JPS6052755B2 - New cephalosporins - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel cephalosporins, specifically compounds of the general formula [wherein R1 is a hydrogen atom or a carboxyl protecting group, and R2 is an aromatic hydrocarbon with or without a substituent] R3 is a hydrogen atom or an alkoxy group;
4 is a hydrogen atom or a halogen atom, R5 is a hydrogen atom or an optionally protected or substituted amino group, A
is the formula -CH. - or a group of the formula R (wherein R° represents a hydrogen atom or an alkyl group, and ~ may be a syn or anti isomer, or a mixture thereof), and z is]S or]S-0 The dotted line in the Cefem ring is 2 to 3.
It means that there is a double bond between positions or between positions 3 and 4.

] and its salts.

Therefore, the object of the present invention is to provide a drug that has a broad antibacterial spectrum, exhibits excellent antibacterial activity against Gram-positive bacteria and Gram-negative bacteria, and is stable against β-lactamases produced by bacteria. Moreover, it has excellent properties such as low toxicity and good absorption when administered orally or parenterally.
The object of the present invention is to provide cephalosporins or their intermediates that exhibit excellent therapeutic effects against epidemics in humans and animals.

The cephalosporin compound represented by the general formula [1] of the present invention is an aromatic hydrocarbon group with or without a substituent at the 3-position exomethylene group of the cefem ring, an acylamino group, an aromatic heterocyclic ring having a carbon-to-carbon bond. A triazolyl or tetrazolyl group having a formula group or a carbon-nitrogen bond is bonded to the amino group at the 7th position [in the formula, A, R4
and R5 have the meanings given above.

] are combined.

Hereinafter, the present invention will be explained in further detail.

R1 in each general formula herein is a hydrogen atom or a carboxyl protecting group, and examples of the carboxyl protecting group include those conventionally used in the field of penicillin and cephalosporin compounds.

These carboxyl-protecting groups include ester-forming groups that have the property of being eliminated by treatment under catalytic reduction, chemical reduction, or other mild conditions, or ester-forming groups that are easily eliminated in vivo; Various other known ester-forming groups may be mentioned, such as an organic silyl group, an organic phosphorus group, or an organic tin group, which have the property of being easily eliminated by treatment with water or alcohol. Among these types of protecting groups, preferable protecting groups include the following.

(a) Alkyl group; especially methyl, ethyl, n-propyl, IsO. -Propyl, n-butyl, Sec. -butyl, IsO. -butyl, Tert. - straight-chain or branched C1-14 alkyl groups such as butyl and pentyl.

(mouth) At least one of the substituents is chloro, bromo, fluoro, nitro, carbalkoxy, acyl, alkoxy, oxo, cyano, alkylmercapto, alkylsulfinyl, alkylsulfonyl, alkoxycarbonyl, 1-indanyl, 2-indanyl, furyl, Pyridyl, 4-imidazolyl, phthalimide, acetidino, aziridino, hyrolidino, piperidino, morpholino, thiomorpholino, N-lower alkylpiperazino, 2,5-dimethylpyrrolidino, 1,4,5,6-tetrahydropyrimidinyl, 4- Methylpiperidino, 2,6-dimethylpiperidino, alkylamino, dialkylamino, acyloxy, acylamino, dialkylaminocarbonyl, alkoxycarbonylamino, alkoxycarbonyloxy or alkylanilino or chloro, bromo,
A substituted lower alkyl group that is an alkylanilino substituted with lower alkyl or lower alkoxy.

(c) Cycloalkyl or lower alkoxy-substituted cycloalkyl consisting of 3 to 7 carbon atoms or l[2,2-
dilower alkyl-1,3-dioxolan-4-yl]methyl group.

(d) Alkenyl groups having up to 10 carbon atoms.

(e) Alkynyl groups having up to 10 carbon atoms. (fart)
At least one phenyl group or substituent; Substituted phenyl which is a substituent arbitrarily selected from the substituents exemplified above (2), or the formula [wherein,
, -CH=CH-S-, -CH2CH2S-, -CH=
N-CH=N-, -CH=CH-CH=CH-, -CO
-CH=CH-CO- or -CO-CO-CH=C
It's H-.

] or a substituted derivative thereof (the substituents are arbitrarily selected from those exemplified above), or a group represented by the formula [wherein Y is 1(CH2)3-, -(CH2)4-] It is a lower alkylene group such as.

] or a substituted derivative thereof (the substituents are arbitrarily selected from those exemplified above).

``(卜)Aralkyl group such as benzyl or a substituted benzyl in which the substituent is at least one substituent arbitrarily selected from the substituents exemplified above.

(h) Furyl, quinolyl, methyl-substituted quinolyl, phenazinyl, 1,3-benzodioxolanyl, 3-(2-methyl-4-pyrrolinyl), 3-(4-pyrrolinyl) or N-(methylpiperidinyl) A substituted heterocyclic group, wherein the heterocyclic group or substituent is at least one substituent arbitrarily selected from the substituents exemplified above.

(ri)Alicyclic indanyl or phthalidyl and their substituted derivatives in which the substituent is methyl, chloro, bromo or fluoro, alicyclic tetrahydronaphthyl and its substituted derivatives in which the substituent is methyl, chloro, bromo or fluoro, trityl, cholesteryl , Bicyclo [4,
4,0,] decyl et al.

The carboxyl protecting groups exemplified above are representative examples, and protecting groups described in the following documents can be arbitrarily selected.

U.S. Patents 3,499,909, 3,573,296 and 3
No. 641018: West German Patent Publication No. 2301014,
Nos. 2253287 and 2337105.

Particularly preferred carboxyl protecting groups include acyloxymethyl groups and carboxyl protecting groups that are easily eliminated in vivo, such as those represented by the following formula.

[In the formula, R7 is a straight chain or branched alkyl, alkenyl, aryl, aralkyl, alicyclic or heterocyclic group with or without a known substituent, R8 is a hydrogen atom or an alkyl group, R9 is a hydrogen atom, a halogen atom, an alkyl, cycloalkyl, aryl, or heterocyclic group with or without a known substituent, or one (CH2)R1COOR7 (wherein R7 has the above meaning, n is 0, 1 or 2), m means 0, 1 or 2.

[R2 is an aromatic hydrocarbon group with or without a substituent, an acylamino group, an aromatic heterocyclic group having a carbon-to-carbon bond with the 3-position exomethylene group, or a carbon-to-nitrogen bond with the 3-position exomethylene group The aromatic hydrocarbon group includes, for example, phenyl, indanyl, or naphthyl.

Further, the acylamino group is represented by R10C0NH-, and R1O is, for example, methyl, ethyl, n-propyl, IsO. -propyl, n-butyl, IsO. -butyl, Sec-butyl, Tert. - Straight chain and branched alkyl groups such as butyl, pentyl, hexyl, heptyl, octyl, dodecyl; alkenyl groups such as vinyl, allyl; alkadienyl groups such as 1,3-ptadienyl, 1,3-pentadienyl; cyclopropyl, cyclobutyl,
Cycloalkyl groups such as cyclopentyl, cyclohexyl, and cycloheptyl; Cycloalkenyl groups such as cyclopentenyl and cyclohexenyl; cycloalkadienyl groups such as cyclopentadienyl and cyclohexadienyl; Aryl groups such as phenyl and naphthyl; benzyl and phenethyl , 4-methylbenzyl, naphthylmethyl; aralkyl groups containing at least one heteroatom selected from oxygen, nitrogen and sulfur, such as furyl, thienyl, benzofuran, benzothiophene, coumarin, triazole, tetrazole, pyridone; Cyclic group; examples include heterocyclic alkyl groups such as thienylmethyl and furylmethyl. In addition, examples of aromatic heterocyclic groups include:
Furyl, thienyl, benzofuran, benzothiophene,
Examples include quinolyl and isoquinolyl groups. Also,
As the triazolyl or tetrazolyl group, 1,2
, 3-triazolyl, 1,2,4-triazolyl or 1,2,3,4-tetrazolyl group. Isomers exist in these triazolyl or tetrazolyl groups, and any nitrogen atom in the ring may be bonded to the 3-position exomethylene group, and either case is included in the present invention. Furthermore, the aromatic hydrocarbon group, acylamino group, aromatic heterocyclic group, and triazolyl and tetrazolyl group of R2 are, for example, a halogen atom, an alkyl group, an aralkyl group, an aryl group, an alkenyl group, a hydroxyl group, an alkoxy group, an alkylthio group, nitro group, cyano group, amino group, alkylamino group, dialkylamino group,
Acylamino group, acyl group, acyloxy group, acylalkyl group, carboxyl group, alkoxycarbonyl group,
Carbamoyl group, aminoalkyl group, N-alkylaminoalkyl group, N,N-dialkylaminoalkyl group,
hydroxyalkyl group, hydroxyiminoalkyl group,
Alkoxyalkyl group, carboxyalkyl group, alkoxycarbonylalkyl group, sulfoalkyl group, sulfo group, sulfamoylalkyl group, sulfamoyl group, carbamoylalkyl group, carbamoylalkenyl group, N
-It may be substituted with one or more substituents such as a hydroxycarbamoyl alkyl group.

