DESCRIPTION

3-Pyrazoliomethylcephem compounds as antimicrobial agents

TECHNICAL FIELD

The present invention relates to a new cephem compound and a salt thereof which are useful as a medicament.

BACKGROUND ART A cephem compound which is more effective against MRSA, etc is needed.

DISCLOSURE OF INVENTION

The object cephem compound of the present invention can be represented by the following formula [I] :

1 wherein R- ¹ is amino or a protected amino,

R^ is halogen, lower alkyl, cyano or lower alkylthio, is a group of the formula :

[wherein

R is hydrogen, lower alkyl which may have one or more substituent (s) , lower alkenyl which may have one or more substituent (s) , lower alkynyl,

cyclo (lower) alkenyl, or acyl], lower alkylidene or oxo, R ⁴ is a group of the formula :

-/-

Θ _N ' -+ ^ Th- ^RC

^ ^pt

\0

[wherein

R is hhyydc roxy (lower) alkyl or protected hydroxy (lower) alkyl, R ⁸ is amino or a protected ammo, and R ⁹ is hydrogen or lower alkyl], or a group of the formula :

© _N ;

^V W "NH

KJ (wherein A is lower alkylene) ,

R ⁵ is -COO® / carboxy or a protected carboxy, Y© IS an anion, and with proviso that

(l) when R ⁵ is -COO® , then n is 0, and (ii) when R ⁵ is carboxy or a protected carboxy, then n is 1.

As to the object compound [I], the following points are to be noted.

That is, the object compound [I] includes Z isomer, E isomer and a mixture thereof. Z isomer means one geometrical isomer having the partial structure represented by the following formula :

(wherein X, R- ^* -, R ² and R" are each as defined above), and E isomer means the other geometrical isomer having the partial structure represented by the following formula :

(wherein X, R , R ² and R ⁶ are each as defined above), and all of such geometrical isomers and mixture thereof are included within the scope of this invention.

In the present specification and claim, the partial structure of these geometrical isomers and mixture thereof are represented for convenient sake by the following formula :

(wherein X, R ¹ , R ² and R ⁶ are each as defined above) .

Another point to be noted is that the pyrazolio moiety of the compound [I] can also exist in the tautomeric form, and such tautomeric equilibrium can be represented by the following scheme.

(A) (B)

7 R Q (wherein R , R° and R^ are each as defined above,

Both of the above tautomeric isomers are included within the scope of the present invention, and m the present specification and claim, however, the object compound [I] is represented for the convenient sake by one expression of the pyrazolio group of the formula (A) .

As for the group of the formula :

^N-^^NH

(wherein A is as defined above) , this group can also exist in the similar tautomeric form.

The cephem compound [I] of the present invention can be prepared according to the following reaction schemes.

Process 1

[II] [III] or its reactive derivative or its reactive derivative at the ammo group, at the carboxy group, or a salt thereof or a salt thereof

[I] or a salt thereof

Process 2

[la] or a salt thereof

Elimination of the amino

[lb] or a salt thereof

Process 3

IV ^η or a salt thereof

K [V] or a salt

[I] or a salt thereof

Process 4

[lc] or a salt thereof

[Id] or a salt thereof

Process 5

[VI] or a salt thereof

Introduction reaction of halogen

[Ie] or a salt thereof

wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , X, Y© and n are each as defined above, R^ is a protected amino, R|j is halogen, R ⁴ is a compound of the formula :

η o q

(wherem R , R° and R^ are each as defined above) or a compound of the formula :

(wherem A is as defined above) R^ IS carboxy or a protected carboxy, R ⁶ IS cyclo (lower) alkenyl or acyl, Z is a leaving group.

Some of the starting compound [III] can be prepared according to the following reaction schemes.

Process A

[VII [VIII]

or a salt thereof

[Ilia] or a salt thereof

wherein R ¹ , R , X and Z are each as defined above, and R^ is lower alkyl which may have one or more substituent (s) .

Suitable salts of the object compound [I] are pharmaceutically acceptable, conventional non-toxic mono or di salts and include 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], an ammonium salt, an organic base salt [e.g. tnmethylamine salt, triethylamine salt, pyridine salt, picolme salt, dicyclohexylamme salt, N,N-dibenzylethylenediamme salt, etc], an organic acid addition salt [e.g. formate, acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, toluenesulfonate, etc] , an inorganic acid addition salt [e.g. hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, etc], a salt with an ammo acid [e.g. arginine salt, aspartic acid salt, glutamic acid salt, etc] , and the like.

In the above and subsequent descriptions of this specification, suitable examples of the various definitions are explained in detail as follows :

The term "lower" is intended to mean 1 to 6 carbon atom(s) , unless otherwise indicated.

Suitable protective group in "a protected ammo" may include ar (lower) alkyl such as mono or di or triphenyl (lower) alkyl [e.g. benzyl, phenethyl, 1-phenylethyl, benzhydryl, trityl, etc] , acyl as explained hereinbelow, and the like.

Suitable "acyl" may be aliphatic acyl, aromatic acyl, arylaliphatic acyl and heterocyclic-aliphatic acyl derived from carboxylic acid, carbonic acid, carbamic acid, sulfonic acid, and the like. Suitable example of the acyl group thus explained may be lower alkanoyl [e.g. formyl, acetyl, propionyl, hexanoyl, pivaloyl, etc], mono(or di or tn ) halo (lower) alkanoyl [e.g. chloroacetyl, trifluoroacetyl, etc], lower alkoxycarbonyl [e.g. methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, tert-pentyloxycarbonyl, hexyloxycarbonyl, etc], mono (or di or tn) halo (lower) alkoxycarbonyl [e.g. chloromethoxycarbonyl, dichloroethoxycarbonyl, trichloroethoxycarbonyl, etc], aroyl [e.g. benzoyl, toluoyl, xyloyl, naphthoyl, etc], ar (lower) alkanoyl such as phenyl (lower) alkanoyl [e.g. phenylacetyl, phenylpropionyl, etc], aryloxycarbonyl [e.g. phenoxycarbonyl, naphthyloxycarbonyl, etc] , aryloxy (lower) alkanoyl such as phenoxy (lower) alkanoyl [e.g. phenoxyacetyl, phenoxypropionyl, etc], arylglyoxyloyl [e.g. phenylglyoxyloyl, naphthylglyoxyloyl, etc], ar (lower) alkoxycarbonyl which may have suitable substituent (s) such as phenyl (lower) alkoxycarbonyl which may have nitro or lower alkoxy [e.g. benzyloxycarbonyl, phenethyloxycarbonyl, p-mtrobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, etc], thienylacetyl, lmidazolylacetyl, furylacetyl, tetrazolylacetyl, triazolylacetyl, thiadiazolylacetyl, thienylpropionyl, thiadiazolylpropionyl, lower alkylsulfonyl [e.g. methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, pentylsulfonyl, butylsulfonyl, etc], arylsulfonyl [e.g. phenylsulfonyl, tolylsulfonyl,

xylylsulfonyl, naphthylsulfonyl, etc], ar (lower) alkylsulfonyl such as phenyl (lower) alkylsulfonyl [e.g. benzylsulfonyl, phenethylsulfonyl, benzhydrylsulfonyl, etc], and the like. Preferable example of "a protected amino" thus defined may be ar (lower) alkylamino, lower alkanoylamino and lower alkoxycarbonylamino, more preferable one may be triphenyl-

(C _j -C^ ) alkylamino, C-^-C^ alkanoylamino and (C^-C^)- alkoxycarbonylammo, and the most preferable one may be tntylamino, formamido, acetamido and t-butoxycarbonylamino. Suitable "lower alkyl" may be straight or branched ones such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, 2-ethylpropyl, hexyl or the like, in which the preferred "lower alkyl" may be (C-^-C^ ) alkyl .

Suitable "lower alkenyl" may be straight or branched ones such as vmyl, allyl, 2-butenyl, 2-methyl-3-butenyl,

3-pentenyl, 1-hexenyl, or the like, m which the preferred one may be (C ₂ ~C^ ) alkenyl .

Suitable "lower alkynyl" may be straight or branched ones such as ethynyl, 2-propynyl, 3-butynyl, 2-methyl-3- butynyl, 2-pentynyl, 5-hexynyl, or the like, m which the preferred one may be (C ₂ -C^ ) alkynyl .

Suitable "halogen" may be fluoro, chloro, bromo, or lodo.

Suitable examples of "substituent (s) " in "lower alkyl which may have one or more substituent (s) " may mclude 1 to 3 halogen; cyano; aryl [e.g. phenyl, naphthyl, anthryl, etc]; lower alkylthio ; carboxy; protected carboxy; hydroxy (lower) alkyl; protected hydroxy (lower) alkyl; heterocyclic group which may have one or more (preferably 1 to 3) substituent (s) such as lower alkyl, ar (lower) alkyl or the like; heterocyclicthio; and the like.

Suitable "lower alkylthio" may include methylthlo, ethylthio, propylthio, butylthio, t-butylthio, pentylthio, hexylthio, and the like, in which the preferred one may be (C ₁ -C ₄ )alkylthιo.

Suitable "protected carboxy" may be

(1) an esterified carboxy, in which concrete examples of esterified carboxy may be the ones such as lower alkoxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, t-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, 1-cyclopropylethoxycarbonyl, etc) which may have suitable substituent (s) , for example, lower alkanoyloxy (lower) alkoxycarbonyl [e.g. acetoxymethoxycarbonyl, propionyloxymethoxycarbonyl, butyryloxymethoxycarbonyl, valeryloxymethoxycarbonyl, pivaloyloxymethoxycarbonyl, 1-acetoxyethoxycarbonyl, 1-propιonyloxyethoxycarbonyl, pivaloyloxymethoxycarbonyl, 2-propionyloxyethoxycarbonyl, hexanoyloxymethoxycarbonyl, etc] ; lower alkanesulfonyl (lower) alkoxycarbonyl [e.g. 2-mesylethoxycarbonyl, etc]; mono(or di or tn) halo ( lower) alkoxycarbonyl [e.g. 2-ιodoethoxycarbonyl, 2,2, 2-trιchloroethoxycarbonyl, etc] ; lower alkenyloxycarbonyl [e.g. vmyloxycarbonyl, allyloxycarbonyl, etc] ; lower alkynyloxycarbonyl [e.g. ethynyloxycarbonyl, propynyloxycarbonyl, etc] ; ar ( lower) alkoxycarbonyl [preferably mono- (or di- or tri-) phenyl (lower) alkoxycarbonyl] which may have suitable substituent (s) [e.g. benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 4-nιtrobenzyloxycarbonyl, phenethyloxycarbonyl, trityloxycarbonyl, benzhydryloxycarbonyl, bis (methoxyphenyl)methoxycarbonyl, 3, 4-dιmethoxybenzyloxycarbonyl, 4-hydroxy-3, 5-dι-t- butylbenzyloxycarbonyl, etc] ; aryloxycarbonyl which may have suitable substituent (s) [e.g. phenoxycarbonyl, 4-chlorophenoxycarbonyl, tolyloxycarbonyl, 4-t-butylphenoxycarbonyl, xylyloxycarbonyl, mesityloxycarbonyl, cumenyloxycarbonyl, etc]; or the like;

(2) amidated carboxy, m which concrete examples of amidated carboxy may be carbamoyl;

N- (lower) alkylcarbamoyl (e.g. N-methylcarbamoyl, N-ethylcarbamoyl, N-isopropylcarbamoyl, N-butylcarbamoyl, N-pentylcarbamoyl, N-hexylcarbamoyl, etc) ;

N- (higher) alkylcarbamoyl (e.g. N-heptylcarbamoyl, N- (2-methylheptyl) carbamoyl, N-nonylcarbamoyl,

N-decanylcarbamoyl, N-tricyclo [3.3.1.1 ^J ' ] decanylcarbamoyl, N-undecanylcarbamoyl, N- (bicyclo [4.3.2] undecanyl) carbamoyl, N-dodecanylcarbamoyl, N-tridecany1carbamoyl, N-tetradecanylcarbamoyl, N-pentadecanylcarbamoyl, N-hexadecanylcarbamoyl, N-heptadecanylcarbamoyl, N-octadecanylcarbamoyl, N-nonadecany1carbamoyl, N-icosanylcarbamoyl, etc) ;

N, N-di (lower) alkylcarbamoyl [e.g. N, N-dimethylcarbamoyl, N, N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, N,N-dipropylcarbamoyl, N,N-di (t-butyl) carbamoyl, N-pentyl-N- hexylcarbamoyl, etc]; and the like, in which the preferred one may be lower alkoxycarbonyl and carbamoyl, and the more preferred one may be (C-^-C )- alkoxycarbonyl and carbamoyl. Suitable "hydroxy (lower) alkyl" may include hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 3-hydroxypropyl, 1- (hydroxymethyl) ethyl, 1-hydroxybutyl, 1-hydroxymethyl-l-methylethyi, 3-hydroxypentyl, 3-hydroxy-2- ethylpropyl, 6-hydroxyhexyl and the like, in which the preferred one may be hydroxy(C^-C ) alkyl.

Suitable "protected hydroxy (lower) alkyl" may include acyloxy (lower) alkyl and the like, in which suitable "acyl" moiety can be referred to the ones as exemplified for "a protected ammo" before and suitable examples of said "acyloxy (lower) alkyl may be lower alkanoyloxy(lower) alkyl [e.g. formyloxymethyl, 1-formyloxyethyl, 2-formyloxyethyl, 2-acetoxyethyl, 3-acetoxypropyl, 1- (propionyloxymethyl) ethyl, 1-butyryloxybutyl, 1-hexanoyloxybutyl, 1-pivaloyloxymethyl-l- methylethyl, 3-formyloxypentyl, 3-formyloxy-2-ethylpropyl, 6-acetoxyhexyl, etc], carbamoyloxy (lower) alkyl [e.g.

carbamoyloxymethyl, 1-carbamoyloxyethyl, 2-carbamoyloxyethyl, 3-carbamoyloxypropyl, 1- (carbamoyloxymethyl) ethyl, 1-carbamoyloxybutyl, 1-carbamoyloxymethyl-l-methylethyl, 3-carbamoyloxypentyl, 3-carbamoyloxy-2-ethylpropyl, 6-carbamoyloxyhexyl, etc] or the like; in which the preferred one may be (C-^-C^) alkanoyloxy- (C _] _-C ₄ ) alkyl or carbamoyloxy (C-^-C^ ) alkyl and the most preferred one may be 2-formyloxyethyl, 2-acetoxyethyl or 2-carbamoyloxyethyl .

Suitable "heterocyclic group" and "heterocyclic" moiety in the term of "heterocyclicthio" may include saturated or unsaturated, monocyclic or polycyclic heterocyclic group such as unsaturated 3 to 8-membered (more preferably 5 to 7- membered) heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example, azepinyl (e.g. lH-azepinyl, etc), pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl and its N-oxide, dihydropyridyl, pyrimidmyl, pyrazinyl, pyridazinyl, triazolyl (e.g. 4H-1, 2, 4-triazolyl, 1H-1, 2, 3-triazolyl, 2H-1, 2, 3-trιazolyl, etc) , tetrazolyl (e.g lH-tetrazolyl, 2H-tetrazolyl, etc) , etc; saturated 3 to 8-membered (more preferably 5 to 7- membered) heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example, perhydroazepmyl (e.g. perhydro-lH- azepinyl, etc), pyrrolidinyl, imidazolidinyl, piperidyl, piperazinyl, etc; unsaturated condensed heterocyclic group containing 1 to 4 nitrogen atom(s) , for example, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, quinoxalinyl, imidazopyridyl [e.g. imidazo [4, 5-c]pyridyl, etc], tetrahydroimidazopyridyl [e.g. 4 , 5, 6, 7-tetrahydro [4 , 5-c]pyridyl, etc], etc; saturated condensed heterocyclic group containing 1 to 4 nitrogen atom(s), for example, 7-azabicyclo [2.2.1] heptyl,

3-azabicyclo [3.2.2] nonanyl, etc; unsaturated 3 to 8-membered (more preferably 5 or 6- membered) heteromonocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, oxazolyl, isoxazolyl, oxadiazolyl (e.g. 1, 2, 4-oxadiazolyl, 1, 3, 4-oxadιazolyl, 1, 2, 5-oxadιazolyl, etc) , etc; saturated 3 to 8-membered (more preferably 5 or 6- membered) heteromonocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, morpholinyl, sydnonyl, etc; unsaturated condensed heterocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, benzoxazolyl, benzoxadiazolyl, etc; unsaturated 3 to 8-membered (more preferably 5 or 6- membered) heteromonocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s) , for example, thiazolyl, isothiazolyl, thiadiazolyl (e.g. 1, 2, 3-thiadiazolyl, 1,2,4- thiadiazolyl, 1, 3, 4-thiadiazolyl, 1, 2, 5-thιadιazolyl, etc), dihydrothiazinyl, etc; saturated 3 to 8-membered (more preferably 5 or 6- membered) heteromonocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s) , for example, thiazolidinyl, etc; unsaturated condensed heterocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, benzothiazolyl, benzothiadiazolyl, etc; saturated condensed heterocyclic group containing 1 to 4 nitrogen atom(s), and saturated 3 to 8-membered heteromonocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s) , unsaturated 3 to 8-membered (more preferably 5 or 6- membered) heteromonocyclic group containing an oxygen atom, for example, furyl, etc; unsaturated 3 to 8-membered (more preferably 5 or 6- membered) heteromonocyclic group containing an oxygen atom

and 1 to 2 sulfur atom(s), for example, dihydrooxathiinyl, etc; unsaturated condensed heterocyclic group containing 1 to 2 sulfur atom(s) , for example, benzothienyl, benzodithiinyl, etc; unsaturated condensed heterocyclic group containing an oxygen atom and 1 to 2 sulfur atom(s) , for example, benzoxathiinyl, etc; or the like.

Suitable examples of "substituent (s) " in the term of "heterocyclic group which may have one or more substituent (s) " may include 1 to 3 lower alkyl and ar (lower) alkyl, in which the preferred one may be (C^- C^)alkyl and triphenyl (C-^-C^ ) alkyl . Suitable "lower alkylidene" may include methylene, ethylidene, propylidene, 1-methylethylidene, butylidene, pentylidene, hexylidene, and the like, in which the preferred one may be ( C-^ -Cq ) alkylidene.

Suitable "cyclo (lower) alkenyl" may be cyclo (C3~Cg) - alkenyl such as cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl or the like, in which the preferred one may be cyclo (C5-C7) alkenyl such as cyclopentenyl, cyclohexenyl or cycloheptenyl . Suitable examples of "substituent (s) " in lower alkenyl which may have one or more substituent (s) " may include 1 to 3 carboxy, protected carboxy, and the like, in which the preferred one may be carboxy and lower alkoxycarbonyl, the more preferred one may be carboxy and (C- _j _-C ₄ ) alkoxycarbonyl . Suitable "lower alkylene" may be straight or branched ones such as methylene, ethylene, trimethylene, methylethylene, tetramethylene, pentamethylene, hexamethylene or the like, in which the preferred one may be (C-^-C^)- alkylene. Suitable "an anion" may be formate, acetate,

trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, toluenesulfonate, chloride, bromide, iodide, sulfate, phosphate, or the like.

Suitable "a leaving group" may be halogen [e.g. chlorine, bromine, iodine, etc] , acyloxy such as sulfonyloxy [e.g. benzenesulfonyloxy, tosyloxy, mesyloxy, etc] , lower alkanoyloxy [e.g. acetyloxy, propionyloxy, etc], or the like.

One of the preferred embodiments of the present invention is the compound [I] wherein

R ¹ is amino, lower alkanoylamino, lower alkoxycarbonylammo or triphenyl (lower) alkylamino,

9

R^ is halogen, lower alkyl, cyano or lower alkylthio, R ^J is a group of the formula :

[wherein

R ⁶ is hydrogen; lower alkyl; halo (lower) alkyl; dihalo (lower) alkyl; cyano (lower) alkyl; triphenyl (lower) alkyl; lower alkylthio (lower) alkyl; carboxy (lower) alkyl; lower alkoxycarbonyl (lower) alkyl; carbamoyl (lower) alkyl; hydroxy (lower) alkyl; lower alkanoyloxy (lower) alkyl; pyrazolyl (lower) alkyl or tetrazolyl (lower) alkyl, each of which may have lower alkyl or triphenyl (lower) alkyl; triazolylthio (lower) alkyl; lower alkenyl; carboxy (lower) alkenyl; lower alkoxycarbonyl (lower) alkenyl; lower alkynyl; cyclo (lower) alkenyl; or lower alkanoyl], lower alkylidene, or oxo, R is a group of the formula :

[wherein

-7

R is hydroxy (lower) alkyl, lower alkanoyloxy (lower) - alkyl, or carbamoyloxy (lower) alkyl, p

R is amino or lower alkanoylamino, and

R ^y is hydrogen] , or a group of the formula :

® N.

