) 32. The compound of the claim 15, wherein R1 is 2-aminothiazol-4-yl, and R^ is substituted 25 benzyloxycarbony1 or alkanoyloxy(lower)alkoxycarbonyl 33. The compound of the claim 32, wherein R^ is p-nitrobenzyloxycarbonyl or hexanoyloxy-1 methoxycarbonyl. 30 34. The compound of the claim 33, which is 223 4 6 6 7 4 5 35. 10 36. 15 37. 20 38. 25 39. 30 40. p-nitrobenzyl 7-[2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-cephem-4-carboxylate (syn isomer). The compound of the claim 33, which is p-nitrobenzyl 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate (syn isomer). The compound of the claim 33, which is p-nitrobenzyl 7-[2-(2-aminothiazol-4-yl)-2-ethoxyiminoacetamido]-3-cephem-4-carboxylate (syn isomer). The compound of the claim 33, which is p-nitrobenzyl 7-[2-(2-aminothiazol-4-yl)-2-propoxyimirioacetamido]-3-cephem-4-carboxylate (syn isomer). The compound of the claim 33, which is p-nitrobenzyl 7-[2-(2-aminothiazol-4-yl)-2-isopropoxyiminoacetamido]- 3-cephem-4-carboxylite (syn isomer). 1 The compound of the claim 33, which is hexanoyloxymethyl 7-[2- (2-aminothiazol-4-yl)-2-methoxyiminoacetamido]- 3-cephem-4-carboxylate (syn isomer). The compound of the claim 13, wherein 4 6 6 7 4 is lower alkanamido. 41. The compound of the claim 40, wherein 1 ■ . ' ? R is 2-formamidothiazolyl, and R~ is methyl, 5 butyl, isobacyl or pentyl. 42. The compound of the claim 41, whereih R] is 2-formamidothiazol-4-yl, and R^ is carboxy. 10 43. The compound of the claim 42, which is 7- [2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer). 44. The compound of the claim 42, which is 15 7-[2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetamido]- 3-cephem-4-carboxylic acid (anti isomer). 45. The compound of the claim 42, which is 7- [2-(2-formamidothiazol-4-yl)-2-butoxyiminoacetamido]-20 3-cephem-4-carboxylic acid (syn isomer) . 46. The compound of the claim 42, which is 7-[ 2 - (2 - fonnamidothi ;i zol - 4-yl)-2 - isobutoxyiminoacetamido ] 3-cephem-4-carboxylic acid (syn isomer). 25 47. The compound of the claim 42, which is 7-[2 -(2-formamidothiazol-4-yl)-2-pentyloxyiminoacetamido] 3-cephem-4-carboxylic acid (syn isomer). 30 48. The compound of the claim 41, wherein 125 46674 R1 is 2-forraamidothiazol-4-yl, and R^ is substituted b'enzyloxycarbonyl. 49. The compound of the claim 48, wherein » R is p-nitrobenzyloxycarbonyl. 10 50. The compound of the claim 49, which is p-nitrobenzyl 7-[2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate (syn isomer). 15 51. The compound of the claim 49, which is j ! • p-nitrobenzyl 7-[2-(2-formamidothiazol-4-yl) -j2-butoxyiminoacetamido]- 3-cephem-4-carboxylate (syn isomer). 20 52. The compound of the claim 49, which is ; p-nitrobenzyl 7-[2-(2-formamidothiazol-4-yl)-2-isobutoxyiminoacetamido]-3-cephem-4-carboxylate (syn isomer). 25 53. The compound of the claim 49, which is j i p-nitrobenzyl 7-[2-(2-formamidothiazol-4-yl)-2-pentyioxyiminoacetninido] - 3- cephem- 4-carboxylat.e (syn isomer). t ' 54. The compound of the claim 12, wherein 2 / R is cycloalkyl and R is amino or lower alkanamido. 30 55. The compound of the claim 54, wherein 226 4 6 6 7 4 R1 is 2-aminothiazolyl or 2-formamidothiazolyl, 2 5 R is cycloalkyl, and R is carboxy. 56. The compound of the claim 55, which is 5 7- [2- (2-aminothia zol-4-yl)-2-eyelohcxyloxyiminoacetamido] 3-cephem-4-carboxylic acid (syn isomer). 57. The compound of the claim 55, which is 7- [2-(2-formamidothiazol-4-yl)-2- 10 cyclohexyloxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer). 58. The compound of the claim 54, wherein R1 is 2-aminothiazolyl or 2-formamidothiazolyl, 15 and R^ is substituted benzyloxycarbonyl. 