Among these substituents, hydroxyl groups, amino groups, carboxyl groups, etc. may be protected with suitable protecting groups commonly used in the field. Here, the hydroxyl group-protecting group includes all groups that can be normally used as hydroxyl group-protecting groups, such as benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 4-methoxybenzyl oxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 4-(phenylazo)benzyloxycarbonyl, 4-(4-methoxyphenylazo)benzyloxycarbonyl, Tel. -butoxycarbonyl, 1,1-dimethylpropoxycarbonyl, isopropoxycarbonyl, diphenylmethoxycarbonyl, 2
,2,2-trichloroethoxycarbonyl,2,2,2
-tribromoethoxycarbonyl, 2-furfuryloxycarbonyl, 1-adamantyloxycarbonyl, 1
Examples include acyl groups that are easily eliminated such as -cyclopropylethoxycarbonyl, 3-quinolyloxycarbonyl, or trifluoroacetyl, and benzyl, trityl, methoxymethyl, 2-nitrophenylthio, and 2,4-dinitrophenylthio groups. In addition, the protecting group for an amino group includes all groups that can be normally used as an amino protecting group, such as trichloroethoxycarbonyl, tribromoethoxycarbonyl, benzyloxycarbonyl, p-toluenesulfonyl, p-nitrobenzyloxycarbonyl. , o-bromobenzyloxycarbonyl, o
-Nitrophenylsulfenyl, (mono, di, tri)chloroacetyl, trifluoroacetyl, formyl, Tert. -amyloxycarbonyl, Tert. −
Butoxycarbonyl, p-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 4-(phenylazo)benzyloxycarbonyl, 4
1-(4-methoxyphenylazo)benzyloxycarbonyl, pyridin-1-oxide-2-ylmethoxycarbonyl, 2-furyloxycarbonyl, diphenylmethoxycarbonyl, 1,1-dimethylpropoxycarbonyl, isopropoxycarbonyl, 1-cyclopropylethoxycarbonyl , putalol, succinyl, 1-
Examples include acyl groups that are easily eliminated such as adamantyloxycarbonyl and 8-quinolyloxycarbonyl;
Trityl, 2-nitrophenylthio, 2,4-dinitrophenylthio, 2-hydroxybenzylidene, 2-hydroxy-5-chlorobenzylidene, 2-hydroxy-1
-naphthylmethylene, 3-hydroxy-4-pyridylmethylene, 1-methoxycarbonyl-2-propyldene,
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-ethoxycarbonylcyclopentylidene, 2-acetylcyclohexylidene,
Examples include groups that are easily eliminated such as 3,3-dimethyl-5-oxocyclohexylidene, and protecting groups for amino groups such as di- or tri-alkylsilyl. Change
12, the carboxyl group-protecting group includes all groups that can be used as ordinary carboxyl group-protecting groups, such as methyl, ethyl, n-propyl, IsO. −
Propyl, Tert. -butyl, n-butyl, benzyl, diphenylmethyl, trityl, p-nitrobenzyl,
p-methoxybenzyl, benzoylmethyl, acetylmethyl, p-nitrobenzoylmethyl, p-bromobenzoylmethyl, p-methanesulfonylbenzoylmethyl,
Phthalii midomethyl, trichloroethyl, 1,1-dimethyl-2-propenyl, 1,1-dimethylpropyl,
Acetoxymethyl, propionyloxymethyl, pivaloyloxymethyl, 1,1-dimethyl-2-propenyl, 3-methyl-3-butynyl, -succinimidomethyl, 1-cyclopropylethyl, methylsulfenylmethyl, phenylthiomethyl, When protected with groups such as dimethylaminomethyl, quinoline-1-oxide-2-methyl, pyridin-1-oxide-2-yl-methyl, bis(p-methoxyphenyl)methyl, or with non-metallic compounds such as titanium tetrachloride. In the case of protection, examples include cases where the compound is further protected with a silyl compound such as dimethylchlorosilane as described in JP-A-46-7073 and Dutch Publication No. 710525@.

In the formula, R5 means a hydrogen atom or an optionally protected or substituted amino group, and examples of the protecting group for the amino group include groups commonly used in the fields of penicillin and cephalosporin, and specifically, Examples include the amino group-protecting group explained in the section of R2.

Further, examples of substituents for the amino group that may be substituted include methyl, ethyl, n-propyl, IsO. −
Propyl, n-butyl, ISO. -Butyl, Sec. −
Butyl, Tel. - straight-chain and branched alkyl groups such as butyl, pentyl, hexyl, heptyl, octyl, dodecyl; alkenyl groups such as allyl; cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclobutyl; phenyl, naphthyl, etc. Aryl groups; aralkyl groups such as benzyl, phenethyl, 4-methylbenzyl, naphthylmethyl; at least one group selected from oxygen, nitrogen and sulfur such as furyl, thienyl, benzofuran, benzothiophene, coumarin, triazole, tetrazole, pyritone, etc. Examples include a heterocyclic group containing one hetero atom, a heterocyclic alkyl group such as thienylmethyl and furylmethyl, and the amino group may be substituted with one or more of these substituents.

These protecting groups and substituents further include, for example, a halogen atom, an alkyl group, a nitro group, a hydroxyl group, an alkoxy group, an oxo group, a thioxo group, an alkylthio group, an acylamino group, an acyl group, an acyloxy group, an aryloxy group, carboxyl group, carbamoyl group, hydroxyalkyl group, alkoxyalkyl group, carboxyalkyl group, alkoxycarbonyl group, amino group, alkylamino group, aminoalkyl group, N-alkylaminoalkyl group, sulfoalkyl group, sulfo group, sulfamoyl group,
It may be substituted with one or more substituents such as a carbamoyl alkyl group, an aryl or furyl group, a heterocyclic group such as a thienyl group, and the like. Here, the hydroxyl group, amino group and carboxyl group as substituents may be further protected with a commonly used suitable protecting group. For example, each protecting group may be a hydroxyl, amino or carboxyl group protecting group as explained in R2. are mentioned. Further, A represents -CH2- or R, and R6 means a hydrogen atom or an alkyl group, and examples of the alkyl group include methyl, ethyl, propyl, and butyl groups.

The oxime in which A is represented by N 2 includes both syn and anti isomers and mixtures thereof.

In the R5- group of general formula [1], if R5 is an optionally protected or substituted amino group, tautomers exist as shown in the following balanced formula,
In the present invention, salts of the compound represented by the tautomer general formula [1] include salts at the amino group or carboxyl group commonly known in the field of penicillin and cephalosporin. Salts at the amino group include, for example, salts with mineral acids such as hydrochloric acid or sulfuric acid; salts with organic carboxylic acids such as oxalic acid, formic acid, trichloroacetic acid or trifluoroacetic acid; methanesulfonic acid, p-toluenesulfonic acid or Salts with sulfonic acids such as naphthalene sulfonic acid, and salts at carboxyl groups include, for example, salts with alkali metals such as sodium or potassium; salts with alkaline earth metals such as calcium or magnesium; ammonium salts: procaine; , dibenzylamine, N-benzyl-β-phenethylamine, 1
-Salts with nitrogen-containing organic bases such as ephenamine, N,N-dibenzylethylenediamine, or triethylamine, trimethylamine, tributylamine, pyridine, dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, synchlohexylamine, etc. Examples include salts with nitrogen-containing organic bases. Also,
The present invention covers all optical isomers and racemates, as well as all crystal forms, L and hydrates of cephalosporin represented by general formula [1] and its salts. Among the compounds of the present invention, preferred examples include:
For example, A is a Δ3-cephem compound, or its oxime form, or its syn isomer, or even R2
Compounds having or not having a substituent that forms a carbon-nitrogen bond with exomethylene at the 3-position or having a triazolyl or tetrazolyl group are mentioned.

Next, the pharmacological effects of representative compounds of the present invention will be shown.

1 Antibacterial action Japanese Society of Chemotherapy Standard Methods [(C8) MOTHERAPY] Volume 2 pages 1-2 (19
7 Master)], HeadInfusiOnbrO mountain (
3rC. ．． The bacterial solution cultured for an extended period of time was inoculated into HeartImluSlOnagar medium (manufactured by Eiken Kagaku Co., Ltd.) containing the drug, and after culturing between 3rC12c@, the presence or absence of bacterial growth was observed, and the minimum concentration at which bacterial growth was inhibited was determined. It was set as MIC (Py/ml).

However, the amount of inoculated bacteria is 101 bacteria/plate (1Cf' bacteria/ml
). Test compound CA) 7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamide]-3-[1-(3-acetamide 1,
2,4-triazolyl)methyl]-Δ3-cefemu 4
- Trifluoroacetate of carboxylic acid (B) 7-[2-(
Trifluoroacetate of 2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamide]-3-(furan-2-carboxamide)methyl-Δ3-cefemu-4-carboxylic acid (C)7-[2- (2-Aminothiazol-4-,yl)-2-(syn)-methoxyiminoacetamide]-3-acetamidomethyl-Δ3-cefemu-4-carboxylic acid trifluoroacetate ([17
-[2-(2-aminothiazol-4-2yl)-2-
(syn)-methoxyiminoacetamide]-3-(4-
Trifluoroacetate (E) of hydroxybenzyl)-Δ3-cefemu-4-carboxylic acid (E)7-[2-(2-aminothiazol-4-5yl)-2-(syn)-hydroxyiminoacetamide]-3-[ 2-(5-methyl-1,
2,3,4-tetrazolyl)methyl]-Δ3-cefemu-4-carboxylic acid trifluoroacetate
? (F)7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamide]-3-[2-(5-acetamide 1,2
,3,4-tetrazolyl)methyl]-Δ3-cefemu-4-carboxylic acid trifluoroacetate (G)7-[2-
(2-aminothiazol-4-yl)-2-(syn)-
Methoxyiminoacetamide]-3-[2-(5-methyl-1,2,3,4-tetrazolyl)methyl]-Δ3-
Trifluoroacetate of cefemu 4-carboxylic acid 01)
7-[2-(2-aminothiazol-4-yl)-2-
(syn)-methoxyiminoacetamide]-3-[2-
(5-Ethyl-1,2,3,4-tetrazolyl)methyl]-Δ3-cefemu-4-carboxylic acid trifluoroacetate σ)7-[2-(2-aminothiazol-4-yl)-2-(syn )-methoxyiminoacetamide]-3
-[1-(5-chloro1,2,4-triazolyl)methyl]-Δ3-cefemu-4-carboxylic acid trifluoroacetate 0)7-[2-(2-aminothiazole-4-
trifluoroacetate (K) 7
-[2-(2-aminothiazol-4-yl)acetamide]-3-[2-(1,2,3,4-tetrazolyl)
Trifluoroacetate of methyl]-Δ3-cefemu-4-carboxylic acid 2 urinary recovery rate of the test compound per mouse (ICR, ↑, 4 weeks old)
m9 was orally administered and the urinary recovery rate was increased.

The results are shown in Table-2. 2 In addition, the ethyl group of all test compounds is easily eliminated in the body after absorption and becomes the corresponding free carboxylic acid, so the free carboxylic acid excreted in the urine is quantified and recovered in the urine. percentage. Administration method The test compound was suspended in 0.5% CMC and then orally administered.