^* κr " ^* NNH:

-A-

(wherein A is lower alkylene) , and R , X, Y© and n are each as defined above, in which the more preferred one may be the compound [I] wherein R is amino,

9

R is halogen, lower alkyl, cyano or lower alkylthio, R is a group of the formula :

[wherein

R° is hydrogen; lower alkyl; halo (lower) alkyl; dihalo (lower) alkyl; cyano (lower) alkyl; triphenyl (lower) alkyl; lower alkylthio (lower) alkyl; carboxy (lower) alkyl; lower alkoxycarbonyl (lower) alkyl; carbamoyl (lower) alkyl; hydroxy (lower) alkyl; lower alkanoyloxy (lower) alkyl; pyrazolyl (lower) alkyl or

tetrazolyl (lower) alkyl, each of which may have lower alkyl or triphenyl (lower) alkyl; triazolylthio (lower) alkyl; lower alkenyl; carboxy (lower) alkenyl; lower alkoxycarbonyl (lower) alkenyl; lower alkynyl; cyclo (lower) alkenyl; or lower alkanoyl], R ⁴ IS a group of the formula :

[wherein k> R is hydroxy (lower) alkyl, or R is amino, and R ^y is hydrogen] , or a group of the formula :

(wherem A is lower alkylene) , R ⁵ is -COO® , and X is -S-.

The processes for preparing the object compound of the present invention are explained m detail in the following.

Process 1

The object compound [I] or a salt thereof can be prepared by reacting a compound [II] or its reactive derivative at the ammo group or a salt thereof with a compound [III] or its reactive derivative at the carboxy group or a salt thereof.

Suitable reactive derivative at the ammo group of the compound [II] may mclude Schiff's base type immo or its

tautomeric enaraine type isomer formed by the reaction of the compound [II] with a carbonyl compound such as aldehyde, ketone or the like; a silyl derivative formed by the reaction of the compound [II] with a silyl compound such as bis (trimethylsilyl) acetamide, mono (trimethylsilyl) acetamide, bis (trimethylsilyl) urea or the like; a derivative formed by reaction of the compound [II] with phosphorus trichloride or phosgene, and the like.

Suitable salts of the compound [II] and its reactive derivative can be referred to the ones as exemplified for the compound [I] .

Suitable reactive derivative at the carboxy group of the compound [III] may include an acid halide, an acid anhydride, an activated amide, an activated ester, and the like. Suitable examples of the reactive derivatives may be an acid chloride; an acid azide; a mixed acid anhydride with an acid such as substituted phosphoric acid [e.g. dialkylphosphoric acid, phenylphosphoπc acid, diphenylphosphoric acid, dibenzylphosphoric acid, halogenated phosphoric acid, etc] , dialkylphosphorous acid, sulfurous acid, thiosulfuric acid, sulfuric acid, sulfonic acid [e.g. methanesulfonic acid, etc], aliphatic carboxylic acid [e.g. acetic acid, propionic acid, butyric acid, isobutyric acid, pivalic acid, pentanoic acid, isopentanoic acid, 2-ethylbutyrιc acid, trichloroacetic acid, etc] or aromatic carboxylic acid [e.g. benzoic acid, etc] ; a symmetrical acid anhydride; an activated amide with imidazole, 4-substιtuted imidazole, dimethylpyrazole, triazole, tetrazole or 1-hydroxy-lH-benzotrιazole; or an activated ester [e.g. cyanomethyl ester methoxymethyl

+ ester, dimethylimmomethyl [ (CH3) ₂ N=CH-] ester, vmyl ester, propargyl ester, p-nitrophenyl ester, 2, 4-dιnιtrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, mesylphenyl ester, phenylazophenyl ester, phenyl thioester, p-nitrophenyl thioester, p-cresyl thioester, carboxymethyl thioester, pyranyl ester, pyridyl ester, piperidyl ester,

8-qumolyl thioester, etc] , or an ester with a N-hydroxy compound [e.g. N, N-dimethylhydroxylamme, l-hydroxy-2- (IH) - pyridone, N-hydroxysuccinimide, N-hydroxyphthalimide, 1-hydroxy-lH-benzotrιazole, etc], and the like. These reactive derivatives can optionally be selected from them according to the kind of the compound [III] to be used.

Suitable salts of the compound [III] and its reactive derivative can be referred to the ones as exemplified for the compound [I] . The reaction is usually carried out m a conventional solvent such as water, alcohol [e.g. methanol, ethanol, etc], acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N, N-dimethylacetamide, N, N-dimethylformamide, pyridme or any other organic solvent which does not adversely influence the reaction. These conventional solvent may also be used in a mixture with water.

In this reaction, when the compound [III] is used in a free acid form or its salt form, the reaction is preferably carried out in the presence of a conventional condensing agent such as N,N' -dicyclohexylcarbodnmide; N-cyclohexyl-N' -morpholinoethylcarbodnmide; N-cyclohexyl-N' - (4-dιethylammocyclohexyl) carbodiimide; N, N ' -diethylcarbodnmide, N, N' -diisopropylcarbodiimide; N-ethyl-N'- (3-dιmethylammopropyl) carbodiimide;

N,N' -carbonylbis- (2-methylimidazole) ; pentamethyleneketene-N- cyclohexylimine; dipheny1ketene-N-cyclohexylimine; ethoxyacetylene; 1-alkoxy-l-chloroethylene; trialkyl phosphite; ethyl polyphosphate; isopropyl polyphosphate; phosphorus oxychloride (phosphoryl chloride) ; phosphorus trichloride; phosphorus pentachloride; thionyl chloride; mesyl chloride; oxalyl chloride; lower alkyl haloformate [e.g. ethyl chloroformate, isopropyl chloroformate, etc] ; triphenylphosphine; 2-ethyl-7- hydroxybenzisoxazolium salt; 2-ethyl-5- (m-sulfophenyl) -

isoxazolium hydroxide intramolecular salt; 1- (p-chlorobenzenesulfonyloxy) -6-chloro-lH-benzotrιazole; so-called Vilsmeier reagent prepared by the reaction of N,N-dimethylformamide with thionyl chloride, phosgene, tnchloromethyl chloroformate, phosphorus oxychloπde, methanesulfonyl chloride, etc; or the like.

The reaction may also be carried out in the presence of an inorganic or organic base such as an alkali metal carbonate, alkali metal bicarbonate, tn (lower) alkylamine, pyridine, N- (lower) alkylmorpholine, N,N- di (lower) alkylbenzylamme, or the like.

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

Process 2

The object compound [lb] or a salt thereof can be prepared by subjecting a compound [Ia] or a salt thereof to elimination reaction of the ammo protective group in R^ . This reaction is carried out in accordance with a conventional method such as hydrolysis, reduction or the like.

The hydrolysis is preferably carried out in the presence of a base or an acid including Lewis acid.

Suitable base may mclude an inorganic base and an organic base such as an alkali metal [e.g. sodium, potassium, etc], an alkaline earth metal [e.g. magnesium, calcium, etc], the hydroxide or carbonate or bicarbonate thereof, trialkylamme [e.g. trimethylamme, triethylamine, etc], picolme, 1, 5-diazabicyclo [4.3.0]non-5-ene, 1, 4-dιazabιcyclo [2.2.2] octane, 1, 8-dιazabιcyclo [5.4.0] undec- 7-ene, or the like.

Suitable acid may include an organic acid [e.g. formic acid, acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid, etc] and an inorganic acid [e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, etc] .

The elimination using Lewis acid such as trihaloacetic acid [e.g. trichloroacetic acid, trifluoroacetic acid, etc] or the like is preferably carried out in the presence of cation trapping agents [e.g. anisole, phenol, etc] . The reaction is usually carried out in a solvent such as water, an alcohol [e.g. methanol, ethanol, etc], methylene chloride, tetrahydrofuran, a mixture thereof or any other solvent which does not adversely influence the reaction. A liquid base or acid can be also used as the solvent. The reaction temperature is not critical and the reaction is usually carried out under cooling to warming.

The reaction method applicable for the elimination reaction may include chemical reduction and catalytic reduction. Suitable reducing agents to be used in chemical reduction are a combination of metal [e.g. tin, zinc, iron, etc] or metallic compound [e.g. chromium chloride, chromium acetate, etc] and an organic or inorganic acid [e.g. formic acid, acetic acid, propionic acid, trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid, etc] .

Suitable catalysts to be used in catalytic reduction are conventional ones such as platinum catalysts [e.g. platinum plate, spongy platinum, platinum black, colloidal platinum, platinum oxide, platinum wire, etc] , palladium catalysts [e.g. spongy palladium, palladium black, palladium oxide, palladium on carbon, colloidal palladium, palladium on barium sulfate, palladium on barium carbonate, etc], nickel catalysts [e.g. reduced nickel, nickel oxide, Raney nickel, etc], cobalt catalysts [e.g. reduced cobalt, Raney cobalt, etc], iron catalysts [e.g. reduced iron, Raney iron, etc], copper catalysts [e.g. reduced copper, Raney copper, Ullman copper, etc] and the like.

The reduction is usually carried out in a conventional solvent which does not adversely influence the reaction such

as water, methanol, ethanol, propanol, N, N-dimethylformamide, or a mixture thereof. Additionally, in case that the above- mentioned acids to be used in chemical reduction are in liquid, they can also be used as a solvent. Further, a suitable solvent to be used in catalytic reduction may be the above-mentioned solvent, and other conventional solvent such as diethyl ether, dioxane, tetrahydrofuran, etc, or a mixture thereof.

The reaction temperature of this reduction is not critical and the reaction is usually carried out under cooling to warming.

Process 3

The object compound [I] or a salt thereof can be prepared by reacting a compound [IV] or a salt thereof with a compound [V] or a salt thereof.

Suitable salts of the compounds [IV] can be referred to the ones as exemplified for the compound [I] .

Suitable salts of the compounds [V] may be an organic acid salt [e.g. formate, acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, toluenesulfonate, etc], an inorganic acid salt [e.g. hydrochloride, hydrobromide, sulfate, phosphate, etc] , or the like. The present reaction may be carried out in a solvent such as water, phosphate buffer, acetone, chloroform, acetonitrile, nitrobenzene, methylene chloride, ethylene chloride, formamide, N, N-dimethylformamide, methanol, ethanol, diethyl ether, tetrahydrofuran, dimethyl sulfoxide, or any other organic solvent which does not adversely affect the reaction, preferably in ones having strong polarities. Among the solvents, hydrophilic solvents may be used in a mixture with water. When the compound [V] is m liquid, it can also be used as a solvent. The reaction is preferably conducted in the presence of a base, for example, inorganic

base such as alkali metal hydroxide, alkali metal carbonate, alkali metal bicarbonate, organic base such as trialkylamme, and the like. The reaction temperature is not critical, and the reaction is usually carried out at ambient temperature, under warming or under heating. The present reaction is preferably carried out in the presence of alkali metal halide [e.g. sodium iodide, potassium iodide, etc], alkali metal thiocyanate [e.g. sodium thiocyanate, potassium thiocyanate, etc] or the like. Anion Y© may be the one derived from a leaving group Z and may be the other one converted therefrom by a conventional method.

Process 4 The object compound [Id] or a salt thereof can be prepared by subjecting a compound [Ic] or a salt thereof to elimination reaction of the hydroxy protective group.

This reaction can be carried out m a similar manner to that of Process 2 mentioned in the above, and therefore the reaction mode and reaction conditions [e.g. base, acid, catalyst, solvent, reaction temperature, etc] of this reaction are to be referred to those as explained in Process 2.

Process 5

The object compound [Ie] or a salt thereof can be prepared by subjecting a compound [VI] or a salt thereof to introduction reaction of halogen.

This reaction can be carried out by reacting a compound [VI] or a salt thereof with an introduction agent of halogen such as N-halo-succmimide (e.g. N-bromosuccimmide, N-iodosuccmimide, etc) , etc.

This reaction can be carried out m a solvent such as N,N-dιmethylformamide, N,N-dimethylacetamide or any other solvent which does not adversely affect the reaction.

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

The object compound [I] or a salt thereof can be prepared according to the methods other than Processes 1 to

5, and then can be carried out, for examples, as described m Examples .

The reactions m Process A for preparing the starting compound [III] or a salt thereof can be carried out according to the methods as described m Preparations or to the similar manners thereto.

In order to show the utility of the compound [I], the test data on MIC (minimal inhibitory concentration) of representative compound [I] of this invention is shown in the following .

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

One loopful of an overnight culture of each test strain m Trypticase-soy broth (10 ⁶ viable cells per ml) was streaked on heart infusion agar (Hl-agar) containing graded concentrations of representative test compound, and the minimal inhibitory concentration (MIC) was expressed m terms of μg/mf after incubation at 37°C for 20 hours.

Test Compound (1) 7β- [ (Z) -2-Cyanomethoxyιmmo-2- (2-ammo-5-chlorothιazol- 4-yl) acetamido] -3- [5-ammo-l- (2-hydroxyethyl) -2- pyrazol10]methyl-3-cephem-4-carboxylate (the compound of Example 8)

Test Result

MI C ( μg /mC ;

For therapeutic administration, the object compound [I] and a pharmaceutically acceptable salt thereof of the present invention are used in the form of conventional pharmaceutical preparation which contains said compound as an active ingredient, in admixture with pharmaceutically acceptable carriers such as an organic or inorganic solid or liquid excipient which is suitable for oral, parenteral and external administration. The pharmaceutical preparations may be m solid form such as tablet, granule, powder, capsule, or liquid form such as solution, suspension, syrup, emulsion, lemonade and the like.

If needed, there may be mcluded m the above preparations auxiliary substances, stabilizing agents, wetting agents and other commonly used additives such as lactose, citric acid, tartaric acid, stearic acid, magnesium stearate, terra alba, sucrose, corn starch, talc, gelatin, agar, pectin, peanut oil, olive oil, cacao butter, ethylene glycol, and the like.

While the dosage of the compound [I] may vary from and also depend upon the age, conditions of the patient, a kind of diseases, a kind of the compound [I] to be applied, etc. In general, amounts between 1 mg and about 4,000 mg or even more per day may be administered to a patient. An average single dose of about 50 mg, 100 mg, 250 mg, 500 mg, 1000 mg, 2000 mg of the object compound [I] of the present mvention may be used m treating diseases infected by pathogenic microorganisms .

The following Preparations and Examples are given for the purpose of illustrating some preferred embodiments of the

present invention in more detail.

Preparation 1

A solution of bromoacetonitrile (8.82 g) in 67 ml of N, N-dimethylformamide was treated portionwise with

N-hydroxyphthalimide (10.0 g) and powdered potassium carbonate (16.9 g) at 0°C. The mixture was allowed to stir at room temperature. The reaction mixture was poured mto 670 ml of water to afford 8.03 g of N- (cyanomethoxy) phthalimide as precipitates.

IR (KBr) : 1740 cm ^"1

NMR (DMSO-d ₆ , δ) : 7.92 (4H, s), 5.25 (2H, s)

Preparation 2 A solution of N-hydroxyphthalimide (3.38 g) and 1-bromo- 2, 2-dιfluoroethane (3.0 g) in 8 ml of N, N-dimethylformamide was treated with triethylamine (6.2 ml) at 0°C. The mixture was allowed to warm to 80°C. After 24 hours, additional 1- bromo-2, 2-dιfluoroethane (1.5 g) in 4 ml of N,N- dimethylformamide was introduced. The reaction mixture was quenched by water and extracted with ethyl acetate. The combined extracts were washed with water, aqueous sodium hydrogen carbonate and brine, and were dried with magnesium sulfate. The solvent was removed under reduced pressure and the residue was washed with isopropyl ether to afford 3.50 g of N- (2, 2-difluoroethoxy) phthalimide.

NMR (DMSO-d _β , δ) : 7.89 (4H, s) , 6.34 (IH, tt, J=54Hz, 3.8Hz), 4.50 (IH, dd, J=14.2Hz, 3.8Hz), 4.43 (IH, dd, J=14.2Hz, 3.8Hz) MS (APCI) m/z : 228 (M ⁺ +l)

Preparation 3

To a solution of N- (2-fluoroethoxy) phthalimide (9.3 g) in tetrahydrofuran (180 ml) was added dropwise hydrazine monohydrate (2.9 ml) under ice-cooling with stirring and the

mixture was stirred for 1.5 hours at 25 to 35°C. The insoluble material was filtered off, and the filtrate was adjusted to pH 7.0 with aqueous sodium hydrogen carbonate. To the neutral solution was added 2- (2-formylammo-5- chlorothιazol-4-yl) -2-oxoacetιc acid (10.5 g) , and the mixture was stirred at room temperature for 3 hours with keeping the pH value between 4.5-5.0 with saturated aqueous sodium hydrogen carbonate. The reaction mixture was poured into ethyl acetate (300 ml), and adjusted to pH 3.0 with lN-hydrochloric acid. The separated organic phase was washed with water (200 ml) and dried with magnesium sulfate and evaporated m vacuo to give (Z) -2- (2-formylammo-5- chlorothιazol-4-yl) -2- (2-fluoroethoxyimmo) acetic acid (9.6 g ⁾ • NMR (DMSO-d ₆ , δ) : 4.25-4.35 (IH, m) , 4.45-4.55 (IH, m) , 4.50-4.60 (IH, m) , 4.75-4.85 (IH, m) , 8.55 (IH, s) , 12.89 (IH, br s)

Preparation 4 A solution of N- (2, 2-dιfluoroethoxy) phthalimide (1.94 g) in 39 ml of methanol and 14 ml of dichloromethane was treated with hydrazine monohydrate (0.64 g) at 0°C. The insoluble material was filtered off and 2-oxo-2- (2-formylammo-5- chlorothιazol-4-yl) acetic acid (2.0 g) was added to the filtrate at room temperature. After 3 hours, the insoluble material was filtered off and the solvent was removed under reduced pressure. Ethyl acetate was added and the insoluble material was filtered off again, and the filtrate was removed under reduced pressure, and the residue was washed with isopropyl ether to afford 2.44 g of (Z) -2- (2, 2-dιfluoro¬ ethoxyimino) -2- (2-formylammo-5-chlorothιazol-4-yl) acetic acid.

IR (KBr) : 3169, 1720, 1659, 1068, 1045 cm ^-1

NMR (DMSO-d ₆ , δ) : 8.55 (IH, s) , 7.84 (IH, s), 6.26 (IH, tt, J=54.6Hz, 3.7Hz) , 4.45 (IH, dd, J=14.5Hz,

3 . 7H z ) , 4 . 37 ( IH , dd , J=14 . 5Hz , 3 . 7Hz )

Preparation 5

(Z) -2-Cyanomethoxyimino-2- (5-chloro-2- formylaminothiazol-4-yl) acetic acid (12.61 g) was obtained according to a similar manner to that of Preparation 4. NMR (DMSO-d ₆ , δ) : 12.93 (IH, s), 8.57 (IH, s) ,

5.16 (2H, s)

Example 1

A mixture of N,N-dimethylformamide (0.67 ml) and phosphorus oxychloride (0.8 ml) in tetrahydrofuran (20 ml) was stirring for 30 minutes at 5°C, (Z) -2- (2-formylammo-5- chlorothιazol-4-yl) -2-allyloxyimmoacetic acid (2.09 g) was added thereto with stirring and ice-cooling, and the mixture was stirred for 30 minutes at 5°C to produce an activated acid solution. On the other hand, 7β-amino-3- [S-ammo-1- (2- hydroxyethyl) -2-pyrazolio]methyl-3-cephem-4-carboxylate hydrochloride (2.3 g) was dissolved in a solution of mono- trimethylsilylacetamide (8 g) in N, N-dimethylformamide (23 ml) and tetrahydrofuran (23 ml) . To the solution was at a time added the above obtained activated acid solution at 5°C and the mixture was stirred for 1.5 hours at 5°C. The resulting solution was poured into ethyl acetate (1 C) . The resulting powder was collected by filtration, and dried in vacuo to give 7β- [ (Z) -2- (2-formylamino-5-chlorothiazol-4-yl) - 2-allyloxyiminoacetamido] -3- [5-amino-l- (2-hydroxyethyl) -2- pyrazolio]methyl-3-cephem-4-carboxylate (4.4 g) .

NMR (DMSO-d ₆ , δ) : 3.2-3.40 (2H, m) , 3.50-3.65 (2H, m) , 4.05-4.55 (2H, m) , 4.50-4.65 (2H, m) , 5.05-5.40

(2H+2H, m) , 5.15 (IH, d, J=4.9Hz), 5.80-6.05 (1H+1H+1H, m) , 7.96 (2H, br s) , 8.07 (IH, d, J=3.2Hz) , 8.53 (IH, s) , 9.74 (IH, d, J=8.4Hz), 12.9 (IH, s)

Example 2

A mixture of N,N-dιmethylformamide (2.8 ml) and phosphorus oxychloride (3.4 ml) in tetrahydrofuran (90 ml) was stirred for 30 minutes at 5°C. (Z) -2- (2-Formylamιno-5- chlorothιazol-4-yl) -2- (2-fluoroethoxyimmo) acetic acid (9 g) was added thereto with stirring and ice-cooling, and the mixture was stirred for 30 minutes at 5°C to produce an activated acid solution. On the other hand, 7β-amιno-3- [5- amιno-1- (2-hydroxyethyl) -2-pyrazolio]methyl-3-cephem-4- carboxylate hydrochloride (12.7 g) was dissolved in a solution of mono-trimethylsilylacetamide (44.4 g) in N,N-dimethylformamide (120 ml) and tetrahydrofuran (120 ml) . To the solution was at a time added the above obtained activated acid solution at 5°C, and the mixture was stirred for 1.5 hours at 5 ^C C. The resulting solution was poured mto ethyl acetate (3 f) . The precipitate was collected by filtration and dried under reduced pressure. The powder was dissolved in water (300 ml), adjusted to pH 4.0 with aqueous sodium hydrogen carbonate and then subjected to column chromatography on HP-20 (Trademark : Mitsubishi Kasei

Corporation) (500 ml), and eluted with 20% 2-propanol and the eluate was lyophilized to give 7β- [ (Z) -2- (2-formylammo-5- chlorothιazol-4-yl) -2- (2-fluoroethoxyimmo) acetamido] -3- [5- ammo-1- (2-hydroxyethyl) -2-pyrazolιo]methyl-3-cephem-4- carboxylate (5.8 g) .