59. The compound of the claim 58, which is p-nitrobenzyl 7-[2-(2-formamidothiazol-4-yl)-2-cyclohexy 1oxyiminoacetamido]- 3-cephem-4-carboxylate 20 (syn isomer). 60. The compound of the claim 12, wherein 2 6 R is alkenyl and R is amino or lower alkanamido. 25 61. The compound of the claim 60, wherein 1 2 R is 2-aminothiazolyl, and R is alkenyl. 62. The compound of the claim 61, wherein ; 2- 30 and R^ is carboxy. 1 2 R is 2-aminothiazol-4-yl, R is lower alkenyl 46674 25 30 63. The compound of the claim 62, which is 7-[2-(2-aminothiazol-4-yl)-2- allyloxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer). 64. The compound .of the claim 61, wherein R1 is 2-aminothiaz benzyloxycarbonyl. R1 is 2-aminothiazol-4-yl, and R^ is substituted 10 65. The compound of the claim 64, which is p-nitrobenzyl 7-[2-(2-aminothiazol-4-yl)-2-allyloxyiminoacetamido]-3-cephem-4-carboxylate (syn isomer). 15 66. The compound of the claim 12, wherein 2 6 R is alkynyl and R is amino or lower alkanamido 67. The compound of the claim 66, wherein R1 is 2-aminothiazol"4-yl or 2-(lower)alkanamidothiazol-2 20 4-yl and R, is lower alkynyl. 68. The compound of the claim 67, which is ' 7-[2-(2-aminothiazol-4-yl)-2-propargyloxyiminoacetamido] 3-cephem-4-carboxylic acid (syn isomer). 69. The compound of the claim 67, which is 7- [2- (2-formnmj dothiazol-4-yl)-2-propargyloxyiminoacetami do]- 3-cephem-4-carboxylic acid (syn isomer). 228 46 67 4 The compound of the cl.-iim 12, wherein 2 6 R is. haloalkyl, and R is amino or lower alkanamido. The compound of the claim 70, wherein 2 R is nionohalo (lower)alkyl or trihalo (lower) alky 1, •and R^ is carboxy. The compound of the claim 71, wherein R1 is 2-aminothiazol-4-yl or 2-(lower)alkanamido- thiazol-4-yl. The compound of the claim 72, which is 7- [2- (2-aminothiazol.- 4-yl)-2 - (2 -chloroethoxy)i minoacet.-uiii.do ] - 3- cephcm- 4-carboxy1i acid (syn isomer). The compound of the claim 72 , which is 7- [2- (2-formaihi dothiazol-4-yl) -2 - (2- chloroethoxy)iminoacetamido]-3-cephem-4 -carboxylic acid (syn isomer). The compound of the claim 72, which is 7-[2 -(2-aminothiazol-4-yl)-2 -(2,2,2-trifluoroet.hoxy)iminoacetamido] -3-cephem-4-carboxylic acid (syn isomer). The compound of the claim 72, which is 7- [2 - (2-formaii!idotliiazol-4-yl) - 2-(2,2,2-tri f luoroe thoxy)iminoacctamido ] - 3- cephem - 4 -carboxylic acid (syn isomer). 229 The compound of the claim 12, wherein- 2 ^ R is carboxy(lower)alkyl and R is amino or lower alkanamido. The compound of the claim 77, wherein R1 is 2-aminothiazol-4-yl or 2 - (lower)alkanamido- thiazol-4-yl. . The compound of the claim 78, whi,ch is » » 7- [2-(2-aminothiazol-4-yl)-2 - carboxymethoxyiminoacetamido]-3-cephem-4- carboxylic acid (syn isomer). ; The compound of the claim 78, which is 7-[2- (2-formamidothiazol-4-yl)-2 - carboxymethoxyiminoacctamido]- 3-cephcm-4-carboxy1 acid (syn isomer). 2.The compound of the claim 12, wherein R is lower alkoxycarbonylalkyl and R^ is amino or lower alkanamido. The compound of the claim 81, wherein R1 is 2-aminothiazol-4-yl or 2-(lower)-alkanamidothiazol-4-yl, and R^ is carboxy. The compound of the claim 82, which is 7- [2-(2-aminothiazol-4-yl)-2- ethoxycarbonylmethoxyiminoacetamido]- 3-cephem-4-carboxylic acid (syn isomer). .130 4 6 6 7 4 84. The compound of the claim 82, which is 7-[2-(2-formamidothiazol-4-yl)-2- ethoxycarbonylmethoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer). 85. The compound of the claim 82, which is 7-[2-(2-formamidothiazol-4-yl)-2-tert-butoxycarbonylmethoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer). 86. The compound of the claim 81, wherein R1 is 2-(lower)alkanamidothiazol-4-yl, and R^ is substituted benzyloxycarbonyl. 