Quantification method Quantification was carried out using the vapor disk method using the test bacteria listed in Table 1-a.

3 Acute Toxicity The results of acute toxicity of the three test compounds when administered intravenously to mice (ICR, ages 3 and 4) were as follows.

The manufacturing method will be explained below.

The compound of this invention can be produced, for example, according to the method shown below.

[In the above formula, R1, R2, R3, R4, R5,
R6, A and \Z and the dotted line in the Cefem ring
/ has the above meaning, R6 is an alkyl group,
\R1l is an amino group or the formula /O-
! -NH- (formula NlS, R14, R1
5 and R16 are the same or different and represent a hydrogen atom or an organic residue that does not participate in the reaction.

)5 or the formula ≧O-N- (wherein R17 and R1
8 is the same or different and is a hydrogen atom or a hydrogen atom that does not participate in the reaction.
Indicates an organic residue. ), R12 means an acyloxy group or carbamoyloxy group with or without a substituent, and R13 means a halogen atom. ] (a) First, an aromatic hydrocarbon with or without a substituent, a substituent is added to a cephalosporanic acid represented by the general formula [ ] or a salt thereof in an organic solvent in the presence of an acid or an acid complex. by reacting nitrile compounds with or without substituents, aromatic heterocyclic compounds with or without substituents, or triazoles or tetrazoles in which the carbon atoms in the ring may be substituted, and optionally Then, by removing the protecting group or converting the carboxyl group into protected I or a salt, 7-monosubstituted or unsubstituted amino-3-monosubstituted methyl cefemcarboxylic acids represented by the general formula [] or their salts are produced. Can be done.

Furthermore, if desired, the substituent at the 7-position amino group can be removed by a conventional method to obtain a 7-mono-unsubstituted amino compound.

According to this production method, if a compound represented by the general formula [] or a salt thereof is reacted with an aromatic hydrocarbon with or without a substituent, R2 is the corresponding aromatic hydrocarbon group [] Compounds of the formula and salts thereof, in which R2 is the corresponding acylamino group, can also be reacted with a nitrile compound with or without a substituent. If an aromatic heterocyclic compound having or not having is reacted, R2 is the corresponding aromatic heterocyclic group []
When the compound of the formula and its salt is reacted with a triazole or tetrazole in which the carbon atoms in the ring may be substituted, R2 is a triazolyl or tetrazolyl group which may have a substituent. The compound of the formula [] and its salts can be obtained in good yield and with high purity through easy industrial operations.

Furthermore, according to this method, Δ3-cephem compounds can also be converted to Δ2-
Cefem compounds can also give favorable results, and also ? Not only the compound that is potash, but also the compound? Compounds in which →O can also be used as starting materials, in which case during the reaction or in the work-up step? It is also possible to set =o to ).

To explain in detail below, R6a includes an alkyl group such as methyl, ethyl, propyl, or butyl group;
1l equation 1. ? The group represented by C-S-NH- also includes its isomer, a group represented by the formula: CH-S-N-.

And R14, R15, R16, R17 and R18
Organic residues that do not participate in the reaction include organic residues known in the art, specifically aliphatic residues, alicyclic residues, and aromatic residues with or without substituents. , aromatic aliphatic residues, heterocyclic residues, acyl groups, etc., and specific examples include the following = groups. (1) Aliphatic residues: e.g. methyl, ethyl, propyl, butyl,
Alkyl groups such as isobutyl and pentyl; alkenyl groups such as vinyl, propenyl and butenyl.

(2) Alicyclic residue: For example, cycloalkyl group such as cyclopentyl, cyclohexyl, cycloheptyl; cycloalkenyl group such as cyclopentenyl, cyclohexenyl.

(3) Aromatic residues: for example, aryl groups such as phenyl and naphthyl. (4) Aroaliphatic residues: for example, aralkyl groups such as benzyl and phenethyl.

(5) Heterocyclic residues: For example, heteroatoms (oxygen, a heterocyclic group optionally containing nitrogen or sulfur atoms).

(6) Acyl group: An acyl group that can be derived from an organic carboxylic acid, such as an aliphatic carboxylic acid, an alicyclic carboxylic acid, an alicyclic aliphatic carboxylic acid, or an aliphatic carboxylic acid. Aromatic substituted aliphatic carboxylic acids, aromatic oxyaliphatic carboxylic acids, aromatic thioaliphatic carboxylic acids, heteroaromatics in which an aromatic residue or a heterocyclic group is bonded to an acid with or without an oxygen or sulfur atom Ring-substituted aliphatic carboxylic acids, heterocyclic oxyaliphatic carboxylic acids, heterocyclic thioaliphatic carboxylic acids, or organic carboxylic acids in which aromatic rings, aliphatic groups, or alicyclic groups are bonded via carboxylic oxygen, nitrogen, or sulfur atoms. Alternatively, organic carboxylic acids such as aromatic carboxylic acids and heterocyclic carboxylic acids may be mentioned.

Here, examples of aliphatic carboxylic acids include formic acid, acetic acid, propionic acid, butanoic acid, isobutanoic acid, pentanoic acid, methoxyacetic acid, methylthioacetic acid, acrylic acid, crotonic acid, etc., and examples of alicyclic carboxylic acids include: Examples of the alicyclic aliphatic carboxylic acids include cyclohexanoic acid, cyclopentaneacetic acid, cyclohexaneacetic acid, cyclohexanepropionic acid, and cyclohexadieneacetic acid.

Further, aromatic residues in the above-mentioned organic carboxylic acids include phenyl, naphthyl, etc., and further examples of the above-mentioned heterocyclic groups include furan, thiophene, pyrrole, pyrazole, imidazole, triazole, thiazole,
isothiazole, oxazole, isoxazole, thiadiazole, oxadiazole, thiadriazole,
Examples include residues of heterocyclic compounds containing one or more heteroatoms in the ring, such as oxatriazole, tetrazole, benzoxazole, and benzofuran.

Each group constituting these organic carboxylic acids is, for example, a halogen atom, one hydroxyl group, a protected hydroxyl group, an alkyl group, an alkoxy group, an acyl group,
It may be further substituted with a substituent such as a nitro group, an amino group, a protected amino group, a carboxyl group, or a protected carboxyl group.

2 In addition, the acyloxy and carbamoyloxy groups of R12 include, for example, alkanoyloxy groups such as acetoxy, propionyloxy or butyryloxy; alkenyloxy groups such as acryloyloxy; aroyloxy groups such as benzoyloxy or naph≧toyloxy; and carbamoyloxy These include halogen atoms, nitro groups, alkyl groups,
A type of alkoxy group, alkylthio group, acyloxy group, acylamino group, hydroxyl group, carboxyl group, trisulfamoyl group, carbamoyl group, carbalkoxycarbamoyl group, aroylcarbamoyl group, carbalkoxysulfamoyl group, aryl group, carbamoyloxy group, etc. It may be substituted with any of the above substituents.
3. Among the substituents for R12 mentioned above, the hydroxyl group, amino group, carboxyl group, etc. may be protected with a commonly used protecting group. and a protecting group for a carboxyl group and a carboxyl group. In addition, as the aromatic hydrocarbon group with or without a substituent which is a reaction reagent in this reaction, the aromatic hydrocarbon group with or without a substituent of 28R2 explained in relation to general formula [1] is used. The corresponding aromatic hydrocarbon groups are used, namely R2H (herein R2 means the aromatic hydrocarbon group with or without substituents of R2 as defined above), and also nitriles with or without substituents. As a compound, a nitrile compound corresponding to an acylamino group with or without a substituent of R2, that is, R1℃N(R1
(O has the above-mentioned meaning) is used, and the aromatic heterocyclic compound with or without a substituent similarly corresponds to the aromatic heterocyclic group with or without a substituent of R2. An aromatic heterocyclic compound, namely R2H (where R2 means an aromatic heterocyclic group with or without a substituent for R2 as described above), is used, and a carbon atom in the ring is substituted. Examples of triazoles or tetrazoles which may be substituted with R2 include triazoles or tetrazoles corresponding to triazolyl or tetrazolyl groups with or without R2 substituents, that is, R2H (where R2 has the above-mentioned R2 substituents). (meaning a triazolyl or tetrazolyl group with or without a triazolyl group) is used.

Triazoles and tetrazoles in which carbon atoms in the ring may be substituted may be subjected to the reaction in the form of basic salts or acidic salts, if necessary. , the same salt forms as the salts of the carboxyl group and amino group explained in the section of the salt of the compound represented by the general formula [1]. Also,
Examples of the salts of the compounds represented by the general formulas [] and [] include salts at the carboxyl group or amino group, and these salts are similar to those explained above for the salts of the compounds represented by the general formula [1]. The shape of

Incidentally, the salt of the compound represented by the general formula [] may be used after being isolated in advance, or may be prepared within the system. The acids or acid complexes used in this reaction include:
Examples include protonic acids, Lewis acids, or complex compounds of Lewis acids.

Examples of protonic acids include sulfuric acids, sulfonic acids, or super strong acids (super strong acids mean acids stronger than 100% sulfuric acid, and include some of the aforementioned sulfuric acids and sulfonic acids)
More specifically, sulfuric acid such as sulfuric acid, chlorosulfuric acid or fluorosulfuric acid; alkyl (mono or di-5-
) Sulfonic acids such as aryl (mono, di or tri) sulfonic acids such as sulfonic acid or p-toluenesulfonic acid; perchloric acid, magic acid (FSO3H-SbF'5)
, FSO3H-AsF5, CF3SO3H-SbF5,
Examples include super strong acids 1 such as BF3 and H2SO4-SO3. Examples of Lewis acids include boron trifluoride, etc. Complex compounds of Lewis acids include:
For example, dialkyl 1j ether complex salts of boron trifluoride with diethyl ether, di-n-propyl ether, di-n-butyl ether, etc.; amine complex salts with ethylamine, n-propylamine, n-butylamine, triethanolamine, etc.; ethyl formate. , carboxylic acid ester complex salts with ethyl acetate, etc.; fatty acid complex salts with acetic acid, propionic acid, etc.; or nitrile complex salts with acetonitrile, probionitrile, etc., and the like. Furthermore, as the organic solvent used in this reaction, all organic solvents that do not have an adverse effect on the reaction can be mentioned, such as nitromethane, 2-
Nitroalkanes such as nitroethane and nitropropane;
Organic carboxylic acids such as formic acid, acetic acid, trifluoroacetic acid, dichloroacetic acid, and propionic acid; ketones such as acetone, methyl ethyl ketone, and methyl isobutyl ketone; diethyl ether, diisopropyl ether, dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, anisole, dimethyl Ethers such as Cellsolve, esters such as ethyl formate, diethyl carbonate, methyl acetate, ethyl acetate, ethyl chloroacetate, butyl triacetate;
Examples include nitriles such as acetonitrile and butyronitrile; and sulfolanes such as sulfolane, and two or more of these solvents may be used as a mixture.

