KR870000611B1 - Process for preparing cephalosporin derivatives - Google Patents

Abstract

Cephalospolins (I) [R1=H or carboxyl-protecting gp. ; R2=a gp. (II)- (V); R6=H, OH, NO2, (thio)carbamoyl or opt. substd. alkyl, alkynyl, cycloalk(en)yl, NR16R17, etc.; R16=R17=H or alkyl; R7-R12 and R14- 15=H, halo, or opt. substd. alkyl, aralkyl, or aryl; R13=H, halo, carboxy, sulpho, etc.; R3=H or alkoxy; R4=H or halo; R5=H or opt. protected amino; A=methylene or :CN:N-OR18 (syn and/or anti); R18=H, alk(en)yl, alkynyl, cycloalk(en)yl, or a gp. -P(O)(R19)(R20), etc; R19=R20=OH, (ar)alkyl, aryl, (ar)alkoxy or aryloxy! and their salts are prepd. (I) are anti-bacterials with a broad spectrum of activity, good stability against betalactamase.

Description

Method for preparing cephalosporin

The present invention relates to a process for the preparation of the novel cephalosporins of the general formula (I) or salts thereof useful as antibacterial agents.

Wherein R ¹ is a hydrogen atom or a carboxyl protecting group:

R ² is a general formula

,

또는

의

,

or

of

Group;

의 그룹이며 ;R ⁶ represents a hydrogen atom, a hydroxyl group, a nitro group, a carbamoyl group, a thiocarbamoyl group, a sulfamoyl group, or a substituted or unsubstituted alkyl, alkayl, alkynyl, alkadienyl, cycloalkyl, cycloalkenyl , Cycloalkadienyl, aryl, aralkyl, acyl, alkoxy, alkylthio, acyloxy, cycloalkyloxy, aryloxy, alkoxycarbonyl, cycloalkyloxycarbonyl, acyloxycarbonyl, aralkyloxycarbonyl, alkyl Sulfonyl, cycloalkyl sulfonyl, arylsulfonyl, heterocyclic sulfonyl, alkylcarbamoyl, dialkylcarbamoyl, alkylthiocarbamoyl, dialkylthiocarbamoyl, acylcarbamoyl, acylthiocarbamoyl, alkylsulfur Ponycarbamoyl, arylsulfonylcarbamoyl, alkylsulfonylthiocarbamoyl, allylsulfonylthiocarbamoyl, alkylsulfamoyl, dialkylsulfamoyl, alkoxythiocarbonyl, alkylideneamino, cycloalkylmethyleneamino, arylmethyleneamino , Heterocyclic methyleneamino, or heterocyclic group, or general formula

Is a group of;

R ¹⁵ and R ¹⁷ may be the same or different and each is a hydrogen atom or an alkyl group, or R ¹⁵ and R ¹⁷ together with the adjacent nitrogen atom form a ring;

R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹⁴ and R ¹⁵ may be the same or different and each is a hydrogen atom, a halogen atom or a substituted or unsubstituted alkyl, aralkyl or aryl group. ;

R ¹³ is a hydrogen atom, halogen atom, carboxyl, sulfo, carbamoyl or thiocarbamoyl group or substituted or unsubstituted alkyl, aralkyl, aryl, alkoxy, alkylthio, acyl, alkoxycarbonyl, cycloalkyloxycarbonyl , Acyloxycarbonyl, aralkyloxycarbonyl, alkylsulfonyl, cycloalkylsulfonyl, arylsulfonyl, heterocyclicsulfonyl, alkylcarbamoyl, dialkylcarbamoyl, alkylthiocarbamoyl, dialkylthiocarbamoyl Acyl carbamoyl, acylthiocarbamoyl, alkylsulfonylcarbamoyl, arylsulfonylcarbamoyl, alkylsulfonylthiocarbamoyl or arylsulfonylthiocarbamoyl groups;

R ³ is a hydrogen atom or an alkoxy group;

R ⁴ is hydrogen or halogen;

R ⁵ is a hydrogen atom or a protected or unprotected amino group;

의 그룹이고 ;A is -CH ₂ -group or general formula

Is a group of;

의 그룹이며 ;R ¹⁸ is a hydrogen atom, substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl, heterocyclo group or hydroxyl-protecting group; Or general formula

Is a group of;

R ¹⁹ and R ²⁰ may be the same or different and each is a hydroxyl, alkyl, aralkyl, aryl, alkoxy, aralkyloxy or aryloxy group;

결합은 화합물이 신(syn)이성질체 또는 안티(anti)이성질체 또는 그의 혼합물임을 나타낸다.

Binding indicates that the compound is a syn isomer or an anti isomer or a mixture thereof.

Moreover, this invention relates to the novel cephalosporin of general formula (I), the manufacturing method of this cephalosporin, the antibacterial agent containing this cephalosporin, the intermediate for this cephalosporin manufacture, and the manufacturing method of this intermediate.

The present inventors have a broad antimicrobial spectrum, exhibit excellent antimicrobial activity against Gram-positive and Gram-negative bacteria, are stable to β-lactamase produced by bacteria, have low toxicity, and at the same time by oral or parenteral administration. Research has been conducted to find compounds that can be absorbed well and have excellent therapeutic effects on human and animal diseases. As a result, substituted or unsubstituted 2,3-dioxo-1,2,3,4, -tetrahydropyrazinyl, 2-oxo-1,2-dihydropyrazinyl, 3,6-dioxo-1 A 2,3,6-tetrahydropyridazinyl or 6-oxo-1,6-dihydropyridazinyl group is attached to an exomethylene group at the 3-position of the cefe ring via a carbon-nitrogen bond, It has been found that the new cephalosporin attached at the 7-position of this amino group has the above excellent properties.

Wherein A, R ⁴ and R ⁵ are as described above.

It is an object of the present invention to have a broad antimicrobial spectrum, to be stable against β-lactamase produced by bacteria, to be low in toxicity, to be well absorbed by oral or parenteral administration, and to have excellent therapeutic effects on human and animal diseases. To provide a novel cephalosporin having the above chemical structural characteristics.

Another object of the present invention is to provide a method for producing the novel cephalosporin.

Another object of the present invention is to provide an intermediate for producing the novel cephalosporin and a method for producing the intermediate.

Other objects and advantages of the invention will be apparent from the following description.

The present invention also provides a method for producing the cephalosporin and its salt, an antimicrobial agent containing the cephalosporin, the intermediate for producing cephalosporin and the method for producing the intermediate.

The invention will be explained in more detail below. Herein, unless specifically stated otherwise, the term "alkyl" refers to, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secondary butyl, tertiary butyl, pentyl, hexyl, Straight chain or branched C _1-14 alkyl including heptyl, octyl, dodecyl, lauryl and the like; The term "alkoxy" means -O-alkyl, wherein alkyl is as defined above; The term "lower alkyl" refers to straight or branched C _1-15 alkyl, including, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secondary butyl, tertiary butyl, pentyl and the like. Means; The term "lower alkoxy" means -O-lower alkyl, wherein lower alkyl is as described above; The term "acyl" refers to a formyl group; C _2-5 alkanoyl groups include, for example, acetyl, propionyl, isovaleryl, pivaloyl, pentanecarbonyl and the like; C _5-8 cycloalkanecarbonyl group includes, for example, cyclopentylcarbonyl, cyclohexylcarbonyl and the like; Aroyl groups include, for example, benzoyl, toluoyl, 2-naphthoyl and the like; Heterocyclic carbonyl groups include, for example, tennoyl, 3-furoyl, nicotinoyl, and the like; The term "acyloxy" means -O-acyl, wherein acyl is as defined above; The term "alkylthio" means -S-alkyl, wherein alkyl is as defined above; The term "alkenyl" refers to C _2-10 alkenyl, including, for example, vinyl, allyl, isopropenyl, 2-phenphenyl, butenyl, and the like; The term “alkynyl” means C _2-10 alkynyl, including, for example, ethynyl, 2-propynyl, and the like; The term “cycloalkyl” refers to C _3-7 cycloalkyl, including, for example, cyclopropyl, cyclobutyl, cyclophene, cyclohexyl, cycloheptyl, and the like; The term "alkadienyl" means C _4-10 alkadienyl, including, for example, 1,3-butadienyl, 1,4-hexadienyl, and the like; The term “cycloalkenyl” means C _5-7 cycloalkenyl, including, for example, cyclopentenyl, cyclohexenyl, and the like; The term "cycloalkadienyl" means C _5-7 cycloalkadienyl, including, for example, cyclopentadienyl, cyclohexadienyl, and the like; The term "aryl" means, for example, phenyl, naphthyl, indanyl, or the like; The term "aralkyl" means, for example, benzyl, phenethyl, methylbenzyl naphthylmethyl, and the like; The term “heterocyclic group” includes, for example, furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxdiazolyl, Thiatriazolyl, oxatriazolyl, triazolyl, tetrazolyl, pyridyl, 4- (5-methyl-2-pyrrolinyl), 4- (2-pyrrolinyl), N-methyl piperidinyl, quinolyl At least one selected from oxygen, nitrogen, sulfur, including phenazinyl, 1,3-benzodioxolanil, benzofuryl, benzothienyl, benzooxazolyl, benzothiazolyl, phthalidyl, comalinyl, and the like. Heterocyclic group containing a hetero atom; The term “heterocyclicalkyl” means a group consisting of the heterocyclic group and the alkyl group; The term "halogen atom" means, for example, fluorine, chlorine, bromine, iodine.

In the present specification, R ¹ of Formula (I) represents a hydrogen atom or a carboxyl-protecting group, which is conveniently used in the penicillin and cephalosporin fields, for example, hydrogenation by a catalyst, Ester forming groups which can be separated by chemical reduction or by treatment under other gentle conditions; Ester forming groups that can be easily separated in vivo; Or organosilyl-containing groups, organophosphorus-containing groups, or organotin-containing groups which can be easily separated by treatment with water or alcohol; And several other known ester forming groups. Appropriate of these protection groups are:

(a) alkyl groups, for example C _1-14 alkyl,

(b) substituted lower alkyl groups wherein at least one of the substituents in this group is a halogen atom or nitro, acyl, alkoxy, oxo, cyano, hydroxyl, cycloalkyl, aryl, alkylthio, alkylsulfinyl, alkylsul Phonyl, alkoxycarbonyl, 5-alkyl-2-oxo-1,3-dioxol-4-yl, 1-indanyl, 2-indanyl, furyl, pyridyl, 4-imidazolyl, phthalimide, Succinimido, azetidino, aziridino, pyrrolidano, piperidino, morpholino, thiomorpholino, N-lower-alkylpiperazino, pyrrolyl, pyrazolyl, thiazolyl, isothiazolyl, Oxazolyl, isoxazolyl, thiadiazolyl, oxdiazolyl, thiadiazolyl, oxatriazolyl, triazolyl, tetrazolyl, quinolyl, phenazinyl, benzofuryl, benzothienyl, benzooxazolyl, benzothiazolyl, Comarinyl, 2,5-dimethylpyrrolidino, 1,4,5,6-tetrahydropyrimidinyl, 4-methylpiperidino, 2,6-dimethylpiperidino, 4- ( 5-methyl-2-pyrrolinyl), 4- (2-pyrrolinyl), N-methyl-piperidinyl, 1,3-benzodioxolanyl, alkylamino, dialkylamino, acyloxy, acylthio , Acylamino, dialkylaminocarbonyl, alkoxycarbonylamino, alkenyloxy, aryloxy, aralkyloxy, cycloalkyloxy, cycloalkenyloxy, heterocyclicoxy, alkoxycarbonyloxy, alkenyloxycarbonyl Oxy, aryloxycarbonyloxy, aralkyloxycarbonyloxy, heterocyclicoxycarbonyloxy, alkenyloxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl, cycloalkyloxycarbonyl, cycloalkenyloxy Carbonyl, heterocyclicoxycarbonyl or alkylanilino groups or alkylanilino groups or alkylanilino groups substituted with halogen atoms, lower alkyl or lower alkoxy groups);

(c) cycloalkyl groups; Lower alkyl-substituted cycloalkyl groups; Or (2,2-di-lower-alkyl-1,3-dioxol-4-yl) methyl group,

(d) alkenyl groups,

(e) alkynyl groups,

(f) phenyl group; Substituted phenyl group (where at least one of the substituents is selected from the substituents specifically mentioned in (b) above; or general formula); Or general formula

또는

or

(Wherein -Y ¹ -is -CH = CH-O-, -CH = CH-S-, -CH ₂ CH ₂ S-, -CH = N-CN = N-, -CH = CH-CH = CH -, -CO-CH = CH-CO-, or -CO-CO-CH = CH- and -Y ² -is a lower alkylene group such as-(CH ₂ ) ₃ -or-(CH ₂ ) _4- Aryl groups or substituted derivatives thereof, wherein the substituents are selected from those specifically mentioned in (b) above,

(g) aralkyl groups, such as benzyl or substituted benzyl groups, wherein at least one of the substituents is selected from those specifically mentioned in (b) above,

(h) heterocyclic groups or substituted heterocyclic groups, wherein at least one of the substituents is selected from those specifically mentioned in (b) above,

(i) indanyl or phthalidyl group or substituted derivatives thereof, wherein the substituents are methyl or halogen; Tetrahydro naphthyl groups or substituted derivatives thereof, wherein the substituents are methyl or halogen; Trityl, cholesteryl, bicyclo [4,4,0] decyl, and the like,

(j) a phthalidylidene-lower alkyl group or a substituted derivative thereof, wherein the substituent is a halogen or lower alkyl group.

The carboxyl protecting group is a typical example, and the carboxyl protecting group is described in the literature (see, for example, US Patent Nos. 3,499,909 and 3,573,296 and 3,641,018, German Patent Application Publication No. 2,301,014 and 2,253,287 and 2,337,105). You can also choose from other protection groups listed.

Preferred among these carboxyl protecting groups are diphenylmethyl, 5-lower alkyl-2-oxo-1,3-dioxol-4-yl-lower alkyl group, acyloxyalkyl group, acylthioalkyl group, substituted or unsubstituted A group that can be easily separated in vivo, such as a phthalidylidene lower alkyl group or a group of the following general formula:

In which R ²¹ is a known substituted or unsubstituted alkyl, alkenyl, aryl, aralkyl, alicyclic or heterocyclic group;

R ²² is a hydrogen atom or a known substituted or unsubstituted alkyl, alkenyl, aryl, aralkyl, alicyclic or heterocyclic group;

R ²³ is hydrogen, halogen or known substituted or unsubstituted alkyl, cycloalkyl, aryl or heterocyclic group, or — (CH ₂ ) _n COOR ²¹ ;

n is 0, 1 or 2;

m is 0, 1 or 2.

More specifically, 5-methyl-2-oxo-1,3-dioxol-4-yl-methyl, 5-ethyl-2-oxo-1,3-dioxol-4-yl-methyl, 5-propyl 2-lower alkyl-2-oxo-1,3-dioxol-4-yl-methyl group such as 2-oxo-1,3-dioxol-4-yl-methyl and the like; Acetoxymethyl, pivaloyloxymethyl, propionyloxymethyl, butyryloxymethyl, isobutyryloxymethyl, valeryloxymethyl, 1-acetoxyethyl, 1-acetoxy-n-propyl, 1-pivalo Acyloxyalkyl groups such as yloxyethyl and 1-pivaloyloxy-n-propyl; Acetylthiomethyl, pivaloylthiomethyl, benzoylthiomethyl, p-chlorobenzoylthiomethyl, 1-acetylthioethyl, 1-pivaloylthioethyl, 1-benzoylthioethyl, 1- (p-chlorobenzoylthio) Acylthioalkyl groups such as ethyl and the like; Alkoxymethyl groups such as methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, n-butyloxymethyl and the like; Methoxycarbonyloxymethyl, ethoxycarbonyloxymethyl, propoxycarbonyloxymethyl, isopropoxycarbonyloxymethyl, n-butoxycarbonyloxymethyl, tert-butoxycarbonyloxymethyl, 1- Methoxycarbonyloxyethyl, 1-ethoxycarbonyloxyethyl, 1-propoxycarbonyloxyethyl, 1-isopropoxycarbonyloxyethyl, 1-3-butoxycarbonyloxyethyl, 1-n Alkoxycarbonyloxyalkyl groups such as butoxycarbonyloxyethyl and the like; Alkoxycarbonylmethyl groups such as methoxycarbonylme and ethoxycarbonylmethyl; Phthalidyl group; Indanyl group; Phenyl group; Such as 2- (phthalidylidene) ethyl, 2- (5-fluorophthalidylidene) 2-ethyl, (6-chlorophthalidylidene) ethyl, 2- (6-methoxyphthalidylidene) ethyl and the like Phthalidelylidenealkyl group can be used.

In formula (I), R ² is a group of the following formula;

or

의 그룹이고 ;Wherein R ⁶ is hydrogen atom, hydroxyl group, nitro group, carbamoyl group, thiocarbamoyl group, sulfamoyl group or substituted or unsubstituted alkyl, alkenyl, alkynyl, alkadienyl, cycloalkyl, cyclo Alkenyl, cycloalkadienyl, aryl, aralkyl, acyl, alkoxy, alkylthio, acyloxy, cycloalkyloxy, aryloxy, alkoxycarbonyl, cycloalkyloxycarbonyl, acyloxycarbonyl, aralkyloxycarbonyl , Alkylsulfonyl, cycloalkylsulfonyl, arylsulfonyl, heterocyclicsulfonyl, alkylcarbamoyl, dialkylcarbamoyl, alkylthiocarbamoyl, dialkylthiocarbamoyl, acylcarbamoyl, acylthiocarbamoyl, alkyl Sulfonylcarbamoyl, arylsulfonylthiocarbamoyl, alkylsulfamoyl, dialkylsulfamoyl, alkoxythiocarbonyl, alkylideneamino, cycloalkylmethyleneamino, arylmethyleneamino, heterocyclic methyleneamino or hete Cyclic group or

Is a group of;

R ¹⁷ and R ¹⁶ may be the same or different and each is a hydrogen atom or an alkyl group, or R ¹⁶ and R ¹⁷ together with the adjacent nitrogen atom form a ring;

R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹⁴ and R ¹⁵ may be the same or different and each is a hydrogen atom, a halogen atom or a substituted or unsubstituted alkyl, aralkyl or aryl group. ego ;

R ¹³ represents a hydrogen atom, a halogen atom, a carboxyl group, a sulfo group, a carbamoyl group, a thiocarbamoyl group, or a substituted or unsubstituted alkyl, aralkyl, aryl, alkoxy, alkylthio, acyl, alkoxycarbonyl, cycloalkyl Oxycarbonyl, acyloxycarbonyl, aralkyloxycarbonyl, alkylsulfonyl, cycloalkylsulfonyl, arylsulfonyl, heterocyclicsulfonyl, alkylcarbamoyl, dialkylcarbamoyl, alkylthiocarbamoyl, dialkyl Thiocarbamoyl, acylcarbamoyl, acylthiocarbamoyl, alkylsulfonylcarbamoyl, arylsulfonylcarbamoyl, alkylsulfonylthiocarbamoyl or arylsulfonylthiocarbamoyl groups.