15 87. The compound of the!claim 86, which is j p-nitrobenzyl 7-[2-(2-formamidothiazol-4-yl) 2-ethoxycarbonylmethoxyiminoacetamido]- 3-cephem-4-carboxylate (syn isomer). 10 20 88. The compound of the 4 R is halogen. claim 4, wherein 89. The compound of the claim 88, wherein R* is thiazolyl of the formula: R in which 25 R is amino or lower alkanamido, R is hydrogen, alkyl, alkynyl or haloalkyl and R^ is carboxy or esterified carboxy. 90. The compound of the claim 89, wherein .azol - 231 30 R1 is 2-aminothiazol-4-yl or 2.-(lower)- 46674 2 alkanamidothiazol-4-yl, and R is hydrogen, and R^ is carboxy. 91. The compound of the claim 90, which is 5 7- [2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]- 3-chloro-3-cephem-4-carboxylic acid (syn isomer). 92. The compound of the claim 90, which is 7-[2-(2-formamidothiazol-4-yl)-2- 10 hydroxyiminoacetamido]-3-chloro-3-cephem-4- carboxylic acid/(syn isomer). I j 93. The compound of the claim 89, wherein R1 is 2-aminothiazol-4-yl or 2-(lower)- 2 5 15 alkanamidothiazol-4-yl, R is alkyl, and R is carboxy. 94. The compound of the claim 93, which is 7-[2 - (2-aminothiazol-4-yl)-2-methoxyiminoacetamido] 20 3-chloro-3-cephem-4-carboxylic acid (syn isomer or anti isomer) or its hydrochloride. 95. The compound of the claim 93, which is 7-[2-(2-formamidothiazol-4-yl)-2- 25 methoxyiminoacetamido]-3-chloro-3-cephem-4- carboxylic acid (syn isomer or anti isomer). ; 96. The compound of the claim 93, which is 7-[2-(2-aminothiazol-4-yl)-2-ethoxyiminoacetamido]-30 3-chloro-3-cephem-4-corboxylic acid (syn isomer) -232 46674 10 or its sodium salt . 97. The compound of the claim 93, which is 7-[2 (2-airinothin.zol-4-yl) -2 - propoxyiminorcctamido] -3-chloro-3-cephem-4-carboxylic acid (syn isomer). 98. The compound of the claim 93, which is 7- [2-(2-formamidothiazol-4-yl)-2-propoxyiminoacetamido] 3-chloro-3,-cephem-4-carboxylic acid (syn isomer). 99. The compound of the claim 93, which is 7- [2-(2-aminothiazol-4-yl)-2-butoxyiminoacetamido]-3-chloro-3-cephem-4-carboxylic acid (syn isomer). 15 100. The compound of the claim 93, which is 7-[2-(2-formamidothiazol-4-yl)-2-butoxyiminoacetamido] 3-chloro-3-cephem-4-carboxylic acid (syn isomer). 101. The compound of the claim 93, which is 20 7-[2-(2-aminothiazol-4-yl)-2-hexyloxyiminoacetamido]- 3-chloro-3-cephem-4-carboxylic acid (syn isomer). 102. The compound of the claim 93, which is 7- [2-(2-formamidothiazol-4-yl)-2- 25 hcxyloxyiminoacetamido]-3-chloro-3-cephem-4- carboxylic acid (syn isomer). 103. The compound of the claim 89, wherein 30 R1 is 2-aminothiazol-4-yl or 2 - (lower)alkanamidothiazol• 2 5 4-yl, R is alkyl and R is esterified carboxy. 233 4 6 674 7-[2-(2-aminothiazol-4-yl)-2- j methoxyiminoacetamido]-3-methoxy-3-cephem-4-carboxylic acid (syn isomer). 5 132, The compound of the claim 130, which is 7-[2-(2,2,2-trifluoroacetamidothiazol-4-yl)-2-methoxyiminoacetamido]-3-methoxy-3-cephem-4-carboxylic acid (syn isomer). 10 133. The compound of the dlaim 130, which is 7- [2-(2-aminothiazol-r4-yl)-2-butoxyiminoacetamido] -3-methoxy-3-cephem-4/-carboxylic acid (syn isomer). 134. The compound of7 the claim 130, which is 15 7- [2- (2-;formamidothiazol-4-yl)-2-butoxyiminoacetamido] 3-methoxy-3-cephem-4-carboxylic acid (syn isomer). 135. The compound of the claim 130, which is p-nitrobenzyl 7-[2-(2-formamidothiazol-4-yl)-2- 20 butoxyiinino&cetamido] - 3-methoxy-3-cephem-4- carboxylate (syn isomer). ; J 136. The compound of the claim 129, wherein R1 is 2-aminothiazol-4-yl or 2-(lower)- 2 25 alkanamidothiazol-4-yl, and R is lower alkynyl and R^ is carboxy. 