Moreover, a complex compound formed by these organic solvents and a Lewis acid may be used as a solvent. The amount of the acid or acid complex compound to be used may be at least the equivalent molar amount of the compound represented by the general formula [] or its salt, and can be increased or decreased as appropriate depending on the individual case.

In particular, use of 2 to 1 molar amount is preferred. When using an acid complex compound, it can be used by itself as a solvent, or two or more types of complex compounds may be used in combination. In addition, the amount of the aromatic hydrocarbon, nitrile compound, aromatic heterocyclic compound, or triazole or tetrazole used as a reaction reagent for this reaction should be at least 1 mol or more based on the compound represented by the general formula [] or its salt. Any value is acceptable, especially 1.0 to 5. The use of highly molar amounts is preferred.

This reaction is usually carried out at 0 to 80 °C, and the reaction time is generally several minutes to several tens of hours. If moisture is present in the reaction system, there is a risk of causing undesirable side reactions such as lactonization of the raw materials or products and cleavage of the β-lactam ring, so it is desirable to maintain the reaction system in an anhydrous state. To meet this demand, a suitable dehydrating agent is added to the reaction system, such as phosphorus compounds such as phosphorus pentoxide, polyphosphoric acid, phosphorus pentachloride, phosphorus trichloride, and phosphorus oxychloride; N,O-bis(trimethylsilyl)acetamide. , organic silylating agents such as trimethylsilylacetamide, trimethylchlorosilane, and dimethyldichlorosilane; organic acid chlorides such as acetyl chloride and p-toluenesulfonyl chloride; acid anhydrides such as acetic anhydride and trifluoroacetic anhydride; anhydrous magnesium sulfate, anhydrous chloride An inorganic desiccant such as calcium, molecular sieve, calcium carbide, etc. may be added. When a compound represented by the general formula [] in which R1 represents a carboxyl protecting group is used as a raw material, a compound of the corresponding formula [] in which R1 is a hydrogen atom may be obtained by post-reaction treatment, but if desired, It is also possible to remove the protecting group by a conventional method to obtain a compound of the formula [ ] in which R1 is a hydrogen atom.

When the substituent to be substituted on the carbon atom in the ring of the aromatic hydrocarbon, nitrile compound, aromatic heterocyclic compound, or triazole or tetrazole that is the reaction reagent for this reaction is a hydroxyl group, amino group, carboxyl group, etc.
Before carrying out this reaction, these groups are protected with the above-mentioned protecting group, and after the reaction is completed, the desired compound can be obtained by subjecting them to a conventional elimination reaction.

In addition, compounds in which R2 in the formula [] is an aromatic hydrocarbon group with or without a substituent or an aromatic heterocyclic group having a carbon-to-carbon bond with the 3-position exomethylene group of the cefem ring are as explained above. In addition to the 3-position conversion reaction, using penicillins as starting materials, opening the thiazolidine ring,
A known method in which a ring is opened by reacting with 3-R-probu-2-ynyl bromide, followed by a reaction to form a dihydrothiazine ring (i.e., cepherosporin skeleton) [JP-A-5]
0-5393; J. M. C, 20, 1082 (1977
);1 bid. , 20, 1086 (1977)].

In addition, the compound represented by the general formula [] may optionally be
The carboxyl group can be protected or converted into a salt according to a conventional method, and a corresponding compound can also be obtained.

In addition, in the case of a Δ2-cephem compound having a double bond between the 2nd and 3rd positions in the cefem ring of general formula [], it is isomerized to between the 3rd and 4th positions by a conventional method, and the corresponding Δ3 - cefem compounds. (b) Next, the compound represented by the general formula [] or a salt thereof obtained as described above is reacted with the compound represented by the general formula [] or a reactive derivative thereof. A compound represented by the general formula [1] or a salt thereof is obtained. Reactive derivatives of the compound represented by the general formula [] include acid halides, acid anhydrides, mixed acid anhydrides, active acid amides, active esters, and the combination of the compound represented by the general formula [] with the Bils-3-Mayer reagent. Examples include reactive derivatives.

Examples of the mixed acid anhydride include mixed acid anhydrides with carbonic acid monoesters such as carbonic acid monoethyl ester and carbonic acid monoisobutyl ester, and lower alkanoic acids which may be trisubstituted with halogens such as pivalic acid and trichloroacetic acid. Mixed acid anhydrides and the like are used. In addition, examples of active acid amides include N-acylsaccharin, N-acylimidazole, N-acylbenzoylamide, N,N''
-dicyclohexyl-N-a41silurea, N-acylsulfonamide, etc. are used. In addition, examples of active esters include cyanomethyl ester, substituted phenyl ester, substituted benzyl ester, and substituted thienyl ester.
32 tel etc. are used.

In addition, as a reactive derivative with Vilsmeier reagent,
Halogenation of acid amides such as dimethylformamide, N,N-dimethylacetamide, etc. with phosgene, thionyl chloride, phosphorus trichloride, phosphorus tribromide, phosphorus oxychloride, phosphorus pentachloride, trichloromethyl dichloroformate, oxalyl chloride, etc. Examples include derivatives reactive with Vilsmeier's reagent, which are obtained by reacting with Vilsmeier's reagent.

Furthermore, when the compound of formula () is used in the form of a free acid or salt, a suitable condensing agent is used.

Examples of condensing agents include N,N''-disubstituted carbodiimides such as N,N''-dicyclohexylcarbodiimide, azolade compounds such as N,N''-thionyldiimidazole, N-ethoxycarbonyl-2-ethoxyl
, 2-dihydroxynoline, phosphorus oxychloride, alkoxyacetylene, and the like, 2-halogenopyridinium salts (for example, 2-chloropyridinium methyl iodide, 2-fluoropyridinium methyl iodide), and the like are used. This acylation reaction is generally carried out in a suitable solvent in the presence or absence of a base. As the solvent, for example, halogenated hydrocarbons such as chloroform and methylene dichloride, ethers such as tetrahydrofuran and dioxane, dimethylformamide, N,N-dimethylacetamide, acetone, water, etc., or mixtures thereof are often used. The base used here includes inorganic bases such as alkali hydroxide, alkali hydrogen carbonate, alkali carbonate, or alkali acetate, or trimethylamine, triethylamine, tributylamine, pyridine, N-methylpiperidine, N-methylmorpholine, lutidine, colicin, etc. Examples include tertiary amines and secondary amines such as synchlohexylamine and diethylamine. [
The amount of the compound of formula [] to be used is usually about 1 to several moles per mole of the compound of formula [].

The reaction is generally carried out in the range of -50 to 40°C. The reaction time is usually between 1 powder and 4 particles. Furthermore, in the case of a compound of general formula [1] in which R1 is a carboxyl protecting group,
In the case of compounds of general formula [1] where R1 is a hydrogen atom or their salts; in the case of compounds of general formula [1] where R1 is a hydrogen atom, general formula [1] where R1 is a carboxyl protecting group;
1] or their salts; also general formula [1]
When the compound is a salt, it can be converted into the corresponding free compound according to a conventional method. Also,
In this acylation reaction, if a reactive group exists in R1, R2, and R5, it can be optionally protected with a conventional protecting group during the reaction, and it can be protected by a conventional method after the reaction. It is also possible to remove the protecting group.

The compound of formula [1] of the present invention and its salts obtained as described above can be isolated by a conventional method.

(c) Furthermore, the compounds represented by [1a] and [Ib] of the present invention and their salts can also be produced as follows. To obtain the compound represented by the general formula [] or its salts from the compound represented by the general formula [] or its salts, the reaction of diketene with a halogen such as chlorine or bromine [Journal●Off◆The◆Chemical● Society, 97, 1987 (1910)] by reacting 4-halogeno-3-oxobutyryl halide with a compound represented by the general formula [] or a salt thereof according to a conventional method. It will be done. The reaction conditions and operations are those well known in the art. In addition, the salts of the compound represented by the general formula [] can be easily obtained according to conventional methods, and the salts are the same as those explained above for the salts of the compound represented by the general formula [1]. Examples include: The resulting compound represented by formula [V] and its salts may be isolated and purified by conventional methods, but without separation,
It can also be used in the next reaction. (d) Next, the general formula [V
] To obtain the compound represented by the general formula [ ] or its salts from the compound represented by the general formula [
] or its salts are reacted with a nitrosating agent.

This reaction is usually carried out in a solvent, and water, acetic acid, benzene, methanol, ethanol, tetrahydrofuran, and other solvents that do not adversely affect the reaction can be used. Preferred examples of nitrosating agents include nitrosating agents.
Jq acid and its derivatives, such as nitrosyl halides such as nitrosyl chloride and nitrosyl bromide, alkali metal nitrites such as sodium nitrite and potassium nitrite, alkyl nitrites such as butyl nitrite and pentyl nitrite, etc. can be mentioned.

When using a salt of nitrous acid as a nitrosating agent, the reaction is preferably carried out in the presence of an inorganic or organic acid such as hydrochloric acid, sulfuric acid, formic acid, acetic acid, or the like. When a nitrite is used as a nitrosating agent, it is preferably carried out in the presence of a strong base such as an alkali metal alkoxide.
Although the reaction temperature is not particularly limited, it is usually preferable to carry out the reaction under cooling or at room temperature. In addition, salts of the compound represented by the general formula [] can be easily obtained according to conventional methods, and the same salts as those explained for the salts of the compound represented by the general formula [1] can be used. Can be mentioned.
The compound of the formula [] and its salts thus obtained can be isolated and purified by known means, but can also be used as a raw material for the next reaction without being separated. Next, to obtain the compound represented by the general formula [] or its salts from the compound represented by the general formula [] or its salts, the compound represented by the general formula [] or its salts is subjected to an alkylation reaction.