알킬을 의미하고 ; "시클로알킬옥시카보닐"이라는 용어는

시클로알킬을 의미하며 ; "아실옥시카보닐"이라는 용어는

아실을 의미하고 ; "아르알킬옥시카보닐"이라는 용어는

아르알킬을 의미하며 ; "알킬설포닐"이라는 용어는 -SO₂-알킬을 의미하고 ; "시클로알킬설포닐"이라는 용어는 -SO₂-시클로알킬을 의미하며 ; "아릴설포닐"이라는 용어는 -SO₂-아릴을 의미하고 ; "헤테로시클릭설포닐"이라는 용어는 -SO₂-헤테로시클릭환을 의미하며 ; "알킬카바모일"이라는 용어는

알킬을 의미하고 ; "디알킬카바모일"이라는 용어는

을 의미하며 ; "알킬티오카바모일"이라는 용어는

알킬을 의미하고 ; "디알킬티오카바모일"이라는 용어는

을 의미하며 ; "아실카바모일"이라는 용어는

아실을 의미하고 ; "알킬설포닐카바모일"이라는 용어는

알킬을 의미하며 ; "아릴설포닐카바모일"이라는 용어는

아릴을 의미하고 ; "알킬설포닐티오카바모일"이라는 용어는

알킬을 의미하며 ; "아릴설포닐티오카바모일"이라는 용어는

아릴을 의미하고 ; "알킬설파모일"이라는 용어는 -SO₂-NH-알킬을 의미하며 ; "디알킬설파모일"이라는 용어는

을 의미하고 ; "알콕시티오카보닐"이라는 용어는

알킬을 의미하며 ; "알킬리덴아미노"라는 용어는 -N=CH-알킬을 의미하고 ; "시클로알킬메틸렌아미노"라는 용어는 -N=CH-시클로알킬을 의미하며 ; "아릴메틸렌아미노"라는 용어는 -N=CH-아릴을 의미하고 ; "헤테로시클릭메틸렌아미노"라는 용어는 -N=CH-헤테로시클릭환이다.In each of the above R ⁶ and R ¹³ groups, the term “cycloalkyloxy” means —O-cycloalkyl; The term "aryloxy" means -O-aryl; The term "alkoxycarbonyl"

Alkyl; The term "cycloalkyloxycarbonyl"

Cycloalkyl; The term "acyloxycarbonyl"

Means acyl; The term "aralkyloxycarbonyl"

Aralkyl; The term "alkylsulfonyl" refers to -SO ₂ -alkyl; The term “cycloalkylsulfonyl” refers to —SO ₂ -cycloalkyl; The term "arylsulfonyl" refers to -SO ₂ -aryl; The term “heterocyclicsulfonyl” refers to a —SO ₂ -heterocyclic ring; The term "alkylcarbamoyl"

Alkyl; The term "dialkylcarbamoyl"

Means; The term "alkylthiocarbamoyl"

Alkyl; The term "dialkylthiocarbamoyl"

Means; The term "acyl carbamoyl"

Means acyl; The term "alkylsulfonylcarbamoyl"

Alkyl; The term "arylsulfonylcarbamoyl"

Aryl; The term "alkylsulfonylthiocarbamoyl"

Alkyl; The term "arylsulfonylthiocarbamoyl"

Aryl; The term "alkylsulfamoyl" refers to -SO ₂ -NH-alkyl; The term "dialkylsulfamoyl"

Means; The term "alkoxythiocarbonyl"

Alkyl; The term "alkylideneamino" refers to -N = CH-alkyl; The term "cycloalkylmethyleneamino" refers to -N = CH-cycloalkyl; The term "arylmethyleneamino" means -N = CH-aryl; The term "heterocyclic methyleneamino" is a -N = CH-heterocyclic ring.

(여기에서 R¹⁶및 R¹⁷은 상술한 바와 같다)의 그룹은 아미노그룹, -NH-알킬로 나타낸 알킬아미노그룹,

로 나타낸 디알킬아미노 그룹General formula

Wherein R ¹⁶ and R ¹⁷ are as defined above, the group is an amino group, an alkylamino group represented by -NH-alkyl,

Dialkylamino group represented by

의 그룹을 포함한다.And

Includes groups of.

로 나타낸 디알킬아미노그룹, -NH-아실로 나타낸 아실아미노그룹,

알킬로 나타낸 알콕시카보닐그룹, 아세틸메틸, 프로피오닐메틸 등과 같은 아실알킬그룹, 아미노메틸, 아미노에틸 등과 같은 아미노알킬그룹, N-메틸 아미노메틸, N-메틸아미노에틸 등과 같은 N-알킬 아미노 알킬그룹, N,N-디메틸아미노메틸, N,N-디메틸아미노에틸 등과 같은 N,N-디알킬아미노 알킬그룹, 하이드록시메틸, 하이드록시에틸 등과 같은 하이드록시알킬그룹, 하이드록시이미노메틸, 하이드록시이미노에틸 등과 같은 하이드록시이미노알킬그룹, 메톡시메틸, 메톡시에틸, 에톡시메틸, 에톡시에틸 등과 같은 알콕시 알킬그룹, 카복시메틸, 카복시에틸 등과 같은 카복시알킬그룹, 메톡시카보닐메틸, 메톡시카보닐에틸, 에톡시카보닐메틸, 에톡시카보닐에틸 등과 같은 알콕시 카보닐알킬그룹, 벤질옥시카보닐메틸, 벤질옥시카보닐에틸 등과 같은 아르알킬옥시카보닐알킬그룹, 설포메틸, 설포에틸 등과 같은 설포알킬그룹, 설파모일메틸, 설파모일에틸 등과 같은 설파모일 알킬그룹, 카바모일메틸, 카바모일에틸 등과 같은 카바모일알킬그룹, 카바모일알릴 등과 같은 카바모일알케닐그룹, N-하이드록시카바모일메틸, N-하이드록시카바모일에틸 등과 같은 N-하이드록시카바모일알킬그룹, 일반식

(여기에서 R²⁴는 저급알킬그룹 등이다)의 그룹을 포함한다. 상기의 치환체중에서, 하이드록실그룹, 아미노그룹 및 카복실그룹은 본 분야에서 통상적으로 유용한 적절한 보호그룹에 의해서 보호될 수 있다. 하이드록실 보호그룹은, 예를들면 벤질옥시카보닐, 4-니트로벤질옥시카보닐, 4-브로모 벤질옥시카보닐, 4-메톡시 벤질옥시카보닐, 3,4-디메톡시벤질옥시카보닐, 4-(페닐아조) 벤질옥시 카보닐, 4-(4-메톡시페닐아조)벤질옥시카보닐, 3급-부톡시카보닐, 1,1-디메틸프로폭시카보닐, 이소프로폭시카보닐, 디페닐메톡시카보닐, 2,2,2-트리클로로에톡시카보닐, 2,2,2-트리브로모에톡시카보닐, 2-푸르푸릴옥시카보닐, 1-아다만틸옥시카보닐, 1-시클로프로필에톡시카보닐, 8-퀴놀릴옥시카보닐, 포르밀, 아세틸, 클로로아세틸, 벤조일, 트리플루오로 아세틸 등과 같은 쉽게 분리할 수 있는 아실그룹 ; 예를들면 메탄설포닐, 에탄설포닐 등과 같은 알킬설포닐그룹 ; 벤질그룹 ; 디페닐메틸그룹 ; 트리틸그룹 ; 메톡시메틸그룹 ; 테트라하이드로피라닐그룹 ; 테트라하이드로푸라닐그룹 ; 2-니트로 페닐티오그룹 ; 2,4-디니트로페닐티오그룹 등과 같은, 통상적으로 사용할 수 있는 모든 하이드록실-보호그룹을 포함한다. 또한 아미노-보호그룹은, 예를들면 2,2,2-트리클로로에톡시카보닐, 2,2,2-트리브로모에톡시카보닐, 벤질옥시카보닐, p-톨루엔설포닐, 4-니트로벤질옥시카보닐, 2-브로모벤질옥시카보닐, 아세틸, (모노-, 디-, 트리-)클로로아세틸, 트리플루오로아세틸, 포르밀, 3급-아밀옥시카보닐, 3급-부톡시카보닐, 4-메톡시벤질옥시카보닐, 3,4-디메톡시벤질옥시카보닐, 4-(페닐아조) 벤질옥시카보닐, 4-(4-메톡시페닐아조) 벤질옥시카보닐, 피리딘-1-옥사이드-2-일-메톡시카보닐, 2-푸릴옥시카보닐, 디페닐 메톡시카보닐, 1,1-디메틸프로폭시카보닐, 이소프로폭시카보닐, 1-시클로프로필에톡시카보닐, 프탈로일, 석시닐, 1-아다만틸옥시카보닐, 8-퀴놀릴옥시카보닐 등과 같은 쉽게 분리할 수 있는 아실그룹 ; 예를들면 트리틸, 0-니트로페닐설포닐, 2,4-디니트로페닐티오, 2-하이드록시벤질리덴, 2-하이드록시-5-클로로벤질리덴, 2-하이드록시-1-나프틸메틸렌, 3-하이드록시-4-피리딜메틸렌, 1-메톡시카보닐-2-프로필리덴, 1-에톡시카보닐-2-프로필리덴, 3-에톡시카보닐-2-부틸리덴, 1-아세틸-2-프로필리덴, 1-벤조일-2-프로필리덴, 1-[N-(2-메톡시페닐)카바모일]-2-프로필리덴, 1-[N-(4-메톡시페닐)카바모일]-2-프로필리덴, 2-에톡시카보닐시클로 헥실리덴, 2-에톡시카보닐 클로펜틸리덴, 2-아세틸시클로 헥실리덴, 3,3-디메틸-5-옥소시클로 헥실리덴, 4-니트로푸르푸릴리덴 등과 같은 쉽게 분리할 수 있는 그룹 ; 디-또는 트리-알킬 실릴그룹 등과 같이 통상적으로 유용한 모든 아미노-보호그룹을 포함한다. 그리고 카복실-보호그룹은 통상적으로 유용한 모든 카복실 보호그룹을 포함하고, 여기에서 카복실그룹은 메틸, 에틸, n-프로필, 이소-프로필, 3급-부틸, n-부틸, 벤질, 디페닐메틸, 트릴릴, 4-니트로벤질, 4-메톡시벤질, 벤조일메틸, 아세틸메틸, 4-니트로벤조일메틸, p-브로모벤조일메틸, 4-메탄설포닐벤조일메틸, 프탈리미도메틸, 2,2,2-트리클로로에틸, 1,1-디메틸-2-프로페닐, 1,1-디메틸프로필, 아세톡시메틸, 프로피오닐옥시메틸, 피발로일옥시메틸, 3-메틸-3-부티닐, 석신이미도메틸, 1-시클로프로필에틸, 메틸티오메틸, 페닐티오메틸, 디메틸아미노메틸, 퀴놀린-1-옥사이드-2-일메틸, 피리딘-1-옥사이드-2-일메틸, 비스(p-메톡시페닐)메틸 등과 같은 그룹(여기에서 카복실 그룹은 사염화티탄과 같은 비금속화합물로 보호되고, 이 카복실그룹은 일본국 특허원 공개공보(Japanese Patent Application kokai) 제7073/71호와 네덜란드왕국 특허원 공개공보(Dutch Patent Application) 제7105259호에 기술된 디메틸클로로 실란과 같은 실릴화합물로 보호되어 있다)으로 보호되어 있다.Substituents of the various groups are halogen atom, alkyl group, aralkyl group, aryl group, alkenyl group, hydroxyl group, oxo group, alkoxy group, alkylthio group, nitro group, cyano group, amino group, acyl group, Acyloxy group, carboxyl group, carbamoyl group, sulfo group, sulfamoyl group, alkyl amino group represented by -NH-alkyl,

Dialkylamino group represented by, acylamino group represented by -NH-acyl,

Alkoxycarbonyl groups represented by alkyl, acylalkyl groups such as acetylmethyl, propionylmethyl and the like, aminoalkyl groups such as aminomethyl, aminoethyl and the like, N-alkyl aminoalkyl groups such as N-methyl aminomethyl and N-methylaminoethyl N, N-dialkylamino alkyl groups such as N, N-dimethylaminomethyl, N, N-dimethylaminoethyl, hydroxyalkyl groups such as hydroxymethyl, hydroxyethyl, hydroxyiminomethyl, hydroxyimino Hydroxyiminoalkyl groups such as ethyl, methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl and the like, carboxyalkyl groups such as carboxymethyl, carboxyethyl, methoxycarbonylmethyl and methoxycarbo Alkoxycarbonylalkyl groups such as nitrile ethyl, ethoxycarbonylmethyl, ethoxycarbonylethyl, and the like, benzyloxycarbonylmethyl, benzyloxycarbonylethyl and the like Alkyloxycarbonylalkyl groups, sulfoalkyl groups such as sulfomethyl, sulfoethyl and the like, sulfamoyl alkyl groups such as sulfamoylmethyl and sulfamoylethyl, carbamoylalkyl groups such as carbamoylmethyl and carbamoylethyl, carbamoylallyl and the like N-hydroxycarbamoylalkyl groups, such as carbamoyl alkenyl groups, N-hydroxycarbamoylmethyl, N-hydroxycarbamoylethyl, etc.

In which R ²⁴ is a lower alkyl group or the like. Among the substituents described above, hydroxyl groups, amino groups and carboxyl groups may be protected by appropriate protecting groups commonly available in the art. The hydroxyl protecting group is for example benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-bromo benzyloxycarbonyl, 4-methoxy benzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl , 4- (phenylazo) benzyloxy carbonyl, 4- (4-methoxyphenylazo) benzyloxycarbonyl, tert-butoxycarbonyl, 1,1-dimethylpropoxycarbonyl, isopropoxycarbonyl , Diphenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2,2,2-tribromoethoxycarbonyl, 2-furfuryloxycarbonyl, 1-adamantyloxycarbonyl Easily acyl groups such as 1-cyclopropylethoxycarbonyl, 8-quinolyloxycarbonyl, formyl, acetyl, chloroacetyl, benzoyl, trifluoro acetyl and the like; Alkylsulfonyl groups such as methanesulfonyl, ethanesulfonyl and the like; Benzyl group; Diphenylmethyl group; Trityl group; Methoxymethyl group; Tetrahydropyranyl group; Tetrahydrofuranyl group; 2-nitro phenylthio group; All hydroxyl-protecting groups which can be used conventionally are included, such as a 2, 4- dinitrophenylthio group etc. Further amino-protecting groups are, for example, 2,2,2-trichloroethoxycarbonyl, 2,2,2-tribromoethoxycarbonyl, benzyloxycarbonyl, p-toluenesulfonyl, 4-nitro Benzyloxycarbonyl, 2-bromobenzyloxycarbonyl, acetyl, (mono-, di-, tri-) chloroacetyl, trifluoroacetyl, formyl, tert-amyloxycarbonyl, tert-butoxy Carbonyl, 4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 4- (phenylazo) benzyloxycarbonyl, 4- (4-methoxyphenylazo) benzyloxycarbonyl, pyridine -1-oxide-2-yl-methoxycarbonyl, 2-furyloxycarbonyl, diphenyl methoxycarbonyl, 1,1-dimethylpropoxycarbonyl, isopropoxycarbonyl, 1-cyclopropylethoxy Easily separable acyl groups such as carbonyl, phthaloyl, succinyl, 1-adamantyloxycarbonyl, 8-quinolyloxycarbonyl and the like; For example trityl, 0-nitrophenylsulfonyl, 2,4-dinitrophenylthio, 2-hydroxybenzylidene, 2-hydroxy-5-chlorobenzylidene, 2-hydroxy-1-naphthylmethylene , 3-hydroxy-4-pyridylmethylene, 1-methoxycarbonyl-2-propylidene, 1-ethoxycarbonyl-2-propylidene, 3-ethoxycarbonyl-2-butylidene, 1 -Acetyl-2-propylidene, 1-benzoyl-2-propylidene, 1- [N- (2-methoxyphenyl) carbamoyl] -2-propylidene, 1- [N- (4-methoxyphenyl) Carbamoyl] -2-propylidene, 2-ethoxycarbonylcyclohexylidene, 2-ethoxycarbonyl clopentylidene, 2-acetylcyclohexylidene, 3,3-dimethyl-5-oxocyclo hexide Easily separable groups such as silicide, 4-nitrofurfurylidene and the like; All amino-protecting groups which are commonly useful, such as di- or tri-alkyl silyl groups and the like. And the carboxyl-protecting group typically includes all useful carboxyl protecting groups, wherein the carboxyl group is methyl, ethyl, n-propyl, iso-propyl, tert-butyl, n-butyl, benzyl, diphenylmethyl, tril Reyl, 4-nitrobenzyl, 4-methoxybenzyl, benzoylmethyl, acetylmethyl, 4-nitrobenzoylmethyl, p-bromobenzoylmethyl, 4-methanesulfonylbenzoylmethyl, phthalimidomethyl, 2,2,2 -Trichloroethyl, 1,1-dimethyl-2-propenyl, 1,1-dimethylpropyl, acetoxymethyl, propionyloxymethyl, pivaloyloxymethyl, 3-methyl-3-butynyl, succinimidomethyl , 1-cyclopropylethyl, methylthiomethyl, phenylthiomethyl, dimethylaminomethyl, quinolin-1-oxide-2-ylmethyl, pyridin-1-oxide-2-ylmethyl, bis (p-methoxyphenyl) methyl And the like (where the carboxyl group is protected by a non-metallic compound such as titanium tetrachloride, which is a member of the Japanese Patent Office). Publication is protected by a (Japanese Patent Application kokai) is first protected with a silyl compound such as No. 7073/71 and the Kingdom of the Netherlands Patent Application Laid-Open (Dutch Patent Application) the dimethylchlorosilane described in claim No. 7,105,259).

R ⁵ is a hydrogen atom or a protected or unprotected amino group, which includes many groups which are commonly applied in the penicillin and cephalosprin fields, in particular all of the aminoprotective groups represented by R ² above.

의 그룹을 나타낸다. 상기식에서 R¹⁵은 수소원자 ; 치환되거나 비치환된 알킬, 알케닐, 알키닐, 시클로알킬, 시클로알케닐, 아르알킬, 아릴, 헤테르 시클릭그룹 또는 하이드록실-보호그룹, 또는 일반식

(여기에서 R¹⁹및 R²⁰은 같거나 다를 수도 있으며, 각기 하이드록실, 알킬, 아르알킬, 아릴, 알콕시, 아르알킬, 아릴, 알콕시, 아르알킬옥시 또는 아릴옥시 그룹이다)의 그룹이고,

결합은 이 화합물이 신 이성질체 또는 안티 이성질체 또는 그의 화합물일 수 있다는 것을 의미한다. 상기 하이드록실-보호그룹은 R²로 표시된 하이드록실-보호그룹을 포함한다. 또한 상기 여러 R¹⁸그룹은 할로겐원자, 옥소그룹, 시아노그룹, 하이드록실그룹, 알콕시그룹, 아미노그룹, 알킬아미노그룹, 디알킬아미노그룹, 헤테로시클릭그룹 및 일반식A is a group of the formula -CH _2- , or a general formula

Represents a group of. In the formula, R ¹⁵ is a hydrogen atom; Substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl, heterocyclic or hydroxyl-protecting groups, or general formula

Wherein R ¹⁹ and R ²⁰ may be the same or different and each is a hydroxyl, alkyl, aralkyl, aryl, alkoxy, aralkyl, aryl, alkoxy, aralkyloxy or aryloxy group,

Binding means that the compound may be a new isomer or an anti isomer or a compound thereof. Said hydroxyl-protecting group comprises a hydroxyl-protecting group denoted by R ² . In addition, the various R ¹⁸ groups are halogen atom, oxo group, cyano group, hydroxyl group, alkoxy group, amino group, alkylamino group, dialkylamino group, heterocyclic group and general formula

의 옥심은 신-이성질체 및 안티-이성질체와 그의 혼합물을 포함한다. 본 발명에서 각 일반식

의 그룹중에서 다음 평형식으로 나타내는 토오토머가 존재하며, 이러한 토오토머는 본 발명에 포함된다 :Substituted with at least one substituent selected from the group of R ¹ , wherein R ¹ is as defined above and R ²⁵ , R ²⁶ and R ²⁷ may be the same or different and each is a hydrogen atom, an alkyl group, an aralkyl group or an aryl group Can be. Among these substituents, hydroxyl groups, amino groups and carboxyl groups can be protected, respectively, with hydroxyl-protecting groups represented by R ² and amino-protecting groups and carboxyl-protecting groups represented by R ¹ . General formula

The oxime of contains the neo-isomers and the anti-isomers and mixtures thereof. Each general formula in the present invention

Among the groups of tautomers are present in the following equilibrium, which are included in the present invention:

In which R ⁴ is as described above; R ⁵ is a protected or unprotected amino group; R ^5a is a protected or unprotected amino group.

In the above formula, the R ^5a iminoprotective group includes groups used in the penicillin and cephalosporin arts, in particular groups such as monovalent groups among the amino protecting groups represented by R ² .

-CH ₂ R ² group in formula (I) is a general formula

또는

or

In which R ⁶ , R ¹⁰ , R ¹¹ and R ¹² are as defined above; When R ⁶ and R ¹⁰ are each a hydrogen atom, a tautomer represented by the following equilibrium exists, which is also included in the present invention.