137. The compound of the claim 136, which is 7-[2-(2-aminothiazol-4-yl)-2- 30 propargyloxyiminoacetamido)-3-methoxy-3-cephem- 238 4 6 6 7 4 4-carboxylic acid (syn isomer). The compound of the claim 136, which is 7-[2-(2-formamidothiazol-4-yl)-2-propargyloxyiminoacetamido]-3-methoxy-3-cephem-4-carboxylic acid (syn isomer). The compound of the claim 115, wherein R7 is acyl. The compound of the claim 139, wherein R1 is thiazolyl of the formula: R^_^-rfc- in 6 S which R is amino or lower alkanamido, 2 5 R is lower alkyl, and R is carboxy or esterified carboxy. The compound of the claim 140, wherein R1 is 2-aminothiazol-4-yl or 2-(lower)-alkanamidothiazol-4-yl. The compound of the claim 141, wherein 7 R is arenesulfonyl. The compound of the claim 142, which is 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamidoJ- 3-tosyloxy-3-cephem-4-carboxylic acid (syn isomer). The compound of the claim 3, wherein 3 4 R and R arc each lower alkyl. 259 The compound of the claim 144, wherein R1 is thiazolyl of the formula : R* in which R** is amino or halo (lower)alkanamido, and R2 is alkyl. The compound of the claim 145, wherein R1 is 2-aminothiazol-4-yl or 2-halo(lower)- alkanamidothiazol-4-yl. • The compound of the claim 146, which is 7-[2 -(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]- 2,3-dimethyl-3-cephcm-4-carboxylic acid (syn isomer). The compound of the claim 146, which is 7- [2-(2-trifluoroacetamidothiazol-4-yl)-2-methoxyiminoacetamido] - 2 ,3-dime thy 1- 3-cephem-; 4-carboxylic acid (syn isomer). The compound of the claim 2, wherein the dotted line represents cepham nucleus. The compound of the claim 149, wherein R1 is thiazolyl of the formula R^ is amino or lower alkanamido, R^ is hydrogen, 4 7 R is a grpup of the formula: -0-R in which 7 5 R is hydrogen, and R is carboxy or esterified carboxy. The compound of the claim 150, wherein R1 is 2-aminothiazol-4-yl or 2 -(lower)alkanamido- thiazol-4-yl. 240 The compound of the claim 151, which is 4-nitrobenzyl 7-[2-(2-formamidothiazol-4-yl)-2-methoxyiminoacctamido]-3-hydroxyccpham-4-carboxylate (syn isomer). The compound of the claim 151, which is sodium 7-[2-(2-formamidothiazol-4-yl) -2-methoxyiminoacetamido]-3-hydroxycepham-4-carboxylate (syn isomer). The compound of the claim 1, wherein R* is haloacetyl1, " j: 4 R is hydrogen, halogen, lower alkyl or a group? 7 7 • of the formula: -0-R in which R is lower alkyl, 3 5 R , R and A are each as defined in the claim 1, and the dotted line represents 3-cephem nucleus, and a salt thereof. The compound of the claim 154, wherein 3 4 5 R and R are each hydrogen, and R is carboxy or esterified carboxy. • ! The compound of the claim 155, wherein A is methylene. The compound of the claim 156, which is 7-[2-bromoacetoacetamido]-3-cephem-4-carboxylic acid. .* The compound of the claim 156, which is i 241 4 6 674 p-nitrobenzyl 7-.[2-bromoacetoacetiamido] -3-cephem-4-carboxylate., 159. The compound of the claim 155, wherein 2 A is a grpup of the formula: -C- in which R N j-R2 is hydrogen or alkyl. 10 160. The compound of the claim.159, which is 7- [2-'(2 -bromoacetyl) - 2-hydroxyiminoacetamido] - 3-cephem-4-carboxylic acid (syn isomer). 15 161. The compound of the claim 159, which is p-nitrobenzyl 7-[2-(2-bromoacetyl)-2-hydroxyiminoacetamido]- 3-cephem-4-carboxylate (syn is.omer ) . 20 25 162. The compound of the claim 159, which is 7- [2- (2-bromoacetyl) -2-methoxyiminoacetamidq] 3-cephem-4-carboxylic acid (syn isomer). 163. The compound of the claim 159, which is p-nitrobenzyl 7-[2-(2-bromoacetyl)-2-methoxyiminoacetamido]- 3-cephem-4-carboxylate (syn isomer). 