This alkylation reaction can be carried out according to a conventional method. For example, if the process is carried out in a solvent under ice cooling or at room temperature, the process is often completed within a few minutes to several hours. Any solvent may be used as long as it does not inhibit this reaction, such as tetrahydrofuran, dioxane, methanol, ethanol, chloroform, methylene dichloride, ethyl acetate, butyl acetate, N,N-dimethylformamide, N,N-dimethylacetamide, and water. or a mixture thereof may be used. Examples of alkylating agents include methyl iodide,
Methyl bromide, ethyl iodide, ethyl bromide and other methyl halides, dimethyl sulfate, diethyl sulfate, diazomethane,
Diazoethyl or methyl p-toluenesulfonate is used.

When using an alkylating agent other than diazomethane or diazoethane, alkali metal carbonates such as sodium carbonate or potassium carbonate, alkali metal hydroxides such as sodium hydroxide or potassium hydroxide, triethylamine, pyridine, dimethylaniline, etc. This is generally carried out in the presence of a base such as Furthermore, other routes can be used to obtain the compound represented by the general formula [] or its salts, where A is.

For example, a compound represented by the general formula [] or React with the salts,
A compound represented by the general formula [] or a salt thereof can be obtained. Further, for example, by using the acylation method described in (b) above, 3-oxo-2-alkoxyiminobutyric acid obtained by the method described in JP-A-M-98795 can be used to form a compound represented by the general formula [ ]. or a salt thereof, or a compound represented by the general formula [ ] or a salt thereof is reacted with diketene, and further, using the nitrosation and oxime formation described above, 7-(3-oxo-2-a! A lukoxybutyramide)-cephalosporin derivative or a 7-(3-oxo-2-hydroxyiminobutyramide)-cephalosporin derivative can be obtained. By reacting the compound obtained here with a halogenating agent by a conventional method, a compound represented by the general formula [] or a salt thereof can be obtained. Examples of halogenating agents include halogens such as chlorine, bromine, and iodine, sulfuryl halides such as sulfuryl chloride, haloimide compounds such as N-promosuccinimide and N-chlorosuccinimide, halogens such as pyridinium hydrobromide perbromide, and pyridine. The amount used is usually about 1 to several moles per mole of the compound obtained above. This reaction is preferably carried out in the presence of a Lewis acid such as aluminum chloride, boron trifluoride, or titanium tetrachloride. Any solvent may be used as long as it does not inhibit this reaction, and for example, one or a mixed solvent of two or more such as tetrahydrofuran, dioxane, chloroform, methylene chloride, and benzene can be used. Further, the reaction temperature is appropriately selected from the range of cooling and heating, and the reaction is usually between one powder and two powders.

In addition, salts of the compound represented by the general formula [] can be easily obtained according to conventional methods, and the same salts as explained in the section of the salts of the compound represented by the general formula [1] can be used. Can be mentioned.

The compound of the formula [] and its salts thus obtained can be isolated and purified by known means, but can also be used as a raw material for the next reaction without being separated. → Next, if the compound represented by the general formula [V], [] or [] or its salt is reacted with the thioformamide or thiourea represented by the general formula [], the general formula [1a] or A compound represented by [Ib] or a salt thereof is obtained. This reaction is usually carried out in a solvent. Any solvent may be used as long as it does not inhibit this reaction, such as water, methanol, ethanol, acetone, tetrahydrofuran, dioxane, N,N
One or more mixed solvents such as -dimethylformamide, N,N-dimethylacetamide, and N-methylpyridone are used. Although the addition of a deoxidizing agent is not particularly necessary, the reaction may proceed smoothly by adding a deoxidizing agent as long as the cephalosporin skeleton is not changed. Those used for this purpose include inorganic or organic bases such as alkali metal hydroxides, alkali metal bicarbonates, triethylamine, pyridine and N,N-dimethylaniline. The reaction is carried out under ice cooling, room temperature, or heating. usually〔〕
, [] or [] 1 to several equivalents of thioformamide or thioureas are used per equivalent of the compound of formula [].

The reaction time is 1 to 4 hours, preferably 1 to 10 hours. Furthermore, compounds of general formula [1a] or [Ib] can be converted into the corresponding target compound by protecting the carboxyl group, removing the protecting group, and further salifying the compound in accordance with conventional methods. In addition, when a group active in this reaction exists in R1, R2, and R5, it can be optionally protected with a normal protecting group during the reaction, and after the reaction, the protecting group can be removed by a conventional method. can also be removed. The target compound of the formula [1a] or [Ib] of the present invention obtained as described above or a salt thereof can be isolated by a conventional method. As explained above, the target compound of the present invention can be easily obtained by the above-mentioned method, but the Δ2-
The cefem compound may be converted into the corresponding Δ3-cefem compound by a conventional method after the above-mentioned reactions (a), (c), and (d). Thereafter, the Δ-cephem compound can be converted into a Δ3-cepheme compound by a conventional method with or without isolation. 2 again? Similarly, for the compound where (g) → 0, after the above-mentioned reaction (1) or (e), the compound can be isolated or not isolated and subsequently prepared by a conventional method. can be converted into a compound that is

Furthermore, the compound represented by the general formula [1] and its salts can also be produced according to the methods known per se as shown below.

(In the formula, R", R2, R3, R", R5, R6, R",
The dotted lines in ``YZ'' and the Cefem ring have the meanings described above.

) The compound represented by the general formula [1] of the present invention, particularly '/Z, which has a strong antibacterial effect). The Δ3-cephem compounds 5 and their salts can be administered to humans and animals in the form of free acids, non-toxic salts or physiologically acceptable esters.

In that case, the dosage form usually applied for cephalosporin drugs, such as tablets, capsules, syrups, etc.
It is prepared in the form of an injection and can be administered orally or parenterally. Next, the present invention will be further explained with reference to reference examples and examples, but the present invention is not limited thereto.

Reference Example 1 (1) 7-Aminocephalosporanic acid (hereinafter referred to as
It is abbreviated as 7-ACA.

)2.72f was suspended in 15ml of anhydrous acetonitrile,
After adding and dissolving 5.68 f of boron trifluoride/diethyl ether complex salt, the mixture was allowed to react at room temperature for 5 hours. After the reaction, the solvent is distilled off under reduced pressure, and the resulting residue is dissolved in 20 ml of aqueous acetone (containing 50% water by volume), and the pH is adjusted to 3.5 with 28% aqueous ammonia under ice cooling. Collect the precipitated crystals and add 5 m of hydrated acetone (containing 50% water by volume)
7-amino-3-acetamidomethyl-Δ3-cefemu-4-carboxylic acid 2.1 having a melting point of 155°C (decomposed) after being precleaned with 5 ml of acetone and 5 ml of acetone in sequence and dried.
4f (yield 79%) is obtained. IR(KBr)o-1:ν
C=01795, 1640, 1610, 1520NMR
(CF3COOD) Ppm value; 2.37 (3H; s; -CH3), 3.82 (2H; s; C2-H), 5.41 (ShaB ratio; C6-H, C7-H) (2) (1
) 7-amino-3-acetamidomethyl-Δ
2.71 y of 3-cefemu-4-carboxylic acid is suspended in 30 ml of methanol, and 1.90 y of p-toluenesulfonic acid monohydrate is added and dissolved therein.

Next, diphenyldiazomethane 4y was gradually added at room temperature, and the mixture was allowed to react at the same temperature for 30 minutes. After the reaction was completed, the solvent was distilled off under reduced pressure, and the resulting residue was dissolved in a mixed solvent consisting of 20 ml of water and 20 ml of ethyl acetate, and the pH was adjusted to 7.0 with sodium hydrogen carbonate. Adjust to O. If the precipitated crystals are removed, thoroughly washed with water, and dried, the melting point will be 190-194.
Diphenylmethyl di-7-amino-3 showing water C (decomposition)
-acetamidomethyl-Δ3-cefemu 4-carboxylate 2.84y (yield 65%) is obtained. IR(KB
r) Cm-1゜νC=01758, 1720, 1647
, NMR (CDCl3) Ppm value; 1.87 (3H, s, -CH3), 3.59 (2H, s, C2-H), 3.65, 4.27 (2H, ABq, J = 14CpS)
, 4.71 (1H, d, J=5Hz, C6-H), 4.
89 (1H, d, J = 5Hz, C7-H), 6.12 (
1H, bs, -NHCO-), 6.90 (1H, S, (
00H●, 7.36 (10H, s, -<'○>×2) Reference Example 2 Reference Example 1-(
By reacting and treating in the same manner as in 1), the products shown in Table 2 are obtained.

Reference Example 3 If reacted and treated in the same manner as Reference Example 1-(2), Table-
Compound 3 is obtained.

Reference Example 4 (1) 7-ACA2.72y was suspended in 13ml of sulfolane, and boron trifluoride/diethyl ether complex salt 14
．． Add 2f and 1.0y of 5-methyltetrazole and react at room temperature for 17 hours.

After the reaction was completed, the reaction solution was poured into 15 ml of water, and cooled on ice for 2 hours.
Adjust the pH to 3.5 with 8% ammonia water. The precipitated crystals are taken off, washed sequentially with 5 ml of water and 5 Tn of acetone, and then dried to give 7-amino-3-[2-(5-methyl-1,2,3,4-tetrazolyl)methyl]-Δ3-cefemu 4- Carboxylic acid and 7-amino-3-[1-
(5-Methyl-1,2,3,4-tetrazolyl)methyl]-Δ3-cephemu-4-carboxylic acid mixture crystal 1
．． Get 76y. (2) 1.76 crystals obtained in (1)
y was suspended in 18 mL of methanol, 1.13 V of p-toluenesulfonic acid monohydrate was added and dissolved, and then 4.6 Y of diphenyldiazomethane was gradually added.
React for 15 minutes at room temperature.