Salts of compounds of formula (I) include salts of base groups and acid groups known in the penicillin and cephalosporin arts. Salts of base groups include salts of inorganic acids such as hydrochloric acid, nitric acid and sulfuric acid; Salts of organic carboxylic acids such as oxalic acid, succinic acid, formic acid, trichloroacetic acid, trifluoro acetic acid, and the like; Methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluene-2-sulfonic acid, toluene-4-sulfonic acid, mesitylenesulfonic acid (2,4,6-trimethylbenzenesulfonic acid), naphthalene-1-sulfonic acid, Naphthalene-2-sulfonic acid, phenylmethane sulfonic acid, benzene-1,3-disulfonic acid, toluene-3,5-disulfonic acid, naphthalene-1,5-disulfonic acid, naphthalene-2,6-disulfonic acid, naphthalene- Salts of sulfonic acids such as 2,7-disulfonic acid, benzene-1,3,5-trisulfonic acid, benzene-1,2,4-trisulfonic acid, naphthalene-1,3,5-trisulfonic acid and the like do.

Salts of the acid groups include salts of alkali metals such as sodium and potassium; Salts of alkaline earth metals such as calcium and magnesium; Ammonium salts; Procaine, dibenzylamine, N-benzyl-β-phenethyl amine, 1-ephenamine, N, N-dibenzylethylenediamine, triethylamine, trimethylamine, tributylamine, pyridine, N, N-dimethylaniline Salts of nitrogen-containing organic bases such as N-methylpiperidine, N-methylmorpholine, diethylamine, dicyclohexylamine and the like.

의 그룹, 특히 그의 신-이성질체이고 ; R¹⁶은 바람직하게는 알킬그룹, 특히 메틸, 에틸 ; 또는 치환된 알킬그룹, 특히 -CH₂COOR¹또는

이며 ; R¹은 상술한 바와 같다)이다.The present invention includes all optical isomers and racemic compounds of the general formula (I) cephalosporin and salts thereof, and all crystal forms and hydrates of the compounds. More particularly, more suitable examples of compounds of formula (I) are oximes, where A is

Is a group of, especially its neo-isomers; R ¹⁶ is preferably an alkyl group, in particular methyl, ethyl; Or substituted alkyl groups, in particular -CH ₂ COOR ¹ or

And; R ¹ is as described above).

(여기에서 R⁶는 수소원자, 치환되거나 비치환된 저급알킬그룹 또는 일반식

의 그룹이고 ; R¹⁵및 R¹⁷는 상술한 바와 같다)의 그룹 ; 일반식Suitable examples of R ² are

Wherein R ⁶ is a hydrogen atom, a substituted or unsubstituted lower alkyl group, or a general formula

Is a group of; R ¹⁵ and R ¹⁷ are as described above); General formula

A group of wherein R ⁷ , R ⁸ and R ⁹ may be the same or different and each is a hydrogen atom or an alkyl group; General formula

(Wherein R ¹⁰ , R ¹¹ and R ¹² may be the same or different and each is a hydrogen atom, a halogen atom or an alkyl group); General formula

Wherein R ¹³ , R ¹⁴ and R ¹⁵ may be the same or different and each is a hydrogen atom or an alkyl group.

The following pharmacological effects occur in some compounds of general formula (I).

1) Antimicrobial Activity (Table 1)

Japan Society of Chemotherapy [Vol. 23, "CHEMOTHERAPY". 1-2 (1975)], inoculated in drug-containing heart-injected agar with a culture medium obtained by incubating in Heart Infusion broth (Aiken Kagaku) for 20 hours at 37 ° C. After observing the growth of the bacteria, the embryos are incubated at 37 ° C. for 20 hours to determine the minimum concentration at which bacterial growth is inhibited by MIC (µg / ml). The amount of bacteria inoculated is 10 ⁴ Cells / plate (10 ⁶ Cells / ml). The MIC values for the following test compounds are shown in Table 1:

(A) 7- [2- (2-aminothiazol-4-yl) -2- (cin) -methoxy imino acetamido] -3-{[1- (4-methyl-2,3- Trifluoro acetate of dioxo-1,2,3,4-tetrahydropyrazinyl)] methyl} -Δ ³ -cef-4-carboxylic acid,

(B) 7- [2- (2-aminothiazol-4-yl) -2- (cin) -methoxy imino acetamido] -3-{[1- (4-methyl-2,3- Trifluoro acetate of dioxo-1,2,3,4-tetrahydropyrazinyl)] methyl} -Δ ³ -cef-4-carboxylic acid,

(C) 7- [2- (2-aminothiazol-4-yl) -2- (cin) -methoxy imino acetamido] -3-{[1- (4-methyl-2,3- Trifluoro acetate of dioxo-1,2,3,4-tetrahydropyrazinyl)] methyl} -Δ ³ -cef-4-carboxylic acid,

(D) 7- [2- (2-aminothiazol-4-yl) -2- (cin) -methoxy imino acetamido] -3-{[1- (4-isopropyl-2,3 Trifluoro acetate of -dioxo-1,2,3,4-tetrahydropyrazinyl)] methyl} -Δ ³ -cef-4-carboxylic acid,

(E) 7- [2- (2-aminothiazol-4-yl) -2- (cin) -methoxy imino acetamido] -3-{[1- (4-dimethylamino-2,3 Trifluoro acetate of -dioxo-1,2,3,4-tetrahydropyrazinyl)] methyl} -Δ ³ -cef-4-carboxylic acid,

(F) 7- [2- (2-aminothiazol-4-yl) -2- (cin) -carboxymethoxy imino acet amido] -3-{[1- (2,3-dioxo- 1,2,3,4-tetrahydropyrazinyl)] methyl} -Δ ³ -cef-4-carboxylic acid,

(G) 7- [2- (2-aminothiazol-4-yl) -2- (cin) -carboxymethoxy imino acetamido] -3-{[1- (4-methyl-2,3 Trifluoro acetate of -dioxo-1,2,3,4-tetrahydropyrazinyl)] methyl} -Δ ³ -cef-4-carboxylic acid,

(H) 7- [2- (2-aminothiazol-4-yl) -2- (cin) -carboxymethoxy imino acetamido] -3-{[1- (4-ethyl-2,3 Trifluoro acetate of -dioxo-1,2,3,4-tetrahydropyrazinyl)] methyl} -Δ ³ -cef-4-carboxylic acid,

(I) 7- [2- (2-aminothiazol-4-yl) -2- (cin) -carboxymethoxy imino acet amido] -3-{[1- (4-dimethylamino-2, Trifluoro acetate of 3-dioxo-1,2,3,4-tetrahydropyrazinyl)] methyl} -Δ ³ -cef-4-carboxylic acid,

(J) 7- [2- (2-aminothiazol-4-yl) -2- (cin) -methoxyimino acetamido] -3-{[1- (2-oxo-1,2-di Hydropyrazinyl)] methyl} -Δ ³ -cepem-4-carboxylic acid trifluoro acetate,

(K) 7- [2- (2-aminothiazol-4-yl) -2- (cin) -methoxy imino acetamido] -3-{[1- (3,6-dioxo-1 Trifluoroacetic acid of 2,3,6-tetrahydropyridazinyl)] methyl} -Δ ³ -cepem-4-carboxylic acid,

(L) 7- [2- (2-Aminothiazol-4-yl) -2- (new) -carboxymethoxy imino acetamido] -3-{[1- (3,6-dioxo- 1,2,3,6-tetrahydropyridazinyl)] methyl} -Δ ³ -cepem-4-carboxylic acid formate,

(M) 7- [2- (2-Aminothiazol-4-yl) -2- (cin) -methoxy imino acamido] -3-{[1- (3-methyl-6-oxo- Trifluoro acetate of 1,6-dihydropyridazinyl)] methyl} -Δ ³ -cepem-4-carboxylic acid,

(N) 7- [2- (2-aminothiazol-4-yl) -2- (cin) -carboxymethoxy imino acetamido] -3-{[1- (3-methyl-6-oxo -1,6-dihydropyridazinyl)] methyl} -Δ ³ -cefem-4-carboxylic acid formate,

TABLE 1

Antimicrobial activity

Note: * Penicillinase-producing strain

** Cephalosporins-Producing strains

2) urine recovery

Test compounds are administered orally to mice (ICR, male, 4 weeks) in an amount of 1 mg / mouse and urine recovery is measured. The results obtained are shown in Table 2.

In test compounds (numbers 1 and 2), ester groups are readily separated in vivo and converted to the corresponding free carboxylic acids. Thus, urine recovery is determined by quantitatively measuring the free carboxylic acid excreted in urine. Method of administration: Test compound suspended in 0.5% CMC (carboxy methyl cellulose sac) is administered orally. Quantitative Method: The amount of free carboxylic acid is determined by biological assay (paper-disk method) using the test microorganisms shown in Table 2.

TABLE 2

Note: * 0-6 hours, one group; 5 mice (mean ± S.E.)

3) acute toxicity

When intravenously administered the following test compounds to mice (ICR, male, body weight 20 to 24 g), the LD ₅₀ value was 3 g / kg or more.

Test compound: Sodium 7- [2- (2-aminothiazol-4-yl) -2- (cin) -methoxyiminoacetamino-3-{[1- (2,3-dioxo-1, 2,3,4-tetrahydropyrazinyl)] methyl} -Δ ³ -cepem-4-carboxylate, sodium 7- [2- (2-aminothiazol-4-yl) -2- (cin) -meth Toxyimino acetamido-3-{[1- (4-methyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)] methyl} -Δ ³ -cefe-4-carboxylate , Sodium 7- [2- (2-aminothiazol-4-yl) -2- (cin) -methoxyiminoacetamido] -3-{[1- (3,6-dioxo-1, 2,3,6-tetrahydropyridazinyl)] methyl} -Δ ³ -cepem-4-carboxylate and sodium 7- [2- (2-aminothiazol-4-yl) -2- (cin-meth Toxyiminoacetamido] -3-{[1- (3-methyl-6-oxo-1,6-dihydropyridazinyl)] methyl}-Δ ³ -cefe-4-carboxylate.

The following is a description of the manufacturing process, the compound of the present invention can be produced by the following process. :

결합은 상술한 바와 같고 ;Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁸ , A and

Bonding is as described above;

R ^18a is the same as R ¹⁸ , but not hydrogen;

그룹 또는 일반식

이고 ;R ²⁸ is an amino group, general formula

Group or general formula

ego ;

R ³¹ , R ³² and R ³³ may be the same or different and each is a hydrogen atom or an organic moiety that does not participate in the reaction;

R ³⁴ and R ³⁵ may be the same or different and are a hydrogen atom or an organic moiety that does not participate in the reaction;

R ²⁹ is a substituted or unsubstituted acyloxy or carbamoyl oxy group;

의 그룹이고 ;R ³⁰ is benzyl, phenoxymethyl or a general formula

Is a group of;

R ⁴ , R ⁵ and A are as described above;

X is a halogen atom; > Z is> S or> S → 0;

The dotted line in the ring represents a double bond between the 2- and 3-positions or between the 3- and 4-positions.

그룹 또는 일반식

그룹이고, 일반식

의 그룹은 그의 이성질체인 일반식

의 그룹도 포함한다.In more detail below, R ²⁸ is an amino group,

Group or general formula

Group, general formula

The group of is his isomer, general formula

It also includes groups of.

For R ³¹ , R ³² , R ³³ , R ³⁴ and R ³⁵ , the organic residues which do not participate in the reaction are known in the art, in particular substituted or unsubstituted aliphatic residues, alicyclic residues, aromatic residues, aromatic- Aliphatic residues, heterocyclic residues, acyl groups and the like, and more specifically include the following groups: (1) aliphatic residues: alkyl groups; Alkenyl Group,

(2) alicyclic moiety: cycloalkyl group; Cycloalkenyl groups,

(3) aromatic residues: aryl groups,

(4) aromatic-aliphatic residues: aralkyl groups,

(5) heterocyclic moieties: heterocyclic group,

(6) acyl groups: aliphatic carboxylic acids, alicyclic carboxylic acids and alicyclic-aliphatic carboxylic acids; And aromatic aliphatic carboxylic acids, aromatic-oxyaliphatic carboxylic acids, aromatic-thio aliphatic carboxylic acids, heterocyclic aliphatic carboxylic acids, heterocyclic-oxyaliphatic carboxylic acids and heterocyclic-thioaliphatic carboxylic acids, wherein the aromatic moiety or heterocyclic group is directly Or is bonded to an aliphatic carboxylic acid through oxygen or a sulfur atom); Organic carboxylic acid in which an aromatic moiety, an aliphatic group or an alicyclic group is bonded to a carbonyl group via an oxygen, nitrogen or sulfur atom; Aromatic carboxylic acid; Acyl groups that can be derived from organic carboxylic acids, including heterocyclic carboxylic acids, and the like.

The aliphatic carboxylic acid includes formic acid, acetic acid, propionic acid, butanoic acid, isobutanoic acid, pentanic acid, methoxy-acetic acid, methylthioacetic acid, acrylic acid, crotonic acid, and the like, and cycloaliphatic carboxylic acid includes cyclohexanoic acid, Alicyclic-aliphatic carboxylic acid includes cyclopentane acetic acid, cyclohexane acetic acid, cyclohexane propionic acid, cyclohexadiene acetic acid and the like.

Aromatic residues of the organic carboxylic acid also include phenyl, naphthyl and the like.

Each of the groups constituting such free carboxylic acid is substituted (eg, halogen atom, hydroxyl group, protected hydroxyl group, alkyl group, alkoxy group, acyl group, nitro group, amino group, protected amino group, carboxyl group or protecting group) Carboxyl group).

Substituted or unsubstituted acyloxy and carbamoyloxy groups of R ²⁹ also include alkanoyloxy groups (eg acetoxy, propionyloxy, butyryloxy, etc.), alkenoyloxy groups (eg acryloyloxy Etc) ; Aroyloxy groups such as benzoyloxy, naphthoyloxy and the like and carbamoyloxy groups. Such groups include one or more substituents (e.g., halogen atoms, nitro groups, amino groups, alkyl groups, alkoxy groups, alkylthio groups, acyloxy groups, acylamino groups, hydroxyl groups, carboxyl groups, sulfamoyl groups, carbamoyl) Groups, alkoxycarbonylcarbamoyl groups, aroylcarbamoyl groups, alkoxycarbonylsulfamoyl groups, aryl groups, carbamoyloxy groups and the like).

Among the substituents of R ²⁹ , the hydroxyl group, amino group, carboxyl group and the like can be protected with a protecting group which is usually used, and the protecting group includes, in particular, the hydroxyl-protecting group, amino-protecting group described above for R ² and Carboxyl-protective groups are included.

(a) Conversion reaction at 3-position

2,3-dioxo-1,2,3,4-tetrahydropyrazine of general formula (III-a), 2-oxo-1 of general formula (III-b) using an industrially easy process, 2-dihydropyrazine, 3,6-dioxo-1,2,3,6-tetrahydropyridazine of formula (III-c) or 6-oxo-1,6- of formula (III-d) Reacting dihydropyridazine or a salt thereof with cephalosporranic acid of formula (II) or a salt thereof in the presence of an acid or a complex compound of the acid, separating the protecting group, protecting the carboxyl group or obtaining The compounds can be converted to their salts to prepare 7-substituted or unsubstituted amino-3-substituted methyl cefe carboxylic acids or salts of general formula (IV) that are high purity in high yield. The 2,3-dioxo-1,2,3,4-tetrahydropyrazine can also be prepared by the method described in Journal of Chemical Society, Perkin I, pages 1888-1890 (1975).

In addition, if necessary, the substituent on the amino group at the 7-position may be separated by a conventional method to prepare a 7-substituted amino compound. In the present step, not only the Δ ³ -cepem compound but also the Δ ² -cepem compound can be used as the starting compound, and when the Δ ² -cepem compound is used as the starting compound, the reaction product Δ ² -cepem compound is used as the Δ ³ -cepem compound. Switch.

In addition, not only compounds having> Z of> S but also compounds having> Z of> S → 0 may be used as starting materials. Can be converted to S.

2,3-dioxo-1,2,3,4-tetrahydropyrazine of the general formula (III-c) used as a reactant in this reaction, 2-oxo-1,2- of the general formula (III-b) Dihydropyrazine, 3,6-dioxo-1,2,3,6-tetrahydropyridazine of general formula (III-c) or 6-oxo-1,6-dihydro of general formula (III-d) If pyridazine has basic or acidic groups as substituents, these compounds can be used in the reaction in the form of the corresponding salts, if necessary. In this case, salts in the basic group and salts in the acidic group include the salts mentioned as salts of the compound of general formula (I).

Salts of the compounds of formulas (II) and (IV) also include salts in acidic groups and in basic groups, including salts mentioned as salts of compounds of formula (I). The salt of the compound of formula (II) may be used after separation in advance, or may be prepared in situ.

As the acid or complex of the acid used in the reaction, mention may be made, for example, of protonic acid, Lewis acid or complex of Lewis acid. Protonic acid includes sulfuric acid, sulfonic acid and super acid, where super acid refers to an acid that is stronger than 100% sulfuric acid and includes some of the sulfuric acid and sulfonic acid. More particularly, protonic acid includes sulfuric acid such as sulfuric acid, chlorosulfuric acid and fluorosulfuric acid; Alkyl (mono- or di-) sulfonic acids (e.g. methanesulfonic acid, trifluoromethanesulfonic acid, etc.), aryl (mono-, di-, or tri) sulfonic acids (e.g. p-toluenesulfonic acid, etc.); Sulfonic acids such as; Superacids such as perchloric acid, magic acid (FSO ₃ H-SbF ₅ ), FSO ₃ H-AsF ₅ , CF ₃ SO ₃ H-SbF ₅ , HF-BF ₃ , H ₂ SO ₄ -SO _3, and the like.

Lewis acids include, for example, boron trifluoride, and complexes of Lewis acids include boron trifluoride and dialkyl ethers (for example diethyl ether, di-n-propyl ether, di-n-butyl ether, etc.). ; Amines (for example ethylamine, n-propylamine, n-butylamine, triethanolamine, etc.); Esters (for example ethyl formate, ethyl acetate, etc.); Aliphatic acids (for example acetic acid, propionic acid, etc.); Complexes with nitriles such as acetonitrile, propionitrile and the like.

The reaction is preferably carried out in the presence of an organic solvent. Organic solvents to be used include all organic solvents which are inert to the reaction, for example nitroalkanes such as nitromethane, nitroethane, nitropropane and the like; Organic carboxylic acids such as formic acid, acetic acid, trifluoroacetic acid, dichloroacetic acid, propionic acid and the like; Ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; Ethers such as diethyl ether, diisopropyl ether, dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, anisole, dimethyl cellosolve and the like; Esters such as ethyl formate, diethyl carbonate, methyl acetate, ethyl acetate, ethyl chloroacetate, butyl acetate and the like; Nitriles such as acetonitrile, butyronitrile and the like; Sulfolane such as sulfolane and the like. These solvents may be used in combination of two or more. Moreover, the complex compound produced from such an organic solvent and Lewis acid can also be used as a solvent. The amount of the complex or acid of the acid used is sufficient to be at least an equimolar amount relative to the amount of the compound of formula (II) or a salt thereof, and the amount can be changed in each case. In particular, it is preferable to use in the ratio of 2-10 mol per mol of compound of general formula (II) or its salt. When using an acid complex, it can be used as a solvent itself, and can also mix and use two or more complexes.

2,3-dioxo-1,2,3,4-tetrahydropyrazine of general formula (III-a), 2-oxo-1,2-dihydropyrazine of general formula (III-b), general formula ( The amount of 3,6-dioxo-1,2,3,6-tetrahydropyridazine of III-c) or 6-oxo-1,6-dihydropyridazine of general formula (III-d) or salts thereof is general At least equimolar amounts relative to the amount of the compound of formula (II) or salts thereof are sufficient, particularly preferably in an amount of about 1.0 to 5.0 moles per mole.

This reaction is carried out at 0 to 80 ° C. and is completed in 10 minutes to 30 hours. The presence of water in the reaction system leads to undesirable side reactions such as lactonation of the starting materials or products and decomposition of the β-lactam ring, so it is desirable to maintain the reaction system under anhydrous conditions. To meet these conditions, dehydrating agents suitable for the reaction system (e.g., phosphorus compounds such as phosphorus pentoxide, polyphosphoric acid, phosphorus pentachloride, phosphorus trichloride, phosphorus oxychloride), N, O-bis (trimethylsilyl) acetamide, trimethylsilyl acetamide Organic silicides such as trimethylchlorosilane, dimethyldichlorosilane, etc .; organic acid chlorides such as acetyl chloride, p-toluene sulfonyl chloride, etc .; acid anhydrides such as acetic anhydride, trifluoroacetic anhydride, etc .; magnesium sulfate anhydride, calcium chloride anhydride, powder Itself, an inorganic dehydrating agent such as calcium carbide).