30 2.42 A 6 6 7 4 164. The compound of the claim 1, wherein R1 is thiazolyl of the formula: in which R^ is amino or lower alkanamido, A is methylene 3 5 which may be substituted with amino, hydroxy or oxo, R and 4 5 R are each hydrogen, R is carboxy or esterified carboxy, and the dotted line represents 3-cephem nucleus. 165. The compound of the claim 164, wherein A is methy- lene. 10 166. The compound of the claim 165, which is 7 - PI~r (2 - aminothiazol - 4 - yl)acetamido/ - 3 - cephem - 4 -carboxylic acid. 167. The compound of the claim 165, which is p - nitrobenzyl - 7 -/2~~- (2 - aminothiazol - 4 - yl) acetamido/ - 3 - 15 cephem - 4 - carboxylate. 168. The compound of the claim 164, wherein A is amino-methylene. 169. The compound of the claim 168, which is 7 - /2~-(2 - aminothiazol - 4 - yl)glycinamido7 - 3 - cephem - 4 - 20 carboxylic acid or its formate. 170. The compound of the claim 164, wherein A is hydroxy-methylene. 171 The compound of the claim 170, which is 7 - fT - (2 - aminothiazol - 4 - yl)- 2 - hydroxyacetamido7 - 3 -25 cephem - 4 - carboxylic acid. 172. The compound of the claim 164, wherein A is oxo- methylene. 243 . V 46 67 4 173. The compound of the claim 172, which is 7 - /?" - (2 "- formamidothiazol - 4 - y 1)q 1yoxylamido7 - 3 - cephejm - 4 - carboxylic acid. •' - I ■ ' 174 . The compound of the claim 172, which is 7 - JTT - 5 (2 - aminothiazol - 4 - y 1) glyoxylamido7 - 3 - cephem r- 4 -carboxylic acid. 175. The compound of the claim 172, which is p r nitro- benzyl 7 - /2 - (2 - formamidothiazol - 4 - yl) - glVoxvlamido/ I - 3 - cephem - 4 - carboxylate. j 10 176. A process for preparing the compound of th£ formula:- R1-A-0CNH | 15 I R5 I . wherein R1 is thiadiazolyl, thiazolyl of the formula: 1J- in which is amino :or protected amino, or i haloacetyl, A is methylene which may be substituted with amino, hydroxy • i i or oxo, or a group of the formula: . ! . II I* N S 2 1 0 R ' 2 1 2q in which R is hydrogen or an aliphatic hydro carbon residue which may be substituted with halogen,,' i carboxy or esterified carboxy, i 244 4 6 6 7 4 3 R is hydrogen or lower alkyl, 4 R is hydrogen, halogen, lower alkyl or a group of the 7 7 formula:- 0 R in which R is hydrogen, lower alkyl or acyl, R^ is carboxy or functionally modified carboxy, and the dotted line represents 3-cephem and cepham nuclei, inclusively, provided that 4 7 i) R is hydrogen, halogen or a group of the formula —0 R 7 3 in which R is as defined above, when R is hydrogen, 4 3 il) R is lower alkyl, when R is lower alkyl, 4 1 iii) R is hydrogen, when R is thiadiazolyl or thiazolyl of the formula: N >•— in which R^ is amino or protected amino and A is 15 methylene which may be substituted with amino, hydroxy or oxo, and iv) A is methylene or a group of the formula: N U,> 2 4 in which R is as defined above, R is hydrogen, 20 halogen, lower alkyl or a group of the formula: 0 R7 in which R7 is lower alkyl and the dotted line represents 3 - cephem nucleus, when R1 is haloacetyl, pharmaceutically acceptable salt and pharmaceutically acceptable bioprecursor thereof, which comprises 245 4G67 4 10 (1) reacting a 7 - amino - 3 - cephem(or cepham) compound of the formula: 3 4 5 wherein R , R and R are each as defined above, its reactive derivative at the amino or a salt thereof, with a carboxylic acid of the formula: R1 a COOH wherein R1 and A are each as defined above, its reactive derivative at the carboxy or a salt thereof, to provide the above object compound, j ! i (2)reacting a compound of the formula: [ 15 20 R£-CH2C0NH wherein .3 r" and r are each as defined above, 1 4 R^ is haloacetyl and Rg is hydrogen, halogen, lpwer alkyl 7 J 1 ' or a group of the formula: 0—r in which r is lower alkyl, or its salt, with nitrosating agent, to provide \ the