After the reaction is completed, the solvent is distilled off under reduced pressure. The obtained residue is dissolved in a mixed solvent consisting of 30 ml of ethyl acetate and 30 ml of water, and the pH is adjusted to 8 with sodium hydrogen carbonate. Next, the organic layer is separated, dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure. The obtained residue was subjected to column chromatography (Wako silica gel C-200
: developing solvent, benzene diacetate di-ethyl diacetate 4:1), diphenylmethyl di-7-amino-3-[2-(5-methyl-1,2
,3,4-tetrazolyl)methyl]-Δ3-cephemu-4-carboxylate with a melting point of 97C (decomposition) and a melting point of 97C (decomposition).
(5-Methyl-1,2,3,4-tetrazolyl)methyl]-Δ3-cefemu 4-carboxylate 0.14f
get. O diphenylmethyl di-7-amino-3-[2-
(5-Methyl-1,2,3,4-tetrazolyl)methyl]-Δ3-cefemu 4-carboxylate IR (KB
r) Cm-1; νC=01770,1720NMR(C
DCl2) Ppm value: 1.75 (2H, 卜, -NH2)
, 2.48 (3H, s, -CH3), 3.20 (2H, s, C2-H), 4.70 (1H, d, J=5Hz, C6-H), 4.8
7 (1H, d, J = 5Hz, C7-H), 5.30, 5
．． 72(211,ABq,J=16Hz,6.92(1
H,S,. -CH [), 7.30 (10H, S, -<.
○〉×2) O diphenylmethyl di-7-amino-3-[1
-(5-methyl-1,2,3,4-tetrazolyl)methyl]-Δ3-cefemu 4-carboxylate IR (K
Br)Cr! t-1; νC=01770,1725NM
R(CDCl3)Ppm value; 1.80 (2H, s, -N
H2), 2.15 (3H, s, -CH3), 3.30, (?, S, C2-H), 4.70 (1H, d, J=5Hz, C6-H), 4.8
5 (1H, d, J = 5Hz, C7-H), 5.00, 5
．． 38 (2H, ABq, J=16Hz6.90 (1H,
S, -CH●,7.30(10H,S,-.((●[)
3,)〉×2)(3) Diphenylmethyl di-7-amino-3-[2-(5-methyl-1,2,3,4-tetrazolyl)methyl]-Δ3-cefemu-4-carboxylate 0.462y in anisole 0.5 mt and 5 ml of trifluoroacetic acid, and reacted at room temperature for 1 hour.

After the reaction was completed, the solvent was distilled off under reduced pressure, 10 mL of water and 10 ml of ethyl acetate were added to the resulting residue, and the mixture was stirred for 2 hours under ice cooling.
Adjust the pH to 8 with 8% ammonia water. Next, the aqueous layer is separated, and the pH is adjusted to 3.5 with Beau's hydrochloric acid while cooling on ice. The precipitated crystals are collected, washed sequentially with 5 ml of water and 5 ml of acetone, and dried to give 7-amino-3-[2-(5-methyl-1,2,3,4-tetrazolyl) with a melting point of 178°C (decomposition). ) Methyl]-Δ3-cephemu-4-carboxylic acid 0.26 fI is obtained. IR(KBr)CT! t-1; ν
C=01790, 1610, 1530, NMR (CF3
COOD) Ppm value; 2.70 (3H, s, -CH3), 3.73 (2H, s, C2-H), 5.40, (2H, s, C6-H, C7-H), 5. 8
0,6.12(2H,,ABq,J=16Hz, Diphenylmethylni-7-amino-3-[1-(5-
Methyl-1,2,3,4-tetrazolyl)methyl]-Δ
7-amino-3-[1-(
5-Methyl-1,2,3,4-tetrazolyl)methyl]
0.25 g of Δ3-cefemu-4-carboxylic acid is obtained.

IR(KBr)Cm-1; νC=01795,1615
, 1530, NMR (CF3COOD) Ppm value; 2.95 (3H, s, -CH3), 3.90 (2H, ratio, C2-H), 5.45 (2H, s, C6-H, C7-H ), 5.57
, 5.92 (2H, ABq, J = 16Hz, Reference Example 5 (
1) The same reaction as in Reference Example 4 (1) was carried out under the conditions shown in Table 4, and the results shown in Table 4 were obtained.

(2) The product obtained in (1) was reacted and treated in the same manner as in (2) of Reference Example 4 to obtain the results shown in Table 5.

The physical properties of the compound obtained here were consistent with those of the compound obtained in Reference Example 4 (2). Reference Example 6 (1) 7-ACA2.72y was converted into trifluoroacetic acid 19m
1. Boron trifluoride diethyl ether complex salt 7.1V and 5-acetamidotetrazole 1.
Add 4y and react at room temperature for 7 hours.

After the reaction, the solvent was distilled off under reduced pressure, 15 ml of water was added to the resulting residue, and the pH was adjusted to 3 with 28% ammonia water under ice cooling.
．． Adjust to 5. The precipitated crystals are collected, washed sequentially with 5 nt of water and 5 ml of acetone, and dried to give 7-amino-3-[2-(5-acetamido-1,2,3,4-tetrazolyl)methyl]-Δ3-cefemu-4- 1.0y of crude crystals of carboxylic acid are obtained. (2) 1.0y of the crude crystals obtained in (1) were suspended in 10Tn1 of methanol, and after adding and dissolving 0.56y of p-toluenesulfonic acid monohydrate, 2.3g of diphenyldiazomethane was added. Gradually add the mixture and allow to react at room temperature for 15 minutes.

After the reaction is complete, the solvent is distilled off under reduced pressure, and the resulting residue is dissolved in a mixture of 20 ml of ethyl acetate and 20 ml of water, and the pH is adjusted to 8 with sodium hydrogen carbonate. Then,
The organic layer is separated, dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure. Purification of the residue by column chromatography (Wako silica gel C-200: developing solvent, benzene diacetate 4:1) yields diphenylmethyl di-7-amino-3-, which has a melting point of 106-1°C (decomposition).
0.35 g of [2-(5-acetamido-1,2,3,4-tetrazolyl)methyl]-Δ3-cefemu 4-carboxylate is obtained. IR(KBr)o-1; νC=0
1750, 1720, 1700, NMR (CDCl3)
Ppm value; 1.95 (2FI, ratio, -NH2), 2.20 (3H, s, -NHCOCH3), 3.20,
(2H, Yf8,, C2-H), 4.67 (1H, d,
J = 5Hz, C6-H), 4.82 (1H, d, J = 5
Hz, C7-H), 5.32, 5.68 (2H,, AB
q, J=16Hz, 6.90 (1H, s,>CH-),
/＾ゝ7.25(10H,S,-<.
,(.,2),2×2),9.75(1H,ratio,;:N
H) (3) Diphenylmethyl di-7-amino-3-[2-
(5-acetamido 1,2,3,4-tetrazolyl)
Methyl]-Δ3-cefemu 4-carboxylate 0.
505y is dissolved in a mixture of 0.5mt of anisole and 5rn1 of trifluoroacetic acid, and reacted at room temperature for 1 hour.

After the reaction is complete, the solvent is distilled off under reduced pressure, and the residue is mixed with 10ml of water.
1 and 10 ml of ethyl acetate were added, and the pH was adjusted to 8 with 28% aqueous ammonia under ice cooling. Next, separate the aqueous layer,
Under ice cooling, adjust the pH to 3.5 with hydrochloric acid. Precipitated crystals?
7-amino-3-[2-(5-acetamido-1,2,3,4-tetrazolyl)methyl]- which has a melting point of 179°C (decomposed) after being washed with 5 ml of water and 5 ml of acetone in sequence and dried. 0.31y of Δ3-cefemu 4-carboxylic acid is obtained. IR(KBr)Cm-1:νC=
01790, 1690, 1610, 1530NMR (C
F3COOD) Ppm value: 2.42 (3H, s, -CII,), 2.20 (3H, s, -NHCOCH3), 3.70,
(2H,s,C2-H), 5.40(2H,s,C6-
H, C7-H), 5.94 (2H, me, ]) Reference Example 7 (1) Using other tetrazoles in place of 5-acetamidotetrazole, (1) of Reference Example 4 or (1) of Reference Example 6
The same reaction as in 1) was carried out, and the results shown in Table 16 below were obtained.

(2) Esterification was carried out in the same manner as in (2) of Reference Example 6 to obtain the compounds shown in Table 17.

The physical properties of the product are shown in Table 8. (3) Reference example 6 (3)
The compounds shown in Table 19 were obtained by deesterification in the same manner as above.

In the table above, products D and E, . I and J. ．． K., LIF, and G. Separation of C<15M was performed using column chromatography (Wako silica gel C-!?20
0: developing solvent, benzene ethyl diacetate (4:1) treatment.

Reference Example 8 7-ACA2.72V was dissolved in 19mt of trifluoroacetic acid, and boron trifluoride/diethyl ether complex salt 7.
1f1 and 0.75f of 1,2,4-triazole are added and reacted at room temperature for 7 hours.

After the reaction, the solvent was distilled off under reduced pressure, 15 ml of water was added to the resulting residue, and the pH was adjusted to 3 with 28% ammonia water under ice cooling.
．． Adjust to 5. The precipitated crystals are collected, washed with 5 ml of water and 5 ml of acetone, and dried to a melting point of 149°C.
7-amino-3-[1-(1,2,4-
2.5y of triazolyl)methyl]-Δ3-cefemu-4-carboxylic acid is obtained. IR(KBr)C7l-1; νC
=01790,1610,1530NMR(CF3CO
OD) Ppm value; 4.00 (2H, ratio, C2-H), 5.47 (4H, ratio, C6-HC7-H,) 8.70,
(1H,S,-?J), 9.80(1H,S,-1st
-Tj~ Reference Example 9 Using the raw material compounds in Table 10 instead of 7-ACA,
By reacting and treating in the same manner as in Reference Example 8, the products shown in Table 10 are obtained.

Reference example 10 3-methyl-1, instead of 1,2,4-triazole
When reacted and treated in the same manner as in Reference Example 8 using 2,4,1-triazole, 7-amino-3-[1-(3-methyl-1,2,4-triazolyl)methyl having a melting point of 195°C (decomposition) was obtained. ]-Δ3-cefemu 4-carboxylic acid is obtained.