When a compound of formula (I) wherein R ¹ is a carboxyl-protecting group is used as starting material, a compound of formula (IV) wherein R ¹ is a hydrogen atom is in some cases obtained directly from the reaction or protected by conventional means Can be obtained by removing the group.

The following describes the conversion reaction at the 3-position described in Preparation Route 2.

Halogenated compounds of formula (VI) may be prepared according to the methods described in Terathedron Letters, 46, pages 3991-3994 (1974) and Tetrahedron Letters, 40, pages 3915-3918 (1981). Can be.

The compound of formula (VII) or a salt thereof is a 2,3-dioxo-1,2,3,4-tetra of formula (III-a) in the presence of a halogenated compound of formula (XVI) or a salt thereof It can be prepared by reaction with hydropyrazine or a salt thereof. Examples of the base include alkali metal carbonates (for example, sodium carbonate and potassium carbonate); Alkali metal carbonates (for example, sodium bicarbonate, potassium bicarbonate, etc.); Alkali metal hydroxides (eg sodium hydroxide, potassium hydroxide, etc.); Nitrogen-containing organic bases such as triethylamine, pyridine, N, N-dimethylaniline, and the like.

Conversion at the 3-position is usually carried out in a suitable solvent. Examples of the solvent include halogenated hydrocarbons such as chloroform and methylene chloride; Ethers such as tetrahydrofuran, dioxane and the like; N, N-dimethylformamide; N, N-dimethylacetamide; Acetone; Water; And mixtures thereof.

In this case, the compound of formula (III-a) or a salt thereof is preferably used in an amount of about 1.0 to 2.0 moles per mole of the compound of formula (XIV) or a salt thereof. The reaction is typically carried out at 0 to 50 ° C. for 30 minutes to 10 hours.

Compounds of the general formula (VIII) thus obtained, ie, mixtures of Δ ² -and Δ ³ -cepem compounds, or salts thereof, are easily converted into Δ ³ -cepem compounds to prepare compounds of formula (XIII) or salts thereof. It may then be deacylated to convert it to a compound of formula (XIX) or a salt thereof. Such conversion reactions and deacylation are known in the penicillin and cephalosporin arts, in particular, in the Journal of Organic Chemistry, 35, No. 7, 2430-2433 (1970) and "Cephalosporins and Penicillins" (Flynn, Academic). Press), pages 56-64.

2,3-dioxo-1,2,3,4-tetrahydropyrazine of the general formula (III-a) used as a reactant in the reaction, 2-oxo-1,2-di of the general formula (III-b) Hydropyrazine, 3,6-dioxo-1,2,3,6-tetrahydropyridazine of general formula (III-c) or 6-oxo-1,6-dihydropyridine of general formula (III-d) When the substituents of the chopped or salts thereof are substituted with hydroxyl groups, amino groups, carboxyl groups and the like, these groups are protected with the above protecting groups before the reaction, and after the reaction is completed, conventional separation reactions give the desired compounds. Can be.

The compounds of formula (IV) or (XIX) may also be protected in the carboxyl group or converted to salts according to conventional methods, if desired, to afford the desired compounds. In addition, compounds of formula (IV) wherein R ²⁸ is an amino group can be converted to a reactive derivative in an amino group or to compounds of formula (XIX) by conventional methods as follows.

(b) acylation reaction

A compound of formula (V), (VI), (iii), (iii) or (XIII) or a salt thereof, or a reactive derivative thereof, to a compound of formula (IV) or a salt thereof, or a reactive derivative in an amino group When reacted with, a compound of the general formula (I), (IX), (IX), (XI) or (XIV) or a salt thereof is obtained.

Salts of compounds of formula (V), (VI), (IX), (XIII) or (XIII) include salts in basic or acidic groups, in particular mentioned as salts of compounds of general formula (I) Things are included.

Reactive derivatives in the amino group of the compound of formula (IV) include all derivatives often used for acylation, for example isocyanates; Schiff base (ketimine form or isomer thereof, ie, enamine form) produced by reacting a compound of formula (IV) or a salt thereof with a carbonyl compound such as aldehyde, ketone or the like; Compounds of general formula (IV) or salts thereof (e.g. bis (trimethylsilyl) acetamide, trimethylsilyl acetamide, trimethylsilyl chloride, etc.), phosphorus compounds [e.g. phosphorus trichloride,

(CH ₃ CH ₂ ) ₂ PCl, etc.] or a tin (Tin) compound [eg, (C ₄ H ₉ ) ₃ SnCl, etc.] to be a silyl derivative, phosphorus derivative or tin derivative produced.

Reactive derivatives of compounds of formulas (V), (VI), (IX), (XIII) and (XIII) include, in particular, acid halides, acid anhydrides, mixed acid anhydrides, active acid amides, active esters, Reactive derivatives obtained by reacting compounds of (VI), (IX), (IX) and (XIII) with a Vilsmeier reagent are included. Mixed acid anhydrides include mixed acid anhydrides with monoalkyl carbonates such as monoethyl carbonate, monoisobutyl carbonate, and the like, with lower alkanoic acids (e.g. pivalic acid, trichloroacetic acid, etc.) which may be substituted with halogens. Acid anhydrides are included. Active acid amides include N-acylsaccharin, N-acylimidazole, N-acylbenzoylamide, N, N'-dicyclohexyl-N-acylurea, N-acylsulfonamide and the like. Active esters include cyanomethyl esters, substituted phenyl esters, substituted benzyl esters, substituted thienyl esters, and the like.

Reactive derivatives obtained by reaction with Vilsmeier reagents include acidamides (e.g., N, N-dimethylformamide, N, N-dimethylacetamide, etc.) and halogenating agents (e.g., phosgene, thionyl chloride, phosphorus trichloride, Phosphorus tribromide, phosphorus oxychloride, phosphorus pentachloride, trichloromethyl chloroformate, oxalyl chloride, etc.) and those produced by reacting with Vilsmeier reagent obtained.

When each of the compounds of the formulas (V), (VI), (IX), (XIII) and (XIII) is used in the form of free acids or salts, suitable condensing agents are used. Examples of condensing agents include N, N'-disubstituted carbodiimides (for example, N, N'-dicyclohexylcarbodiimide); Azolide compounds (eg, N, N'-thionyldiimidazole); Dehydrating agents (for example, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, phosphorus oxychloride, alkoxyacetylene, etc.); 2-halogenopyridinium salts such as 2-chloropyridiniummethyl iodide and 2-fluoropyridinium methyl iodide, and the like.

Such acylation reactions are usually carried out in a suitable solvent in the presence or absence of a base. As a solvent, a solvent inert to the reaction (e.g., halogenated hydrocarbons such as chloroform, methylene chloride, etc .; ethers such as tetrahydrofuran, dioxane, etc .; N, N-dimethylformamide; N, N-dimethylacetamide; acetone; water Or mixtures thereof) can be used. As a base, an inorganic base (for example, alkali metal hydroxide, alkali metal hydrocarbonate, alkali metal carbonate, alkali metal acetate, etc.); Tertiary amines (eg trimethylamine, triethylamine, tributylamine, pyridine, N-methyllipridine, N-methylmorpholine, lutidine, collidine, etc.); Or secondary amines (eg dicyclohexylamine, diethylamine, etc.) may be used.

The compound of general formula (VII) or its salt which can be converted into the compound of general formula (Ia) or (Ib) or its salt can be manufactured by the following process.

4-halogeno-obtained by reacting diketone with halogen (e.g. chlorine or bromine) to give a compound of formula (IV) or a salt thereof using a compound of formula (IV) or a salt thereof 3-oxo-butyryl halide (Journal of the Chemical Society, 97, 1987 (1910)) may be reacted with a compound of formula (IV) or a salt thereof according to conventional methods. Reaction conditions and processes known in the art can be applied to this reaction. Salts of the general formula compounds can be readily prepared according to conventional methods, which include those salts mentioned as salts of the general formula (I) compounds. Although the compound of general formula or its salt can also be isolate | separated and refine | purified, it can also be used for the next reaction, without isolate | separating.

In addition, the compound of formula (V), (VI), (IX), (X) or (XIII) or a salt thereof, or a reactive derivative thereof may be a compound of formula (IV) or a salt thereof, or a reactivity thereof in an amino group Preference is given to using in an amount of about 1 to several moles per mole of derivative. The reaction is usually carried out at a temperature of -50 to 40 ℃, the reaction time is usually 10 minutes to 48 hours.

In addition, R ¹ is a carboxyl-in the formula protected group (Ⅰ), (Ⅸ), (Ⅹ), (XI) and a compound of (XIV) of the general formula (Ⅰ) is R ¹ is a hydrogen atom in a conventional manner, Can be converted into a compound of (iii), (iii), (XI) and (XIV) or a salt thereof; Similarly, R ¹ is a formula (Ⅰ), (Ⅸ), (Ⅹ), (XI) and a compound of (XIV) is R ¹ is a carboxyl hydrogen atoms in the general formula (Ⅰ) protection group, (Ⅸ), ( Iii) a compound of (XI) and (XIV) or a salt thereof; Salts of the compounds of formula (I), (IV), (IX), (XI) and (XIV) can each be converted into the corresponding free acid form.

In addition, when R ¹ , R ² and R ⁵ in this acylation reaction contain an active group in the reaction, these groups can be suitably protected with conventional protecting groups before the reaction, and the protecting group is also after the reaction It can be separated by conventional methods.

The compound of formula (I) of the present invention obtained by the above method and salts thereof can be separated by conventional methods.

(c) nitrosation reactions

Subsequently, in order to obtain a compound of the general formula or a salt thereof from the general compound or a salt thereof, the general compound or a salt thereof is reacted with a nitrosizing agent. This reaction is usually carried out in a solvent, and a solvent inert to the reaction (for example, water, acetic acid, benzene, methanol, ethanol, tetrahydrofuran, etc.) may be used as the solvent. Preferred examples of nitrogenating agents include nitric acid and derivatives thereof such as nitrosyl halides (eg nitrosyl chloride, nitrosyl bromide, etc.), alkali metal nitrates (eg sodium nitrate, potassium nitrate, etc.), alkyl nitrites (eg Butyl nitrite, pentyl nitrite, etc.). When nitrite is used as the nitrosizing agent, it is preferable to react in the presence of an inorganic or organic acid such as hydrochloric acid, sulfuric acid, formic acid, acetic acid and the like. When alkyl nitrite is used as the nitrogenating agent, it is preferable to react in the presence of a strong base such as an alkali metal alkoxide or the like. The reaction is usually carried out at -15 to 30 ℃, the reaction time is usually 10 minutes to 10 hours. Salts of the general formula compounds can be readily prepared according to conventional methods, including salts as mentioned as salts of the general formula (I) compounds. The compound of general formula or a salt thereof thus obtained may be separated and purified by a known method, but may be used in the next reaction without separation.

(d) etherification and phosphorylation

In order to obtain a compound of the general formula (XI) or a salt thereof from the general compound or a salt thereof, the compound of the general formula or a salt thereof is subjected to an etherification reaction or a phosphorylation reaction.

The etherification reaction and phosphorylation reaction can be carried out by conventional methods as described in Japanese Patent Application Laid-Open Nos. 137,988 / 78, 105,689 / 80, 149,295 / 80 and the like.

For example, alkylation can be carried out according to conventional methods. This reaction is usually carried out at -20 to 60 DEG C and completed in 5 minutes to 10 hours.

Examples of the solvent include solvents which are inert to the reaction (eg, tetrahydrofuran, dioxane, methanol, ethanol, chloroform, methylene chloride, ethyl acetate, butyl acetate, N, N-dimethylformamide, N, N-dimethylacetamide, Water or mixtures thereof) may be used.

As the alkylating agent, for example, lower alkyl halides such as methyl iodide, methyl bromide, ethyl iodide, ethyl bromide and the like, dimethyl sulfate, diethyl sulfate, diazomethane, diazoethane, methyl p-toluene sulfonate, and the like Can be used. When an alkylating agent other than diazomethane and diazoethane is used, the reaction may include alkali metal carbonates such as sodium carbonate, potassium carbonate and the like; Alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; Or in the presence of an organic base such as triethylamine, pyridine, N, N-dimethylaniline and the like.

Or salts of the general formula (IV) compounds can be readily obtained according to conventional methods, including salts as mentioned as salts of the general formula (I) compounds.

The protecting group can also be introduced and separated according to conventional methods, thereby converting the compound into the corresponding desired compound.

The general formula (XI) compound or salt thereof thus obtained may be separated and purified by conventional methods, but may be used in the next reaction without separation.

(e) ring closure reaction

The compound of formula (Ia) or (Ib) of the present invention or a salt thereof may be prepared by combining the compound of formula (X), (X) or (XI) or a salt thereof with thiourea or thioformamide of formula (XII). It can be obtained by reaction. This reaction is usually carried out in a solvent. As a solvent, a solvent inert to the reaction (for example, water, methanol, ethanol, acetone, tetrahydrofuran, dioxane, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyridone) It may be used alone or in combination of two or more. Although it is not necessary to add the acid-separating agent, the reaction often proceeds smoothly by adding the acid separating agent in an amount that does not affect the cephalosporin backbone. Acid separators used in the reaction include inorganic and organic bases such as alkali metal hydroxides, alkali metal carbonates, triethylamine, pyridine, N, N-dimethylaniline. The reaction is usually carried out at 0 to 100 ° C. Thioformamide or thiourea is typically used in amounts of about 1 to several moles per mole of the compound of formula (VII), (X) or (XI) or salts thereof. The reaction time is 1 to 48 hours, preferably 1 to 10 hours. Also for compounds of formula (la) or (lb), the protection of the carboxyl group and the separation of the carboxyl protecting group or the conversion of the product into salts are carried out according to conventional methods to convert this compound to the corresponding desired compound. . If R ¹ , R ² and R ⁵ in a compound of formula (Ia) or (Ib) contain groups active in the reaction, these groups can be suitably protected with conventional protecting groups before the reaction and the reaction is After completion, the protection group can be separated by conventional means. The desired compound of formula (Ia) or (Ib) or salt thereof obtained in this way can be separated by conventional methods.

(f) oxime reaction

A compound of formula (Ib) or a salt thereof is obtained by reacting a compound of formula (XIV) or a salt thereof with a compound of formula (XV) or a salt thereof. Salts of the general formula (XV) compounds include hydrogen chloride, hydrogen bromide, sulfates and the like. This reaction is usually carried out in solvents such as water, alcohols, N, N-dimethylacetamide and the like, as well as in other compounds or mixed solvents thereof which are inert to the reaction. This reaction is carried out at 0 to 100 ° C, preferably 10 to 50 ° C. The reaction time is usually 10 minutes to 48 hours. The compound of formula (XV) or a salt thereof is used in an amount of about 1 to several moles per mole of the compound of formula (XIV) or salt thereof. Salts of the general formula (XV) compounds may also be used by themselves in the reaction, but also bases [e.g. alkali metal hydroxides (e.g. sodium hydroxide, potassium hydroxide, etc.), alkaline earth metal hydroxides (e.g. magnesium hydroxide, hydroxides). Potassium, etc.), alkali metal carbonates (e.g. sodium carbonate, potassium carbonate, etc.), alkaline earth metal carbonates (e.g. magnesium carbonate, calcium carbonate, etc.), alkali metal carbonates (e.g. sodium bicarbonate, potassium hydrogen carbonate, etc.) Minerals such as alkaline earth metal phosphates (e.g. magnesium phosphate, calcium phosphate, etc.), alkali metal phosphides (e.g. disodium hydrogen phosphate, dipotassium hydrogen phosphate) or alkali metal acetic acid (e.g. sodium acetate, potassium acetate) Base; Trialkylamines (eg trimethylamine, triethylamine, etc.), picoline, N-methylpyrrolidine, N-methylmorpholine, 1,5-diazabicyclo [4,3,0] -5-nonene , Organic base such as 1,4-diazabicyclo [2,2,2] octane, 1,5-diazabicyclo [5,4,0] -7-undecene, etc.]. The compound of formula (lb) or a salt thereof of the present invention thus obtained can be converted to R ¹ in a conventional manner and separated in a conventional manner.

(g) alkoxylation reactions

Compounds of formula (IV) wherein R ³ is an alkoxy group are known methods, for example the methods described in the Journal of Synthetic Organic Chemistry, Japan, 35, (7), pages 563-574 (1977). Can be synthesized from the compound of formula (IV) wherein R ³ is a hydrogen atom.

In addition, compounds of the general formulas (I), (Ia), (Ib), (IX), (VII), (XI) or (XIV) wherein R ³ is an alkoxy group are known methods, for example, references [Japan ( ³ ), (Ia), (Ib), ( ⁱⁱⁱ ), (iii), wherein R ³ is a hydrogen atom by the method described in Published Patent Application Nos. 24,888 / 79 and 103,889 / 79. XI) or (XIV), respectively.

The compound of formula (I) or a salt thereof thus obtained can be administered to a human animal in the form of a free acid or in the form of a pharmaceutically acceptable salt or ester for the purpose of preventing and treating bacterial infections. Parenteral administration of the compound in the form of a free acid or in the form of a pharmaceutically acceptable salt, or oral administration of the compound in the form of a pharmaceutically acceptable ester is preferred. In such cases, it is sufficient to mold the compound into dosage forms commonly used in cephalosporin medicine (eg tablets, capsules, powders, microgranules, granules, syrups, injections (including red wine), suppositories, etc.). . When the drug is molded into dosage forms, diluents and / or additives (e.g., starches, lactose, sugars, calcium phosphates, calcium carbonates, etc.); gum arabic, starch, microcrystalline cellulose, carboxymethyl cellulose, hydride Binders such as oxypropyl cellulose and the like; lubricants such as talc, magnesium stearate and the like; disintegrants such as carboxymethyl calcium, talc and the like).

When administering the compound of formula (I) or a salt thereof, the dosage, time and administration method can be changed according to the patient's symptoms. Usually, a dose of about 50 to 5000 mg is divided into 1 to 4 parts per day orally or in adults. Parenteral administration.

The following examples and examples are not intended to limit the scope of the present invention, but to explain the present invention in detail.

Reference Example 1

(1) To a 20.0 g solution of ethyl N- (2,2-diethoxyethyl) oxamate in 60 ml of ethanol, 6.1 ml of an aqueous 70% by weight ethylamine solution is added and the mixture is allowed to react for 1 hour at room temperature. After the reaction was completed, precipitated crystals were collected by filtration, and recrystallized with ethanol, 17.0 g of N-ethyl-N '-(2,2-diethoxyethyl) oxamide having a melting point of 131 to 132 ° C (yield: 85.1% ) Is obtained.

IR (KBr) cm ^-1 : ν _{c = 0} 1650

In a similar manner, the compounds shown in Table 3 are obtained.

TABLE 3

(CH ₃ CH ₂ O) ₂ CHCH ₂ NHCOCONHR ⁶

(2) 0.05 ml of concentrated hydrochloric acid is added to a solution of 17.0 g of N-ethyl-N '-(2,2-diethoxyethyl) oxamide obtained in (1) above in 85 ml of acetic acid. The mixture is refluxed for 30 minutes. After the reaction is completed, the solvent is distilled off under reduced pressure, 70 ml of acetone is added to the residue, and the crystals are collected by filtration. Recrystallization of the crystals with methanol yielded 6.8 g (yield: 61.8%) of 4-ethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazine having a melting point of 173 to 174 캜.

IR (KBr) cm ^-1 : ν _{c = 0} 1680-1620

In a similar manner the compounds shown in Table 4 are obtained.

TABLE 4

(3) 4- (2,4-dimethoxybenzyl) -2,3-dioxo-1,2,3,4-tetrahydropyrazine 5.2 obtained in (2) above in 26 ml of N, N-dimethylformamide. 4.1 g of potassium carbonate is added to the suspension of g and the mixture is stirred at room temperature for 30 minutes. Then 5.8 g of 4-bromomethyl-5-methyl-1,3-dioxol-2-one are added and the mixture is reacted at 50 to 60 ° C. for 3 hours. The reaction mixture was poured into a mixed solvent of 200 ml of ethyl acetate and 200 ml of water, the organic layer was separated, washed with 100 ml of water, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and purified by column chromatography (Wako silica gel C-200, eluent; chloroform), and the melting point was 1- (2,4-dimethoxybenzyl) -4- ( 5-methyl-2-oxo-1,3-dioxol-4-yl) -methyl-2,3-dioxo-1,2,3,4-tetrahydropyrazine (4: 9% yield) was obtained do.