compound of the formula: ! * 1 VC-CONH 1 | r R' OH 1 3 4 5 ! wherein R,, R , R= and R are each as defined aboved and D a its salt, j -246- >16674 (3) reaching a compound of the formula' .3 13 4 5 wherein R , R , R and R are each as defined above, or its salt, with etherifying agent, to provide a compound of the formula: R1—C- CCNH /\ N oAr ^ 2 5 0-R R a 13 4 5 wherein R , R , R and R are each as defined above, and ■ 2 Ra is an aliphatic hydrocarbon residue which may be substituted with halogen, carboxy or esterified carboxy, and 10 its salt, (4) reacting a compound of the formula: R-^A' - CONH 1 2 3 4 5 wherein R^, R , R ^ R and R are each as defined above, or its salt, with a thiourea compound of the formula: S 6 I 15 R 0 lm2 wherein R^ is as defined above, to provide a compound of the formula: 2,4 7 46674 wherein A' is methylene or a group of the formula: B N $ 2 0 R ; in which R^ is as defined abojk, and R^, R^, and R^ and R^ are each as defined above, aijid its salt, (5) subjecting a compound of the formula: ! R6 Ka—^ -4- A-CONH-r—( ]— wherein A, R"*, R^ and R^ are each as defined above, and R® a is protected amino, or its salt to elimination reaction of the protective group in the protected amino group for R^ , to provide a compound of the formula: I A-CONH 3 4 5 wherein A, R , R and R are each as defined above, and its salt, (6) reducing a compound of the formula: 248 4 6 6 7 4 R^-g-CONH-T-fl a 10 N o^sy-°H O ■ R^ j^5 2 5 1 wherein R and R are each as defined above, and R is a thiadiazolyl or thiazolyl of the formula: -0- 5 in which is as defined above, or its salt, to provide a compound of the formula: R^-C-CONH —|—( \ ... ^ 0 R2 5 R 12 5 wherein R , R and R are each as defined above, and its CL salt, (7) reacting a compound of the formula: R1 -C-CONH ... (S a „ -I"! I QH N k~R2 R5 12 5 wherein R_, R and R are each as defined above, or its a salt with a compound of the formula: R7 OH a 7 25 wherein R& is acyl, its salt or its reactive derivative, to provide a compound of the formula: 249 >4.6 6 7 4 R^-C-CONH aH N ^ 2 o—R A 7 ^Nyl-O-Ra T, 12 5 7 wherein Ra, R , R and R are each as defined above, and its salt, (8) treating a compound of the formula: R - C-CCNH a -o—R: ^—R2 / r L 1 2 5 71 wherein R , R , R and Rj are each as defined above, or its a a i salt with a base, to provide a compound of the formula: RI-C- CCNH a 12 5 wherein R , R and R are each as defined above, and its & 10 salt, (9) halogenating a compound of the formula:; R-C- CCNH 3 II N 0 2 Lr2 12 5 i wherein R_, R and R are each as defined above, or its d salt, to provide a compound of the formula: 250 46674 1 2 ' 3 4 wherein Ra, R and R are each as defined above, and is halogen, and its salt, (10) reacting a compound of the formula: Ra C CONH -l—fY" R2 I ( 2 ' 5 0 R R 13 4 5 wherein Rq, R , R and R are each as defined above, or its salt with a compound of the formula: R2 ONH2 2 wherein R is as defined above, to provide a compound of the formula: R1——C CONH -t—/ i £ 2 n 0 RZ R5 wherein R1, R^, R^, R^ and R~* are each as defined above, and its salt, (11) reducing a compound of the formula: ? °- I 0—R2 r5 251 46674 XO 15 1 "i A c i wherein R ., R , R■ , R and R are each as defined above, a . , > or its salt, to provide a compound of the formula: l s R-CH- OONH-,—/ V-R"^ 2 R5 13 4 5 wherein R » R , R and R are each as defined above, and a 5 its salt, (12) reducing a compound of the formula: 13 4 5 wherein R . R , R and R are each as defined above, or its cl ■ ! salt, to provide a compound of the formula: 13 4 5 wherein R , R , R and R are each as defined above, and its cl salt, l (13) reacting a free carboxy compound of th^ formula: ,• R1—ft—CCNH