1R (KBr) -1; νC=0, 1690, 1610
, 1 Seki 0NMR (CF3COOD+D2O) Ppm value;
2.60 (3H, s, -CH3), 3.93 (2H, s
, C2-H), 5.30, (2H,s,C6-H,C7-H), 5.1
0,5.75 (2H, ABq, J=16H,,')9.
45(IH,S,')U) Reference Example 11 If the reaction is carried out in the same manner as in Reference Example 8 using 3-methylthio-1,2,4-triazole instead of 1,2,4-triazole, the melting point is 147. 7-amino-3-[1-(3-methylthio-1,2,4-triazolyl))methyl]-Δ3-cefemu-4-carboxylic acid exhibiting decomposition.

51R(KBr)Crft-1; νC=01770,1
605,1530NMR (CF3COOD) Ppm value;
2.75 (3H, s, -SCH3), 4.00 (2H,
s, C2-H), 5.40 (211, s, C6-H, C7-H), 05.
23,5.85 (2H, ABq, J=16Hz, 9.5
5(1H,S9y...) Reference Example 12 3-chloro 1, instead of 1,2,4-triazole
When reacted and treated in the same manner as in Reference Example 8 using 2,4-triazole, 7-amino-3-[1-(5-chloro-1,2,4-triazolyl)methyl] exhibits a melting point of 191°C (decomposition). -Δ3-cefemu-4-carboxylic acid is obtained.

IR(KBr)C7n-1; νC=011790,16
10,1530NMR (CF3COOD) Ppm value; 3
．． 75 (2H, s, C2-H), 5.40 (2H, s, C6-H, C7-H), 5.47
,5.80(2H,ABq,J=16Hz,8.50(
1H,S7ΣU) Reference Example 13 If 3-acetamido-1,2,4-triazolyl is used instead of 1,2,4-triazole and reacted and treated in the same manner as in Reference Example 8, the melting point will be 150 to 155. C(
7-Amino-3-[1-(3-acetamido-1,2,4-triazolyl)methyl]-Δ3-cefemu-4-carboxylic acid was obtained.

IR(KBr)Cm-1; νC=0, 1795,168
0,1610,1540NMR(CF3COOD)Pp
m value; 2.43 (3H, s, -CH3), 3.19 (21 (,S, C2-H), 5.35, (2H, s, C6-H, C7-H),
-\5.30~5.95 (2FI, m, 1
), 9.45 (1H,s,/>-H.) Reference Example 14 Same as Reference Example 8 using 3-ethoxycarbonyl-1,2,4-triazole instead of 1,2,4-triazole. Upon reaction and treatment, 7-amino-3-[11-(3-ethoxycarbonyl-1,2,4-triazolyl)methyl]-Δ3-cefemu-4-carboxylic acid having a melting point of 176°C (decomposition) is obtained.

IR(KBr)c1-1; νC=01795,1720
, 1610, 1530NMR (CF3COOD+D2O
) Ppm value; 1.50 (3H, t, -CH2CH3),
3.72 (2H, ratio, C2-H), 4.65, (2H, q, -CH2CH3), 5.35 (
2H, s, C6-H, C7-H), 5.95 (2H, ratio, ] ), 8.65 (1H, S, >-U) Reference Example 15 4 instead of 1,2,4-triazole ,5-dimethoxycarbonyl-1,2,3-triazole and treated in the same manner as in Reference Example 8, 7-amino-3-[1-(4,5-dimethoxycarbonyl)] having a melting point of 16rC (decomposition) Ni-1,2,3-triazolyl)methyl]-
Δ3-cefemu 4-carboxylic acid is obtained.

IR(KBr)Crn-1; νC=01795,172
5,1610,1530NMR(CF3COOD)Pp
m value: 3.55 (2H, ratio, C2-H), 4.10 (6H, s, -0CH3x2),
]-5.35, (2FI, s,), 5.90 (2H, S, C6-H, C7-H), Reference Example 1
4-cyano5 instead of 61,2,4-triazole
-Using phenyl-1,2,3-triazole, Reference Example 8
If reacted and treated in the same manner as above, the melting point is 204℃ (decomposition).
7-Amino-3-(4-cyano-5-phenyl-1,2,3-triazolyl)methyl]-Δ3-cefemu-4-carboxylic acid is obtained.

In the name of the compound, the expression (4-cyano-5-phenyl-1,2,3-triazolyl)methyl is
-Cyano-5-phenyl-1,2,3-triazolyl group This name was chosen because it is not yet clear which nitrogen atom at the 1st, 2nd or 3rd position of the group is bonded to the carbon atom of the 3rd position of the exomethylene group. Also, in the presentation method, as shown below, 1? ? K, \, \wa 7. Similarly, in this specification, in the case of 1,2,3-triazolyl having a substituent, when the bonding position is not clear, the same nomenclature and notation are followed. )IR(KB
r) c! n-1; νC...N222OνC=01790,
1610, 1530, NMR (CF3COOD) Ppm
Value; 3.75 (2H, s, C2-H), 5.35 (2H, s, C6-H, C7-H),
) 5.85, (2H, ratio, I), 7.
40-7.70 (3H, m, wipe juice 1), 7.80-8
．． 10 (2H, m, b○〉) ▼1 (1) 71 ACA2.72f with 20m of trifluoroacetic acid
1, and 7.1y of boron trifluoride/diethyl ether complex salt and 1.24V of 4-carboxy 1,2,3-triazole are added thereto, and the mixture is reacted at room temperature for 5 hours.

After the reaction was completed, the solvent was distilled off under reduced pressure, 15 ml of water was added to the resulting residue, and the pH was adjusted to 3.0 with 28% ammonia water under ice cooling.
Adjust to 5. The precipitated crystals are collected, washed with 5 ml of water and 5 ml of acetone, and then dried to obtain 7-amino-3.
Crude crystals of -(4-carboxy1,2,3-triazolyl)methyl-Δ3-cefemu-4-carboxylic acid 1.45
Get y. (2) 1.45f of the crystals obtained in (1) were suspended in 15ml of methanol, 0.85V of p-toluenesulfonic acid monohydrate was added and dissolved, and then 3.44y of diphenyldiazomethane was added. Gradually add at room temperature 1
Allow to react for 5 minutes.

After the reaction is completed, the solvent is distilled off under reduced pressure, and the resulting residue is dissolved in a mixed solvent of 15 ml of ethyl acetate and 15 ml of water, and the pH is adjusted to 8 with sodium hydrogen carbonate. Next, the organic layer was separated and washed twice with 15TfLt of water.
The residue obtained by drying over anhydrous magnesium sulfate and distilling off the solvent under reduced pressure is purified by column chromatography (Wako silica gel C-200; developing solvent: benzene ethyl diacetate 5:1). 96-101 le C (
Diphenylmethyl di-7-amino-3-(4
-diphenylmethoxycarbonyl-1,2,3-triazolyl)methyl-Δ3-cefemu 4-carboxylate 0.24y is obtained. IR(KBr)CTn-1; νC
= 01770, 1720 NMR (CDCl3) PPm value; 2.33 (2H, ratio, -NH2), 2.78, 3.21 (2H, ABq, J = 18Hz, C
2-H) 4.71 (1H, d, J=5Hz, C6-H)
, 4.90 (1H, d, J=5Hz, C7-H), 5.
32,5.92(2H,ABq,J=16,6.86(
2H,s,-COOCH(C6H5)2X2), Reference Example 18 The compounds shown in Table 11 were obtained by reacting in the same manner as in Reference Example 17 (1).

The physical properties (IR and IMR) of the product in Table 11 were consistent with those of Reference Example 8.

Reference Example 19 7-Amino-3-[1-(1,402,
If 4-triazolyl)methyl]-Δ3-cephemu-4-carboxylic acid is reacted and treated in the same manner as in Reference Example 17-(2), diphenylmethylni7-amino-3- having a melting point of 61 to 65°C (decomposition) can be obtained. [1-(1,2,4-triazolyl)methyl]-Δ3-cefemu 4-carboxylate is obtained.

1R (KBr) -1; νC=01775,1720N
MR (CDCl3) Ppm value; 2.00 (2H, s, -
NH2), 3.43 (2H9s9C2-H), 4.70, (1H, d, J=5Hz, C6-H), 4.
88 (1H, d, J = 5Hz, C7-H), 5.00 (
2H,S,''), 6.95(1H,s,)CH-)
, 7.30 (10H, s, pe●ha 2), 7.85 (1H, S, ゛) d), 8.07 (1H, S, -? 岑 1) Reference Example 20 Obtained in Reference Example 10 7-Amino-3-[1-(3-methyl-1,2,4-triazolyl)methyl]-Δ3-cefemu-4-carboxylic acid was reacted in the same manner as in Reference Example 17-(2), and the treated material had a melting point of 90 Diphenylmethyl di-7-amino-3-(5-methyl-1,2,
4-triazolyl)methyl-Δ3-cefemu 4-carboxylate is obtained.

IR(KBr)Cm-1; νC=01770,1720
NMR (CDCl3) Ppm value; 2.32 (3H, s,
-CH3), 3.42 (2H, s, C2-H), 4.70, (1H, d, J=5Hz, C6-H), 4.
85 (1H, d, J = 5Hz, C7-H), 4.90 (
Reference Example 21 7-Amino-3-[1-(5-chloro-1,2,4-triazolyl)methyl]-Δ3-cefemu-4-carboxylic acid obtained in Reference Example 12 was reacted in the same manner as in Reference Example 17-(2). and treatment yields diphenylmethyl di-7-amino-3-[1-(5-chloro-1,2,4-triazolyl)methyl]-Δ3-cefemu-4-carboxylate having a melting point of 79-87C (decomposition). .

IR(KBr)Cln-1: νC=01770,172
0NMR (CDCl3) Ppm value; 11.82 (21)
, Me, -NH2), 3.10 (2H, s, C2-H), 4.55 (1H, d, J=5Hz, C6-H), 4.7
2 (1H, d, J=5Hz, C7-H), 4.705.
33 (2H, ABq, J=16Hz,) 6.93 (1H
,bS,mi ℃to), 7.30(10H,s,1''())
X2), Xi-7/″7.70 (1H,
s,\3→) N Compounds shown in Table 12-a and Table 12-b were obtained in the same manner.