IR (KBr) cm ^-1 : ν _{c = 0} : 1820, 1675, 1630

In a similar manner, the compounds shown in Table 5 are obtained.

TABLE 5

(4) 1- (2,4-dimethoxybenzyl) -4- (5-methyl-2-oxo-1,3 obtained in (3) above in a mixed solvent of 37 ml of trifluoroacetic acid and 10.8 g of anisole. 3.7 g of -dioxol-4-yl) methyl-2,3-dioxo-1,2,3,4-tetrahydro-pyrazine are dissolved and the mixture is reacted at 50 to 60 ° C. for 2 hours. The solvent is then removed by distillation under reduced pressure. 30 ml of dimethyl ether was added to the residue, and the crystals were collected by filtration. 4- (5-methyl-2-oxo-1,3-diosol-4-yl) -methyl-2,3 having a melting point of 225 to 226 캜. 2.0 g (yield 90.9%) of -dioxo-1,2,3,4-tetrahydropyrazine are obtained.

IR (KBr) cm ^-1 : ν _{c = 0} 1825, 1805, 1725, 1690, 1670

In a similar manner, the compounds shown in Table 6 are obtained.

TABLE 6

(5) 3.9 g of diphenyl diazomethane was added to a solution of 2.6 g of 1-carboxymethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazine in 13 ml of N, N-dimethylacetamide at room temperature. The reaction mixture was added to a mixed solution of 25 ml of ethyl acetate and 25 ml of water, and the mixture was stirred for 15 minutes. The precipitated crystals were collected by filtration, washed with 10 ml of ethyl acetate and 10 ml of diethyl ether, and then 1-diphenylmethyloxycarbonylmethyl-2,3-dioxo-1,2,3, having a melting point of 97 to 98 ° C. 2.9 g of 4-tetrahydropyrazine (yield: 80.4%) are obtained.

IR (KBr) cm ^-1 : ν _{c = 0} 1750, 1675, 1645

Example 1

(1) 2.72 g of 7-aminocephalos-folanic acid (hereinafter referred to as 7-ACA) and 4-ethyl-2,3-dioxo-1 in a solution of 10 ml of ethyl acetate containing 2.71 g of boron trifluoride 1.54 g of 2,3,4-tetrahydropyrazine is added and the mixture is allowed to react for 16 hours at room temperature. After completion of the reaction, the reaction mixture was cooled to 50 ml of methanol and 3.16 g of pyridine was added dropwise. The precipitated crystals were collected by filtration, washed thoroughly with 30 ml of methanol and dried, and then 7-amino-3-{[1- (4-ethyl-2,3-dioxo-) having a melt of 191 to 195 ° C. (decomposition). 1,2,3,4-tetrahydropyrazinyl)] methyl} -Δ ³ -cefe-4-carboxylic acid (yield: 88.1%) is obtained.

IR (KBr) cm ^-1 : ν _{c = 0} 1795, 1670, 1620

NMR (CF ₃ COOD) δ value: 1.44 (3H, t, j = 7 Hz,> NCH ₂ CH ₃ ), 3.69 (2H, bs, C ₂ -H), 4.08 (2H, q, J = 7 Hz,> NCH ₂ CH ₃ ), 5.14, 5.51 (2H, ABq, J = 15 Hz, 5.48 (2H, s, C ₆ -H, C ₇ -H), 6.74, 7.00 (2H, ABq, J = 6 Hz,

(2) The conversion reaction at the 3-position mentioned in (1) above was carried out under the reaction conditions shown in Table 7, and yielded 7-amino-3-{[1- (4-ethyl-2, 3-dioxo-1,2,3,4-tetrahydropyrazinyl)] methyl} -Δ ³ -cef-4-carboxylic acid is obtained.

TABLE 7

(3) In a similar manner to (1) above, the compound shown in Table 8 is obtained (in this case, after adjusting to pH3.5 using an aqueous 28% by weight aqueous solution of ammonia while switching in the 3-position and ice-cooling, The mixture is poured into ice water to give the desired compound).

TABLE 8

(4) 7-amino-3-{[1- (3,6-dioxo) in the yield shown in Table 9 by carrying out the conversion reaction in the 3-position mentioned in (1) above under the reaction conditions shown in Table 9. -1,2,3,6-tetrahydropyridininyl)] methyl} -Δ ³ -cepem-4-carboxylic acid is obtained.

TABLE 9

(5) In a similar manner to (1) above, crude crystals shown in Table 10 are obtained.

TABLE 10

Note: Compounds 10, 11, 12, 13, 14 and 15 are obtained by reaction using sulfolane as solvent.

* 1: This compound is obtained by adding methanol to the filtrate and filtering insoluble material.

* 2: This is because the chlorine atom is in the 4- or 5-position and the product is not identified as a single substance or mixture (these indications in the table hereafter have the same meaning).

* 3: Indicates that the product is a mixture of 4-substituted and 5-substituted compounds.

Example 2

7-amino-3-{[1- (4-ethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl) obtained in Example 1- (1)-in 30 ml of methanol)] 1.62 g of p-toluene sulfonic acid monohydrate was added to a suspension of 3.0 g of methyl} -Δ ³ -cephm-4-carboxylic acid to form a solution, and the resulting mixture was slowly added to a solution of 5.0 g of diphenyl diazomethane, and the resulting mixture was stirred at room temperature. React for 15 minutes. After the reaction was completed, the solvent was removed by distillation under reduced pressure, and the residue thus obtained was dissolved in a mixed solvent of 20 ml of ethyl acetate and 20 ml of water. Using sodium hydrogen carbonate, the solution is adjusted to pH 7.0. The organic layer is then separated, dried over anhydrous magnesium sulfate and distilled off under reduced pressure to remove the solvent. The residue was purified by column chromatography (Wako Silica gel C-200, eluent; benzene: ethyl acetate = 1: 4 volume ratio) to obtain diphenylmethyl 7-amino-3- {having a melting point of 183 to 186 占 폚 (decomposition). 3.1 g of [1- (4-ethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)] methyl} -Δ ³ -cepem-4-carboxylate (yield: 70.3%) Obtained.

IR (KBr) cm ⁻¹ : v _{c = 0} 1765, 1730, 1680, 1630.

In a similar manner, the compounds shown in Table 11 are obtained

TABLE 11

Example 3

Diphenylmethyl 7-amino-3- [1- (2,3-dioxo-1,2,3,4-tetrahydropyrazinyl) methyl] -Δ in a mixed solvent of 25 ml of trifluoroacetic acid and 10 ml of anisole 4.9 g of ³ -cefe-4-carboxylate is dissolved and the solution is allowed to react for 2 hours at room temperature. After the reaction was completed, the solvent was removed by distillation under reduced pressure, 50 ml of diethyl ether was added to the residue, and the crystals were collected by filtration. After sufficiently washing the crystals with 40 ml of diethyl ether and drying, 7-amino-3-{[1- (2,3-dioxo-1,2,3,4) having a melting point of 105 to 106 ° C (decomposition) -tetrahydro-pyrazinyl)] - methyl} - △ ³ - acid salt 4.25g (yield trifluoroacetic cephem-4-carboxylic acid: the 97.0%) are obtained.

IR (KBr) cm ^-1 : ν _{c = 0} 1780, 1700-1630

), 5.44(2H, s, C₆-H, C₇-H), 6.78, 6.98(2H, ABq, J=6Hz,

,NMR (CF ₃ COOD) δ value: 3.72 (2H, bs, C ₂ -H), 5.14, 5.52 (2H, ABq, J = 15 Hz,

), 5.44 (2H, s, C ₆ -H, C ₇ -H), 6.78, 6.98 (2H, ABq, J = 6 Hz,

,

In a similar manner, the compounds shown in Table 12 are obtained.

TABLE 12

* =: Free compound: The target compound is reacted in a mixed solvent of trifluoroacetic acid and anisole, and after removing the solvent, the residue is dissolved in water and obtained by adjusting the pH to 3.5 in 28% aqueous ammonia solution. do.

** =: Free compound: obtained by treating trifluoroacetic acid salt with pyridine in methanol.

Example 4

To a suspension of 5.0 g of 7-amino-3-{[1- (3-methyl-6-oxo-1,6-dihydropyridazinyl)] methyl} -Δ ³ -cefe-4-carboxylic acid in 15 ml of acetone 1 2.36 g of, 8-diazabicyclo [5,4,0] -7-undecene and 4.51 g of pivaloyloxymethyl iodide are added at 10 to 15 ° C. and the mixture is allowed to react for 30 minutes. After completion of the reaction, the reaction mixture was placed in a mixed solvent of 50 ml of water and 50 ml of ethyl acetate, the organic layer was separated, washed with water and dried over anhydrous magnesium sulfate. Then, 10 ml of an ethi acetate solution containing 1.40 g of oxalic acid was added, and the precipitated crystals were collected by filtration and washed with ethyl acetate to give pivaloyloxymethyl 7-amino-3- {with a melting point of 145 to 147 ° C (decomposition). 4.59 g (yield: 56.2%) of an oxylate of [1- (3-methyl-6-oxo-1,6-dihydropyridazinyl)] methyl} -Δ ³ -cepem-4-carboxylate are obtained.

IR (KBr) cm ^-1 : ν _{c = 0} 1790, 1750, 1660

), 5.14(1H, d, J-5Hz, C₆-H), 5.76-6.23(3H, m, C₇-H, -OCH₂O-), 7.01, 7.53(H2, ABq, J=10Hz,

), 7.44(3H, bs, -NH3

)NMR (d ₆ -DMSO) δ value: 1.21 (9H, s, —CH ₃ X ₃ ). 2.29 (3H, s, -CH ₃ ), 3.52 (2H, bs, C ₂ -H), 4.94, 5.33 (2H, ABq, J = 15 Hz,

), 5.14 (1H, d, J-5 Hz, C ₆ -H), 5.76-6.23 (3H, m, C ₇ -H, -OCH ₂ O-), 7.01, 7.53 (H2, ABq, J = 10 Hz,

), 7.44 (3H, bs, -NH3

)

Example 5

(1) 1- (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl-2,3-dioxo-1,2,3,4 in 27 ml of N, N-dimethylformamide 1.52 g of potassium carbonate is added to a solution of 2.69 g of tetrahydropyrazine, and the resulting mixture is stirred at room temperature for 20 minutes. Subsequently, 4.67 g of tertiary butyl 7-phenylacetamido-3-bromomethyl-Δ ² -cefe-4-carboxylate is added with ice cooling, and the mixture is allowed to react for 2 hours at room temperature. The reaction mixture is placed in a mixed solvent of 200 ml of ethyl acetate and 150 ml of water, the organic layer is separated, washed with 150 ml of water and dried over anhydrous magnesium sulfate. The solvent is then removed by distillation under reduced pressure and the resulting residue is dissolved in 10 ml of chloroform. 2.45 g of m-chlorobenzoic acid (purity: 70%) was added to the solution, and the mixture was reacted at room temperature for 1 hour.

The solvent was removed by distillation under reduced pressure, and 100 ml of ethyl acetate and 100 ml of water were added to the residue. The organic layer is separated, washed with 100 ml of water and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography (Wako Silica gel C-200, eluent; chloroform) to give tert-butyl 7-phenylacetic acid having a melting point of 135 to 136 占 폚 (decomposition). Amido-3-{[1- [4- (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl-2,3-dioxo-1,2,3,4-tetra 2.70 g (yield: 43.2%) of hydropyrazinyl]] methyl} -Δ ³ -cepem-4 -carboxylate-1-oxide are obtained.

IR (KBr) cm ⁻¹ : v _{c = 0} 1820, 1790, 1720, 1685, 1650.

(2) Tertiary butyl 7-phenylacetamido-3-{[1- [4- (5-methyl-2-oxo-1,3) in a mixed solvent of 12 ml of N, N-dimethylformamide and 6 ml of acetonitrile. -Dioxol-4-yl) methyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl]] methyl} -Δ ³ -cefe-4-carboxylate-1-oxide Dissolve. While cooling with ice, 1.0 g of stannous chloride and 1.58 g of acetyl chloride were added sequentially, and the mixture was allowed to react at room temperature for 30 minutes. The solvent was removed by distillation under reduced pressure, and 50 ml of ethyl acetate and 50 ml of water were added to the residue, and then the pH of the resulting mixture was adjusted to 6.0 using sodium hydrogen carbonate. The organic layer is then separated, washed with 50 ml of water and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the residue was purified by column chromatography (Wako Silica gel C-200, eluent; toluene: ethyl acetate = 3: 2 by volume) to obtain tert-butyl 7 having a melting point of 120 to 122 占 폚 (decomposition). -Phenylacetamido-3-{[1- [4- (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl-2,3-dioxo-1,2,3, 2.12 g (yield: 72.4%) of 4-tetrahydropyrazinyl]] methyl} -Δ ³ -cepem-4-carboxylate are obtained.

IR (KBr) cm ^-1 : ν _{c = 0} 1820, 1775, 1685, 1645

), 4.53, 5.13(2H, ABq, J=15Hz,

), 4.71(2H, S,

), 5.03(1H, d, J=5Hz, C6-H), 5.93(1H, dd, J=5Hz, J=5Hz, J=8Hz, C₇-H), 6.53, 6.89(2H, ABq, J=6Hz,

), 7.32-7.51(5H, m,

), 7.57(1H, d, I=8Hz, -CONH-)NMR (CDCl ₃ ) δ value: 1.58 (9H, S, -C (CH ₃ ) ₃ ), 2.28 (3H, S, -CH ₃ ), 3.17, 3.61 (2H, ABq, J = 18Hz, C ₂ -H ), 3.77 (2H, S,

), 4.53, 5.13 (2H, ABq, J = 15 Hz,

), 4.71 (2H, S,

), 5.03 (1H, d, J = 5 Hz, C6-H), 5.93 (1H, dd, J = 5 Hz, J = 5 Hz, J = 8 Hz, C ₇ -H), 6.53, 6.89 (2H, ABq, J = 6 Hz,

), 7.32-7.51 (5H, m,

), 7.57 (1H, d, I = 8 Hz, -CONH-)

In a similar manner to (1) and (2) above, the compounds shown in Table 13 are obtained.

TABLE 13

(3) tertiary butyl 7-phenylacetamido-3-{[1- [4- (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl-2,3-dioxo 2.0 g of -1,2,3,4-tetrahydropyrazinyl]] methyl} -Δ ³ -cepem-4-carboxylate are dissolved in 30 ml of anhydrous methylene chloride. To this solution was added 1.59 g of N, N-dimethylaniline and 0.57 g of trimethylsilyl chloride in this order, and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture is cooled to −40 ° C., 0.89 g of phosphorus pentachloride is added and the mixture is allowed to react at −30 to −20 ° C. for 2.5 hours. The reaction mixture is then cooled to −40 ° C., 5.2 g of anhydrous methanol is added and the reaction is continued with ice cooling for 1 hour. 20 ml of water is added to the reaction mixture and stirring is continued for 30 minutes. The pH of the reaction mixture is then adjusted to 0.5 with 6N hydrochloric acid and the aqueous layer is separated. 50 ml of ethyl acetate is added to the aqueous layer, and the pH of the mixture is adjusted to 6.5 using sodium bicarbonate. The organic layer is separated, washed with 50 ml of water and dried over anhydrous magnesium sulfate. Distillation under reduced pressure removes the solvent, and 50 ml of diethyl ether is added to the residue. When the crystals are collected by filtration, tertiary butyl 7-amino-3-{[1- [4- (5-methyl-2-oxo-1,3-dioxo-4-) having a melting point of 185 to 188 ° C (decomposition). I) -methyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl]] methyl} -Δ ³ -cefe-4-carboxylate 1.05 g (yield: 64/8%) obtained do.

IR (KBr) cm ^-1 : ν _{c = 0} 1820, 1765, 1705, 1690, 1635

), 4.76-5.09(4H, m, >NCH₂, C₆-H, C₇-H) : 6.74(2H, S,

)NMR (CDCl ₃ + d ₆ -DMSO) δ value: 1.52 (9H, S, -C (CH ₃ ) ₃ ), 2.24 (3H, S, -CH ₃ ), 3.46 (2H, bs, C ₂ -H) , 4.35, 5.08 (2H, ABq, J = 15 Hz,

), 4.76-5.09 (4H, m,> NCH ₂ , C ₆ -H, C ₇ -H): 6.74 (2H, S,

)

In a similar manner, the compounds shown in Table 14 are obtained.

TABLE 14

Note: *** Pour the imino ether compound into water and separate the precipitated hydrogen chloride.

Example 6

(1) 2.29 g of 2- (2-formamidothiazol-4-yl) -2- (new) -methoxyiminoacetic acid was dissolved in 2.29 ml of N, N-dimethylacet-amide and 4.58 ml of acetonitrile. Then, 1.62 g of phosphorus oxychloride was added dropwise to the resulting solution, and the mixture was reacted at -5 to 0 ° C for 1 hour. Then diphenylmethyl 7-amino-3-{[1- (4-methyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)] methyl} -Δ ³ -cepem-4- 5.18 g of carboxylate is added to the reaction mixture and the mixture is reacted at -5 to 0 <0> C for 1 hour. After the reaction was completed, the reaction mixture was poured into a mixed solvent of 80 ml of water and 80 ml of ethyl acetate, and the pH of the resulting solution was adjusted to 6.5 using sodium hydrogen carbonate. The organic layer is then separated and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and 60 ml of diethyl ether was added to the residue. When the crystals were collected by filtration, diphenylmethyl 7- [2- (2-formamidothiazol-4-yl) -2- (new) -methoxy-iminoacetamido] having a melting point of 165 to 168 占 폚. 6.05 g of -3-{[1- (4-ethyl-2, 3-dioxo-1,2,3,4-tetrahydropyrazinyl)]-methyl} -Δ ^3-4 -carboxylate (yield: 83.0 %) Is obtained.

IR (KBr) cm ^-1 : ν _{c = 0} 1780, 1720, 1680, 1640

), 5.30(1H, d, J=5Hz, C₆-H), 6.02(1H, dd, J=5Hz, J=8Hz, C-H), 6.50, 6.62(2H, ABq, J=6Hz,

), 7.04(1H, S, -CH<, 7.17-7.82(11H, m,

), 8.63(1H, S, HCO-), 9.89(1H, d, J=8Hz, -CONH-), 12.68(1H, bs, HCONH-)NMR (d ₆ -DMSO) δ value: 1.18 (3H, t, J = 7 Hz,> N-CH ₂ CH ₃ ), 3.59 (2H, bs, C ₂ -H), 3.72 (2H, q, J = 7 Hz ,> N-CH ₂ CH ₃ ), 3.97 (3H, S, -OCH ₃ ), 4.42, 5.04 (2H, ABq, J = 15 Hz,

), 5.30 (1H, d, J = 5 Hz, C ₆ -H), 6.02 (1H, dd, J = 5 Hz, J = 8 Hz, CH), 6.50, 6.62 (2H, ABq, J = 6 Hz,

), 7.04 (1H, S, -CH < 7.17-7.82 (11H, m,

), 8.63 (1H, S, HCO-), 9.89 (1H, d, J = 8 Hz, -CONH-), 12.68 (1H, bs, HCONH-)

In a similar manner, the compounds shown in Tables 15, 16 and 17 are obtained.

TABLE 15

TABLE 16

TABLE 17

(2) Diphenylmethyl 7- [2- (2-formamidothiazol-4-yl) -2- (cin) -methoxy-iminoacetamido] in 31 ml of methanol 0.5 ml of concentrated hydrochloric acid was added to a solution of 6.05 g of (4-ethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)] methyl} -Δ ³ -cepem-4-carboxylate, The mixture is reacted at 35 ° C. for 2 hours. After the reaction is completed, the solvent is distilled off under reduced pressure. 100 ml of ethyl acetate and 100 ml of water are added to the residue, and the pH of the resulting solution is adjusted to 6.0 using sodium bicarbonate. The organic layer is then separated and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and 50 ml of diethyl ether was added to the residue. When the crystals were collected by filtration, diphenylmethyl 7- [2- (2-aminothiazol-4-yl) -2- (new) -methoxyiminoacetamido] having a melting point of 165 to 167 캜. 5.1 g of {[1- (4-ethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)] methyl} -Δ ³ -cepem-4-carboxylate (yield: 87.7%) Is obtained.