cl OOCH wherein R1, R^v R^ and A are each as defined above, its reactive derivative at the carboxy or its salt, with an esterifying agent, to provide a compound of the formula: 252 4 6 6 7 4 R1 - A - CONH ' O 13 4 5 wherein R , R , R and A are each as defined above and R is esterified carboxy, and its salt or (14) transforming a compound of the formula: R - A - ITKH-,—( \— R^ 13 4^ 5 wherein R , R , R and A are each as defined above, and R^ is functionally modified carboxy, into a compound of the formula: R1 - A - R^ )H wherein R^, r3, r4 an(j ^ are each as defined above, and its 10 salt. 177. A process for preparing the compound as defined in the claim 176, which comprises reacting a 7 - amino - 3 -cephem (or cepham) compound of the formula: H„N - 253- 4 667 4 I 3 4 5' ' wherein R , R and R are each as defined above, its reactive derivative at the amino or a salt thereof, with a carboxylic acid of the formula: r1 a cooh 5 wherein R1 and A are each as defined above, its reactive derivative at the carboxy or a salt thereof. \ 178. A process for preparing the compound of the formulas 13 4 5 wherein R^, R , R^ and R are each as defined in claim 176, 10 or its salt, which comprises reacting a compound of the formula: l s v ch2conh / l 3 4 5 wherein R, , R R^ and R are each as defined above, or 'its b a salt with a nitrosating agent. S 179. A process for preparing the compound of the formula: -254- 46 6 R1 - - CONH N I r; 1 2 3 4 5 wherein r , Ra, R , R and R are each as defined in claim 176/ or its salt, which comprises reacting a compound of the formula: c 13 4 i» wherein R , R , R and R^ are each as defined above or its' salt, with an etherifying agent. 180. formula: 10 A process for preparing the compound of the wherein R2, R3, R*, R5 and R6 are each as defined in claim 176, or its salt, which comprises reacting a compound of the formula: ; -255- 4667 4 RT - C - CONH b II N ^ 2 O-R 2 3 4 5 wherein R , R , Ra and R are each as defined above, and R^ is haloacetyl, or its salt with a thiourea compound of the formula: -NH, wherein R^ is as defined above. 181. A process for preparing the compound of the formula: 10 15 O—R 2 3 4 5 wherein R , R , R and R are each as defined in claim 176, or its salt, which comprises subjecting a compound of the formula: XI ,2 0-R 3 4 5 i R , R and R are each as defined above, jand wherein R^ 6 i R is protected amino, or its salt, to elimination reaction cl 6 of the protective group in the protected amino group; Ra 182. A process for preparing the compound of the fprmula: -256- 46674 1 s R, - C - CONH —;— f \ a II Li ' I* R5 1 2 5 wherein 9 r and R are each as defined in claim 176, or its a salt, which comprises reducing a compound of the formula: %- J-CONH N i-N J- OH l*> 0 h R 12 5 5 wherein Ra, R and R are each as defined above, or its salt. 183. A process for preparing the compound of the formula: R1- C - CONH a it S [ I ( I 7 10 i., """• R wherein R1, r2, and rZ are each as defined in claim 176, a a or its salt, which comprises reacting a compound of the formula: Ra " [j " C0NH 0 - R^ c R 12 5 wherein R , R and R are each as defined above, or its salt, a with a compound of the formula: R1 OH 15 -257- V 46674 wherein R is as defined above, its salt or its reactive cL derivative. 