IR (KBr) : 1774, 1673, 1608, 1542, 1284, 1068 cm ^"1 NMR (DMSO-d ₆ , δ) : 2.96 and 3.24 (2H, ABq, J=17.1Hz), 3.40-3.60 (2H, m) , 4.05-4.40 (2H+1H) , 4.40-4.50 (IH, m) , 4.50-4.60 (IH, m) , 4.70-4.80 (IH, m) , 5.04 (IH, d, J=4.9Hz) , 5.07 and 5.23 (2H, ABq,

J=18.0Hz), 5.68 (IH, dd, J=4.9Hz, 8.4Hz), 5.84 (IH, d, J=3.1Hz), 7.39 (2H, br s), 8.09 (IH, d, J=3.1Hz) , 8.54 (IH, s) , 9.68 (IH, d, J=8.4Hz)

Example 3

To a solution of (Z) -2- (2, 2-dιfluoroethoxyimmo) -2- (2- formylamιno-5-chlorothιazol-4-yl) acetic acid (1.67 g) in 16 ml of N, N-dimethylacetamide, powdered potassium carbonate (0.74 g) and methanesulfonyl chloride (1.22 g) were added stepwise at 0°C. On the other hand, a suspension of 7β- amιno-3- [5-ammo-l- (2-hydroxyethyl) -2-pyrazolio]methyl-3- cephem-4-carboxylate (2.0 g) in 20 ml of N,N- dimethylacetamide was treated portionwise with N- (trimethylsilyl) acetamide (4.19 g) at room temperature. Both reaction mixture were combined at 0°C and stirred for 3 hours. The reaction was quenched by dropping mto 300 ml of ethyl acetate to get precipitates, which were purified by column chromatography on HP-20 resm to get 0.71 g of 7β-[ (Z)-2- (2, 2-dιfluoroethoxyimmo) -2- (5-chloro-2- formylammothiazol-4-yl) acetamido] -3- [5-ammo-l- (2- hydroxyethyl) -2-pyrazolio]methyl-3-cephem-4-carboxylate. IR (KBr) : 1772, 1676, 1650, 1610 cm ^-1

NMR (DMSO-d ₆ , δ) : 9.71 (IH, d, J=8.4Hz), 8.53 (IH, s) , 8.11 (IH, d, J=2.9Hz), 7.32 (2H, br s) , 6.24 (IH, br t, J=54.6Hz), 5.82 (IH, d, J=2.9Hz) , 5.65 (IH, dd, J=8.4Hz, 4.7Hz) , 5.22, 5.06 (2H, ABq, J=14.9Hz), 5.03 (IH, d, J=4.7Hz) , 4.2-4.6 (2H, m) , 4.37 (2H, br t, J=14.6Hz) , 3.5-3.7 (2H, m) , 3.21, 2.94 (2H, ABq, J=16.9Hz) MS (FAB) m/z : 635.1 (M ⁺ ), 637.1 (M ⁺ +2)

Example 4

7β- [ (Z) -2-Cyanomethoxyιmmo-2- (5-chloro-2-formylammo- thιazol-4-yl) acetamido] -3- [5-ammo-l- (2-hydroxyethyl) -2- pyrazolio]methyl-3-cephem-4-carboxylate (3.24 g) was obtained according to a similar manner to that of Example 3.

MS (FAB) m/z : 610.3 (M ⁺ )

Example 5 To a suspension of 7β- [ (Z) -2- (2-formylammo-5-

chlorothiazol-4-yl) -2-allyloxyiminoacetamido] -3- [5-amino-1- (2-hydroxyethyl) -2-pyrazolio]methyl-3-cephem-4-carboxylate (3.74 g) in methanol (37 ml) was added concentrated hydrochloric acid (2.9 ml) under stirring at 25°C to 30°C. The stirring was continued for 3 hours at 20°C to 30°C. The reaction mixture was poured into a cooled water (100 ml) and adjusted to pH 4.0 with saturated aqueous sodium hydrogen carbonate. To the resulting solution was evaporated in vacuo. The residue was subjected to column chromatography on HP-20 (200 ml), and eluted with 15% 2-propanol and the eluate was lyophilized to give 7β- [ (Z) -2- (2-amino-5-chlorothiazol-4- yl) -2-allyloxyiminoacetamido] -3- [5-amino-1- (2-hydroxyethyl) - 2-pyrazolio]methyl-3-cephem-4-carboxylate (520 mg) . IR (KBr) : 1776, 1666, 1585, 1539, 1388, 1352, 1016 cm ^-1

NMR (DMSO-dg, δ) : 2.91 and 3.17 (2H, ABq, J=17Hz), 3.40-3.65 (2H, m) , 4.20-4.60 (2H, m) , 4.50-4.60 (2H, m) , 4.99 (IH, d, J=5Hz), 5.05-5.50 (2H+2H, m) ,

5.61 (IH, dd, J=5Hz, 8Hz), 5.81 (IH, d, J=3Hz), 5.85-6.05 (IH, m) , 7.27 (2H, br s) , 7.41 (2H, br s), 8.10 (IH, d, J=3Hz) , 9.54 (IH, d, J=8Hz)

Example 6

7β-[ (Z) -2- (2-Amino-5-chlorothiazol-4-yl)-2-(2- fluoroethoxyimmo) acetamido] -3- [5-amino-l- (2-hydroxyethyl) -2- pyrazolio]methyl-3-cephem-4-carboxylate (2.75 g) was obtained according to a similar manner to that of Example 5.

IR (KBr) : 1772, 1612, 1538, 1392, 1355, 1064 cm ^'1 NMR (DMSO-d ₆ , δ) : 2.94 and 3.21 (2H, ABq, J=17.2Hz) , 3.40-3.65 (2H, m) , 4.15-4.25 (IH, m) , 4.25-4.50

(1H+1H, m) , 4.55-4.65 (IH, m) , 4.70-4.85 (IH, m) , 5.01 (IH, d, J=4.8Hz), 5.04 (2H, ABq, J=18.2Hz) ,

5.62 (IH, dd, J=4.8Hz, 1 . 9Hz ) , 5.82 (IH, d, J=2.9Hz), 7.34 (2H, br s) , 7.39 (2H, br s) , 8.09 (IH, d, J=2.9Hz), 9.54 (IH, d, J=7.9Hz)

Example 7

A solution of 7β- [ (Z) -2- (2, 2-difluoroethoxyimino) -2- (5- chloro-2-formylaminothiazol-4-yl) acetamido] -3- [5-amino-1- (2- hydroxyethyl) -2-pyrazolio]methyl-3-cephem-4-carboxylate (0.71 g) in 3.6 ml of methanol was treated with hydrochloric acid (0.47 ml) , and stirred for 4 hours at room temperature. The reaction mixture was dropped into 300 ml of ethyl acetate to get precipitates, which were purified by column chromatography on HP-20 resin to get 0.40 g of 7β- [ (Z) -2- (2- amino-5-chlorothiazol-4-yl) -2- (2, 2-difluoroethoxyimino) - acetamido] -3- [5-amino-l- (2-hydroxyethyl) -2-pyrazolio]methyl- 3-cephem-4-carboxylate.

IR (KBr) : 1770, 1649, 1616 cm ^-1

NMR (DMSO-d ₆ , δ) : 9.60 (IH, d, J=8.4Hz) , 8.11 (IH, d, J=3.1Hz), 7.44 (2H, br s) , 7.30 (2H, br s), 6.20

(IH, tt, J=54.9Hz, 3.7Hz) , 5.82 (IH, d, J=3.1Hz), 5.61 (IH, dd, J=8.4Hz, 4.9Hz), 5.22, 5.05 (2H, ABq, J=15.1Hz) , 5.00 (IH, d, J=4.9Hz), 4.2-4.6 (2H, m) , 4.31 (2H, dt, J=3.7Hz, 14.1Hz) , 3.5-3.7 (2H, m) , 3.20, 2.93 (2H, ABq, J=17.6Hz)

MS (FAB) m/z : 606.9 (M ⁺ ) , 609.1 (M ⁺ +2)

Example 8

7β- [ (Z) -2-Cyanomethoxyimino-2- (2-amino-5-chlorothiazol- 4-yl) acetamido] -3- [5-amino-l- (2-hydroxyethyl) -2-pyrazolio] - methyl-3-cephem-4-carboxylate (92 mg) was obtained according to a similar manner to that of Example 7. IR (KBr) : 1770, 1666, 1614 cm ^"1

NMR (DMSO-d ₆ , δ) : 9.72 (IH, d, J=8.4Hz) , 8.11 (IH, d, J=3.2Hz), 7.49 (2H, br s) , 7.28 (2H, br s) , 5.81

(IH, d, J=3.2Hz), 5.59 (IH, dd, J=8.4Hz, 4.9Hz), 5.19, 5.07 (2H, ABq, J=15Hz) , 5.01 (IH, d, J=4.9Hz) , 5.00 (2H, s) , 4.2-4.6 (2H, m) , 3.2-3.8 (2H, m) , 2.88, 3.21 (2H, ABq, J=17.1Hz) MS (FAB) m/z : 582.0 (M ⁺ ) , 584.1 (M ⁺ +2)

5

Preparation 6

A solution of ethyl 2-hydroxyimino-3-oxopentanoate (20 g) in 140 ml of ethyl acetate was treated with diethyl sulfate (19.59 g) and powdered potassium carbonate (18.36 g) . The reaction mixture was quenched by water and extracted with ethyl acetate. The combined extracts were washed with water and brine, and were dried with magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel

(hexanerethyl acetate = 19:1) to afford 11.11 g of ethyl 2-ethoxyimino-3-oxopentanoate.

IR (Neat) : 1747, 1695 cm ^"1

NMR (DMSO-d ₆ , δ) : 1.00 (3H, t, J=7.3Hz), 1.23 (3H, t, J=7.1Hz), 1.27 (3H, t, J=7.1Hz), 2.81 (2H, q,

J=7.3Hz), 4.27 (2H, q, J=7.1Hz), 4.32 (2H, q, J=7.1Hz)

Preparation 7 A solution of ethyl 2-ethoxyimino-3-oxopentanoate (11.11 g) in 11 ml of acetic acid was treated dropwise with sulfuryl chloride (5.06 ml) . The mixture was stirred for 3 hours at 50°C and quenched by ice-water. The mixture was extracted with ethyl acetate, and the combined extracts were washed with brine and dried with magnesium sulfate. The solvent was removed under reduced pressure to afford 14.15 g of ethyl 4-chloro-2-ethoxyimino-3-oxopentanoate. IR (Neat) : 1747, 1705 cm ^-1

NMR (DMSO-d ₆ , δ) : 1.25 (3H, t, J=7.1Hz) , 1.29 (3H, t, J=7.0Hz), 1.59 (3H, d, J=6.7Hz), 4.31 (2H, q,

J=7.1Hz) , 4.38 (IH, q, J=7.0Hz) , 5.33 (IH, q, J=6.7Hz)

Preparation 8 A solution of ethyl 4-chloro-2-ethoxyιmmo-3-

oxopentanoate (14.15 g) in 44 ml of water and 44 ml of ethanol was treated portionwise with thiourea (6.86 g) and sodium acetate (7.39 g) at room temperature. The mixture was allowed to stir at 40°C. The reaction mixture was stirred overnight at room temperature. The solvent was removed under reduced pressure, and the precipitates were filtered and washed with water and dried under reduced pressure to afford 10.17 g of ethyl (Z) -2-ethoxyιmmo-2- (2-amιno-5- methylthιazol-4-yl) acetate. IR (KBr) : 3138, 1724, 1630, 1545 cm ^"1

NMR (DMSO-d ₆ , δ) : 1.21 (3H, t, J=7.0Hz), 1.24 (3H, t,

J=7.1Hz) , 2.36 (3H, s), 4.12 (2H, q, J=7.0Hz), 4.23 (2H, q, J=7.1Hz), 6.95 (2H, s)

Preparation 9

A solution of ethyl (Z) -2-ethoxyιmmo-2- (2-ammo-5- methylthιazol-4-yl) acetate (10.0 g) in 50 ml of tetrahydrofuran was treated with 19.4 ml of 4N sodium hydroxide solution. The reaction mixture was allowed to 50°C, and then diluted with water and washed with ethyl acetate. Aqueous phase was allowed to pH 2.5 to afford 7.60 g of (Z) -2-ethoxyιmιno-2- (2-ammo-5-methylthιazol-4-yl) acetic acid as precipitates.

IR (KBr) : 1628 cm ^"1 NMR (DMSO-d ₆ , δ) : 1.22 (3H, t, J=7.0Hz), 2.36 (3H, s),

4.10 (2H, q, J=7.0Hz), 6.94 (2H, s) ,

Preparation 10

A solution of ethyl (Z) -2-methoxyιmmo-2- (2- formylammothιazol-4-yl) acetate (5.0 g) in 50 ml of methanol was treated with N-bromosuccinimide (3.81 g) . The reaction mixture was diluted with water and extracted with ethyl acetate. The combined extracts were dried with sodium sulfate. The solvent was removed under reduced pressure to afford 6.8 g of ethyl (Z) -2-methoxyιmιno-2- (5-bromo-2-

formylammothιazol-4-yl) acetate.

NMR (DMSO-d ₆ , δ) : 1.28 (3H, t, J=7.1Hz) , 3.96 (3H, s) 4.31 (2H, q, J=7.1Hz), 8.55 (IH, s), 12.84 (IH, s) MS (APCI) m/z : 336 (M ⁺ )

Preparation 11

A solution of ethyl (Z) -2-methoxyιmmo-2- (5-bromo-2- formylammothιazol-4-yl) acetate (6.8 g) in 68 ml of N, N-dimethylformamide was treated with copper (I) cyanide (2.17 g) . The reaction mixture was allowed to 100°C. The reaction was quenched with ice-water, and extracted with ethyl acetate. The solvent was removed under reduced pressure to afford 1.60 g of ethyl (Z) -2-methoxyιmιno-2- (5- cyano-2-formylammothιazol-4-yl) acetate. IR (KBr) : 2222, 1743, 1691, 1531 cm ^"1

NMR (DMSO-d ₆ , δ) : 1.30 (3H, t, J=6.7Hz) , 4.04 (3H, s) , 4.35 (2H, q, J=6.7Hz) , 8.70 (IH, s), 13.36 (IH, s), MS (APCI) m/z : 283 (M ⁺ +l)

Preparation 12

A solution of ethyl (Z) -2-methoxyιmιno-2- (5-cyano-2- formylammothιazol-4-yl) acetate (0.8 g) in 3.2 ml of dioxane and 3.2 ml of water was treated with sodium hyαroxide (0.57 g) . After 3 hours, the reaction mixture was diluted with water and washed with ethyl acetate. Aqueous phase was allowed to pH 2 and extracted with ethyl acetate and tetrahydrofuran. The solvent was removed under reduced pressure to afford 0.59 g of (Z) -2-methoxyιmmo-2- (5-cyano-2- formylammothιazol-4-yl) acetic acid. IR (KBr) : 2218, 1741 cm ^"1

MS (FAB) m/z : 255.0 (M ⁺ )

Preparation 13

A solution of ethyl 2- (2-formylammothιazol-4-yl) -2- oxoacetate (50 g) in 280 ml of N, N-dimethylformamide was

treated with a solution of trichloroisocyanuric acid (20.2 g) in 70 ml of N, N-dimethylformamide at 60°C. The reaction mixture was poured mto 3.5 I of ice-water to afford 54.15 g of ethyl 2- (5-chloro-2-formylammothιazol-4-yl) -2-oxoacetate as precipitates.

IR (KBr) : 1749, 1676, 1543, 1086 cm ^"1

NMR (DMSO-d ₆ , δ) : 1.32 (3H, t, J=7.lHz) , 4.38 (2H, q, J=7.1Hz) , 8.60 (IH, s) , 12.8 (IH, br s)

Preparation 14

Ethyl 2- (5-chloro-2-formylamιnothιazol-4-yl) -2- oxoacetate (20 g) was added to 45 ml of 4N potassium hydroxide solution. The reaction mixture was diluted with water and washed with ethyl acetate. The aqueous phase was allowed to pH 2, and precipitates were filtered and washed with isopropyl ether to get 15.59 g of 2- (5-chloro-2- formylamιnothιazol-4-yl) -2-oxoacetιc acid.

NMR (DMSO-d ₆ , δ) : 8.59 (IH, s) , 13.56 (IH, br s)

Preparation 15

A solution of (Z) -2-difluoromethoxyιmmo-2- (2- trιtylammothιazol-4-yl) acetic acid (20 g) m 300 ml of methanol was treated with N-chlorosuccmimide (6.13 g) and stirred at 70°C. After 7 hours, additional N-chlorosuccmimide (1.67 g) was introduced. The reaction mixture was diluted with water and allowed to pH 7, and washed with ethyl acetate. The aqueous phase was allowed to pH 2.6, and was extracted with ethyl acetate. The combined extracts were dried with sodium sulfate. The solvent was removed under reduced pressure to afford 8.88 g of (Z)-2- difluoromethoxyimmo-2- (2-ammo-5-chlorothιazol-4-yl) acetic acid.

IR (KBr) : 3305, 3201, 1707, 1645 cm ^"1 NMR (DMSO-d ₆ , δ) : 7.20 (IH, t, J=70.8Hz) , 7.60 (2H, br s)

MS (APCI ) m/ z : 272 (M ⁺ + l )

Preparation 16

N- (Fluoromethoxy) phthalimide was prepared according to a similar manner to that of Preparation 1.

NMR (DMSO-d ₆ , δ) : 5.78 (2H, d, J=53.0Hz), 7.91 (4H, s) MS (APCI) m/z : 195 (M ⁺ )

Preparation 17 (Z) -2-Fluoromethoxyιmmo-2- (2-formylammo-5- chlorothιazol-4-yl) acetic acid was obtained according to a similar manner to that of Preparation 3. IR (KBr) : 1739, 1720, 1685 cm ^"1

NMR (DMS0-d ₆ , δ) : 5.82 (2H, d, J=55.1Hz), 8.57 (IH, s) , 12.94 (IH, br s)

MS (APCI) m/z : 281.7 (M ⁺ )

Preparation 18

A solution of ethyl 2-hydroxyιmιno-3-oxopentanoate (8.0 g) in 56 ml of ethyl acetate was treated with dimethyl sulfate (6.41 g) and powdered potassium carbonate (7.34 g) . The reaction mixture was quenched by water and extracted with ethyl acetate. The combined extracts were washed with water and brine, and were dried with magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (hexanerethyl acetate = 19:1) to afford 6.73 g of ethyl 2-methoxyιmιno-3-oxopentanoate.

IR (Neat) : 1747, 1697 cm ^"1 NMR (DMSO-d ₆ , δ) : 1.00 (3H, t, J=7.3Hz), 1.24 (3H, t,

J=7.1Hz), 2.81 (2H, q, J=7.3Hz) , 4.06 (3H, s), 4.27 (2H, q, J=7.1Hz)

Preparation 19 Ethyl 4 -chloro-2-methoxyιmmo-3-oxopentanoate was

obtained according to a similar manner to that of Preparation 1_ .

IR (Neat) : 1743, 1701, 1039 cm ^"1

NMR (DMSO-d ₆ , δ) : 1.25 (3H, t, J=7.1Hz) , 1.59 (3H, d, J=6.7Hz), 4.12 (3H, s) , 4.31 (2H, q, J=7.1Hz) , 5.31

(IH, q, J=6.7Hz) MS (APCI) m/z : 222 (M ⁺ +l)

Preparation 20 Ethyl (Z) -2-methoxyιmmo-2- (2-ammo-5-methylthιazol-4- yl) acetate was obtained according to a similar manner to that of Preparation 8.

NMR (DMSO-d ₆ , δ) : 1.24 (3H, t, J=7.1Hz) , 2.36 (3H, s) , 3.87 (3H, s), 4.23 (2H, q, J=7.1Hz) 6.94 (2H, br s) ,

MS (APCI) m/z : 244 (M ⁺ +l)

Preparation 21

(Z) -2-Methoxyιmmo-2- (2-ammo-5-methylthιazol-4- yl) acetic acid was obtained according to a similar manner to that of Preparation 9.

NMR (DMSO-d ₆ , δ) : 2.36 (3H, s) , 3.85 (3H, s),

6.96 (2H, br s) MS (APCI) m/z : 216 (M ⁺ +l)

Preparation 22

N- (Carbamoylmethoxy) phthalimide was obtained according to a similar manner to that of Preparation 1.

NMR (DMSO-d _β , δ) : 4.60 (2H, s), 7.63 (2H, br s), 7.89 (4H, s)

Preparation 23

(Z) -2-Carbamoylmethoxyιmmo-2- (2-formylammo-5- chlorothιazol-4-yl) acetic acid was obtained according to a similar manner to that of Preparation 3.