IR (KBr) cm ^-1 : ν _{c = 0} 1780, 1720, 1680, 1640

), 5.26(1H, d, J=5Hz, C₆-H), 6.01(1H, dd, J=5Hz, J=8Hz, C₇-H), 6.52, 6.65(2H, ABq, J=6Hz,

), 6.88(1H, S,

), 7.07(1H, S, -CH<), 7.15-7.84(10H, m,

), 9.81(1H, d, J=8Hz, -CONH-) 유사한 방법으로, 표 18에 나타낸 화합물이 수득된다.NMR (d ₆ -DMSO) δ value: 1.18 (3H, t, J = 7 Hz,> N-CH ₂ CH ₃ ), 3.55 (2H, bs, C ₂ -H), 3.75 (2H, q, J = 7 Hz ,> N-CH ₂ CH ₃ ), 3.90 (3H, S, -OCH ₃ ), 4.41, 5.02 (2H, ABq, J = 15 Hz,

), 5.26 (1H, d, J = 5 Hz, C ₆ -H), 6.01 (1H, dd, J = 5 Hz, J = 8 Hz, C ₇ -H), 6.52, 6.65 (2H, ABq, J = 6 Hz,

), 6.88 (1 H, S,

), 7.07 (1H, S, -CH <), 7.15-7.84 (10H, m,

), 9.81 (1H, d, J = 8 Hz, -CONH-) In a similar manner, the compounds shown in Table 18 are obtained.

TABLE 18

(3) Diphenylmethyl 7- [2-aminothiazol-4-yl) -2- (new) -methoxyiminoacetamido] in a mixed solvent of 25.5 ml of trifluoroacetic acid and 7.86 g of anisole Dissolve 5.1 g of 3-{[1- (4-ethyl-2,3-dioxo-1,2,3,4-tetra-hydropyrazinyl)] methyl} -Δ ³ -cefem-carboxylate and solution The reaction is allowed to react at room temperature for 2 hours. After the reaction is completed, the solvent is distilled off under reduced pressure. 40 ml of diethyl ether was added to the residue, and the crystals were collected by filtration. 7- [2- (2-aminothiazol-4-yl) -2- (cin) -meth having a melting point of 155 to 157 占 폚 (decomposition). Toxyiminoacetamido] -3-{[1- (4-ethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)] methyl} -Δ ³ -cefe-4- 4.3 g (yield: 91.9%) of trifluoroacetic acid salt of carboxylic acid are obtained.

IR (KBr) cm ^-1 : ν _{c = 0} 1775, 1710-1630

), 5.21(1H, d, J=5Hz, C₆-H), 5.83(1H, dd, J=5Hz, J=8Hz, C₇-H), 5.86(3H, bs, -NH₃

), 6.71(2H, bs,

), 6.95(1H, S,

), 9.90(1H, d, J=8Hz, -CONH-)NMR (d ₆ -DMSO) δ value: 1.21 (3H, t, J = 7 Hz,> N-CH ₂ CH ₃ ), 3.52 (2H, bs, C ₂ -H), 3.73 (2H, q, J = 7 Hz ,> N-CH ₂ CH ₃ ), 3.96 (3H, S, -OCH ₃ ), 4.44, 5.12 (2H, ABq, J = 15 Hz,

), 5.21 (1H, d, J = 5 Hz, C ₆ -H), 5.83 (1H, dd, J = 5 Hz, J = 8 Hz, C ₇ -H), 5.86 (3H, bs, -NH ₃

), 6.71 (2H, bs,

), 6.95 (1H, S,

), 9.90 (1H, d, J = 8 Hz, -CONH-)

In a similar manner, the compounds shown in Tables 19 and 20 are obtained.

TABLE 19

TABLE 20

(4) 7- [2- (2-aminothiazol-4-yl) -2- (new) -methoxyiminoacetamido] -3-{[1- (2,3-dioxo-1 The trifluoroacetic acid salt of 2,3,4-tetrahydropyrazinyl)] methyl} -Δ ³ -cepem-4-carboxylic acid was dissolved in 30 ml of water, and the pH of the resulting solution was adjusted to 7.4 using sodium hydrogen carbonate. Adjust to. The solution was then purified by passing through an Ambolite XAD-2 column to give sodium 7- [2- (2-aminothiazol-4-yl) -2- (new) -methoxyiminoacet with a melting point of 200 ° C. or higher. Amido] -3-{[1- (2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)] methyl} -Δ ³ -cefe-4-carboxylate 4.7 g (yield: 86.6 %) Is obtained.

IR (KBr) cm ^-1 : ν _{c = 0} 1763, 1670, 1650-1620

In a similar manner, the following compounds are obtained:

Sodium 7- [2- (2-aminothiazol-4-yl) -2- (cin) -methoxyiminoacetamido] -3-{[1- (4-methyl-2,3-dioxo -1,2,3,4-tetrahydropyrazinyl)] methyl} -Δ ³ -cepem-4-carboxylate, melting point: 190 to 195 ° C. (decomposition)

IR (KBr) cm ^-1 : ν _{c = 0} 1760, 1670, 1650, 1630

Sodium 7- [2- (2-aminothiazol-4-yl) -2- (cin) -methoxyiminoacetamido] -3-{[1- (3,6-dioxo-1,2 , 3,6-tetrahydropyridazinyl)] methyl} -Δ ³ -cef-4-carboxylate.

Sodium 7- [2- (2-aminothiazol-4-yl) -2- (cin) -methoxyiminoacetamido] -3-{[1- (3-methyl-6-oxo-1, 6-dihydropyridazinyl)] methyl} -Δ ³ -cef-4-carboxylate.

Example 7

(1) -10 to a solution of 3 g of 2- (2-tritylaminothiazol-4-yl) -2- (new) -tert-butoxy-carbonylmethoxyaminoacetic acid in 15 ml of N, N-dimethylacetamide 0.93 g of phosphorus oxychloride is added dropwise at 占 폚 and the mixture is reacted at -5 to 0 占 폚 for 1 hour. This solution was diluted with 7-amino-3-{[1- (4-ethyl-2,3-dioxo-1,2,3,4-tetrahydro-pyrazinyl)] methyl} -Δ ³ -cefe-4- To a solution of 19.4 ml of anhydrous methylene chloride containing 1.94 ml of carboxylic acid and 2.25 g of bis (trimethylsilyl) acetamide are added dropwise at -5 to 0 ° C. After completion of the dropwise addition, the mixture is allowed to react for 30 minutes at the same temperature and then for 30 minutes at 0-10 占 폚. After the reaction was completed, the mixture was distilled off under reduced pressure to remove methylene chloride, and the residue was added to a mixed solvent of 100 ml of saturated aqueous sodium chloride solution and 100 ml of acetonitrile. The organic layer was then separated, washed twice with 50 ml of saturated aqueous sodium chloride solution, and then distilled under reduced pressure to remove the solvent. After dissolving the resulting residue in 50 ml of methanol, 1 g of diphenyldiazomethane is added to this solution at 5 to 10 DEG C, and the mixture is reacted at the same temperature for 30 minutes. After the reaction is completed, the solvent is distilled off under reduced pressure. The residue was purified by column chromatography (WACO silica gel C-200, eluent; benzine: ethyl acetate = 3: 1) to give diphenylmethyl 7- [2- (2- with a melting point of 98 to 100 ° C (decomposition). Tritylaminothiazol-4-yl) -2- (new) -tert-butoxycarbonylmethoxyiminoacetamido] -3-{[1- (4-ethyl-2,3-dioxo-1 1.6 g (yield: 27.8%) of 2,3,4-tetrahydro-pyrazinyl)] methyl} -Δ ³ -cepem-4-carboxylate are obtained.

IR (KBr) cm ^-1 : ν _{c = 0} 1780, 1720, 1680, 1630

). 4.51, 5.16(2H, ABq, J=15Hz,

), 5.27(1H, d, J=5Hz, C₆-H), 5.87(1H, dd, J=5Hz, J=8Hz, C₇-H), 6.55(2H, bs,

), 6.80(1H, s, -CH<), 6.97(1H, s,

),

7.05-7.67(25H, m,

), 8.86(1H, bs,

), 9.54(1H, d, J=8Hz, -CONH-)NMR (d ₆ -DMSO) δ value: 1.17 (3H, t, J = 7 Hz,> NCH ₂ CH ₃ ), 1.44 (9H, s, -C (CH ₃ ) ₃ ), 3.62 (2H, bs, C ₂ -H), 3.74 (2H, q, J = 7 Hz,> N-CH ₂ CH ₃ ), 4.55 (2H, s,

). 4.51, 5.16 (2H, ABq, J = 15 Hz,

), 5.27 (1H, d, J = 5 Hz, C ₆ -H), 5.87 (1H, dd, J = 5 Hz, J = 8 Hz, C ₇ -H), 6.55 (2H, bs,

), 6.80 (1H, s, -CH <), 6.97 (1H, s,

),

7.05-7.67 (25H, m,

), 8.86 (1H, bs,

), 9.54 (1H, d, J = 8 Hz, -CONH-)

In a similar manner, the compounds shown in Tables 21 and 22 are obtained.

TABLE 21

Table 22

(2) To a mixed solvent of 8 ml of trifluoroacetic acid and 3 ml of anisole, diphenylmethyl 7- [2- (2-trityl-aminothiazol-4-yl) -2- (new) -tertiary butoxycarbo Nylmethoxy-Iminoacetamido] -3-{[1- (4-ethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)] methyl} -Δ ³ -cepem- 1.6 g of 4-carboxylate is dissolved and the solution is allowed to react at room temperature for 1 hour. After the reaction is completed, the solvent is distilled off under reduced pressure. 10 ml of diethyl ether was added to the residue, and the crystals were collected by filtration. The obtained crystals are dissolved in 20 ml of 50% by weight aqueous formic acid solution, and the solution is reacted at 45 to 55 ° C for 1 hour. After the reaction was completed, the precipitated crystals were separated by filtration and distilled under reduced pressure to remove the solvent. 10 ml of ethyl acetate is added to the residue, and the crystals are collected by filtration. The crystals were then washed thoroughly with 10 ml of ethyl acetate and dried to give 7- [2- (2-aminothiazol-4-yl) -2- (new) -carboxymethoxyimide having a melting point of 139 to 140 ° C. (decomposition). Noacetamido] -3-{[1- (4-ethyl-2,3-dioxo-1,2,3,4-tetrahydro-pyrazinyl)] methyl} -Δ ³ -cefe-4-carboxylic acid 0.7 g (yield: 80.7%) is obtained.

IR (KBr) cm ^-1 : ν _{c = 0} 1755, 1695, 1680, 1635

), 5.23(1H, d, J=5Hz, C₆-H), 5.90(1H, dd, J=5Hz, J=8Hz, C₇-H), 6.69(2H, bs,

), 6.94(1H, s,

), 9.70(1H, d, J=8Hz, -CONH-)NMR (d ₆ -DMSO) δ value: 1.22 (3H, t, J = 7 Hz,> NCH ₂ CH ₃ ), 3.53 (2H, bs, C ₂ -H), 3.74 (2H, q, J = 7 Hz,> NCH ₂ CH ₃ ), 4.70 (2H, s, -OCH ₂ CO-), 4.45, 5.10 (2H, ABq, J = 15 Hz,

), 5.23 (1H, d, J = 5 Hz, C ₆ -H), 5.90 (1H, dd, J = 5 Hz, J = 8 Hz, C ₇ -H), 6.69 (2H, bs,

), 6.94 (1H, s,

), 9.70 (1H, d, J = 8 Hz, -CONH-)

In a similar manner, the compounds shown in Table 23 are obtained.

TABLE 23

Note: * 1 Trifluoro Acetate (Convert to diphenylmethyl ester in the usual way to purify the product obtained in the above process, and de-esterification with trifluoro acetic acid to obtain trifluoroacetic acid salt. )

* 2 formate

Example 8

(1) To a solution of 1.68 g of diketone in 8.40 ml of anhydrous methylene chloride was added dropwise a solution of 2.08 g of bromine in 6.25 ml of anhydrous methylene chloride while stirring at 30 ° C., and the mixture was reacted at −30 to −20 ° C. for 30 minutes. . The reaction mixture thus obtained was converted to diphenylmethyl 7-amino-3-{[1- (4-ethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)] methyl} -Δ ³ -To a solution of 50 ml of anhydrous methylene chloride containing 5.20 g of cefem-4-carboxylate and 4.08 g of bis (trimethylsilyl) acetamide are added dropwise at -30 ° C.

After completion of the dropwise addition, the mixture is allowed to react for 30 minutes at -30 to -20 占 폚 and then at 0 to 10 占 폚 for 1 hour. After completion of the reaction, the solvent was removed by distillation under reduced pressure, and the obtained residue was dissolved in 50 ml of ethyl acetate and 40 ml of water. The organic layer is separated, washed sequentially with 40 ml of water and 40 ml of saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. Distillation under reduced pressure removes the solvent. 50 ml of diisopropyl ether was added to the residue, and the obtained crystals were collected by filtration. Diphenylmethyl 7- (4-bromo-3-oxobutyramido) -3 having a melting point of 138 to 142 ° C (decomposition) -3 5.85 g ({: 1- (4-ethyl-2,3-dioxo-1,2,3,4-tetrahydro-pyrazinyl)] methyl} -Δ ³ -cefe-4-carboxylate (yield: 85.6 %) Is obtained.

IR (KBr) cm ^-1 : ν _{c = 0} 1778, 1720, 1680, 1640

), 5.04(1H, d, J=5Hz, C₆-H), 5.90(1H, dd, J=5Hz, J=8Hz, C₇-H), 6.15, 6.50(2H, ABq, J=6Hz,

), 6.98(1H, s, -CH<), 7.40(10H, bs,

), 8.55(1H, d, J=8Hz, -CONH-)NMR (d ₆ -DMSO) δ value: 1.22 (3H, t, J = 7 Hz,> NCH ₂ CH ₃ ), 3.40 (2H, bs, C ₂ -H), 3.85 (2H, q, J = 7 Hz,> NCH ₂ CH ₃ ), 3.87 (2H, bs, BrCH ₂ COCH ₂₋ ), 4.18 (2H, bs, BrCH ₂ CO—), 4.47, 49.6 (2H, ABq, J = 15 Hz,

), 5.04 (1H, d, J = 5 Hz, C ₆ -H), 5.90 (1H, dd, J = 5 Hz, J = 8 Hz, C ₇ -H), 6.15, 6.50 (2H, ABq, J = 6 Hz,

), 6.98 (1H, s, -CH <), 7.40 (10H, bs,

), 8.55 (1H, d, J = 8 Hz, -CONH-)

In a similar manner, the following compounds are obtained.

Diphenylmethyl 7- (4-bromo-3-oxo-butyramido) -3-{[1- (3,6-dioxo-1,2,3) having a melting point of 124 to 126 ° C (decomposition) , 6-tetrahydropyridazinyl)] methyl} -Δ ³ -cefe-4-carboxylate (yield: 62.6%).

IR (KBr) cm ^-1 : ν _{c = 0} 1780, 1725, 1660

), 4.52(2H, s,

), 5.06(1H, bs,

), 5.26(1H, d, J=5Hz, C₆-H), 5.90(1H, dd, J=5Hz, J=8Hz, C₇-H), 7.01, 7.25(2H, ABq, J=10Hz,

), 7.09(1H, s, -CH<), 7.24-7.91(10H, m,

) , 9.34(1H, d, J=10Hz, -CONH-)NMR (d ₆ -DMSO) δ value: 3.49 (4H, bs, C ₂ -H,

), 4.52 (2H, s,

), 5.06 (1H, bs,

), 5.26 (1H, d, J = 5 Hz, C ₆ -H), 5.90 (1H, dd, J = 5 Hz, J = 8 Hz, C ₇ -H), 7.01, 7.25 (2H, ABq, J = 10 Hz,

), 7.09 (1H, s, -CH <), 7.24-7.91 (10H, m,

), 9.34 (1H, d, J = 10 Hz, -CONH-)

(2) Diphenylmethyl 7- (4-bromo-3-oxobutyramido) -3-{[1- (4-ethyl-2,3-dioxo-1,2,3, in acetic acid 30 ml) To a solution of 5.50 g of 4-tetrahydropyrazinyl)] methyl} -Δ ³ -cefe-4-carboxylate, a solution of 5 ml of water containing 0.74 g of sodium nitrate was added dropwise over 1 hour while ice-cooling, and the resulting mixture was added. The reaction is carried out at room temperature for 2 hours. After completion of the reaction, the reaction mixture is poured into 50 ml of water to precipitate crystals. The crystals are collected by filtration, washed sufficiently with water and dried. The crystals were then dissolved in 10 ml of chloroform and purified by column chromatography (Wako Silica gel C-200, eluent; benzene: ethyl acetate = 2: 1 volume ratio), diphenylmethyl having a melting point of 127 to 132 DEG C (decomposition). 7- (4-bromo-2-hydroxyimino-3-oxobutyramido) -3-{[1- (4-ethyl-2,3-dioxo-1,2,3,4-tetra 3.15 g (yield: 54.9%) of hydro-pyrazinyl)] methyl} -Δ ³ -cepem-4-carboxylate are obtained.

IR (KBr) cm ^-1 : ν _{c = 0} 1778, 1720, 1680, 1635

), 5.11(1H, d, J=5Hz, C₆-H), 5.80-6.15(1H, m, C₆-H), 6.13, 6.52(2H, ABq, J=6Hz,

), 7.02(1H, s, -CH<), 7.41(10H, bs,

), 9.20(1H, d, J=8Hz, -CONH-)NMR (CDCl ₃ ) δ value: 1.26 (3H, t, J = 7 Hz,> NCH ₂ CH ₃ ), 3.47 (2H, bs, C ₂ -H), 3.81 (2H, q, J = 7 Hz,> NCH ₂ CH ₃ ), 4.52 (2H, s, BrCH ₂ CO-), 4.53, 4.78 (2H, ABq, J = 15 Hz,

), 5.11 (1H, d, J = 5 Hz, C ₆ -H), 5.80-6.15 (1H, m, C ₆ -H), 6.13, 6.52 (2H, ABq, J = 6 Hz,

), 7.02 (1H, s, -CH <), 7.41 (10H, bs,

), 9.20 (1H, d, J = 8 Hz, -CONH-)

In a similar manner, the following compounds are obtained. : Diphenylmethyl-7- (4-bromo-2-hydroxyimino-3-oxybutyramido) -3- melting at a melting point of 138 to 141 ° C (decomposition) -3-{[1- (3,6-di 4.71 g of oxo-1,2,3,6-tetrahydropyridazinyl)] methyl} -Δ ³ -cepem-4-carboxylate (yield 75.1%).

IR (KBr) cm ^-1 : ν _{c = 0} 1780, 1720, 1660

), 5.18(1H, d, J=5Hz, C₆-H), 5.93(1H, dd, J=5Hz, J=8Hz, C₇-H), 6.89, 7.13(2H, ABq, J=10Hz,

), 6.96(1H, s, -CH<), 7.13-7.72(10H, m,

), 9.45(1H, d, J=8Hz, -CONH-), 13.36(1H, s, =N-OH)NMR (d ₆ -DMSO) δ value: 3.46 (2H, bs, C ₂ -H), 4.62 (2H, s, BrCH ₂ CO-), 4.96 (2H, bs,

), 5.18 (1H, d, J = 5 Hz, C ₆ -H), 5.93 (1H, dd, J = 5 Hz, J = 8 Hz, C ₇ -H), 6.89, 7.13 (2H, ABq, J = 10 Hz,

), 6.96 (1H, s, -CH <), 7.13-7.72 (10H, m,

), 9.45 (1H, d, J = 8 Hz, -CONH-), 13.36 (1H, s, = N-OH)

(3) Diphenylmethyl 7- (4-bromo-2-hydroxyimino-3-oxobutyramido) -3-{[1- (4-ethyl-2,3) obtained in (2) above. Dissolve 3.00 g of -dioxo-1,2,3,4-tetrahydropyrazinyl)] methyl} -Δ ³ -cef-4-carboxylate and 0.42 g of thiourea in 12 ml of N, N-dimethylacetamide, The resulting solution is reacted for 3 hours at room temperature. After the reaction was completed, the reaction mixture was poured into a mixed solvent of 120 ml of water and 240 ml of ethyl acetate. The pH of the mixture is then adjusted to 7.0 using sodium hydrogen carbonate, and the organic layer is separated and washed sequentially with 50 ml of water and 50 ml of saturated aqueous sodium chloride solution. The organic layer is dried over anhydrous magnesium sulfate, and then distilled off under reduced pressure to remove the solvent. 20 ml of diethyl ether was added to the residue, and the crystals were collected by filtration. Diphenylmethyl 7- [2- (2-aminothiazol-4-yl) -2- (syn) had a melting point of 137 to 140 ° C (decomposition). ) -Hydroxyiminoacet-amido] -3-{[1- (4-ethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)] methyl-Δ ³ -cepem 2.10 g of 4-carboxylate (yield: 72.3%) are obtained.