184. formula: A process for preparing the compound of the R- C- CONH 3 II N r o-r" 12 5 wherein R , r and R are each as defined in claim 176, or d its salt, which comprises treating a compound of the formula: ? N $ 0 -R - CONH 2 - R. 10 1 2 5 7 wherein R , R and R are each as defined above, and R is acyl, or its salt with a base. 185. A process for preparing a compound of the formula: R -C-CONH a H N 8—R2 g 15 12 4 5 wherein R&, R , R^ and R are each as defined in claim 176, or its salt, which comprises a halogenating a compound of the formula: R1- C - CONH a ll N 5 2 0-R 12 5 wherein R , R and R are each as defined above, or its salt. a -258- 4 66' 186. ' A process for preparing the compound of the formula: 1 o 3 4 5 wherein Ra, R , R , R and R are each as defined in claim #, 176, or its salt, which comprises reacting a compound of the formula: wherein R1, R3, R4 a,nd R^ are each as defined above, or its a salt, with a compound of the formula: r2 ONH2 2 wherein R is as defined above. 187. A process for preparing a compound of the formula: wherein R1, R3, R4 and R5 are each as defined in claim 176, di or its salt, which comprises reducing a compound of the formula: -259- 4607 4 r5 1 2 3 4 5 wherein R , R , R , R and R are each as defined above, or fit its salt. 188. A process for preparing a compound of the formula: 10 R1- CH - CONH "J—[ L 0^y-R R5 1 3 4 5 ' wherein R . R , R and R are each as defined in claim 176, ? or its salt, which comprises reducing a compound of the formula: R- C - CONH a „ 0 O 13 4 5 wherein R. R , R and R are each as defined above, or its a salt. 189. A process for preparing a compound of the formula: 15 R"- A - CONH cl R5 1 3 4 5 a wherein R , R , R , R and A are each as defined in claim 176, 3 or its salt which comprises reacting a free carboxy compound of the formula: -260- -4667 4 1 4 wherein R , R~ , R and A are each as defined above, or its salt with an esterifying agent. 190. A process for preparing a compound of the formula: 13 4 wherein R , R , R and A are each as defined in claim 176, or its salt, which comprises transforming a compound of the formula: 13 4 5 wherein R , R , R and A are each as defined above and R^ is functionally modified carboxy, or its salt. 191. A pharmaceutical composition comprising, as an effective ingredient, the compound of claim 2 or 164, in association with a pharmaceutically acceptable, substantially nontoxic carrier or excipient. -261- 46674 192. A method,for treating an infectious disease caused by pathogens, which comprises administering the compound of claim 2 or 164 to infected non-human animals. 193. The compound of the claim 42, which is 7 - £i - 5 (2 - formamidothiazol - 4 - yl) - 2 - octyloxyiminoacetamido/ - 3 - cephem - 4 - carboxylic acid (syn isomer) . 194. The compound of the claim 104, which is £ - nitrobenzyl 7 -£L - (2 - aminothiazol -4-yl) - 2 - hydroxy- iminoacetamido7 - 3 - chloro - 3 - cephem - 4 - carboxylate 10 (syn isomer). 195. The compound of the claim 93, which is 7 - -(2 - aminothiazol -4-yl) r 2 - hexyloxyiminoacetamido7 -3 - chloro - 3 - cephem - 4 - carboxylic acid (syn isomer). 196. The compound of tjie claim 93, which is 7 - 25 ZJ - (2 - formamidothiazol -I4 - yl) - 2 - hexyloxyimino-acetamido7 - 3 - chloro - 3 f cephem - 4 - carboxylip acid (syn isomer). 197. The compound of ttie claim 104, which is £i-nitrobenzyl 7 - £2 - (2 - formamidothiazol - 4 - yl) 2 2o hexyloxyiminoacetamidfi7 - 3 - chloro - 3 - cephem - ;4 -carboxylate(syn isomer). 198. The compound of the claim 89, wherein R1 is 2 -262- Sr 46674 -aminothiazol - 4 -!yl or 2 - (lower)alkanamidothiazol 2 c 4-yl, R is lower alkynyl and R is carboxy. 199. The compound of the claim 198 , which is 7 - £T~-(2 -aminothiazol - 4 - yl) - 2 - propargyloxyiminoacetamido7 - 3 - chloro - 3 - cephem - 4 - carboxylic acid (syn isomer). 200. The compound of the claim 198, which is 7 - £Z -(2 - formamidothiazol - 4 - yl) - 2 - propargyloxyimino-acetamido/ - 3 - chloro - 3 - cephem - 4 - carboxylic acid (syn isomer). F.R KELLY & CO. AGENTS FOR THE APPLICANTS. -263-