NMR ( DMSO-dg , δ ) : 4 . 55 ( 2H , s ) , 7 . 09 ( IH , br s ) , 7 . 46

(IH, br s), 8.56 (IH, s) , 12.92 (IH, s) MS (APCI) m/z : 306.9 (M ⁺ )

Preparation 24

(Z) -2- (1-tert-Butoxycarbonyl-l-methylethoxyιmmo) -2- (2- ammo-5-chlorothιazol-4-yl) acetic acid was obtained according to a similar manner to that of Preparation 15. IR (KBr) : 1732, 1720, 1645, 1146 cm ^-1 NMR (DMSO-d ₆ , δ) : 1.39 (9H, s), 1.42 (6H, s),

7.43 (2H, br s) MS (APCI) m/z : 364.2 (M ⁺ +l)

Preparation 25 To a solution of N- (cyanomethoxy) phthalimide (10.0 g) in tetrahydrofuran (100 ml) was added sodium azide (9.65 g) and aluminum chloride (7.26 g) at 0°C. The reaction mixture was refluxed with stirring. The reaction was quenched by 2N hydrochloric acid. The aqueous phase was extracted with ethyl acetate, and the combined extracts were washed with brine and dried with magnesium sulfate. The solvent was removed under reduced pressure, and the residue was washed with isopropyl ether to afford 6.33 g of N- (2H-tetrazol-5- ylmethoxy)phthalimide. NMR (DMSO-d ₆ , δ) : 5.50 (2H, s), 7.8-8.0 (4H, m)

MS (APCI) m/z : 246 (M ⁺ +l)

Preparation 26

To a solution of N- (2H-tetrazol-5-ylmethoxy)phthalimide (2.32 g) m dimethylformamide (20 ml) was added trityl chloride (2.90 g) and triethylamine (1.6 ml) at 0°C. After 4 hours, the reaction was quenched by water and extracted with ethyl acetate. The combined extracts were washed with brine and dried with magnesium sulfate. The solvent was removed under reduced pressure, and the residue was washed with

hexane-ethyl acetate to afford 2.62 g of the mixture of N- (l-trιtyl-lH-tetrazol-5-ylmethoxy) phthalimide and N- (2-trιtyl-2H-tetrazol-5-ylmethoxy) phthalimide.

NMR (DMSO-d ₆ , δ) : 5.48 (2H, s), 6.9-7.0 (6H, m) , 7.2-7.5 (9H, m) , 7.8-7.9 (4H, m)

Preparation 27

A mixture of 2- [ (Z) - (l-tntyl-lH-tetrazol-5- ylmethoxyimino) ] -2- (2-formylamιno-5-chlorothιazol-4-yl) acetic acid and 2- [ (Z) - (2-trιtyl-2H-tetrazol-5-ylmethoxyιmmo) ] -2- ( 2-formylamιno-5-chlorothιazol-4-yl) acetic acid were obtained according to a similar manner to that of Preparation 3. IR (KBr) : 3427, 1732, 1691, 1547 cm ^"1 NMR (DMSO-d ₆ , δ) : 5.49 (2H, s) , 7.0-7.1 (6H, m) , 7.2-7.4 (9H, m) , 8.54 (IH, s) , 12.88 (IH, s)

Preparation 28

A mixture of ethyl chlorofluoroacetate (100 g) , phthaloyl chloride (102.5 ml) and chlorosulfonic acid (47.3 ml) was heated at total reflux m a still conncected to an ice-cooled receiver backed up by a dry ice cooled trap when the pot temperature reached 120°C, distillation was started and the volatile material was distilled from the reaction mixture until the pot temperature rose to 200°C. The condensates m the receiver and the dry ice cooled trap were combined. On the other hand, isopropylidene malonate (51.3 g) was dissolved in a solution of pyridme (69.7 ml) in dichloromethane (160 ml) . To the solution was added dropwise above obtained combined solution at 5°C to 10°C and the mixture was stirred for 3 hours at the same temperature. The resulting solution was poured into a cooled 3N-hydrochloπc acid (200 ml) . The separated organic phase was washed with brine (200 ml) , and dried with magnesium sulfate and evaporated in vacuo. The residue was added methanol (300 ml) at room temperature with stirring. The mixture was refluxed

for 8 hours. The reaction mixture was evaporated m vacuo. The residue was subjected to a column chromatography on silica gel (500 g) and eluted with a mixture of ethyl acetate and hexane (1:2) . The fractions containing the objective compound were collected, evaporated to give methyl 4-chloro- 4-fluoro-3-oxobutyrate (43.2 g) .

NMR (DMSO-d ₆ , δ) : 3.72 (3H, s), 3.88 (2H, d, J=1.6Hz) ,

6.99 (IH, d, J=49Hz)

Preparation 29

To a solution of methyl 4-chloro-4-fluoro-3-oxobutyrate (31 g) and isopentylnitrite (25.8 ml) m dichloromethane (120 ml) was added dropwise acetyl chloride (13 ml) under lce- cooling with stirring and the mixture was stirred for 3 hours at 5°C to 10°C. The resulting solution was poured mto water (300 ml) and adjusted to pH 3.0 with saturated aqueous sodium hydrogencarbonate. The separated organic phase was washed with water (300 ml) and dried with magnesium sulfate and evaporated in vacuo to give methyl 4-chloro-4-fluoro-2- hydroxyιmmo-3-oxobutyrate (44.5 g) .

NMR (DMSO-d ₆ , δ) : 3.82 (3H, s), 7.39 (IH, d, J=49Hz),

14.14 (IH, s)

Preparation 30 To a solution of methyl 4-chloro-4-fluoro-2-hydroxy- ιmmo-3-oxobutyrate (7.8 g) in N,N-dimethylacetamide (80 ml) was added thiourea (15 g) under stirring at 30°C and then the stirring was continued for 12 hours at the same temperature. The resulting solution was poured mto a mixture of ethyl acetate (300 ml) and water (400 ml), and adjusted to pH 3.0 with saturated aqueous sodium hydrogencarbonate. The separated organic phase was washed with water (400 ml) and brine (400 ml) , and dried with magnesium sulfate and evaporated in vacuo to give methyl (Z) -2- (2-ammo-5- fluorothιazol-4-yl) -2-hydroxyιmmoacetate (2.17 g) .

NMR ( DMSO-dg , δ ) : 3 . 7 6 ( 3H , s ) , 7 . 11 ( 2H , br s ) ,

11 . 92 ( IH , s )

Preparation 31 To a suspension of methyl (Z) -2- (2-amιno-5- fluorothιazol-4-yl) -2-hydroxyιmιnoacetate (1 g) in dichloromethane (20 ml) was added dropwise borontrichloride IM solution in dichloromethane (22.8 ml) under ice-cooling with stirring and the mixture was stirred for 3 hours at 5°C to 10°C. The resulting solution was poured into a mixture of tetrahydrofuran (30 ml) and brme (15 ml) , and adjusted to pH 3.0 with saturated aqueous sodium hydrogencarbonate. The separated organic phase was dried with magnesium sulfate and evaporated in vacuo. The residue was subjected to a column chromatography on silica gel and eluted with a mixture of ethyl acetate and methanol (2:1) . The fractions containing the object compound were combined and evaporated in vacuo to give (Z) -2- (2-amιno-5-fluorothιazol-4-yl) -2-hydroxyιmmo- acetic acid (330.26 mg) . NMR (DMSO-d ₆ , δ) : 6.94 (2H, br s)

MS : 206 (M ⁺ )

Preparation 32

A mixture of acetic anhydride (2.7 ml) and formic acid (2.2 ml) was stirred for 30 minutes at 30°C. (Z) -2- (2-Ammo- 5-fluorothιazol-4-yl) -2-hydroxyιmιnoacetιc acid (1.2 g) was added thereto with stirring under ice-coolmg, and the mixture was stirred for 3 hours at 25°C to 35°C. The reaction mixture was poured into an isopropyl ether (50 ml) . The precipitate was collected by filtration, dried under reduced pressure to give (Z) -2- (2-formylammo-5- fluorothιazol-4-yl) -2-formyloxyimmoacetic acid.

NMR (DMSO-d ₆ , δ) : 8.23 (IH, s), 8.50 (IH, s)

Preparation 33

Methyl 4-chloro-4-fluoro-2-ethoxyιmmo-3-oxobutyrate was obtained according to a similar manner to that of Preparation 6.

NMR (DMSO-d ₆ , δ) : 1.37 (3H, t, J=7Hz), 3.85 (3H, s) , 4.05 (2H, m) , 7.38 (IH, d, J=49Hz)

Preparation 34

Methyl (Z) -2- (2-ammo-5-fluorothιazol-4-yl) -2- ethoxyimmoacetate was obtained according to a similar manner to that of Preparation 8.

IR (KBr) : 1743, 1631, 1538, 1438, 1299, 1078 cm ^"1 NMR (DMSO-d ₆ , δ) : 1.19 (3H, t, J=7Hz), 3.78 (3H, s),

4.13 (2H, q, J=7Hz) , 7.20 (2H, br s)

Preparation 35

(Z) -2- (2-Ammo-5-fluorothιazol-4-yl) -2-ethoxyιmιnoacetιc acid was obtained according to a similar manner to that of Preparation 31.

IR (KBr) : 1637, 1604, 1533, 1407, 1359, 1216, 1041 cm ^"1 NMR (DMSO-d ₆ , δ) : 1.76 (3H, t, J=7Hz),

3.60 (2H, q, J=7Hz)

Preparation 36

To a suspension of (Z) -2- (2-tntylammothιazol-4-yl) -2- (2-fluoroethoxyimino) acetic acid m methanol (50 ml), was added N-bromosuccmimide (2.8 g) at room temperature with stirring and the mixture was stirred for 3 hours at 25°C to 35°C. The resulting solution was poured into a mixture of ethyl acetate (250 ml) and water (300 ml), and adjusted to pH 3.0 with aqueous sodium hydrogen carbonate. The separated organic phase was washed with water (200 ml) and dried with magnesium sulfate and evaporated in vacuo to give (Z)-2-(2- amιno-5-bromothιazol-4-yl) -2- (2-fluoroethoxyimmo) acetic acid (2.64 g) . NMR (DMSO-d ₆ , δ) : 4.10-4.15 (IH, m) , 4.18-4.23 (IH, m) ,

4 . 55-4 . 60 ( IH , m) , 4 . 75-4 . 80 ( IH , m) , 7 . 4 5 ( 2H , br s )

Preparation 37

(Z) -2- (2-Formylammo-5-chlorothιazol-4-yl) -2- (2- acetoxyethoxyimino) acetic acid was obtained according to a similar manner to that of Preparation 3.

NMR (DMSO-dg, δ) : 2.00 (3H, s) , 4.05-4.30 (4H, m) ,

8.52 (IH, s)

Preparation 38

(Z) -2- (2-Formylammothιazol-4-yl) -2- (methylthiomethoxy- lmmo) acetic acid (10 g) was suspended into methanol (100 ml) , N-bromosuccmimide (9.7 g) was added thereto at room temperature with stirring and the mixture was stirred for 3 hours at 20°C to 30°C. The resulting solution was poured into a mixture of ethyl acetate (300 ml) and water (300 ml), and adjusted to pH 3.0 with aqueous sodium hydrogencarbonate. The separated organic phase was washed with water (200 ml) and dried with magnesium sulfate and evaporated in vacuo. The residue was suspended mto methanol (100 ml) , thereto was added concentrated hydrochloric acid (17.2 ml) at room temperature. After the reaction mixture was stirred at room temperature for 4 hours, it was poured mto a mixture of ethyl acetate (400 ml) and water (300 ml) . The mixture was adjusted to pH 3.0 with aqueous sodium hydrogen carbonate. The separated organic phase was washed with water (300 ml) and dried with magnesium sulfate and evaporated in vacuo, to give (Z) -2- (2-amιno-5-bromothιazol-4-yl) -2- (methylthio- methoxyimino) acetic acid (5.5 g) . IR (KBr) : 1704, 1639, 1538, 1376, 1297, 1180, 983 cm ^-1

NMR (DMSO-dg, δ) : 2.21 (3H, s) , 5.34 (2H, s),

7.49 (2H, br s)

Preparation 39 To a solution of bromochloromethane (26.4 ml) and

N,N-dιmethylformamιde (160 ml) was added portionwise 4-mercapto-lH-l,2, 3-trιazole sodium salt (20 g) at -20°C, then it was stirred under ice-cooling for 20 minutes, at room temperature for one hour. The reaction mixture was poured into ethyl acetate (500 ml) and water (700 ml), it was adjusted to pH 7. The organic layer was separated, dried over magnesium sulfate, and evaporated. The residue was dissolved in N,N-dimethylformamide (250 ml) and pyridine (12.6 g) , and triphenylmethylchloride (44.6 g) was added to the solution under ice-cooling. After the reaction mixture was stirred at room temperature for 2 hours, it was poured into ethyl acetate (750 ml) and water (900 ml) , adjusted to pH 3.5. The organic layer was separated, dried over magnesium sulfate, and concentrated. The resulting precipitate was collected by filtration, and the precipitate was washed with diisopropyl ether. 5-Chloromethylthιo-l- tπtyl-lH-1, 2, 3-tπazole (38.2 g) was obtained.

NMR (DMSO-dg, δ) : 5.25 (2H, s) , 7.00-7.10 (6H, m) ,

7.35-7.43 (9H, m) , 8.03 (IH, s)

Preparation 40

To a suspension of 5-chloromethylthιo-l-tntyl— 1H-1, 2, 3-trιazole (10.97 g) m acetone (150 ml) was added sodium iodide (8.4 g) at room temperature, and then it was stirred at 50°C for 3 hours. After it was poured into ethyl acetate (300 ml) and water (300 ml), the organic layer was separated, dried over magnesium sulfate, and evaporated. 60% sodium hydride (1.10 g) was added to a solution of N-hydroxyphthalimide (4.49 g) in N,N-dimethylformamide (45 ml) at room temperature, it was stirred at the same temperature for 30 minutes. The above residue was added thereto, the reaction mixture was stirred at 50°C for one hour. After it was poured into ethyl acetate (250 ml) and water (300 ml), the organic layer was separated, dried over magnesium sulfate, and evaporated. To the residue

diisopropyl ether (15 ml) was added, the resulting precipitate was collected by filtration. N- (1-trιtyl-lH- 1, 2, 3-trιazol-5-yl) thiomethoxyphthalimide (5.6 g) was obtained. NMR (DMSO-dg, δ) : 5.62 (2H, s), 6.95-7.02 (6H, m) ,

7.38-7.45 (9H, m) , 7.80 (4H, s) , 8.04 (IH, s) MS (FAB) m/z : 519 (M ⁺ +l)

Preparation 41 (Z) -2- (2-Formylammo-5-bromothιazol-4-yl) -2- (1-trιtyl-

1H-1, 2, 3-trιazol-5-yl) thiomethoxyimmoacetic acid was obtained according to a similar manner to that of Preparation 3_.

NMR (DMSO-dg, δ) : 5.62 (2H, s) , 6.98-7.04 (6H, m) , 7.30-7.40 (9H, m) , 7.85 (IH, s), 8.56 (IH, s)

MS (FAB) m/z : 650 (M ⁺ +l)

Preparation 42

Methanesulfonyl chloride (15.4 g) was added to an lce- cooling solution of 4-hydroxymethyl-l-methylpyrazole (10 g) and triethylamine (19.8 g) in dichloromethane (100 ml), and the mixture was stirred at 5-10°C for two hours. After it was poured mto ice-water (150 ml) , organic layer was separated, dried over magnesium sulfate, and evaporated. On the other hand, N-hydroxyphthalimide (12.5 g) and triethylamine (8.57 g) was dissolved in N, N-dimethylformamide (160 ml) , thereto was added the above residue at room temperature. The reaction mixture was warmed at 60°C, and it was stirred at the same temperature for 2 hours. The solution was poured mto ethyl acetate (500 ml) and water (500 ml) , and then the organic layer was separated, dried over magnesium sulfate, and evaporated. N- (1-Methylpyrazol- 4-yl)methoxyphthalimide (11.3 g) was obtained.

NMR (DMSO-dg, δ) : 3.81 (3H, s) , 5.04 (2H, s) , 7.50 (IH, s) , 7.85 (5H, s)

MS m/ z : 258 (M ⁺ + l )

Preparation 43

(Z) -2- (2-Formylamιno-5-chlorothiazol-4-yl) -2- (1- methylρyrazol-4-yl)methoxyιmιnoacetιc acid (1.15 g) was obtained according to a similar manner to that of Preparation 3.

NMR (DMSO-dg, δ) : 3.82 (3H, s) , 5.03 (2H, s), 7.47

(IH, s), 7.75 (IH, s), 8.54 (IH, s), 12.8 (IH, s) MS (FAB) m/z : 344 (M ⁺ +l)

Preparation 44

To a solution of 4-hydroxymethylpyrazole (5.0 g) in tetrahydrofuran (50 ml) was added di-tert-butyl dicarbonate (11.1 g) and 4-dιmethylammopyrιdme (20 mg) . It was warmed at 50°C for 2 hours. The reaction mixture was concentrated, and subjected to column chromatography (70 g) . It was eluted with ethyl acetate. The active fractions were collected, concentrated to give l-tert-butoxycarbonyl-4- hydroxymethylpyrazole (7.9 g)

NMR (DMSO-dg, δ) : 1.57 (9H, s), 4.38 (2H, d, J=5.4Hz) ,

5.04 (IH, t, J=5.4Hz), 7.73 (IH, s), 8.08 (IH, s) MS m/z : 199 (M ⁺ +l)

Preparation 45

N- (l-tert-Butoxycarbonylpyrazol-4-yl)methoxyphthalimide was obtained according to a similar manner to that of Preparation 42.

NMR (DMSO-d ₆ , δ) : 1.57 (9H, s), 5.12 (2H, s), 7.86 (4H, s), 7.92 (IH, s), 8.43 (IH, s)

MS m/z : 344 (M ⁺ +l)

Preparat ion 46

( Z ) -2- ( 2 -Formylamιno-5-chlorothιazol -4 -yl ) -2 - ( 1-tert- butoxycarbonylpyrazol-4 -yl ) methoxyiminoacetic acid was

obtained according to a similar manner to that of Preparation 3_.

NMR (DMSO-dg, δ) : 1.58 (9H, s) , 5.13 (2H, s), 7.85 (IH, s), 8.33 (IH, s), 8.54 (IH, s) MS (FAB) m/z : 429 (M ⁺ )

Preparation 47

(Z) -2- (2-Formylaminothιazol-4-yl) -2- (3-cyclopentenyl) - oxyiminoacetic acid (15.0 g) was suspended into methanol (150 ml), and N-bromosuccinimide (10.5 g) was added thereto with ice-cooling. After the reaction mixture was stirred at room temperature for 2 hours, it was concentrated to 70 ml. The solution was poured into ethyl acetate (300 ml) and water (300 ml), and then it was adjusted to pH 3.0 with sodium hydrogen carbonate. The organic layer was separated, washed with brme, dried over magnesium sulfate, and evaporated. (Z) -2- (2-Formylammo-5-bromothιazol-4-yl) -2- (3-cyclopentenyl) oxyiminoacetic acid (8.1 g) was obtained.

IR (KBr) : 3159, 3080, 2800, 1774, 1697, 1639, 1192 cm ^"1 NMR (DMSO-dg, δ) : 1.80-2.50 (4H, m) , 5.29 (IH, m) ,

5.90 (IH, m) , 6.13 (IH, m) , 8.05 (IH, m) MS (FAB) m/z : 360 (M ⁺ )

Preparation 48 (Z) -2- (2-Aminothiazol-4-yl) -2-ethoxyimmoacetιc acid

(7.0 g) was suspended into methanol (105 ml) , and N- iodosuccinimide (8.1 g) was added thereto with ice-cooling.

After the reaction mixture was stirred at room temperature for an hour, ethyl acetate (100 ml) was added thereto, and the resulting precipitate was collected by filtration. (Z)-

2- (2-Amιno-5-iodothiazol-4-yl) -2-ethoxyιmmoacetιc acid (3.8 g) was obtained.

IR (KBr) : 1709, 1645, 1599, 1041 cm ^"1

NMR (DMSO-dg, δ) : 1.28 (3H, t, J=7.0Hz) , 4.14 (2H, q, J=7.0Hz), 7.43 (2H, s) , 11.07 (IH, s)

The following compounds (Preparations 49 and 50) were obtained according to a similar manner to that of Preparation ii*

Preparation 49

(Z) -2- (2-Amino-5-bromothiazol-4-yl) -2-ethoxyimιnoacetιc acid

IR (KBr) : 1705, 1643, 1595, 1568 cm ^"1

NMR (DMSO-dg, δ) : 1.24 (3H, t, J=7.0Hz) , 4.14 (2H, q, J=7.0Hz), 7.86 (2H, br)

MS (FAB) m/z : 294 (M ⁺ ) , 296 (M ⁺ +2)

Preparation 50

(Z) -2- (2-Ammo-5-ιodothιazol-4-yl) -2-acetoxyιmmoacetιc

NMR (DMSO-dg, δ) : 2.24 (3H, s), 7.55 (2H, s)

Preparation 51

(Z) -2- (2-Formylamιno-5-chlorothιazol-4-yl) -2- (1- trιtylιmιdazol-4-yl)methoxyiminoacetic acid was obtained according to a similar manner to that of Preparation 3

NMR (DMSO-dg, δ) : 5.05 (2H, s), 6.95 (IH, s), 7.25- 7.40 (16H, m) , 8.54 (IH, s), 12.86 (IH, br s)

Preparation 52

Methyl (Z) -2- (2-tert-butoxycarbonylamιno-5- chlorothιazol-4-yl) -2-pentenoate was obtained according to a similar manner to that of Preparation 13.