IR (KBr) cm ^-1 : ν _{c = 0} 1778, 1720, 1680, 1640

), 5.28(1H, d, J=5Hz, C₆-H), 5.97(1H, dd, J=5Hz, J=8Hz, C₇-H), 6.57, 6.75(2H, ABq, J=6Hz,

), 6.79(1H, s,

), 7.07(1H, s, -CH<), 7.53(10H, bs,

), 9.70(1H, d, J=8Hz, -CONH-)NMR (D ₆ -DMSO) δ value: 1.19 (3H, t, J = 7 Hz,> NCH ₂ CH ₃ ), 3.48 (2H, bs, C ₂ -H), 3.68 (2H, q, J = 7 Hz,> NCH ₂ CH ₃ ), 4.46, 5.04 (2H, ABq, J = 15 Hz,

), 5.28 (1H, d, J = 5 Hz, C ₆ -H), 5.97 (1H, dd, J = 5 Hz, J = 8 Hz, C ₇ -H), 6.57, 6.75 (2H, ABq, J = 6 Hz,

), 6.79 (1 H, s,

), 7.07 (1H, s, -CH <), 7.53 (10H, bs,

), 9.70 (1H, d, J = 8 Hz, -CONH-)

(4) Diphenylmethyl 7- [2- (2-aminothiazol-4-yl) -2- (cin) -hydroxyiminoacetamido obtained in the above (3)]-3-{[1 2.00 g of 4- (4-ethyl-2,3-dioxo-1,2,3,4-tetrahydro-pyrazinyl)] methyl} -Δ ³ -cefe-4-carboxylate with 10.0 ml of trifluoroacetic acid Dissolve in 2.0 ml of anisole solvent and react the resulting solution for 2 hours at room temperature. After the reaction was completed, the solvent was removed by distillation under reduced pressure, and 15 ml of dieth ether was added to the residue, followed by filtration to collect the crystals. Subsequently, the crystals were sufficiently washed with 10 ml of diethyl ether and dried, and 7- [2- (2-aminothiazol-4-yl) -2- (new) -hydroxyimine having a melting point of 112 to 118 ° C (decomposition) Noacetamido] -3-{[1- (4-ethyl-2,3-dioxo-1,2,3,4-tetrahydro-pyrazinyl)] methyl} -Δ ³ -cefe-4-carboxylic acid 1.62 g (yield: 87.6%) of trifluoro-acetic acid salt was obtained.

IR (KBr) cm ^-1 : ν _{c = 0} 1780, 1680, 1620

, C₆-H, C₇-H), 6.59-6.83(3H, m,

)NMR (d ₆ -DMSO) δ value: 1.19 (3H, t, J = 7 Hz,> N-CH ₂ CH ₃ ), 3.47 (2H, bs, C ₂ -H), 3.72 (2H, q, J = 7 Hz ,> NCH ₂ CH ₃ ), 4.45-6.70 (4H, m,

, C ₆ -H, C ₇ -H), 6.59-6.83 (3H, m,

)

Example 9

(1) Diphenylmethyl 7- (4-bromo-2-hydroxyimino-3-oxobutyramido) -3-{[1- (4-ethyl-2,3-di in 70 ml of anhydrous methylene chloride) In a solvent of 7.1 g of oxo-1,2,3,4-tetrahydro-pyrazinyl)] methyl} -Δ ³ -cef-4-carboxylate, a solution of diazomethane in diethyl ether at -5 ° to 0 ° C Add slowly and react the resulting solution for 30 minutes at the same temperature. After confirming that diazomethane is gone, the solvent is distilled off under reduced pressure. The obtained residue was then purified by column chromatography (wacosyl silica gel C-200, eluent; benzene: ethyl acetate = 3: 1 volume ratio), and diphenylmethyl 7- [4 having a melting point of 135 to 140 占 폚 (decomposition). -Bromo-2- (new) methoxyimino-3-oxobutyramido] -3-{[1- (4-ethyl-2,3-dioxo-1,2,3,4-tetrahydro 2.32 g (yield: 32.0%) of pyrazinyl)] methyl} -Δ ³ -cefe-4-carboxylate are obtained.

IR (KBr) cm ^-1 : ν _{c = 0} 1778, 1720, 1682, 1638

), 5.10(1H, d, J=5Hz, C₆-H), 6.05(1H, dd, J=5Hz, J=8Hz, C₇-H), 6.38, 6.73(2H, ABq, J=6Hz,

), 6.98(1H, s, -CH<), 7.32(10H, bs,

), 9.18(1H, d, J=8Hz, -CONH-)NMR (CDCl ₃ ) δ value: 1.25 (3H, t, J = 7 Hz,> NCH ₂ CH ₃ ), 3.48 (2H, bs, C ₂ -H), 3.84 (2H, q, J = 7 Hz,> NCH ₂ CH ₃ ), 4.00 (3H, s, -OCH ₃ ), 4.10 (2H, S, BrCH ₂ CO-), 4.48, 4.67 (2H, ABq, J = 15 Hz,

), 5.10 (1H, d, J = 5 Hz, C ₆ -H), 6.05 (1H, dd, J = 5 Hz, J = 8 Hz, C ₇ -H), 6.38, 6.73 (2H, ABq, J = 6 Hz,

), 6.98 (1H, s, -CH <), 7.32 (10H, bs,

), 9.18 (1H, d, J = 8 Hz, -CONH-)

In a similar manner, the following compounds are obtained: diphenylmethyl 7- [4-bromo-2- (cin) -methoxyimino-3-oxobutyramido] having a melting point of 145 to 148 ° C. (decomposition) 1.70 g of 3--3-[[1- (3,6-dioxo-1,2,3,6-tetrahydropyridazinyl)] methyl} -Δ ³ -cepem-carboxylate (yield: 24.5%).

IR (KBr) cm ^-1 : ν _{c = 0} 1780, 1730, 1660

), 5.30(1H, d, J=5Hz, C₆-H), 6.02(1H, dd, J=5Hz, J=8Hz, C₇-H), 6.02(1H, dd, J=5Hz, J=8Hz, C₇-H), 6.92, 7.16(2H, ABq, J=10Hz),

), 6.99(1H, S, -CH<), 7.17-7.78(10H, m,

), 10.16(1H, d, J=8Hz, -CONH-)NMR (d ₆ -DMSO) δ Value: 3.49 (2H, bs, C ₂ -H), 4.03 (3H, S, -OCH ₃ ), 4.60 (2H, S, BrCH ₂ CO-), 5.02 (2H, bs ,

), 5.30 (1H, d, J = 5 Hz, C ₆ -H), 6.02 (1H, dd, J = 5 Hz, J = 8 Hz, C ₇ -H), 6.02 (1H, dd, J = 5 Hz, J = 8 Hz, C ₇ -H), 6.92, 7.16 (2H, ABq, J = 10 Hz),

), 6.99 (1H, S, -CH &lt;), 7.17-7.78 (10H, m,

), 10.16 (1H, d, J = 8 Hz, -CONH-)

(2) diphenylmethyl 7- [4-bromo-2- (new) -methoxyimino-3-oxobutyramido] -3-{[1- (4-ethyl-2,3-dioxo -1,2,3,4-tetrahydropyrazinyl)] methyl} -Δ ³ -cefe-4-carboxylate 2.3 g and thiourea 0.32 g are dissolved in 14 ml of N, N-dimethylacetamide, and the resulting solution The reaction is reacted at room temperature for 3 hours. After the reaction was completed, the reaction mixture was poured into a mixed solvent of 50 ml of water and 150 ml of ethyl acetate. Then, sodium hydrogen carbonate was added to adjust the pH of the mixture to 6.7, and then the organic layer was separated. The aqueous layer is extracted twice more with 100 ml of ethyl acetate. The organic layers are mixed, washed with water, dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent. 20 ml of diethyl ether was added to the residue, and the crystals were collected by filtration. Diphenylmethyl 7- [2- (2-aminothiazol-4-yl) -2- (cin) -meth having a melting point of 165 to 167 ° C. Toxyimino-acetamido] -3-{[1- (4-ethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)] methyl} -Δ ³ -fem-4- 1.92 g (yield: 86.3%) of carboxylate are obtained.

IR (KBr) cm ^-1 : ν _{c = 0} 1780, 1720, 1680, 1640

In a similar manner, the following compounds are obtained: diphenylmethyl 7- [2- (2-aminothiazol-4-yl-2- (new) -methoxyiminoacet having a melting point of 175 to 178 ° C. (decomposition) -Amido] -3-{[1- (3,6-dioxo-1,2,3,6-tetra-hydropyridazinyl)] methyl} -Δ ³ -cepem-4-carboxylate.

IR (KBr) cm ^-1 : ν _{c = 0} 1780, 1720, 1685, 1660

After carrying out the ring-closure reaction as described above, carrying out the reaction described in Example 6- (3) or Example 7- (2) affords the compounds shown in Tables 24, 25 and 26.

TABLE 24

Note: * Hydrochloride

TABLE 25

TABLE 26

Note: * Hydrochloride

The physical properties (melting point, IR and NMR spectra) of the above compounds are as obtained in Examples 6, 7, 11 and 17.

Example 10

(1) To a suspension of 2.2 g of 2- (2-formamidothiazol-4-yl) glyoxylic acid in 11 ml of N, N-dimethylacetamide, 1.8 g of phosphorus oxychloride at -20 ° C was added dropwise, The mixture is reacted at the same temperature for 2 hours. This reaction mixture was then added to diphenylmethyl 7-amino-3-{[1- (4-ethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)] methyl} -Δ ³ − A solution of 26 ml of methylene chloride containing 5.2 g of cefem-4-carboxylate is added at -30 to -20 ° C. After completion of the dropwise addition, the mixture is allowed to react at the same temperature for 1 hour. After the reaction was completed, 70 ml of water and 50 ml of methylene chloride were added to the reaction mixture. Sodium bicarbonate is added to adjust the pH of the mixture to 65 and filtered to remove insolubles. The organic layer is separated, washed sequentially with 100 ml of water and 100 ml of saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. The solvent is then removed by distillation under reduced pressure. The residue was purified by column chromatography (waco silica gel C-200, eluent; chloroform: methanol = 20: 1 volume ratio) to give diphenylmethyl 7- [2- (2- Formamidothiazol-4-yl) glyoxylamido] -3-{[1- (4-ethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)] methyl} 1.4 g of -Δ ³ -cefe-4-carboxylate (yield: 20.0%) are obtained.

IR (KBr) cm ^-1 : ν _{c = 0} 1780, 1720, 1680, 1670, 1640

), 5.30(1H, d, J=5Hz, C₆-H), 6.00(1H, d, J=5Hz, J=9Hz, C₇-H), 6.50, 6.62(2H, ABq, J=5Hz,),

), 7.04(1H, S, -CH<), 7.30(10H, bs,

), 8.64(1H, S),

), 8.81(1H, S, HCONH-), 10.20(1H, d, J=9Hz, -CONH-), 12.90(1H, bs, HCONH-)NMR (d ₆ -DMSO) δ value: 1.20 (3H, t, J = 7 Hz,> NCH ₂ CH ₃ ), 3.50 (2H, bs, C ₂ -H), 3.69 (2H, q, J = 7 Hz,> NCH ₂ CH ₃ ), 4.40, 5.00 (2H, ABq, J = 15 Hz,

), 5.30 (1H, d, J = 5 Hz, C ₆ -H), 6.00 (1H, d, J = 5 Hz, J = 9 Hz, C ₇ -H), 6.50, 6.62 (2H, ABq, J = 5 Hz, ),

), 7.04 (1H, S, -CH <), 7.30 (10H, bs,

), 8.64 (1H, S),

), 8.81 (1H, S, HCONH-), 10.20 (1H, d, J = 9 Hz, -CONH-), 12.90 (1H, bs, HCONH-)

In a similar manner, the following compounds are obtained: diphenylmethyl 7- [2- (2-formamidothiazol-4-yl) glyoxylamido also having a melting point of 153 to 154 ° C. (decomposition) -3- { 0.09 g of [1- (3,6-dioxo-1,2,3,6-tetrahydropyridazinyl) methyl} -Δ ³ -cepem-4-carboxylate (yield: 19.2%).

IR (KBr) cm ^-1 : ν _{c = 0} 1780, 1725, 1690, 1665

, C₆-H), 5.95(1H, dd, J=5Hz, J=8Hz, C₇-H), 6.72-7.78(13H, m, -CH<,

), 8.66(1H, S,

), 8.73(1H, S, HCO-), 9.86(1H, d, J=8Hz, -CONH-)NMR (CDCl ₃ + d ₆ -DMSO) δ value: 3.42 (2H, bs, C ₂ -H), 4.96-5.40 (3H, m,

, C ₆ -H), 5.95 (1H, dd, J = 5 Hz, J = 8 Hz, C ₇ -H), 6.72-7.78 (13H, m, -CH <,

), 8.66 (1 H, S,

), 8.73 (1H, S, HCO-), 9.86 (1H, d, J = 8 Hz, -CONH-)

(2) diphenylmethyl 7- [2- (2-formamidothiazol-4-yl) glyoxysilamido in 35 ml of N, N-dimethylacetamide] -3-{[1- (4-ethyl- 1.7 g of methoxyamine hydrochloride was added to a 7.0 g solution of 2,3-dioxo-1,2,3,4-tetrahydro-pyrazinyl)] methyl} -Δ ³ -cepem-4-carboxylate with ice cooling, The resulting mixture is reacted at 15-20 ° C. for 3 hours. After the reaction was completed, the reaction mixture was poured into a mixed solvent of 250 ml of water and 250 ml of ethyl acetate, and the organic layer was separated, washed sequentially with 1250 ml of water and 250 ml of saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. Thereafter, the solvent is distilled off under reduced pressure. 50 ml of diethyl ether was added to the residue, and the resulting crystals were collected by filtration, diphenylmethyl 7- [2- (2-formamidothiazol-4-yl) -2- (with a melting point of 165 to 168 ° C). CIN) -methoxyiminoacetamido] -3-{[1- (4-ethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)] methyl} -Δ ³ − 6.1 g of cefem-4-carboxylate (yield: 83.7%) are obtained.

IR (KBr) cm ^-1 : νc = 0 1780, 1720, 1640

In a similar manner, the following compounds are obtained: diphenylmethyl 7- [2- (2-formamidothiazol-4-yl) -2- (new) -methoxyimino having a melting point of 171-173 ° C. (decomposition). -Acetamido] -3-{[1- (3,6-dioxo-1,2,3,6-tetrahydropyridazinyl)] methyl} -Δ ³ -cefe-4-carboxylate.

By carrying out the above oxime reaction and carrying out the reactions mentioned in Examples 6- (2), (3) and / or Examples 7- (2), the compounds shown below and shown in Tables 27, 28 and 29 The compound is obtained:

7- [2- (2-amino-5-bromothiazol-4-yl) -2- (new) -methoxyiminoacetamido having a melting point of 147 ° C. (decomposition) -3-{[1- Trifluoroacetic acid salt of (4-ethyl-dioxo-1,2,3,4-tetrahydropyrazinyl)] methyl} -Δ ³ -cepem-4-carboxylic acid.

IR (KBr) cm ^-1 : ν _{c = 0} 1775, 1680, 1640

TABLE 27

Note: * Hydrogen Chloride

TABLE 28

TABLE 29

Note: * Hydrochloride

The physical properties (melting point, IR and NMR spectra) of the compound are the same as those obtained in Examples 6, 7, 11 and 12.

Example 11

(1) Diphenylmethyl 7- [2- (2-formamidothiazol-4-yl) -2- (new) -methoxyiminoacet in a mixed solvent of 37 ml of trifluoroacetic acid and 10.8 g of anisole Amido] -3-{[1- (4-ethyl-2,3-dioxo-1,2,3,4-tetra-hydropyrazinyl)] methyl} -Δ ³ -cepem-4-carboxylate 7.29 g is dissolved and the resulting solution is allowed to react for 2 hours at room temperature. After the reaction is completed, the solvent is distilled off under reduced pressure. 50 ml of diethyl ether was added to the resulting residue, and the crystals were collected by filtration. After sufficiently washing with 50 ml of diethyl ether, and drying, 7- [2- (2-formami) having a melting point of 155 to 158 占 폚 (decomposition). Dothiazol-4-yl) -2- (new) -methoxyiminoacetamido-3-{[1- (4-ethyl-2,3-dioxo-1,2,3,4-tetra Hydropyrazinyl)] methyl} -Δ ³ -cepem-4-carboxylic acid 5.2 g (yield: 92.4%) is obtained.

IR (KBr) cm ^-1 : ν _{c = 0} 1775, 1710, 1675, 1640

), 5.21(1H, d, J=5Hz, C₆-H), 5.89(1H, dd, J=5Hz, J=8Hz, C₇-H), 6.65(2H, bs,

), 7.46(1H, s,

), 8.59(1H, s, HCONH-), 9.77(1H, d, J=8Hz, -CONH-), 12.58(1H, bs, HCONH-),NMR (d ₆ -DMSO) δ value: 1.20 (3H, t, J = 7 Hz,> NCH ₂ CH ₃ ), 3.49 (2H, bs, C ₂ -H), 3.73 (2H, q, J = 7 Hz,> NCH ₂ CH ₃ ), 3.91 (3H, s, -OCH ₃ ), 4.42, 4.95 (2H, ABq, J = 15 Hz,

), 5.21 (1H, d, J = 5 Hz, C ₆ -H), 5.89 (1H, dd, J = 5 Hz, J = 8 Hz, C ₇ -H), 6.65 (2H, bs,

), 7.46 (1H, s,

), 8.59 (1H, s, HCONH-), 9.77 (1H, d, J = 8 Hz, -CONH-), 12.58 (1H, bs, HCONH-),

In a similar manner, the compounds shown in Table 30 are obtained.

TABLE 30

(2) 7- [2- (2-formamidothiazol-4-yl) -2- (new) -methoxy-iminoacetamido] -3- {in 25 ml of N, N-dimethylacetamide 1,8 while ice-cooling in a solution of 5.63 g of [1- (4-ethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)] methyl} -Δ ³ -cepem-4-carboxylic acid 1.52 g of diazabicyclo [5,4,0] -7-undecene and 3.84 g of 1-pivaloyloxyethyl iodide are added and the resulting mixture is allowed to react for 30 minutes. After the reaction was completed, the reaction mixture was poured into a mixed solvent of 100 ml of water and 100 ml of ethyl acetate. The organic layer is then separated, washed with water and dried over anhydrous magnesium sulfate. Distillation under reduced pressure removes the solvent. 50 ml of diethylethyl ether was added to the residue, and the crystals were collected by filtration. Then, 1-pivalooxyethyl 7- [2- (2-formamidothiazol-4-yl) -2 having a melting point of 140 to 142 ° C was obtained. -(New) -methoxyimino-acetamido-3-{[1- (4-ethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)] methyl} -Δ ³ 5.5 g of cefem-4-carboxylate (yield: 79.6%) are obtained.

IR (KBr) cm ^-1 : ν _{c = 0} 1780, 1740, 1680, 1640

In a similar manner, the compounds shown in Table 31 are obtained. In this case, the compounds shown in Table 31 can also be obtained in the same manner as in Example 6- (1), except that the compounds represented by the corresponding esters are substituted for the diphenylmethyl esters.