NMR (CDC1 ₃ , δ) : 1.10 (3H, t, J=7.5Hz), 1.52 (9H, s), 2.47 (2H, qm, J=7.5Hz), 3.78 (3H, s), 6.56 (IH, t,

J=7.5Hz)

Preparation 53

To a solution of methyl (Z) -2- (2-tert- butoxycarbonylammo-5-chlorothιazol-4-yl) -2-pentenoate (3 g)

in 2-propanol (9 ml) was added lN-sodium hydroxide solution (27 ml) under at 30°C. The stirring was continued for 3 hours at the same temperature. The reaction mixture was poured mto a mixture of ethyl acetate (200 ml) and water (50 ml) . The separated organic phase was washed with brme (100 ml) and dried over magnesium sulfate and evaporated in vacuo to give (Z) -2- (2-tert-butoxycarbonylammo-5-chlorothιazol-4- yl) -2-pentenoιc acid (1.7 g) .

NMR (DMSO-dg, δ) : 1.07 (3H, t, J=7.5Hz) , 1.47 (9H, s) , 2.44 (2H, qin, J=7.5Hz) , 6.38 (IH, t, J=7.5Hz)

Preparation 54

Ethyl (Z) -2- (2-tert-butoxycarbonylammo-5-chlorooxazol- 4-yl) -2-ethoxyιmmoacetate was obtained according to a similar manner to that of Preparation 13.

NMR (DMSO-dg, δ) : 1.15-1.35 (6H, m) , 1.42 (9H, s) , 4.23 (2H, q, J=7.0Hz), 4.32 (2H, q, J=7.1Hz)

Preparation 55 To a solution of ethyl (Z) -2- (2-tert- butoxycarbonylamιno-5-chlorooxazol-4-yl) -2-ethoxyιmmoacetate (1.85 g) in dichloromethane (5.6 ml) and anisole (1.85 ml) was added dropwise trifluoroacetic acid (3.7 ml) at 20°C. The stirring was continued for 2 hours at 30°C. The reaction mixture was poured mto isopropyl ether (100 ml) . The resulting powder was collected by filtration, and dried in vacuo to give ethyl (Z) -2- (2-ammo-5-chlorooxazol-4-yl) -2- ethoxyiminoacetate (930 mg) .

NMR (DMSO-d _β , δ) : 1.05-1.35 (6H, m) , 4.10-4.4 (4H, m) , 7.25 (2H, br s)

MS (APCI) m/z : 262 (M+H) ⁺

Preparation 56

(Z) -2- (2-Ammo-5-chlorooxazol-4-yl) -2-ethoxyιmmoacetιc acid was obtained accordmg to a similar manner to that of

Preparation 31.

NMR (DMSO-dg, δ) : 1.10-1.40 (6H, m) , 4.00-4.40 (4H, m) , 7.02 (2H, br s) MS (APCI) m/z : 234 (M+H) ⁺

The following compounds (Examples 9 to 21) were obtained according to a similar manner to that of Example 3.

Example 9 7β- [ (Z) -2- (2-Amino-5-fluorothiazol-4-yl) -2-ethoxyimino- acetamido] -3- [5-amino-l- (2-hydroxyethyl) -2-pyrazolio]methyl- 3-cephem-4-carboxylate

IR (KBr) : 1770, 1614, 1535, 1353, 1220, 1062 cm ^"1 NMR (DMSO-dg, δ) : 1.20 (3H, t, J=7Hz) , 2.93 and 3.19 (2H, ABq, J=17Hz), 3.50-3.70 (2H, m) , 4.07 (2H, q,

J=7Hz), 4.15-4.55 (2H, m) , 5.00 (IH, d, J=5Hz), 5.05 and 5.22 (2H, ABq, J=18Hz), 5.60 (IH, dd, J=5Hz, 8Hz), 5.81 (IH, d, J=3Hz) , 7.12 (2H, br s) , 7.28 (2H, br s), 8.10 (IH, d, J=3Hz), 9.50 (IH, d, J=8Hz)

MS (FAB) m/z : 555 (M ⁺ )

Example 10

7β-[ (Z) -2- (2-Amιno-5-bromothιazol-4-yl)-2-<2- fluoroethoxyimino) acetamido] -3- [5-ammo-l- (2-hydroxyethyl) -2- pyrazolio]methy1-3-cephem-4-carboxylate

IR (KBr) : 1772, 1666, 1639, 1614, 1535, 1392 cm ^"1 NMR (DMSO-dg, δ) : 2.89 and 3.20 (2H, ABq, J=17Hz) ,

3.40-3.65 (2H, m) , 4.05-4.55 (2H+2H, m) , 4.55-4.95 (2H, m) , 5.00 (IH, d, J=5Hz), 5.05 and 5.21 (2H,

ABq, J=18Hz) , 5.60 (IH, dd, J=5Hz, 8Hz), 5.81 (IH, d, J=3Hz), 7.27 (2H, br s) , 7.42 (2H, br s) , 8.10 (IH, d, J=3Hz), 9.52 (IH, d, J=8Hz)

Example 11

7β- [ (Z) -2- (2-Amino-5-bromothiazol-4-yl) -2- (methylthiomethoxyimino) acetamido] -3- [5-amino-l- (2- hydroxyethyl) -2-pyrazolio]methy1-3-cephem-4-carboxylate IR (KBr) : 1772, 1612, 1537, 1351, 1218, 1064 cm ^"1 NMR (DMSO-dg, δ) : 2.21 (3H, s) , 2.90 and 3.17 (2H,

ABq, J=17Hz), 3.40-3.65 (2H, m) , 4.23-4.60 (2H, m) , 5.00 (IH, d, J=5Hz) , 5.05-5.25 (2H+2H, m) , 5.69 (IH, dd, J=5Hz, 8Hz), 5.81 (IH, d, J=3Hz), 7.28 (2H, br s) , 7.45 (2H, br s) , 8.10 (IH, d, J=3Hz) , 9.56 (IH, d, J=8Hz)

Example 12

7β- [ (Z) -2- (2-tert-Butoxycarbonylamino-5-chlorothiazol-4- yl) -2-pentenoylamino] -3- [1- (2-hydroxyethyl) -5-amino-2- pyrazolio]methyl-3-cephem-4-carboxylate

NMR (DMSO-dg, δ) : 1.01 (3H, t, J=7.5Hz) , 1.46 (9H, s) , 2.10-2.30 (2H, m) , 3.10-3.30 (2H, m) , 3.30-3.70 (2H, m) , 4.00-4.45 (2H, m) , 5.10-5.40 (3H, m) , 5.80-5.95 (2H, m) , 6.37 (IH, t, J=7.5Hz) , 7.32 (2H, br s) , 8.08 (IH, d, J=3.1Hz), 9.30 (IH, d, J=8.0Hz)

Example 13

7β- [ (Z) -2- (2-Amino-5-chlorooxazol-4-yl) -2-ethoxyimino- acetamido] -3- [1- (2-hydroxyethyl) -5-amino-2-pyrazolio] — methyl-3-cephem-4-carboxylate

IR (KBr) : 1772, 1668, 1602, 1585, 1392, 1043 cm ^-1 NMR (DMSO-dg, δ) : 1.21 (3H, t, J=7.0Hz), 3.00 and 3.23 (2H, ABq, J=17.3Hz), 3.35-3.80 (2H, m) , 4.06 (2H, q, J=7.0Hz), 4.20-4.55 (2H, m) , 5.06 (IH, d, J=5.0Hz) , 5.0-5.45 (2H, m) , 5.66 (IH, dd, J=8.4Hz,

5.0Hz), 5.83 (IH, d, J=3.1Hz), 7.15 (2H, br s), 7.28 (2H, br s) , 8.08 (IH, d, J=3.1Hz) , 9.57 (IH, d, J=8.4Hz)

Example 14

7β- [ (Z) -2-tert-Butoxycarbonylmethoxyιmιno-2- (5-chloro-2- formylamιnothιazol-4-yl) acetamido] -3- [5-ammo-l- (2- hydroxyethyl) -2-pyrazolio]methyl-3-cephem-4-carboxylate

MS (FAB) m/z : 684.9 (M ⁺ )

Example 15

7β- [ (Z) -2-Carbamoylmethoxyιmιno-2- (5-chloro-2- formylamιnothιazol-4-yl) acetamido] -3- [5-ammo-l- (2- hydroxyethyl) -2-pyrazolio]methyl-3-cephem-4-carboxylate MS (FAB) m/z : 628.2 (M ⁺ ), 630.2 (M ⁺ +2)

Example 16

7β- [ ( Z) -2- ( 1-tert-Butoxycarbonyl-l-methylethoxyιmmo) -2- (2-amιno-5-chlorothιazol-4-yl) acetamido] -3- [ 5 -amino- 1- (2- hydroxyethyl) -2-pyrazolio] methyl-3-cephem-4-carboxylate

IR (KBr) : 1788, 1643 cm ^"1 MS (FAB) m/z : 685.1 (M ⁺ ), 687.2 (M ⁺ +2)

Example 17 7β- [ (Z) -2- (3-tert-Butoxycarbonylallyloxyιmmo) -2- (5- chloro-2-f ormylammothιazol-4-yl) acetamido] -3- [5-ammo-l- (2- hydroxyethyl) -2 -pyrazolio] methy 1-3 -cephem- 4 -carboxy late IR (KBr) : 1772, 1749, 1684, 1649, 1541 cm ^"1 MS (FAB) m/z : 711.0 (M ⁺ ) , 713.2 (M ⁺ +2)

Example 18

7β- [ (Z) -2-Ethoxyimmo-2- (2-amιno-5-methylthιazol-4-yl) - acetamido] -3- [5-ammo-l- (2-hydroxyethyl) -2-pyrazolιo]methyl- 3-cephem-4-carboxylate IR (KBr) : 3336, 1772, 1649, 1610 cm ^"1

NMR (DMSO-dg, δ) : 1.22 (3H, t, J=7.0Hz) , 2.33 (3H, s) 3.18, 2.91 (2H, ABq, J=17.0Hz) , 3.5-3.7 (2H, m) , 4.07 (2H, q, J=7.0Hz), 4.2-4.6 (2H, m) , 4.99 (IH, d, J=4.8Hz), 5.21, 5.04 (2H, ABq, J=15Hz) , 5.59 (IH, dd, J=8.6Hz, 4.8Hz) , 5.81 (IH, d, J=3.1Hz),

6.90 (2H, br s) , 7.27 (2H, br s) , 8.10 (IH, d, J=3.1Hz), 9.34 (IH, d, J=8.6Hz) MS (FAB) m/z : 551.0 (M ⁺ +l)

Example 19

7β- [ (Z) -2-Trityloxyimino-2- (2-tπtylammo-5- methylthιazol-4-yl) acetamido] -3- [5-ammo-l- (2-hydroxyethyl) - 2-pyrazolio]methyl-3-cephem-4-carboxylate IR (KBr) : 1792, 1774 cm ^'1 MS (FAB) m/z : 1007.3 (M ⁺ )

Example 20

7β- [ (Z) -2-Methoxyimmo-2- (2-amino-5-methylthιazol-4-yl) - acetamido] -3- [5-amino-l- (2-hydroxyethyl) -2-pyrazolio]methyl- 3-cephem-4-carboxylate

IR (KBr) : 1770, 1649, 1614, 1045 cm ^"1

NMR (DMSO-dg, δ) : 2.33 (3H, s) , 2.91, 3.19 (ABq, 2H, J=17.4Hz) , 3.5-3.7 (2H, m) , 3.81 (3H, s) , 4.2-4.6 (2H, m) , 4.99 (IH, d, J=4.8Hz) , 5.04, 5.21 (2H, ABq, J=15.3Hz) , 5.59 (IH, dd, J=8.6Hz, 4.8Hz) ,

5.82 (IH, d, J=3.2Hz) , 6.91 (2H, br s) , 7.33 (2H, br s) , 8.10 (IH, d, J=3.2Hz) , 9.37 (IH, d, J=8.6Hz; MS (FAB) m/z : 537.2 (M ⁺ +l)

Example 21

7β- [ (Z) -2-Methoxyimmo-2- (2-formylamino-5-cyanothiazol- 4-yl) acetamido] -3- [5-amino-l- (2-hydroxyethyl) -2-pyrazolio] - methyl-3-cephem-4-carboxylate

MS (FAB) m/z 576.1 ;M ⁺ +1 ^'

Example 22

To a solution of phosphorus pentachloride (2.3 g) in 40 ml of dichloromethane, (Z) -2-difluoromethoxyimino-2- (2-ammo- 5-chlorothiazol-4-yl) acetic acid (2.0 g) was added at -30°C and stirred at -15°C for 2 hours to generate acid chloride in

situ. A solution of 7β-amιno-3- [5-amino-l- (2-hydroxyethyl) - 2-pyrazolio]methyl-3-cephem-4-carboxylate (2.77 g) and N- (trimethylsilyl) acetamide (9.66 g) in 28 ml of N,N- dimethylformamide and 28 ml of tetrahydrofuran was added to the acid chloride solution at 0°C. After 3 hours, the reaction mixture was dropped mto 600 ml of ethyl acetate to get precipitates, which were purified by column chromatography on HP-20 resm and preparative HPLC to get 57 mg of 7β- [ (Z) -2- (2-ammo-5-chlorothιazol-4-yl) -2- (difluoromethoxyimino) acetamido] -3- [5-ammo-l- (2- hydroxyethyl) -2-pyrazolιo]methyl-3-cephem-4-carboxylate . IR (KBr) : 1774, 1668, 1639, 1614 cm ^"1 NMR (DMSO-dg, δ) : 2.91, 3.20 (2H, ABq, J=17.3Hz), 3.4-3.9 (2H, m) , 4.2-4.6 (2H, m) , 5.03 (IH, d, J=4.9Hz), 5.06, 5.21 (2H, ABq, J=15.1Hz),

5.61 (IH, dd, J=8.2Hz, 4.9Hz) , 5.81 (IH, d, J=3.1Hz), 7.12 (IH, t, J=70.8Hz), 7.28 (2H, br s), 7.54 (2H, br s), 8.10 (IH, d, J=3.1Hz), 9.87 (IH, d, J=8.2Hz), MS (FAB) m/z : 593.0 (M ⁺ )

Example 23

7β-[ (Z) -2- (5-Chloro-2-formylammothιazol-4-yl)-2- (fluoromethoxyimino) acetamido] -3- [5-ammo-l- (2-hydroxyethyl) - 2-pyrazolio]methyl-3-cephem-4-carboxylate was obtained according to a similar manner to that of Example 22.

NMR (DMSO-dg, δ) : 2.94, 3.25 (2H, ABq, J=17.4Hz), 3.5-3.8 (2H, m) , 4.2-4.6 (2H, m) , 5.06 (IH, d, J=4.8Hz), 5.08, 5.21 (2H, ABq, J=15.4Hz), 5.67 (IH, dd, J=8.4Hz, 4.8Hz), 5.77 (2H, d, J=53.7Hz), 5.83

(IH, d, J=3.1Hz), 7.31 (2H, br s) , 8.09 (IH, d, J=3.1Hz), 8.55 (IH, s), 9.81 (IH, d, J=8.4Hz) MS (FAB) m/z : 603.0 (M ⁺ )

Example 24

Phosphorus pentachloride (2.48 g) was suspended mto dichloromethane (19 ml) , and then it was cooled to -20°C, and (Z) -2- (2-amino-5-ιodothιazol-4-yl) -2-ethoxyιmιnoacetιc acid (3.7 g) was added thereto. After it was stirred at -15°C for 2 hours, diisopropyl ether (20 ml) was added thereto, and the resulting precipitate was collected by filtration (Precipitate A) . On the other hand, 7β-amιno-3- [5-ammo-l- (2-hydroxyethyl) -2-pyrazolio]methyl-3-cephem-4-carboxylate monohydrochloride (3.57 g) was suspended mto ethyl acetate (20 ml) and N,N-dιmethylformamide (30 ml) , and then N- trimethylsilylacetamide (11.4 g) was added thereto. It was warmed at 35°C with stirring for 10 minutes to give a clear solution. The precipitate A which was synthesized before was added to this solution with stirring at 5°C, then it was stirred at the same temperature for an hour. After that, the reaction mixture was poured into a mixed solution of ethyl acetate (250 ml), diisopropyl ether (50 ml) , and methanol (7 ml) . The resulting precipitate was collected by filtration, and it was dissolved into water (100 ml) at pH 6.5. After the solution was adjusted to pH 4.0 with IN-hydrochloric acid, it was subjected to column chromatography on Diaion HP-20 (90 ml) [Trademark; Mitsubishi Kasei Co.] . The column was washed with water (500 ml) , and the object compound was eluted with 40% aqueous 2-propanol. The active fractions were collected, concentrated, and lyophilized to give 7β-

[ (Z) -2- (2-ammo-5-iodothιazol-4-yl) -2-ethoxyιminoacetamido] - 3- [5-amino-l- (2-hydroxyethyl) -2-pyrazolio]methyl-3-cephem-4- carboxylate (0.47 g) .

IR (KBr) : 1774, 1614, 1529, 1039 cm ^"1 NMR (DMSO-dg, δ) : 1.29 (3H, t, J=7.0Hz) , 2.93, 3.19

(2H, ABq, J=17Hz) , 3.40-3.70 (2H, m) , 4.12 (2H, q, J=7.0Hz), 4.20-4.60 (2H, m) , 5.00 (IH, d, J=4.8Hz), 5.05, 5.22, (2H, ABq, J=15Hz) , 5.60 (IH, dd, J=4.8Hz, 8.5Hz), 5.82 (IH, d, J=3.2Hz), 7.27 (2H, s) , 7.38 (2H, s), 8.10 (IH, d, J=3.2Hz) , 9.42 (IH,

d , J=8 . 5Hz ) MS ( FAB ) m/ z : 663 ( M ⁺ + l )

The following compounds (Examples 25 to 28) were obtained according to a similar manner to that of Example 24.

Example 25

7β- [ (Z) -2- (2-Amino-5-bromothiazol-4-yl) -2-ethoxyimino- acetamido] -3- [5-amino-l- (2-hydroxyethyl) -2-pyrazolio]methyl- 3-cephem-4-carboxylate IR (KBr) : 1772, 1666, 1649, 1614, 1537, 1041 cm ^"1

NMR (DMSO-dg, δ) : 1.25 (3H, t, J=7.0Hz), 2.93, 3.20

(2H, ABq, J=17Hz), 3.50-3.80 (2H, m) , 4.11 (2H, q, J=7.0Hz), 4.20-4.60 (2H, m) , 5.00 (IH, d, J=4.9Hz) , 5.12, 5.21 (2H, ABq, J=15Hz), 5.59 (IH, dd, J=4.9Hz, 8.4Hz), 5.81 (IH, d, J=3.2Hz), 7.23 (2H, s) , 7.38 (2H, s), 8.10 (IH, d, J=3.2Hz) , 9.43 (IH, d, J=8.4Hz) MS (FAB) m/z : 615 (M ⁺ ), 617 (M ⁺ +2)

Example 26

7β-[ (Z) -2- (2-Amino-5-chlorothiazol-4-yl) -2- ethoxyiminoacetamido] -3- [5-amino-l- (2-hydroxyethyl) -2- pyrazolio]methyl-3-cephem-4-carboxylate

IR (KBr) : 1772, 1612, 1539, 1038 cm ^"1 NMR (DMSO-dg, δ) : 1.23 (3H, t, J=7.0Hz), 2.93, 3.19

(2H, ABq, J=17Hz), 3.40-3.80 (2H, m) , 4.10 (2H, q, J=7.0Hz) , 4.20-4.60 (2H, m) , 5.01 (IH, d, J=4.9Hz), 5.05, 5.22 (2H, ABq, J=15Hz), 5.60 (IH, dd, J=4.9Hz, 8.5Hz) , 5.82 (IH, d, J=3.2Hz), 7.27 (2H, s), 7.37 (2H, s), 8.10 (IH, d, J=3.2Hz), 9.46 (IH, d, J=8.5Hz) MS (FAB) m/z : 571 (M ⁺ )

Example 27 7β-[ (Z)-2- (2-Amino-5-chlorothiazol-4-yl) -2-

methoxyimmoacetamido] -3- [5-ammo-l- (2-hydroxyethyl) -2- pyrazolio]methyl-3-cephem-4-carboxylate

IR (KBr) : 1770, 1653, 1610, 1579, 1539, 1049 cm ^"1 NMR (DMSO-dg, δ) : 2.92, 3.20 (2H, ABq, J=17Hz) , 3.4-3.8 (2H, m) , 3.84 (3H, s) , 4.2-4.6 (2H, m) ,

5.00 (IH, d, J=4.9Hz), 5.05, 5.21 (2H, ABq, J=15Hz), 5.60 (IH, dd, J=4.9Hz, 8.5Hz), 5.82 (IH, d, J=3.2Hz), 7.28 (2H, s) , 7.41 (2H, s) , 8.10 (IH, d, J=3.2Hz), 9.52 (IH, d, J=8.5Hz) MS (FAB) m/z : 557 (M ⁺ )

Example 28

7β- [ (Z) -2- (2-Amino-5-methylthiothιazol-4-yl) -2- methoxyiminoacetamido] -3- [5-ammo-l- (2-hydroxyethyl) -2- pyrazolio]methyl-3-cephem-4-carboxylate

IR (KBr) : 1772, 1649, 1614, 1537, 1525, 1041 cm ^"1 NMR (DMSO-dg, δ) : 2.38 (3H, s) , 2.93, 3.20 (2H, ABq,

J=17Hz), 3.40-3.80 (2H, m) , 3.84 (3H, s), 4.20-4.60 (2H, m) , 5.00 (IH, d, J=4.9Hz) , 5.05, 5.22 (2H, ABq, J=16Hz), 5.60 (IH, dd, J=4.9Hz, 8.5Hz) , 5.82

(IH, d, J=3.2Hz) , 7.26 (2H, s), 7.32 (2H, s), 8.10 (IH, d, J=3.2Hz), 9.41 (IH, d, J=8.5Hz) MS (FAB) m/z : 569 (M ⁺ +l)

The following compounds (Examples 29 to 32) were obtained according to a similar manner to that of Example 1.

Example 29

7β- [ (Z) -2- (2-Formylammo-5-chlorothιazol-4-yl) -2- propargyloxyimino) acetamido] -3- [5-amino-l- [2-hydroxyethyl) -2- pyrazolιo]methyl-3-cephem-4-carboxylate

NMR (DMSO-dg, δ) : 3.15-3.45 (2H+1H, m) , 3.50-3.65 (2H, m) , 4.10-4.45 (2H, m) , 4.65-4.70 (2H, m) , 5.00-5.35 (2H, m) , 5.07 (IH, d, J=4.9Hz) , 5.81 (IH, dd, J=4.9Hz, 8.4Hz) , 5.85 (IH, d, J=3.2Hz), 8.00 (IH,

d, J=3.2Hz), 8.48 (IH, s) , 9.73 (IH, d, J=8.4Hz) , 12.87 (IH, br s)

Example 30 7β- [ (Z) -2- (2-Formylamino-5-chlorothiazol-4-yl) -2-

(methylthiomethoxyimino) acetamido] -3- [5-amino-l- (2- hydroxyethyl) -2-pyrazolio]methyl-3-cephem-4-carboxylate

NMR (DMSO-dg, δ) : 2.10 (3H, s), 3.2-3.4 (2H, m) , 4.05- 4.50 (2H, m) , 5.00-5.40 (2H+2H, m) , 5.18 (IH, d, J=4.9Hz) , 5.85 (IH, dd, J=4.9Hz, 8.4Hz) , 5.90 (IH, d, J=3.1Hz), 8.12 (IH, d, J=3.1Hz), 8.52 (IH, s), 9.65 (IH, d, J=8.4Hz), 12.9 (IH, br s)

Example 31 7β- [2- (2-Formylamino-5-chlorothiazol-4-yl) -2- oxoacetamido] -3- [5-amino-l- (2-hydroxyethyl) -2-pyrazolio] - methyl-3-cephem-4-carboxylate

NMR (DMSO-dg, δ) : 3.20-3.40 (2H, m) , 2.45-2.60 (2H, m) , 4.20-4.45 (2H, m) , 5.10-5.40 (2H+1H, m) , 5.75-5.85 (1H+1H, m) , 8.89 (2H, br s) , 7.97 (IH, d,

J=2.9Hz) , 8.53 (IH, s) , 9.84 (IH, d, J=7.9Hz), 13.00 (IH, s)

Example 32 7β- [ (Z)-2- (2-Formylamino-5-chlorothiazol-4-yl) -2- (1- tritylimidazol-4-yl)methoxyiminoacetamido] -3- [1- (2- hydroxyethyl) -5-amino-2-pyrazolio]methy1-3-cephem-4- carboxylate

NMR (DMSO-dg, δ) : 3.0-3.40 (2H, m) , 3.50-3.75 (2H, m) , 4.0-4.50 (2H, m) , 5.05-5.40 (5H, m) , 5.80-5.95 (2H, m) , 7.14 (IH, s), 7.30-7.60 (18H, m) , 8.03 (IH, d, J=3.1Hz), 8.54 (IH, s) , 9.74 (IH, d, J=8.4Hz) , 12.9 (IH, br s)

The following compounds (Examples 33 to 34) were

obtained according to a similar manner to that of Example 2.

Example 33

7β- [ (Z) -2-(2-Formylamιno-5-chlorothιazol-4-yl) -2- (2- acetoxyethoxyimino) acetamido] -3- [5-ammo-l- (2-hydroxyethyl) - 2-pyrazolιo]methyl-3-cephem-4-carboxylate

IR (KBr) : 1776, 1726, 1673, 1631, 1542, 1390, 1280,

1064 cm ^"1 NMR (DMSO-dg, δ) : 2.00 (3H, s), 3.00-3.40 (2H, m) , 3.45-3.65 (2H, m) , 4.10-4.50 (2H+2H+2H, m) , 5.05

(IH, d, J=4.9Hz), 5.00-5.30 (2H, m) , 5.68 (IH, dd, J=4.9Hz, 7.9Hz), 5.83 (IH, d, J=2.8Hz) , 7.32 (2H, br s) , 8.09 (IH, d, J=2.8Hz), 8.53 (IH, s) , 9.62 (IH, d, J=7.9Hz)

Example 34

7β- [ (Z) -2- (2-Formylamιno-5-fluorothιazol-4-yl) -2- formyloxyimmo) acetamido] -3- (5-ammo-l- (2-hydroxyethyl) -2- pyrazolio]methyl-3-cephem-4-carboxylate NMR (DMSO-dg, δ) : 3.25-3.55 (2H, m) , 3.60-3.70 (2H, m) , 5.05-5.50 (1H+2H, m) , 5.75 (IH, dd, J=5Hz, 7.9Hz) , 5.91 (IH, d, J=3Hz) , 7.48 (2H, br s), 7.95 (IH, s) , 7.98 (IH, d, J=3Hz) , 8.47 (IH, s), 9.75 (IH, d, J=7.9Hz)

The following compounds (Examples 35 to 38) were obtained according to a similar manner to that of Example 5.

Example 35 7β-[ (Z) -2-(2-Ammo-5-chlorothιazol-4-yl)-2-

(propargyloxyimmo) acetamido] -3- [5-ammo-l- (2-hydroxyethyl) - 2-pyrazolio]methyl-3-cephem-4-carboxylate

IR (KBr) : 1770, 1639, 1614, 1540, 1324, 1025 cm ^"1 NMR (DMSO-dg, δ) : 2.89 and 3.20 (2H, ABq, J=17.3Hz) , 3.35-3.45 (IH, m) , 3.45-3.65 (2H, m) , 4.20-4.60

(2H, m) , 4.60-4.80 (2H, m) , 5.00 (IH, d, J=4.8Hz), 5.05 and 5.18 (2H, ABq, J=18.4Hz), 5.60 (IH, dd, J=4.8Hz, 8.3Hz), 5.81 (IH, d, J=3.2Hz), 7.19 (2H, br s), 7.39 (2H, br s), 8.09 (IH, d, J=3.2Hz), 9.55 (IH, d, J=8.3Hz)

Example 36

7β- [ (Z) -2- (2-Amino-5-chlorothiazol-4-yl) -2- (methylthiomethoxyimino) acetamido] -3- [5-amino-l- (2- hydroxyethyl) -2-pyrazolio]methyl-3-cephem-4-carboxylate IR (KBr) : 1772, 1614, 1538, 1390, 1355, 1062 cm ^"1 NMR (DMSO-dg, δ) : 2.20 (3H, s) , 2.92 and 3.19 (2H,

ABq, J=17.3Hz), 3.45-3.65 (2H, m) , 4.20-4.55 (2H, m) , 5.00 (IH, d, J=4.9Hz), 5.05-5.30 (2H, m) , 5.25 (2H, s), 5.60 (IH, dd, J=4.9Hz, 8.3Hz), 5.82 (IH, d, J=3.2Hz), 7.30 (2H, br s), 7.40 (2H, br s) , 8.09 (IH, d, J=3.2Hz), 9.56 (IH, d, J=8.3Hz)

Example 37 7β- [ (Z) -2- (2-Amino-5-chlorothiazol-4-yl) -2-oxo- acetamido] -3- [5-amino-l- (2-hydroxyethyl) -2-pyrazolio]methyl- 3-cephem-4-carboxylate

IR (KBr) : 1772, 1668, 1614, 1538, 1390, 1353, 1062 cm ^"1 NMR (DMSO-dg, δ) : 2.98 and 3.23 (2H, ABq, J=17.2Hz), 3.25-3.65 (2H, m) , 4.15-4.55 (2H, m) , 5.04 (IH, d,

J=4.9Hz) , 5.07 and 5.25 (2H, ABq, J=18.2Hz), 5.63 (IH, dd, J=4.9Hz, 7.9Hz), 5.82 (IH, d, J=2.8Hz), 7.30 (2H, br s) , 7.58 (2H, br s), 8.09 (IH, d, J=2.8Hz), 9.68 (IH, d, J=7.9Hz)

Example 38

7β- [ (Z) -2- (2-Amino-5-chlorothiazol-4-yl) -2- (imidazol-4- yDmethoxyiminoacetamido] -3- [1- (2-hydroxyethyl) -5-amino-2- pyrazolio]methyl-3-cephem-4-carboxylate NMR (DMSO-dg, δ) : 2.89 and 3.17 (2H, ABq, J=17.7Hz) ,

3.40-3.70 (2H, m) , 4.20-4.55 (2H, m) , 4.90-5.30 (5H, m) , 5.60 (IH, dd, J=8.4Hz, 4.8Hz) , 5.82 (IH, d, J=3.1Hz) , 7.08 (IH, s), 7.27 (2H, br s) , 7.35 (2H, br s) , 7.57 (IH, s) , 8.09 (IH, d, J=3.1Hz) , 9.64 (IH, d, J=8.4Hz) MS (FAB) m/z : 624 (M+H) ⁺

The following compounds (Examples 39 to 43) were obtained according to a similar manner to that of Example 7.

Example 39

7β- [ (Z) -2-tert-Butoxycarbonylmethoxyιmmo-2- (2-ammo-5- chlorothιazol-4-yl ) acetamido] -3- [5-ammo-l- (2-hydroxyethyl) - 2-pyrazolio] met hyl-3-cephem-4- car boxy late MS (FAB) m/z : 657.1 (M ⁺ )

Example 40

7β- [ (Z) -2-Carbamoylmethoxyιmιno-2- (2-amιno-5- chlorothιazol-4-yl) acetamido] -3- [5-ammo-l- (2-hydroxyethyl) - 2-pyrazolio]methyl-3-cephem-4-carboxylate

IR (KBr) : 1770, 1676, 1616, 1539 cm ^"1

NMR (DMSO-dg, δ) : 2.89, 3.19 (2H, ABq, J=17.4Hz) , 3.59 (2H, br s) , 4.2-4.6 (2H, m) , 4.67 (2H, s), 5.00 (IH, d, J=4.9Hz), 5.06, 5.20 (2H, ABq, J=15Hz), 5.62 (IH, dd, J=8.6Hz, 4.9Hz), 5.81 (IH, d,

J=3.1Hz), 7.26 (2H, br s) , 7.41 (2H, br s) , 8.10 (IH, d, J=3.1Hz) , 9.45 (IH, d, J=8.6Hz)

Example 41 7β- [ (Z) -2-(2-Amιno-5-chlorothιazol-4-yl)-2- fluoromethoxyimmoacetamido] -3- [5-amino-l- (2-hydroxyethyl) -2- pyrazolio]methyl-3-cephem-4-carboxylate

IR (KBr) : 1770, 1668, 1639, 1614 cm ^"1 NMR (DMSO-dg, δ) : 2.88, 3.21 (2H, ABq, J=17.3Hz) , 3.5-3.7 (2H, m) , 4.2-4.6 (2H, m) , 5.01 (IH, d,

J=4.9Hz), 5.07, 5.18 (2H, ABq, J=15.2Hz) , 5.60 (IH, dd, J=8.3Hz, 4.9Hz), 5.71 (IH, d, J=56.1Hz), 5.81 (IH, d, J=3.2Hz), 7.22 (2H, br s), 7.48 (2H, br s), 8.10 (IH, d, J=3.2Hz), 9.72 (IH, d, J=8.3Hz) MS (FAB) m/z : 575.0 (M ⁺ )

Example 42

7β- [ (Z) -2-Hydroxyimino-2- (2-amino-5-methylthiazol-4-yl) - acetamido] -3- [5-amino-l- (2-hydroxyethyl) -2-pyrazolio]methyl- 3-cephem-4-carboxylate

IR (KBr) : 3332, 1770, 1649, 1618 cm ^"1

NMR (DMSO-dg, δ) : 2.32 (3H, s), 2.88, 3.16 (2H, ABq, J=17.5Hz), 3.5-3.7 (2H, m) , 4.2-4.5 (2H, m) , 4.99 (IH, d, J=4.9Hz), 5.04, 5.21 (2H, ABq, J=15.2Hz) , 5.61 (IH, dd, J=8.6Hz, 4.9Hz), 5.81 (IH, d,

J=3.2Hz), 6.81 (2H, br s), 7.30 (2H, br s) , 8.09 (IH, d, J=3.2Hz), 9.19 (IH, d, J=8.6Hz) MS (FAB) m/z : 523.1 (M ⁺ +l)

Example 43

7β- [ (Z) -2-Methoxyimino-2- (2-amino-5-cyanothiazol-4-yl) - acetamido] -3- [5-amino-l- (2-hydroxyethyl) -2-pyrazolio]methyl- 3-cephem-4-carboxylate

IR (KBr) : 3390, 2210, 1772, 1649, 1618 cm ^-1 NMR (DMSO-dg, δ) : 2.92, 3.22 (2H, ABq, J=17.3Hz),

3.5-3.7 (2H, m) , 3.91 (3H, s), 4.2-4.6 (2H, m) , 5.01 (IH, d, J=4.9Hz), 5.07, 5.21 (2H, ABq, J=15.1Hz), 5.60 (IH, dd, J=8.6Hz, 4.9Hz), 5.82 (IH, d, J=3.1Hz), 7.30 (2H, br s), 8.11 (IH, d, J=3.1Hz) , 8.34 (2H, br s), 9.61 (IH, d, J=8.6Hz)

MS (FAB) m/z : 548.0 (M ⁺ +l)

Example 44

To a suspension of 7β- [ ( Z ) -2- ( 2 -tert- butoxycarbonylamιno- 5-chlorothιazol-4 -yl ) -2-pentenoylammo] -

3- [ 1- (2-hydroxyethyl) -5-ammo-2-pyrazolio]methyl-3-cephem-4- carboxylate (750 mg) in dichloromethane (2.4 ml) and anisole (0.75 ml) was added dropwise trifluoroacetic acid (1.5 ml) at 20°C. The stirring was continued for 2 hours at the room temperature. The reaction mixture was poured mto isopropyl ether (30 ml) . The resulting powder was collected by filtration and dried m vacuo. The powder was dissolved in a water (50 ml), adjusted to pH 3.0 with aqueous sodium hydrogencarbonate and then subjected to column chromatography on HP-20 (30 ml) and eluted with 20% aqueous isopropyl alcohol. And then active fraction was lyophilized to give 7β- [ (Z) -2- (2-amιno-5-chlorothιazol-4-yl) -2-pentenoylammo] -3- [1- (2-hydroxyethyl) -5-ammo-2-pyrazolιo]methyl-3-cephem-4- carboxylate (60 mg) . NMR (DMSO-dg, δ) : 0.98 (3H, t, J=7.5Hz) , 2.2 (2H, qm,

J=7.5Hz), 2.93 and 3.20 (2H, ABq, J=17.9Hz), 3.40- 3.70 (2H, m) , 4.20-4.60 (2H, m) , 5.00 (IH, d, J=4.9Hz) , 5.05 and 5.20 (2H, ABq, J=15.8Hz) , 5.58 (IH, dd, J=4.9Hz, 8.0Hz), 5.80 (IH, d, J=3.1Hz) , 6.28 (IH, t, J=7.5Hz) , 7.20 (2H, br s) , 7.24 (2H, br s), 8.10 (IH, d, J=3.1Hz) , 9.16 (IH, d, J=8.0Hz)

Example 45

A solution of 7β-[ (Z)-2- {3-tert-butoxycarbonylallyloxyιmmo) -2- (5-chloro-2- formylammothιazol-4-yl) acetamido] -3- [5-ammo-l- (2- hydroxyethyl) -2-pyrazolio]methyl-3-cephem-4-carboxylate (0.48 g) in 1.5 ml of dichloromethane and 0.5 ml of anisole was treated with 1 ml of trifluoroacetic acid. After 4 hours, the reaction mixture was poured mto isopropyl ether. The precipitates were solved in 4 ml of methanol, and treated with hydrochloric acid (0.28 ml) , and stirred for 4 hours at room temperature. The reaction mixture was dropped mto ethyl acetate to get precipitates, which were purified by preparative HPLC to get 28 mg of 7β- [ (Z) -2- ( (E) -3-

carboxyallyloxyimino) -2- (2-amino-5-chlorothiazol-4-yl) - acetamido] -3- [5-amino-l- (2-hydroxyethyl) -2-pyrazolio]methyl- 3-cephem-4-carboxylate.

IR (KBr) : 1772, 1651, 1541 cm ^"1 NMR (DMSO-dg, δ) : 2.89, 3.19 (2H, ABq, J=16.9Hz),

3.5-3.7 (2H, m) , 4.2-4.6 (2H, m) , 4.76 (2H, d, J=2Hz), 5.01 (IH, d, J=4.9Hz) , 5.07, 5.21 (2H, ABq, J=15Hz), 5.61 (IH, dd, J=8.5Hz, 4.9Hz) , 5.81 (IH, d, J=3.2Hz), 5.99 (IH, d, J=15.8Hz), 6.84 (IH, dt, J=15.8Hz, 2Hz), 7.26 (2H, br s), 7.41 (2H, br s),

8.10 (IH, d, J=3.2Hz) , 9.62 (IH, d, J=8.5Hz) MS (FAB) m/z : 627.0 (M ⁺ )

Example 46 To a suspension of 7β- [ (Z) -2- (2-formylammo-5- chlorothιazol-4-yl) -2- (2-acetoxyethoxyimino) acetamido] -3- [5- amιno-1- (2-hydroxyethyl) -2-pyrazolio]methyl-3-cephem-4- carboxylate (1.2 g) in methanol (12 ml) was added concentrated hydrochloric acid (0.86 ml) under stirring at 25°C to 30°C. The stirring was continued for 3 hours at the 20°C to 30°C. The reaction mixture was poured into a cooled water (100 ml), and adjusted to pH 3.5 with aqueous sodium hydrogen carbonate. To the resulting solution was evaporated in vacuo by removal of methanol. The residue was added 3N-sodium hydroxide solution (3 ml) under ice-cooling with stirring and the mixture was stirred for 30 minutes at 5°C. The reaction mixture was adjusted to pH 3.5 with 6N- hydrochloric acid. The residue was subjected to column chromatography on HP-20 (50 ml), and eluted with 15% 2-propanol and the eluate was lyophilized to give 7β-[ (Z)-2- (2-amino-5-chlorothiazol-4-yl) -2- (2-hydroxyethoxyimino) - acetamido] -3- [5-amino-l- (2-hydroxyethyl) -2-pyrazolio]methyl- 3-cephem-4-carboxylate (250 mg) .

IR (KBr) : 1774, 1648, 1612, 1538, 1390, 1355, 1218, 1066 cm ^"1

NMR (DMSO-dg, δ) : 2.94 and 3.18 (2H, ABq, J=17.3Hz), 3.40-3.65 (2H+2H, m) , 4.00-4.20 (2H, m) , 4.20-4.65 (2H+1H, m) , 5.01 (IH, d, J=4.9Hz) , 5.04 and 5.22 (2H, ABq, J=18.2Hz), 5.62 (IH, dd, J=4.9Hz, 7.9Hz), 5.81 (IH, d, J=2.9Hz), 7.26 (2H, br s) , 7.40 (2H, br s), 8.10 (IH, d, J=2.9Hz) , 9.43 (IH, d, J=7.9Hz)

Example 47

To a suspension of 7β- [ (Z) -2- (2-formylamino-5- fluorothiazol-4-yl) -2-formyloxyiminoacetamido] -3- [5-amino-l- (2-hydroxyethyl) -2-pyrazolio]methyl-3-cephem-4-carboxylate (562 mg) in methanol (5.6 ml) was added concentrated hydrochloric acid (0.9 ml) under stirring at 25°C to 30°C. The stirring was continued for 3 hours at 20°C to 30°C. The reaction mixture was poured into an ice-cooled water (100 ml), and adjusted to pH 4.0 with aqueous sodium hydrogen carbonate. The resulting solution was evaporated in vacuo. The residue was subjected to column chromatography on HP-20 (50 ml), and eluted with 15% 2-propanol and the eluate was lyophilized to give 7β- [ (Z) -2- (2-amino-5-fluorothiazol-4-yl) - 2-hydroxyiminoacetamido] -3- [5-amino-l- (2-hydroxyethyl) -2- pyrazolio]methyl-3-cephem-4-carboxylate (130 mg) .