Table 31

Note: * 1 Diastereomer

(3) 1-pivaloyloxyethyl 7- [2- (2-formamidothiazol-4-yl) -2- (new) -methoxyaminoacet obtained in (2) above in 27.5 ml of methanol Amido] -3-{[1- (4-ethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)] methyl} -Δ ³ -cepem-4-carboxylate 5.5 g To the solution was added 1.13 ml of concentrated hydrochloric acid, and the resulting mixture was reacted at 35 ° C for 2 hours. After the reaction is completed, the solvent is distilled off under reduced pressure. 50 ml of ethyl acetate and 50 ml of water are added to the residue, and the pH of the mixture is adjusted to 6.0 using sodium bicarbonate. The organic layer is then separated, dried over anhydrous magnesium sulfate and then distilled off under reduced pressure to remove the solvent. 45 ml of diethyl ether was added to the residue, and the crystals were collected by filtration. 1-Pivaloyloxyethyl 7- [2- (2-aminothiazol-4-yl) -2- ( Cin) -methoxyiminoacetamido] -3-{[1- (4-ethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)] methyl} -Δ ³ − 4.65 g of cefem-4-carboxylate (yield: 88.1%) are obtained.

IR (KBr) cm ^-1 : ν _{c = 0} 1780, 1740, 1680, 1640

), 3.52(2H, bs, C₂-H), 3.76(2H, q, J=7Hz, >NCH₂CH₃), 3.88 (3H, s, -OCH₃), 4.38, 5.04(2H, ABq, J=15Hz,

), 5.21(1H, d, J=5Hz, C₆-H), 5.87(1H, dd, J=5Hz, C₇-H), 6.61(2H, bs,

), 6.78(1H, s,

), 7.04(1H, q, J=5Hz,

), 7.22(2H, bs, -NH₂), 9.67(1H, d, J=8Hz, -CONH),NMR (d ₆ -DMSO) δ value: 0.90-1.39 (12H, m, -C (CH ₃ ) ₃ ,> NCH ₂ CH ₃ ), 1.52 (3H, d, J = 5Hz,

), 3.52 (2H, bs, C ₂ -H), 3.76 (2H, q, J = 7 Hz,> NCH ₂ CH ₃ ), 3.88 (3H, s, -OCH ₃ ), 4.38, 5.04 (2H, ABq, J = 15 Hz,

), 5.21 (1H, d, J = 5 Hz, C ₆ -H), 5.87 (1H, dd, J = 5 Hz, C ₇ -H), 6.61 (2H, bs,

), 6.78 (1 H, s,

), 7.04 (1H, q, J = 5 Hz,

), 7.22 (2H, bs, -NH ₂ ), 9.67 (1H, d, J = 8 Hz, -CONH),

In a similar manner, the compounds shown in Table 32 are obtained.

Table 32

Note: * 1 Diastereomer

Hydrogen chloride (salts are prepared in a convenient way)

* 3 The target compound is prepared by reacting a halogen compound with trifluoro acetic acid salt when 1,8-diazabicyclo [5,4,0] -7-undecene is present at -5 to 0 ° C.

(4) 7- [2- (2-formamidothiazol-4-yl) -2- (new) -methoxyimino acetamido obtained in (1) in 10 ml of methanol] -3-{[ 0.38 ml of concentrated hydrochloric acid was added to a solution of 1.05 g of 1- (2,3-dimethyl-6-oxo-1,6-dihydropyrazinyl)] methyl} -Δ ³ -cepem-4-carboxylic acid, and the resulting mixture was The reaction is carried out at 35 ° C. for 2 hours. After the reaction is completed, the solvent is distilled off under reduced pressure. 10 ml of diethyl ether was added to the residue, and the crystals were collected by filtration. 7- [2- (2-aminothiazol-4-yl) -2- (new) -methoxyimino-acetami having a melting point of 250 ° C. or higher. 0.43 g of a hydrochloride of [ ³ -([1- (2,3-dimethyl-6-oxo-1,6-dihydropyrazinyl)] methyl} -Δ ³ -cepem-4-carboxylic acid (yield: 84.8%) ) Is obtained.

IR (KBr) cm ^-1 : ν _{c = 0} 1765, 1660, 1620

), 5.10(1H, d, J=5Hz, C₆-H), 5.78(1H, dd, J=5Hz, J=8Hz, C₇-H), 6.89(1H, s,

), 7.82(1H, s,

), 9.79(1H, dd, J=8Hz, -CONH-)NMR (d ₆ -DMSO) δ values: 2.20 (6H, bs, -CH ₃ x 2), 3.18 (2H, bs, C ₂ -H), 3.90 (3H, s, -OCH ₃ ), 4.94, 5.24 ( 2H, ABq, J = 15 Hz,

), 5.10 (1H, d, J = 5 Hz, C ₆ -H), 5.78 (1H, dd, J = 5 Hz, J = 8 Hz, C ₇ -H), 6.89 (1H, s,

), 7.82 (1H, s,

), 9.79 (1H, dd, J = 8 Hz, -CONH-)

Example 12

(1) In a similar manner to Example 7- (1), the compounds shown in Table 33 are obtained from the starting materials shown below.

Table 33

(2) The compound of Table 34 is obtained by reacting the compound in a manner similar to that of Example 7- (2).

Table 34

Example 13

(1) To a solution of 2.72 g of 2- (2-tertyl amyloxycarboxamidothiazol-4-yl) acetic acid in 40 ml of anhydrous methylene chloride, 2.72 g of N-methyl morpholine was added and the mixture was brought to -35 ° C. Cool. Subsequently, 1.12 g of ethyl chlorocarbonate were added, and the mixture was reacted at -35 to -25 ° C for 1.5 hours, followed by diphenylmethyl 7-amino-3-{[1- (4-ethyl-2,3-dioxo- 1,2,3,4-tetrahydro-pyrazinyl)] methyl} -Δ ³ -cepem-4-carboxylate was added, and the mixture was added at −30 to −20 ° C. for 1 hour, followed by −10 to 10. The reaction is carried out at 1 ° C. for 1 hour. After the reaction is completed, the solvent is distilled off under reduced pressure. The residue is dissolved in 40 ml of ethyl acetate and 30 ml of water. The organic layer is separated and 30 ml of water is added again. While cooling with ice, sodium hydrogen carbonate is used to adjust the pH of the mixture to 7.0. The organic layer is separated, washed sequentially with 30 ml of water and 30 ml of saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. Distillation under reduced pressure removes the solvent. 35 ml of diethyl ether was added to the residue, and the crystals were collected by filtration. Diphenylmethyl 7- [2- (tertiary amyloxycarboxamidothiazole-4-) having a melting point of 152 to 154 占 폚 (as opposed to) was obtained. Yl) acetamido] -3-{[1- (4-ethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)] methyl} -Δ ³ -cepem-4-carboxyl A yield of 3.62 g (yield: 90.5%) is obtained.

IR (KBr) cm ^-1 : ν _{c = 0} 1780, 1720, 1685, 1640

In a similar manner, the following compounds are obtained: diphenylmethyl 7- [2- (2-tert-amyloxycarboxamidothiazol-4-yl) acetamido having a melting point of 136 to 139 ° C. (decomposition)] 6.15 g of 3--3-[[1- (3,6-dioxo-1,2,3,6-tetrahydro-pyridazinyl)] methyl} -Δ ³ -cepem-4-carboxylate (yield: 82.7% ).

(3) The compound shown in Table 35 is obtained by reacting the compound obtained in (1) in the same manner as in Example 6- (3).

Table 35

Example 14

Diphenylmethyl 7- (4-bromo-3-oxobutyramido) -3-{[1- (4-ethyl-2,3-dioxo-1,2 in 48 ml of N, N-dimethylacetamide 6.82 g of 3,4-tetrahydro-pyrazinyl)] methyl} -Δ ³ -cepem-4-carboxylate and 1 g of thiourea are dissolved and the mixture is allowed to react at room temperature for 2 hours. After the reaction was completed, the reaction mixture was added to a mixed solvent of 500 ml of water and 500 ml of ethyl acetate, and the pH of the mixture was adjusted to 6.7 using sodium hydrogen carbonate. The organic layer is separated, dried over anhydrous magnesium sulfate, and then distilled off under reduced pressure to remove the solvent. The residue is then dissolved in 33 ml of trifluoroacetic acid and 8 ml of anisole and the mixture is allowed to react at room temperature for 1 hour. After the reaction is completed, the solvent is distilled off under reduced pressure. 40 ml of diethyl ether was added to the residue, and the crystals were collected by filtration. 7- [2- (2-aminothiazol-4-yl) acetamido] -3-{[1- 4.50 g of trifluoroacetic acid salt of (4-ethyl-2,3, -dioxo-1,2,3,4-tetrahydropyrazinyl)] methyl} -Δ ³ -cepem-4-carboxylic acid (yield: 74.1 %) Is obtained.

In a similar manner, the following compounds are obtained: 7- [2- (2-aminothiazol-4-yl) acetamido] -3-{[1- (3,6-dioxo-) having a melting point of at least 200 ° C. 1,2,3,6-tetrahydropyridazinyl)] methyl} -Δ ³ -cepem-4-carboxylic acid trifluoroacetic acid salt.

The physical properties (IR, NMR values) of this compound were the same as those in Example 13- (2).

Preparation Example 1

7- [2- (2-aminothiazol-4-yl) -2- (cin) -methoxyiminoacetamido] -3-{[1- (2,3-dioxo-1,2, Aqueous solution of sodium salt of 3,4-tetrahydropyrazinyl)] methyl} -Δ ³ -cepem-4-carboxylic acid is treated in a conventional manner to give lyophilized and sterile sodium salt. 1 g (effect) of sodium salt is dissolved in 20 ml of physiological saline to prepare an injection.

Preparation Example 2

1 g of the lyophilized product obtained in Formulation Example 1 (potency) was dissolved in 4 ml of 0.5% (W / V) lidocaine hydrochloride solution to prepare a dilutable injection.

Preparation Example 3

1 g (potency) of the lyophilized product obtained in Formulation Example 1 was dissolved in 20 ml of a 5% glucose solution to prepare an injection.

Other compounds of formula (I) may also be prepared in the same manner as in Preparation Examples 1 to 3 to prepare the corresponding lyophilized products (sodium salts) or injections.

Claims (23)

A method for preparing cephalosporin or salts thereof, characterized by reacting a compound of formula (II) or a salt thereof with a reactive derivative in a compound of formula (III) or a carboxyl group thereof .

Wherein R ¹ is a hydrogen atom, C _1-5 alkyl, diphenylmethyl, C _1-5 acyloxy-C _1-5 alkyl, phthalidyl or 5-C _1-5 alkyl-2-oxo-1,3 -Dioxol-4-yl-methyl group or general formula

Wherein R ⁵ and R ⁷ are C _1-5 alkyl groups; R ² is a general formula,

or

Wherein R ⁶ is hydrogen or C _1-14 alkyl, C _3-7 cycloalkyl, phthalidyl, which may be substituted by phenyl, C _1-5 acyloxy, carboxyl or diphenylmethoxycarbonyl group C _1-5 alkyl-2-oxo-1,3-dioxol-4-yl-methyl or C _1-5 acyloxy-C _1-5 alkyl group or di C _1-5 alkylamino group; A group of ^{R 7, R 8, R 9} , R 10, R 11, R 12, R 13, R 14 and R ¹⁵ are the same or may be different, each a hydrogen atom, a halogen atom or a C ₁ -5 alkyl group) ego ; R ³ is a hydrogen atom; R ⁴ is hydrogen or halogen; R ⁵ is an amino, formylamino, triphenylmethylamino or tert-amyloxycarbonylamino group; A is a group or general formula of the formula -CH _2-

Wherein R ¹⁸ is a hydrogen atom or a C _1-5 alkyl group which may be substituted with a carboxyl, C _1-5 alkoxycarbonyl, phenoxycarbonyl or indanyloxycarbonyl group;

A bond is a group of syn isomers or anti isomers or mixtures thereof); R ²⁸ is an amino group; R ^5a is an amino group which may optionally be protected. The compound of claim 1, wherein A is a general formula

R ¹⁸ and

The binding is as defined in claim 1. The process of claim 2 wherein the reaction is carried out at a temperature of -50 to 40 ° C. A process for preparing cephalosporin or salts thereof, characterized by reacting a compound of formula (IV) or a salt thereof with a compound of formula (V).

Wherein R ¹ is a hydrogen atom, C _1-5 alkyl, diphenylmethyl, C _1-5 acyloxy-C _1-5 alkyl, phthalidyl or 5-C _1-5 alkyl-2-oxo-1,3 -Dioxol-4-yl-methyl group or general formula

Wherein R ⁶ and R ⁷ are C _1-5 alkyl groups; R ² is a general formula

or

Wherein R ⁶ is hydrogen or C _1-14 alkyl, C _3-7 cycloalkyl, phthalidyl, which may be substituted by phenyl, C _1-5 acyloxy, carboxyl or diphenylmethoxycarbonyl group C _1-5 alkyl-2-oxo-1,3-dioxol-4-yl-methyl or C _1-5 acyloxy-C _1-5 alkyl group or di-C _1-5 alkylamino group; R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ and R ¹⁵ may be the same or different and each is a hydrogen atom, a halogen atom or a C _1-5 alkyl group) ego ; R ³ is a hydrogen atom; R ⁵ is an amino, formylamino, triphenylmethylamino or tert-amyloxycarbonylamino group; A is a group or general formula of the formula -CH _2-

Wherein R ¹⁸ is a hydrogen atom or a C _1-5 alkyl group which may be substituted with a carboxyl, phenoxycarbonyl or indanyloxycarbonyl group,

A bond is a group of compounds, which may be syn isomers or anti isomers or mixtures thereof; X is a halogen atom; R ^5a is an amino group which may optionally be protected. A compound according to claim 4 wherein A is a general formula

R ¹⁸ and

The method as defined in claim 23. (Correction) The process according to claim 5, wherein the reaction is carried out at a temperature of from 0 to 100 ° C. (Correction) A method for producing cephalosporin or a salt thereof, characterized by reacting a compound of the general formula (VI) or a salt thereof with a compound of the general formula (IV) or a salt thereof.

Wherein R ¹ is a hydrogen atom, C _1-5 alkyl, diphenylmethyl, C _1-5 acyloxy-C _1-5 alkyl, phthalidyl or 5-C _1-5 alkyl-2-oxo-1,3 -Dioxol-4-yl-methyl group or general formula

(Wherein R ⁵ and R ⁷ are C _1-5 alkyl groups), R ² is a general formula

or

Wherein R ⁶ is hydrogen or C _1-14 alkyl, C _3-7 cycloalkyl, phthalidyl, which may be substituted by phenyl, C _1-5 acyloxy, carboxyl or diphenylmethoxycarbonyl group C _1-5 alkyl-2-oxo-1,3-dioxol-4-yl-methyl or C _1-5 acyloxy-C _1-5 alkyl group or di-C _1-5 alkylamino group; R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ and R ¹⁵ may be the same or different and each is a hydrogen atom, a halogen atom or a C _1-5 alkyl group) ego ; R ³ is a hydrogen atom; R ⁴ is hydrogen or halogen; R ⁵ is an amino, formylamino, triphenylmethylamino or tert-amyloxycarbonylamino group; R ¹⁸ is a hydrogen atom or a C _1-5 alkyl group which may be substituted with a carboxyl, phenoxycarbonyl or indanyloxycarbonyl group;

Binding indicates that the compound may be a syn isomer or an anti isomer or a mixture thereof; R ^5a is an amino group which may optionally be protected. The process of claim 7 wherein the reaction is carried out at a temperature of from 0 to 100 ° C. 9. 8. The method of any one of claims 1, 4 and 7, further comprising removing the protecting group or adding protecting the carboxyl group. The cephalosporin of any one of claims 1, 4 and 7 or a salt thereof is 7- [2- (2-aminothiazol-4-yl) -2- (new). ) -Methoxyiminoacetamido] -3-{[1- (2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)] methyl} -Δ ³ -cepem-4-carboxylic acid , Esters thereof or salts thereof. The cephalosporin of any one of claims 1, 4 and 7 or a salt thereof is 7- [2- (2-aminothiazol-4-yl) -2- (new). ) -Carboxymethoxyiminoacetamido] -3-{[1- (2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)] methyl} -Δ ³ -cepem-4- Carboxylic acid, ester thereof or salt thereof. The cephalosporin of any one of claims 1, 4 and 7 or a salt thereof is 7- [2- (2-aminothiazol-4-yl) -2- (new). ) -Methoxyiminoacetamido] -3-{[1- (4-methyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)] methyl} -Δ ³ -cepem -4-carboxylic acid, ester thereof or salt thereof. The cephalosporin of any one of claims 1, 4 and 7 or a salt thereof is 7- [2- (2-aminothiazol-4-yl) -2- (new). ) -Carboxymethoxyiminoacetamido] -3-{[1-4-methyl- (2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)] methyl} -Δ ^3- Cefem-4-carboxylic acid, ester thereof or salt thereof. The cephalosporin of any one of claims 1, 4 and 7 or a salt thereof is 7- [2- (2-aminothiazol-4-yl) -2- (new). ) -Methoxyiminoacetamido] -3-{[1- (4-ethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)] methyl} -Δ ³ -cepem -4-carboxylic acid, ester thereof or salt thereof. The cephalosporin of any one of claims 1, 4 and 7 or a salt thereof is 7- [2- (2-aminothiazol-4-yl) -2- (new). ) -Carboxymethoxyiminoacetamido] -3-{[1- (4-ethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)] methyl} -Δ ³ − Cefem-4-carboxylic acid, ester thereof or salt thereof. The cephalosporin of any one of claims 1, 4 and 7 or a salt thereof is 7- [2- (2-aminothiazol-4-yl) -2- (new). ) -Methoxyiminoacetamido] -3-{[1- (4-isopropyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)] methyl} -Δ ³ − Cefem-4-carboxylic acid, ester thereof or salt thereof. The cephalosporin of any one of claims 1, 4 and 7 or a salt thereof is 7- [2- (2-aminothiazol-4-yl) -2- (new). ) -Methoxyiminoacetamido] -3-{[1- (4-dimethylamino-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)] methyl} -Δ ³ − Cefem-4-carboxylic acid, ester thereof or salt thereof. The cephalosporin of any one of claims 1, 4 and 7 or a salt thereof is 7- [2- (2-aminothiazol-4-yl) -2- (new). ) -Methoxyiminoacetamido] -3-{[1- (4-dimethylamino-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)] methyl} -Δ ³ − Cefem-4-carboxylic acid, ester thereof or salt thereof. The cephalosporin of any one of claims 1, 4 and 7 or a salt thereof is 7- [2- (2-aminothiazol-4-yl) -2- (new). ) -Methoxyiminoacetamido] -3-{[1- (2-oxo-1,2-dihydropyrazinyl)] methyl} -Δ ³ -cepem-4-carboxylic acid, ester thereof or salt thereof . The cephalosporin of any one of claims 1, 4 and 7 or a salt thereof is 7- [2- (2-aminothiazol-4-yl) -2- (new). ) -Methoxyiminoacetamido] -3-{[1- (3,6-dioxo-1,2,3,6-tetrahydropyrazinyl)] methyl} -Δ ³ -cepem-4-carboxylic acid , Esters thereof or salts thereof. The cephalosporin of any one of claims 1, 4 and 7 or a salt thereof is 7- [2- (2-aminothiazol-4-yl) -2- (new). ) -Carboxymethoxyaminoacetamido] -3-{[1- (3,6-dioxo-1,2,3,6-tetrahydropyridazinyl)] methyl} -Δ ³ -cepem-4- Carboxylic acid, ester thereof or salt thereof. The cephalosporin of any one of claims 1, 4 and 7 or a salt thereof is 7- [2- (2-aminothiazol-4-yl) -2- (new). ) -Methoxyiminoacetamido] -3-{[1- (3-methyl-6-oxo-1,6-dihydropyridazinyl)] methyl} -Δ ³ -cef-4-carboxylic acid, Ester or a salt thereof. The cephalosporin of any one of claims 1, 4 and 7 or a salt thereof is 7- [2- (2-aminothiazol-4-yl) -2- (new). ) -Carboxymethoxyiminoacetamido] -3-{[1- (3-methyl-6-oxo-1,6-dihydropyridazinyl)] methyl} -Δ ³ -cefe-4-carboxylic acid, Its ester or salt thereof.