IR (KBr) : 1770, 1612, 1587, 1535, 1392, 1216, 1066 cm ^"1 NMR (DMSO-dg, δ) : 2.90 and 3.18 (2H, ABq, J=16.9Hz) ,

3.45-3.60 (2H, m) , 4.10-4.60 (2H, m) , 4.99 (IH, d, J=4.8Hz), 5.04 and 5.21 (2H, ABq, J=18.1Hz), 5.61 (IH, dd, J=4.8Hz, 7.9Hz) , 5.81 (IH, d, J=3Hz), 6.99 (2H, br s) , 7.25 (2H, br s) , 8.08 (IH, d, J=3Hz), 9.34 (IH, d, J=7.9Hz), 11.50 (IH, s)

Example 48

A solution of 7β- [ (Z) -2-tert-butoxycarbonylmethoxyimino- 2- (2-amino-5-chlorothiazol-4-yl) acetamido] -3- [5-amino-l- (2- hydroxyethyl) -2-pyrazolio]methyl-3-cephem-4-carboxylate (1.43

g) in 4.5 ml of dichloromethane and 1.5 ml of anisole was treated with trifluoroacetic acid (3 ml) . After 1 hour, the reaction mixture was poured into isopropyl ether. The precipitates were purified by preparative HPLC to afford 0.15 g of 7β- [ (Z) -2-carboxymethoxyimino-2- (2-amino-5- chlorothiazol-4-yl) acetamido] -3- [5-amino-l- (2-hydroxyethyl) - 2-pyrazolio]methyl-3-cephem-4-carboxylate.

IR (KBr) : 1772, 1749, 1649, 1541 cm ^"1

NMR (DMSO-dg, δ) : 2.88, 3.21 (2H, ABq, J=17.3Hz), 3.59 (2H, br s), 4.3-4.6 (2H, m) , 4.48 (2H, br s) , 5.06

(IH, d, J=4.9Hz), 5.1-5.3 (2H, m) , 5.69 (IH, dd, J=9.2Hz, 4.9Hz), 5.83 (IH, d, J=3.1Hz), 7.33 (2H, br s) , 7.42 (2H, br s), 8.07 (IH, d, J=3.1Hz), 10.25 (IH, d, J=9.2Hz) MS (FAB) m/z : 601.0 (M ⁺ )

Example 49

A solution of 7β- [ (Z) -2- (1-tert-butoxycarbonyl-l- methylethoxyimino) -2- (2-amino-5-chlorothiazol-4-yl) - acetamido] -3- [5-amino-l- (2-hydroxyethyl) -2-pyrazolio]methyl- 3-cephem-4-carboxylate (4.15 g) in 12 ml of dichloromethane and 4 ml of anisole was treated with trifluoroacetic acid (8 ml) . After 4 hours, the reaction mixture was poured into isopropyl ether. The precipitates were purified by column chromatography on HP-20 resin and by preparative HPLC to afford 160 mg of 7β- [ (Z) -2- (1-carboxy-l-methylethoxyimino) -2- (2-amino-5-chlorothiazol-4-yl) acetamido] -3- [5-amino-l- (2- hydroxyethyl) -2-pyrazolio]methyl-3-cephem-4-carboxylate. IR (KBr) : 3332, 1774, 1651, 1541 cm ^"1 NMR (DMSO-dg, δ) : 1.44 (3H, s) , 1.47 (3H, s) , 2.95,

3.20 (2H, ABq, J=17.3Hz), 3.59 (2H, br s) , 4.38 (2H, br s), 5.05 (IH, d, J=4.9Hz), 5.08, 5.22 (2H, ABq, J=15Hz), 5.66 (IH, dd, J=8.6Hz, 4.9Hz), 5.82 (IH, d, J=3.2Hz), 7.27 (2H, br s), 7.41 (2H, br s) , 8.09 (IH, d, J=3.2Hz) , 9.61 (IH, d, J=8.6Hz)

MS (FAB) m/z : 629.0 (M ⁺ )

Example 50

Trifluoroacetic acid (0.3 ml) was added to a suspended solution of 7β- [ (Z) -2- (2-ammo-5-bromothιazol-4-yl) -2- (3- cyclopentenyl) oxyimmoacetamido] -3- [5-amino-l- (2- hydroxyethyl) -2-pyrazolio]methyl-3-cephem-4-carboxylate (0.15 g) in dichloromethane (0.6 ml) and anisole (0.15 ml) with stirring and ice-cooling. After it was stirred at 5°C for 10 minutes, it was stirred at room temperature for 2 hours. The reaction mixture was poured mto diisopropyl ether (30 ml) , and the resulting precipitate was collected by filtration. The precipitate was dissolved into water (10 ml) at pH 7.0 with saturated of NaHC03 solution. After the solution was adjusted to pH 4.0 with lN-hydrochloπc acid, it was subjected to column chromatography on Diaion HP-20 (10 ml) . The column was washed with water (50 ml) , and the object compound was eluted with 40% aqueous 2-propanol. The active fractions were collected, concentrated, and lyophilized to give 7β- [ (Z) -2- (2-amιno-5-bromothιazol-4-yl) -2- hydroxyimmoacetamido] -3- [5-ammo-l- (2-hydroxyethyl) -2- pyrazolio]methyl-3-cephem-4-carboxylate (0.11 g) .

IR (KBr) : 1770, 1666, 1645, 1616, 1585, 1539 cm ^-1 NMR (DMSO-dg, δ) : 2.89, 3.17 (2H, ABq, J=17Hz) , 3.40-3.80 (2H, m) , 4.20-4.60 (2H, m) , 5.00 (IH, d,

J=4.9Hz), 5.04, 5.21 (2H, ABq, J=16Hz), 5.61 (IH, dd, J=4.9Hz, 8.5Hz) , 5.81 (IH, d, J=3.2Hz), 7.26 (2H, s) , 7.33 (2H, s), 8.09 (IH, d, J=3.2Hz) , 9.31 (IH, d, J=8.5Hz) MS (FAB) m/z : 587 (M ⁺ ), 589 (M ⁺ +2)

Example 51

To a suspension of 7β- [ (Z) -2- (2-ammo-5-chlorothιazol-4- yl) -2- (3-cyclopentenyl) oxyimmoacetamido] -3- [5-ammo-l- (2- hydroxyethyl) -2-pyrazolio]methyl-3-cephem-4-carboxylate (12

g) and anisole (12 ml) in dichloromethane (40 ml) was added dropwise trifluoroacetic acid (36 ml) under ice-cooling with stirring and the mixture was stirred for 3 hours at 5°C to 10°C. The resulting solution was added to isopropyl ether (800 ml) . The precipitate was collected by filtration and dried under reduced pressure. The powder was dissolved in water (400 ml), adjusted to pH 4.0 with aqueous sodium hydrogencarbonate and then subjected to column chromatography on HP-20 (300 ml), and eluted with 10% 2-propanol and the eluate was lyophilized to give 7β- [ (Z) -2- (2-amino-5- chlorothiazol-4-yl) -2-hydroxyiminoacetamido] -3- [5-amino-l- (2- hydroxyethyl) -2-pyrazolio]methyl-3-cephem-4-carboxylate (3.6 g ⁾ •

IR (KBr) : 1772, 1612, 1538, 1392, 1353, 1064 cm ^"1 NMR (DMSO-dg, δ) : 2.90 and 3.28 (2H, ABq, J=17Hz),

3.40-3.80 (2H, m) , 4.20-4.60 (2H, m) , 4.98 (IH, d, J=5.0Hz), 5.00 and 5.22 (2H, ABq, J=16Hz), 5.62 (IH, dd, J=5Hz, 8Hz), 5.81 (IH, d, J=3.0Hz), 7.10- 7.25 (4H, m) , 8.09 (IH, d, J=3.0Hz), 9.32 (IH, d, J=8Hz) , 11.70 (IH, br s)

Example 52

A mixture of N, N-dimethylformamide (0.67 ml) and phosphorus oxychloride (0.8 ml) in tetrahydrofuran (23 ml) was stirred for 30 minutes at 5°C. (Z) -2- (2-Formylammo-5- chlorothiazol-4-yl) -2- (3-cyclopentenyl) oxyiminoacetic acid (2.27 g) was added thereto with stirring and ice-cooling, and the mixture was stirred for 30 minutes at 5°C to produce an activated acid solution. On the other hand, 7β-amino-3- [5- amino-1- (2-hydroxyethyl) -2-pyrazolio]methyl-3-cephem-4- carboxylate hydrochloride (2.7 g) was dissolved in a solution of mono-trimethyl silylacetamide (8 g) in N,N- dimethylformamide (27 ml) and tetrahydrofuran (27 ml) . To the solution was at a time added the above obtained activated acid solution at 5°C, and the mixture was stirred for 1.5

hours at 5°C. The resulting solution was poured into ethyl acetate (500 ml) . The precipitate was collected by filtration and dried under reduced pressure. The powder was suspended mto methanol (30 ml) , thereto was added concentrated hydrochloric acid (6.8 ml) at room temperature. After the reaction mixture was stirred at room temperature for 3 hours, the reaction mixture was poured mto an ice-cooled water (100 ml) and adjusted to pH 3.5 with aqueous sodium hydrogen carbonate. The resulting solution was evaporated in vacuo by removal of MeOH. To the residual solution was subjected to column chromatography on HP-20 (50 ml) , and eluted with 20% 2-propanol and the eluate was lyophilized to give 7β- [ (Z) -2- (2-ammo-5-chlorothιazol-4-yl) - 2- (3-cyclopentenyl) oxyimmoacetamido] -3- [5-ammo-l- (2-hydroxy ethyl) -2-pyrazolio]methyl-3-cephem-4-carboxylate (530 mg) . IR (KBr) : 1774, 1618, 1538, 1359, 1220, 1062 cm ^"1 NMR (DMSO-dg, δ) : 1.80-2.55 (4H, m) , 2.93 and 3.17 (2H, ABq, J=17Hz), 3.40-3.83 (2H, m) , 4.20-4.60 (2H, m) , 4.98 (IH, d, J=5.0Hz) , 5.00-5.30 (3H, m) , 5.58 (IH, dd, J=5Hz, 8.5Hz), 5.82 (IH, d, J=3.2Hz),

5.92 (IH, m) , 6.07 (IH, m) , 7.26 (2H, s), 7.41 (2H, s) , 8.10 (IH, d, J=3.2Hz) , 9.42 (IH, d, J=8.5Hz)

Example 53 Phosphorus oxychloride (3.52 g) was added to a mixed solution of N,N-dimethylformamide (1.78 ml) and ethyl acetate (5.4 ml) with stirring and ice-cooling. After it was stirred at 5°C for 30 minutes, (Z) -2- (2-formylammo-5-bromothιazol-4- yl) -2- (3-cyclopentenyl) oxyiminoacetic acid (7.5 g) and ethyl acetate (12 ml) was added thereto at the same temperature.

After the reaction mixture was stirred at 5°C for 30 minutes, this is referred to as solution (Aj . On the other hand, N- trimethylsilylacetamide (12.3 g) was added to a suspended mixture of 7β-ammo-3- [5-ammo-l- (2-hydroxyethyl) -2- pyrazolio]methyl-3-cephem-4-carboxylate monohydrochloride

(3.87 g) in N, N-dimethylformamide (20 ml) and ethyl acetate (50 ml) at room temperature, and the suspended mixture was warmed at 35 ^C C with stirring for 10 minutes to give a clear solution. The above solution (A) was added to this clear solution with stirring at 5 ^C C, then it was stirred at the same temperature for 2 hours. After that, the reaction mixture was poured into a mixed solution of ethyl acetate (300 ml) , diisopropyl ether (50 ml), and methanol (10 ml) . The resulting precipitate was collected by filtration, and it was suspended into methanol (60 ml) . Concentrated hydrochloric acid (4.5 ml) was added thereto at room temperature. After the reaction mixture was stirred at room temperature for 3 hours, it was poured into water (60 ml), and the solution was adjusted to pH 4.0 with potassium carbonate. It was concentrated to remove methanol, and it was subjected to column chromatography on Diaion HP-20 (100 ml) [Trademark; Mitsubishi Kasei Co.] . The column was washed with water (500 ml) , and the object compound was eluted with 40% aqueous 2-propanol. The active fractions were collected, concentrated, and lyophilized to give 7β- [ (Z) -2- (2-amino-5- bromothiazol-4-yl) -2- (3-cyclopentenyl) oxyiminoacetamido] -3- [5-amιno-l- (2-hydroxyethyl) -2-pyrazolio]methyl-3-cephem-4- carboxylate (0.22 g) .

IR (KBr) : 1772, 1668, 1645, 1616, 1537 cm ^"1 NMR (DMSO-dg, δ) : 1.80-2.55 (4H, m) , 2.93, 3.17 (2H,

ABq, J=17Hz), 3.40-3.80 (2H, m) , 4.20-4.60 (2H, m) , 4.99 (IH, d, J=4.9Hz), 5.00-5.30 (3H, m) , 5.58 (IH, dd, J=4.9Hz, 8.4Hz), 5.82 (IH, d, J=3.2Hz), 5.92 (IH, m) , 6.07 (IH, m) , 7.26 (2H, s), 7.41 (2H, s), 8.10 (IH, d, J=3.2Hz), 9.42 (IH, d, J=8.4Hz)

MS (FAB) m/z : 653 (M ⁺ ), 655 (M ⁺ +2)

Example 54

To an ice-cooling solution of N, N-dimethylformamide (0.20 ml) and ethyl acetate (1.0 ml) was added phosphorus

oxychloπde (0.385 g) . After it was stirred under lce- coolmg for 30 minutes, (Z) -2- (2-formylamιno-5-bromothιazol- 4-yl)-2-(l-trιtyl-lH-l,2,3-trιazol-5-yl) thiomethoxyimmo- acetic acid (1.5 g) was added thereto, and it was stirred at the same temperature for one hour. On the other hand,

N-tnmethylsilylacetamide (3.03 g) was added to a suspension of 7β-ammo-3- [5-ammo-l- (2-hydroxyethyl) -2-pyrazolio]methyl- 3-cephem-4-carboxylate hydrochloride (0.95 g) in ethyl acetate (5 ml) and N, N-dimethylformamide (10 ml) at room temperature, and it was warmed at 40°C. After it became clear, the reaction mixture was cooled below 5°C, the above solution of acetic acid derivative was added thereto. After it was stirred under ice-cooling for one hour, it was poured into ethyl acetate (40 ml) and diisopropyl ether (300 ml), and the resulting precipitate was collected by filtration. To a suspension of the precipitate in methanol (25 ml) was added concentrated hydrochloric acid (1.13 ml), and it was stirred at room temperature for 3 hours. The reaction mixture was poured into ethyl acetate (20 ml) and diisopropyl ether (80 ml) , and the resulting precipitate was collected by filtration. It was dissolved mto water (60 ml) at pH 4, subjected to column chromatography on Diaion HP-20 (15 ml) . The column was washed with water (150 ml), then the object compound was eluted with 15% aqueous 2-propanol. The active fractions were collected, concentrated, and lyophilized to give 7β- [ (Z) -2- (2-ammo-5-bromothιazol-4-yl) -2- (1H-1, 2, 3- trιazol-5-yl) thiomethoxyiminoacetamido] -3- [5-ammo-l- (2- hydroxyethyl) -2-pyrazolio]methyl-3-cephem-4-carboxylate (0.21 g ⁾ • NMR (DMSO-dg, δ) : 2.86, 3.11 (2H, ABq, J=17Hz) , 3.60

(2H, s), 4.30-4.50 (2H, m) , 4.99 (IH, d, J=4.9Hz) , 5.00-5.25 (2H, m) , 5.44 (2H, s) , 5.54 (IH, dd, J-4.9HZ, 7.9Hz), 5.81 (IH, d, J=3.2Hz) , 7.22 (2H, s) , 7.45 (2H, s), 8.01 (IH, s) , 8.11 (IH, d, J=3.2Hz), 9.39 (IH, d, J=7Hz)

MS (FAB) m/z : 701 (M ⁺ +l)

Example 55

To a solution of the mixture of (Z) -2- (1-trιtyl-lH- tetrazol-5-ylmethoxyιmmo) -2- (2-forrnylammo-5-chlorothιazol- 4-yl) acetic acid and (Z) -2- (2-tntyl-2H-tetrazol-5- ylmethoxyimino) -2- (2-formylamιno-5-chlorothιazol-4-yl) acetic acid (2.14 g) in 22 ml of N,N-dimethylacetamide, powdered potassium carbonate (0.52 g) and methanesulfonyl chloride (0.85 g) were added stepwise at 0°C. On the other hand, a suspension of 7β-amιno-3- [5-amino-l- (2-hydroxyethyl) -2- pyrazolio]methyl-3-cephem-4-carboxylate (1.40 g) in 14 ml of N, N-dimethylacetamide was treated portionwise with N- (trimethylsilyl) acetamide (2.94 g) at room temperature. Both reaction mixture were combined at 0°C and stirred for

5.5 hours. The reaction was quenched by dropping mto ethyl acetate to get precipitates, and which were dissolved m 10 ml of methanol and treated with concentrated hydrochloric acid. The reaction was quenched by dropping into ethyl acetate to get precipitates, and which were purified by column chromatography on HP-20 resin and preparative liquid chromatography to get 0.06 g of 7β- [ (Z) -2- (tetrazol-5- ylmethoxyimmo) -2- (5-chloro-2-ammothιazol-4-yl) acetamido] -3- [5-amιno-l- (2-hydroxyethyl) -2-pyrazolιo]methyl-3-cephem-4- carboxylate.

IR (KBr) : 3412, 1772, 1635 cm ^"1

NMR (DMSO-dg, δ) : 2.86, 3.17 (2H, ABq, J=17.4Hz) , 3.59 (2H, m) , 4.34 (2H, m) , 5.00 (IH, d, J=4.9Hz) , 5.15 (2H, m) , 5.33 (2H, s), 5.65 (IH, dd, J=8.5Hz, 4.9Hz), 5.83 (IH, d, J=3.2Hz), 7.21 (2H, br s),

7.39 (2H, br s), 8.05 (IH, d, J=3.2Hz), 10.03 (IH, d, J=8.5Hz) MS (FAB) m/z : 625.0

Example 56

Potassium carbonate (0.71 g) was added to an ice-cooling solution of (Z) -2- (2-formylammo-5-chlorothιazol-4-yl) -2- (1- methylpyrazol-4-yl)methoxyimmoacetic acid (2.19 g) in N, N-dimethylacetamide (20 ml), and it was stirred at 5-10°C for 20 minutes. After methanesulfonyl chloride (1.17 g) was added dropwise to the solution below 10°C, it was stirred under ice-cooling for one hour. On the other hand, N-trimethylsilylacetamide (7.1 g) was added to a suspension of 7β-ammo-3- [5-ammo-l- (2-hydroxyethyl) -2-pyrazolιo]methyl- 3-cephem-4-carboxylate hydrochloride (2.23 g) in ethyl acetate (10 ml) and N,N-dimethylformamide (20 ml) at room temperature, and it was warmed at 40°C. After it became clear, the reaction mixture was cooled below 5°C, the above N, N-dimethylacetamide solution was added thereto. After it was stirred under ice-cooling for one hour, it was poured mto ethyl acetate (50 ml) and diisopropyl ether (400 ml) , and the resulting precipitate was collected by filtration. To a suspension of the precipitate in methanol (20 ml) was added concentrated hydrochloric acid (2 ml) , and it was stirred at room temperature for 2 hours. The reaction mixture was poured mto ethyl acetate (20 ml) and diisopropyl ether (80 ml) , then the resulting precipitate was collected Dy filtration. It was dissolved into water (70 ml) at pH 4, and subjected to column chromatography on Diaion HP-20 (20 ml) . The column was washed with water (200 ml), then the object compound was eluted with 15% aqueous 2-propanol. The active fractions were collected, concentrated, and lyophilized to give 7β- [ (Z) -2- (2-ammo-5-chlorothιazol-4-yl) - 2- ( l-methylpyrazol-4-yl)methoxyimmoacetamido] -3- [5-amino-1- (2-hydroxyethyl) -2-pyrazolio]methyl-3-cephem-4-carboxylate (0.45 g) .

NMR (DMSO-dg, δ) : 2.88, 3.18 (2H, ABq, J=17Hz) , 3.50- 3.65 (2H, m) , 3.78 (3H, s) , 4.30-4.60 (2H, m) , 4.96 (2H, s) , 4.97 (IH, d, J=4.9Hz) , 5.03-5.25 (2H, m) , 5.59 (IH, dd, J=4.9Hz, 8.4Hz) , 5.82 (IH, d,

J=3.2Hz), 7.27 (2H, s), 7.35 (2H, s) , 7.42 (IH, s), 7.69 (IH, s), 8.10 (IH, d, J=3.2Hz) , 9.47 (IH, d, J=8.4Hz) MS (FAB) m/z : 637 (M ⁺ )

Example 57

Potassium carbonate (332 mg) was added to an ice-cooling solution of (Z) -2- (2-formylamιno-5-chlorothιazol-4-yl) -2- (1- tert-butoxycarbonylpyrazol-4-yl)methoxyιmmoacetιc acid (1.72 g) in N, N-dimethylacetamide (17 ml), and it was stirred at

5-10°C for 10 minutes. After methanesulfonyl chloride (0.50 g) was added dropwise to the solution below 10°C, it was stirred under ice-cooling for one hour. On the other hand, N-trimethylsilylacetamide (4.2 g) was added to a solution of 7β-ammo-3- [5-ammo-l- (2-hydroxyethyl) -2-pyrazolιo]methyl-3- cephem-4-carboxylate hydrochloride (1.32 g) in ethyl acetate (8 ml) and N,N-dimethylformamide (16 ml) at room temperature, and it was warmed at 40°C. After it became clear, the reaction mixture was cooled below 5°C, and the above N, N-dimethylacetamide solution was added thereto. After it was stirred under ice-coolmg for one hour, it was poured mto ethyl acetate (40 ml) and diisopropyl ether (350 ml), and the resulting precipitate was collected by filtration. To a suspension of the precipitate in methanol (20 ml) was added concentrated hydrochloric acid (1.67 ml), and it was stirred at room temperature for 2 hours. The reaction mixture was poured mto ethyl acetate (20 ml) and diisopropyl ether (80 ml), then the resulting precipitate was collected by filtration. To a suspension of the precipitate in dichloromethane (2 ml) and anisole (1 ml) was added trifluoroacetic acid (3 ml) under ice-coolmg, then it was stirred at room temperature for one hour. The reaction mixture was poured mto diisopropyl ether (40 ml) , and the resulting precipitate was collected by filtration. It was dissolved into water (80 ml) at pH 4, and subjected to column

chromatography on Diaion HP-20 (25 ml) . The column was washed with water (250 ml) , then the object compound was eluted with 15% aqueous 2-propanol. The active fractions were collected, concentrated, and lyophilized to give 7β- [ (Z)-2- (2-amιno-5-chlorothιazol-4-yl) -2- (pyrazol-4-yl) - methoxyimmoacetamido] -3- [5-ammo-l- (2-hydroxyethyl) -2- pyrazolιo]methyl-3-cephem-4-carboxylate (0.22 g) .

NMR (DMSO-dg, δ) : 2.88, 3.18 (2H, ABq, J=17Hz), 3.50- 3.70 (2H, m) , 4.20-4.60 (2H, m) , 4.90-5.30 (5H, m) , 5.59 (IH, dd, J=4.8Hz, J=8.6Hz) , 5.82 (IH, d,

J=3.2Hz), 7.25 (2H, s), 7.35 (2H, s), 7.63 (2H, s) , 8.10 (IH, d, J=3.2Hz), 9.48 (IH, d, J=8.6Hz) MS (FAB) m/z : 623 (M ⁺ )

Example 58

Phosphorus pentachloride (1.68 g) was suspended into dichloromethane (18 ml), then it was cooled to -20°C, and (Z) -2- (2-ammo-5-ιodothιazol-4-yl) -2-acetoxyιmmoacetιc acid (2.6 g) was added thereto. After it was stirred at -15°C for 2 hours, diisopropyl ether (20 ml) was added thereto, and the resulting precipitate was collected by filtration. On the other hand, 7β-ammo-3- [5-ammo-l- (2-hydroxyethyl) -2- pyrazolιo]methyl-3-cephem-4-carboxylate monohydrochloric acid salt (2.14 g) was suspended mto ethyl acetate (15 ml) and N, N-dimethylformamide (25 ml) , and then N-trimethylsilyl- acetamide (6.8 g) was added thereto. It was warmed at 35°C with stirring for 10 minutes to give a clear solution. The precipitate which was synthesized above was added to the clear solution with stirring at 5°C, then it was stirred at the same temperature for an hour. After that, the reaction mixture was poured mto a mixed solution of ethyl acetate (200 ml) , diisopropyl ether (50 ml) , and methanol (50 ml) . The resulting precipitate was collected by filtration, and it was suspended mto methanol (25 ml) . Concentrated hydrochloric acid (2.0 ml) was added thereto at room

temperature. After the reaction mixture was stirred at room temperature for 2 hours, it was poured mto water (25 ml) , and the solution was adjusted to pH 4.0 with potassium carbonate. It was concentrated to remove methanol, and it was subjected to column chromatography on Diaion HP-20 (90 ml) [Trademark; Mitsubishi Kasei Co.] . The column was washed with water (500 ml) , and the object compound was eluted with 40% aqueous 2-propanol. The active fractions were collected, concentrated, and lyophilized to give 7β- [ (Z) -2- (2-amιno-5- iodothiazol-4-yl) -2-hydroxyiminoacetamido] -3- [5-ammo-l- (2- hydroxyethyl) -2-pyrazolio]methyl-3-cephem-4-carboxylate (0.18

9 ⁾ •

IR (KBr) : 1770, 1645, 1614, 1537 cm ^"1

NMR (DMSO-dg, δ) : 2.91, 3.18 (2H, ABq, J=17Hz), 3.40-3.80 (2H, m) , 4.20-4.60 (2H, m) , 5.00 (IH, d,

J=4.9Hz) , 5.05, 5.22 (2H, ABq, J=16Hz), 5.62 (IH, dd, J=4.9Hz, 8.5Hz), 5.82 (IH, d, J=3.1Hz) , 7.29 (4H, s), 8.09 (IH, d, J=3.1Hz), 9.25 (IH, d, J=8.5Hz), 11.64 (IH, s) MS (FAB) m/z : 635 (M ⁺ +l)

Example 59

N-Bromosuccinimide (0.68 g) was added to a solution of 7β- [ (Z) -2- (2-ammothιazol-4-yl) -2-methoxyιmmoacetamido] -3- [5-amino-l- (2-hydroxyethyl) -2-pyrazolio]methyl-3-cephem-4- carboxylate (1.0 g) in N, N-dimethylacetamide (10 ml) with ice-cooling, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into ethyl acetate (80 ml) and diisopropyl ether (20 ml), and the resulting precipitate was collected by filtration. The precipitate was dissolved mto water (40 ml) at pH 6.5, and then the solution was adjusted to pH 4.0 with IN-hydrochloric acid. It was subjected to column chromatography on Diaion HP-20 (30 ml) [Trademark; Mitsubishi Kasei Co.] . The column was washed with water (200 ml), and the object compound was

eluted with 30% aqueous 2-propanol. The active fractions were collected, concentrated, and lyophilized to give 7β- [ (Z) -2- (2-amιno-5-bromothιazol-4-yl) -2-methoxyimmo¬ acetamido] -3- [5-ammo-l- (2-hydroxyethyl) -2-pyrazolιo]methyl- 3-cephem-4-carboxylate (0.25 g) .

IR (KBr) : 1770, 1649, 1614, 1537 cm ^"1

NMR (DMSO-dg, δ) : 2.92, 3.20 (2H, ABq, J=17Hz) ,

3.40-3.80 (2H, m) , 3.84 (3H, s), 4.20-4.60 (2H, m) , 5.00 (IH, d, J=4.9Hz), 5.06, 5.21 (2H, ABq, J=15Hz) , 5.60 (IH, dd, J=4.9Hz, 8.5Hz), 5.82 (IH, d, J=3.2Hz) , 7.27 (2H, s), 7.41 (2H, s) , 8.10 (IH, d, J=3.2Hz) , 9.49 (IH, d, J=8.5Hz) MS (FAB) m/z : 601 (M ⁺ ) , 603 (M ⁺ +2)

Example 60

7β- [ (Z) -2- (2-Ammo-5-ιodothιazol-4-yl) -2-methoxyimmo¬ acetamido] -3- [5-amino-l- (2-hydroxyethyl) -2-pyrazolio]methyl- 3-cephem-4-carboxylate was obtained according to a similar manner to that of Example 59. IR (KBr) : 1772, 1649, 1614, 1535, 1039 cm ^"1

NMR (DMSO-dg, δ) : 2.92, 3.20 (2H, ABq, J=17Hz),

3.40-3.80 (2H, m) , 3.86 (3H, s), 4.20-4.60 (2H, m) , 4.99 (IH, d, J=4.8Hz) , 5.06, 5.20 (2H, ABq, J=15Hz), 5.59 (IH, dd, J=4.8Hz, 8.5Hz), 5.82 (IH, d, J=3.2Hz) , 7.27 (2H, s) , 7.38 (2H, s), 8.10 (IH, d, J=3.2Hz), 9.43 (IH, d, J=8.5Hz) MS (FAB) m/z : 649 (M ⁺ +l)

The following compounds (Examples 61 to 66) were obtained according to a similar manner to that of Example 3.

Example 61

7β- [ ( Z ) -2 - ( 2 -Ammo- 5-chlorothιazol-4 -yl ) -2 - methoxyiminoacetamido] - 3- ( 4 , 5 , 6 , 7 -tetrahydro- l -pyra zolo- [ 1 , 5 -a ] pyπmidmio ) methyl-3-cephem- 4 -carboxylate

IR (KBr) : 1770, 1619, 1538, 1438, 1243, 1037 cm ^"1 NMR (DMSO-dg, δ) : 1.85-2.30 (2H, m) , 3.1-3.80 (4H, m) , 3.84 (3H, s), 4.00-4.25 (2H, m) , 4.94 and 5.26 (2H, ABq, J=15Hz) , 4.99 (IH, d, J=4.8Hz), 5.58 (IH, dd, J=8.3Hz, 4.8Hz) , 5.80 (IH, d, J=3.1Hz), 7.39 (2H, br s), 7.94 (IH, br s) , 8.07 (IH, d, J=3.1Hz), 9.48 (IH, d, J=8.3Hz)

Example 62 7β- [ (Z) -2-Ethoxyimino-2- (2-amιno-5-chlorothiazol-4-yl) - acetamido] -3- [2, 3-dihydro-5- (IH-imidazo [1, 2-b]pyrazolio) ] - methyl-3-cephem-4-carboxylate

IR (KBr) : 3390, 1772, 1608, 1539 cm ^"1 NMR (DMSO-dg, δ) : 1.24 (3H, t, J=7.0Hz), 3.11, 3.33 (2H, ABq, J=17.2Hz), 4.02 (2H, t, J=8.8Hz), 4.11

(2H, q, J=7.0Hz), 4.26 (IH, q, J=8.8Hz), 4.52 (IH, q, J=8.8Hz), 4.97, 5.08 (2H, ABq, J=14.6Hz), 5.01 (IH, d, J=4.9Hz), 5.59 (IH, dd, J=4.9, 8.5Hz), 5.87 (IH, d, J=3.0Hz) , 7.38 (2H, br s) , 8.23 (IH, d, J=3.0Hz) , 9.44 (IH, d, J=8.5Hz)

MS (FAB) m/z : 553.0 (M ⁺ ), 555.0 (M ⁺ +2)

Example 63

7β- [ (Z) -2-Ethoxyimmo-2- (2-amino-5-bromothιazol-4-yl) - acetamido] -3- [2, 3-dihydro-5- (IH-imidazo [1, 2-b] pyrazolio) ] - methyl-3-cephem-4-carboxylate

IR (KBr) : 3390, 1770, 1608, 1537 cm ^"1 NMR (DMSO-dg, δ) : 1.25 (3H, t, J=7.0Hz), 3.11, 3.32 (2H, ABq, J=17.0Hz), 4.02 (2H, m) , 4.11 (2H, q, J=7.0Hz), 4.26 (IH, q, J=8.9Hz), 4.52 (IH, q,

J=8.3Hz), 4.9-5.1 (2H, m) , 5.01 (IH, d, J=4.9Hz) , 5.59 (IH, dd, J=4.9, 8.5Hz), 5.87 (IH, d, J=3.0Hz), 7.42 (2H, br s), 7.8 (IH, br s) , 8.23 (IH, d, J=3.0Hz) , 9.44 (IH, d, J=8.5Hz) MS (FAB) m/z : 597.1 (M ⁺ )

2

Example 64

7β- [ (Z) -2-Methoxyιmmo-2- (2-amιno-5-chlorothιazol-4-yl) - acetamido] -3- [2, 3-dihydro-5- (IH-imidazo [1, 2-b] pyrazolio) ] - methyl-3-cephem-4-carboxylate IR (KBr) : 3392, 1770, 1608, 1539 cm ^"1

NMR (DMSO-dg, δ) : 3.12, 3.34 (2H, ABq, J=17.3Hz), 3.84 (3H, s) , 4.02 (2H, m) , 4.26 (IH, q, J=8.7Hz), 4.52 (IH, q, J=8.3Hz), 4.95-5.12 (2H+1H, m) , 5.60 (IH, dd, J=4.8, 8.5Hz), 5.87 (IH, d, J=2.9Hz) , 7.42 (2H, br s), 8.03 (IH, br s), 8.25 (IH, d, J=2.9Hz), 9.49

(IH, d, J=8.5Hz) MS (FAB) m/z : 539.1 (M ⁺ )

Example 65 7β- [ (Z) -2-Acetoxyιmmo-2- (2-ammo-5-chlorothιazol-4-yl) - acetamido] -3- [2, 3-dihydro-5- (IH-imidazo [1, 2-b] pyrazolio) ] - methyl-3-cephem-4-carboxylate

MS (FAB) m/z : 567.1 (M ⁺ ), 569.2 (M ⁺ +2)

Example 66

7β- [ (Z) -2-Cyanomethoxyιmmo-2- (5-chloro-2- formylammothιazol-4-yl) acetamido] -3- [2, 3-dιhydro-5- (1H- lmidazo [1, 2-b]pyrazolio) ]methyl-3-cephem-4-carboxylate

MS (FAB) m/z : 592.1 (M ⁺ )

Example 67

To a solution of 7β-ammo-3- (4, 5, 6, 7-tetrahydro-l- pyrazolo[l,5-a]pyrimidinio)methyl-3-cephem-4-carboxylate (1 g) and monotrimethylsilylacetamide (3.37 g) in a mixture of tetrahydrofuran (10 ml) and N,N-dimethylformamide (10 ml) was added (Z) -2- (2-ammo-5-chlorothιazol-4-yl) -2- ethoxyimmoacetyl chloride hydrochloride (0.85 g) in one portion at 5°C under stirring. The stirring was continued for 1.5 hours at the same temperature. The reaction mixture was poured mto ethyl acetate (300 ml) to form the

precipitates and then the resulting precipitates were collected by filtration and dried in vacuo. The powder was dissolved in a water (50 ml) , and adjusted to pH 3.0 with aqueous sodium hydrogencarbonate. Subsequently, the solution was subjected to column chromatography on HP-20 [Trademark; Mitsubishi Kasei Corporation] (30 ml) and eluted with 20% aqueous isopropyl alcohol, and the eluate was lyophilized to give 7β- [ (Z) -2- (2-ammo-5-chlorothiazol-4-yl) -2-ethoxyιmino] - acetamido-3- (4, 5, 6, 7-tetrahydro-l-pyrazolo[l, 5-a] - pyrιmidinio)methyl-3-cephem-4-carboxylate (249 mg) .

IR (KBr) : 1774, 1666, 1619, 1538, 1322, 1037 cm ^"1 NMR (DMSO-dg, δ ) : 1.23 (3H, t, J=7.1Hz) , 1.80-2.25

(2H, m) , 3.0-3.4 (4H, m) , 4.00-4.30 (4H, m) , 4.86 and 5.28 (2H, ABq, J=15Hz) , 5.00 (IH, d, J=4.9Hz) , 5.61 (IH, dd, J=8.4Hz, 4.9Hz) , 5.80 (IH, d,

J=3.1Hz) , 7.39 (2H, br s) , 8.02 (IH, br s) , 8.06 (IH, d, J=3.1Hz) , 9.48 (IH, d, J=8.4Hz)

Example 68 7β- [ ( Z ) -2-Fluoromethoxyimιno-2- (5-chloro-2- formylamιnothιazol-4-yl ) acetamido] -3- [2 , 3-dihydro-5- ( IH- imidazo [1, 2-b] pyrazolio) ] methyl-3-cephem-4-carboxylate was obtained according to a similar manner to that of Example 22.

Example 69

To a solution of 7β-amino-3- ( 4 , 5, 6, 7-tetrahydro-l- pyrazolo[l, 5-a] pyrimidinio) methyl-3-cephem-4-carboxylate (3 g) and monotrimethylsilylacetamide (10.1 g) in a mixture of tetrahydrofuran (30 ml) and N, N-dimethylformamide (30 ml) was added (Z) -2- (2-formylamino-5-chlorothιazol-4-yl ) -2- acetoxyiminoacetyl chloride (2.86 g) in one portion at 5°C under stirring. The stirring was continued for 1.5 hours at the same temperature. The reaction mixture was poured mto ethyl acetate (800 ml) to form the precipitates and then the resulting precipitates were collected by filtration, and

dried in vacuo to give 7β- [ (Z) -2- (2-formylamino-5- chlorothiazol-4-yl) -2-acetoxyimino] acetamido-3- (4,5,6,7- tetrahydro-1-pyrazolo [1, 5-a]pyrimidinio) methyl-3-cephem-4- carboxylate (5 g) . NMR (DMSO-dg, δ) : 2.00-2.25 (2H, m) , 2.21 (3H, s),

3.25-3.65 (4H, m) , 4.0-4.35 (2H, m) , 5.20-5.45 (3H, m) , 5.8-6.0 (2H, m) , 8.0 (IH, br s), 8.08 (IH, d, J=3.1Hz) , 9.98 (IH, d, J=8.3Hz) , 13.0 (IH, br s)

The following compounds (Examples 70 to 72) were obtained according to a similar manner to that of Example 7.

Example 70

7β- [ (Z) -2-Fluoromethoxyimino-2- (2-amino-5-chlorothiazol- 4-yl) acetamido] -3- [2, 3-dihydro-5- (IH-imidazo [1, 2-b] - pyrazolio) ]methyl-3-cephem-4-carboxylate IR (KBr) : 3429, 1770, 1610 cm ^"1

NMR (DMSO-dg, δ) : 3.09, 3.34 (2H, ABq, J=17.1Hz), 4.02 (2H, t, J=8.1Hz) , 4.26 (IH, q, J=8.1Hz), 4.54 (IH, q, J=8.1Hz), 4.9-5.1 (2H, m) , 5.02 (IH, d,

J=4.8Hz) , 5.57 (IH, s), 5.60 (IH, dd, J=4.8, 8.3Hz) , 5.86 (IH, s) , 5.87 (IH, d, J=3.0Hz), 7.46 (2H, br s) , 8.24 (IH, d, J=3.0Hz), 9.67 (IH, d, J=8.3Hz) MS (FAB) m/z : 557.0 (M ⁺ )

Example 71

7β- [ (Z) -2-Hydroxyimino-2- (2-amino-5-chlorothiazol-4-yl) - acetamido] -3- [2, 3-dihydro-5- (IH-imidazo [1, 2-b]pyrazolio) ] - methyl-3-cephem-4-carboxylate

IR (KBr) : 3390, 1772, 1603 cm ^"1

NMR (DMSO-dg, δ) : 3.08, 3.31 (2H, ABq, J=17.2Hz) , 4.01 (2H, m) , 4.25 (IH, q, J=8.7Hz), 4.53 (IH, q, J=8.0Hz) , 5.00 (IH, d, J=4.7Hz) , 4.97, 5.08 (2H, ABq, J=14.4Hz) , 5.61 (IH, dd, J=4.7, 8.2Hz), 5.87

(IH, d, J=2.9Hz), 7.31 (2H, br s), 8.23 (IH, d, J=2.9Hz), 9.31 (IH, d, J=8.2Hz) MS (FAB) m/z : 525.2 (M ⁺ +l)

Example 72

7β- [ (Z) -2-Cyanomethoxyimino-2- (2-amino-5-chlorothiazol- 4-yl) acetamido] -3- [2, 3-dihydro-5- (IH-imidazo [1, 2-b] - pyrazolio) ]methyl-3-cephem-4-carboxylate IR (KBr) : 3413, 1772, 1606 cm ^"1 NMR (DMSO-dg, δ) : 3.09, 3.35 (2H, ABq, J=17.2Hz), 4.02

(2H, t, J=8.6Hz), 4.26 (IH, q, J=8.6Hz) , 4.53 (IH, q, J=8.6Hz), 5.0-5.1 (2H+2H+1H, m) , 5.59 (IH, dd, J=4.8Hz, 8.4Hz), 5.87 (IH, d, J=3.0Hz), 7.47 (2H, br s), 7.84 (IH, br s), 8.24 (IH, d, J=3.0Hz), 9.68 (IH, d, J=8.4Hz)

MS (FAB) m/z : 564.0 (M ⁺ ) , 566.0 (M ⁺ +2)

Example 73

7β- [ (Z) -2- (2-Amino-5-chlorothiazol-4-yl)-2- hydroxyiminoacetamido] -3- (4, 5, 6, 7-tetrahydro-l-pyrazolo-

[1, 5-a]pyrimidinio)methyl-3-cephem-4-carboxylate was obtained according to a similar manner to that of Example 5.

IR (KBr) : 1772, 1619, 1538, 1520, 1245, 1178 cm ^"1 NMR (DMSO-dg, δ) : 1.8-2.20 (2H, m) , 2.95-3.80 (4H, m) , 4.0-4.25 (2H, m) , 4.96 and 5.28 (2H, ABq, J=15Hz) ,

4.99 (IH, d, J=5Hz, 8.4Hz) , 5.80 (IH, d, J=3.1Hz) , 7.31 (2H, br s) , 8.03 (IH, br s), 8.06 (IH, d, J=3.1Hz), 9.31 (IH, d, J=8.41Hz) , 11.78 (IH, br s)