Substituted-1,2,4-triazoles in Reference Example 4 or 2
The reaction was carried out in the same manner as in 1 to obtain the compounds shown in Table 12-b.

Reference Example 22 (1) 4.07f of p-nitrobenzyl di-7-aminocephalosporanate was dissolved in 30ml of trifluoroacetic acid, and 7.1y of boron trifluoride/diethyl ether complex salt was dissolved therein.
and 0.9y of benzene were added and allowed to react at room temperature for 4 hours.

After the reaction is completed, the solvent is distilled off under reduced pressure, and 30 ml of ethyl acetate and 30 ml of water are added to the resulting residue to dissolve it.
Then, the pH was adjusted to 7.0 with sodium hydrogen carbonate under ice cooling. After adjusting to O, the organic layer is separated. The organic layer is washed with water, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure to obtain p-nitrobenzylni7-amino-3-benzyl-Δ3-cefemu-4-carboxy, which has a melting point of 62-66°C (decomposition). A rate of 2.34y (55% yield) is obtained. IR
(KBr)C77! -1; νC=01765,1725
NMR (CDCl3) Ppm value; 2.07 (2H, Me,
-NH2), 3.05, 3.41 (2H, ABq, J=17Hz, C
2-H), 3.41,399 (2H, ABq, J=14
Hz, 4.65 (1H, d, J=5Hz, C6-H),
4.89 (1H, d, J=5Hz, C7-H), 5.2
8 (211,s, -COOCH2-), 7.15 (5H
,S9A7○)))7.43,8.08(4H,ABq
, J = 9 Hz, (2) 4.25 y of p-nitrobenzyl di-7-amino-3-benzyl-Δ3-cefemu 4-carboxylate obtained in (1) was dissolved in a mixed solvent of 40 ml of methanol and 20 ml of tetrahydrofuran, and 10 % palladium on carbon is added and a reduction reaction is carried out at room temperature.

After the reaction is completed, the reaction solution is filtered, and the furnace solution is concentrated to dryness under reduced pressure. Then, 30 ml of ethyl acetate was added to the obtained residue,
Add 30ml of water and adjust the pH to 3 with sodium hydrogen carbonate under ice-cooling.
．． Adjust to 4. If the precipitated crystals are taken in a furnace, washed sequentially with 5 mι of water and 5 mι of acetone, and then dried, the melting point is 189~
7-amino-3-benzyruΔ showing 197C (decomposition)
2.64y of 3-cefemu-4-carboxylic acid (yield 91.
0%). IR(KBr)Cm-゛;νC=017
90, 1610, 1520NMR (CF3COOD-D
2O) Ppm value; 3.38 (2H, s, C.

-H), 3.90, 4.25 (2H, ABq, J=14
Hz, S\]), I/・, CH2- 5.16, (Out, D, J=5Hz, C6-H), 5.2
9 (IH, d, J = 5 Hz, C7-H), 7.30 (5
H, s, mouth) Reference Example 23 Diphenylmethyl di-7-amino-3-acetoxymethyl-Δ3-cephemu-4-carboxylate 4,38y was dissolved in 30 ml of trifluoroacetic acid, and Ξ boron fluoride diethyl ether complex salt 7 was dissolved in this. .1y and benzene 0.9y
and react at room temperature for 6 hours.

After the reaction is completed, the solvent is distilled off under reduced pressure, and 30 mι of ethyl acetate and 30 mι of water are added to the resulting residue and dissolved. Then, the pH was adjusted to 7.0 with sodium hydrogen carbonate under ice-cooling. Adjust to O. Then, the aqueous layer was separated and adjusted to pH 3 with hydrochloric acid under ice-cooling.
Adjust to 4. If the precipitated crystals are taken out, washed sequentially with 5 ml of water and 5 ml of acetone, and then dried, the melting point is 189-1.
7-amino-3-benzyruΔ3 showing 97C (decomposition)
-cefemu-4-carboxylic acid 1.729 (yield 59.3
%). In addition, the physical properties of this compound (IR and NMR
) was consistent with that obtained in Reference Example 22-(2).

Reference Example 24 4.72y of p-toluenesulfonic acid of ethyl di-7-amino-3-acetoxymethyl-Δ3-cefemu-4-carboxylate was dissolved in 40 mι of trifluoroacetic acid, and boron trifluoride/diethyl ether complex salt 7 was dissolved in this.
．． Add 1f1 and 0.9fI of benzene and react at room temperature for 6 hours.

After the reaction is completed, the solvent is distilled off under reduced pressure, and 30 ml of ethyl acetate and 30 ml of water are added to the resulting residue to dissolve it. Then, the pH was adjusted to 7.0 with sodium hydrogen carbonate under ice-cooling. After adjusting to O, the organic layer is separated. The organic layer is washed with water, then dried over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure, and 20Tnι of ethyl acetate is added to the resulting residue to dissolve it. To this, p-toluenesulfonic acid monohydrate 1.
A 20 mt solution of 79 in ethyl acetate is added. If the precipitated crystals are collected by filtration, p-toluenesulfonate 3 of ethyl di-7-amino-3-benzyl-Δ3-cefemu-4-carboxylate having a melting point of 170 to 177C (decomposition) is obtained.
．． 14y (yield 64.1%) is obtained. IR(KBr)A
n-1; νC=01765,1720NMR(D6-
DMSO) Ppm value; 1.09 (3H, t, J=7Hz
, -CH2CH2), 2.15(:ni(j[-][,S
,10,, ”(,,1-...ノ .,,ray--"i:nii:![!!i:ri ,3.31,(2H,卜,C2-H),3 .46, 4.17 (2H, ABq, J
= 14Hz, 4.10 (2H, q, J = 7Hz, -CH
2CH.

), 4.96 (IH, d, J=5Hz, C6-H), 5
．． 06 (IH, d, J=5Hz, C7-H), 6.94
,7.37(4H,ABq,J=8Hz,7.10(5
H, s, →○冫) Reference Example 25 Using acetic acid instead of trifluoroacetic acid, boron trifluoride.
Using anhydrous stannic chloride instead of diethyl ether complex acid, the reaction is carried out in the same manner as in Reference Example 24, and p-toluenesulfonate of ethyl di-7-amino-3-benzyl-Δ3-cefemu-4-carboxylate is obtained. .

The physical properties (IR and NMR) of this compound are as shown in Reference Example 2.
This was consistent with that obtained in 4. Reference Example 26 4.72y of ethyl di-7-amino-3-acetoxymethyl-Δ3-cefemu-4-carboxylate was dissolved in 40ml of trifluoroacetic acid, and 7.1y of boron trifluoride diethyl ether complex salt and thiophene-2-carboxylic acid 1 Add .6y and allow to react at room temperature for 4 hours.

After the reaction is completed, the solvent is distilled off under reduced pressure, and 30Tn1 of ethyl acetate and 20ml of water are added to the resulting residue to dissolve it. Then, the pH was adjusted to 4.0 with sodium hydrogen carbonate under ice cooling.
After adjusting to O, the organic layer is separated. After drying with anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure! The resulting residue was subjected to column chromatography (Wako silica gel C-2
00; When purified with benzene ethyl diacetate (3:1) as a developing solvent, ethyl di7 has a melting point of 61-64°C (decomposition).
-Amino-3-(5-carboxy-2-tenyl)-Δ3
-cefemu 4-carboxylate 1.32y (yield 3
5.9%). IR(KBr)Cffl-1; νC
=01775,1720,1680NMR(CDCI3
) Ppm value; 1.30 (3H, t, J=7Hz, -CH
2CH3), 3.10-4.0 (4H, m, C2-H,
'I.

2-), 4.27 (2H, q, J=7Hz, -CH2C
H3) 4.92 (1H, d, J=5Hz, C6-H),
5.07 (1H, d, J = 5Hz, C, -H), 7.5
6 (1H, d, J = 3.5Hz, 7.79 (1H, d,
J=3.5Hz, Reference Example 27 The following compound is obtained by reacting and treating in the same manner as in Reference Example 26 using phenol instead of thiophene-2-carboxylic acid.

Oethyl di-7-amino-3-(2-hydroxybenzyl)-Δ3-cefemu-4-carboxylate Melting point: 37
~45°C (decomposition) IR (KBr)Crfl-1; νC=01760,17
20NMR (CDCl3) Ppm value; 1.28 (3H,
t, J=7Hz, -CH2CH3), J3. O9, 3.
42 (2H,, ABq, J=18Hz, C2-H), 3
．． 41, 3.82 (2H, ABq, J=14Hz, 4.
26 (2H, q, J=7Hz, -CH, CH3), 4.
63 (1H, d, J = 5Hz, C6-H), 4.82 (
1H, d, J=5Hz, C7-H), 6.59-7.3
7(41(,M,2?to)Oethylni7-amino-3-
(4-Hydroxybenzyl)-Δ3-cefemu 4-carboxylate Melting point: 55-59°C (decomposition) IR (KBr) c! R-1; νC=01760,172
01.29 (3H, t, J=7Hz, -CH2CH3)
, 3.00, 3.35 (2H, ABq, J=18Hz,
C2-H), 3.30, 3.90 (2H, ABq, J=
14Hz, 4.27 (2H, q, J=7Hz, -CH2
CH3), 4.61 (1H, d, J=5Hz, C6-H
), 4.84 (1H, d, J=5Hz, C7-H), 6
．． 68,701 (4Hz, ABq, J = 8Hz, Reference Example 28 If acetic acid is used instead of trifluoroacetic acid and the reaction is carried out in the same manner as in Reference Example 26, ethylni-7-amino-3-(2-hydroxybenzyl )-Δ3-cefemu 4-carboxylate as well as ethyl di-7-amino-3-(4-hydroxybenzyl)-Δ3-cefemu 4-carboxylate.

Note that these physical properties (IR and NMR) were consistent with those obtained in Reference Example 27.

Example 1 (1) 2.72 y of 2-(2-Tert.-amyloxycarboxamidothiazol-4-yl)acetic acid was dissolved in 40 mt of anhydrous methylene chloride, and 1.
06y was added and the reaction mixture was cooled to -35°C.

Then, 1.12 fI of ethyl chlorocarbonate was added to give -35
~-25 mouth C 1. After reacting for an hour, diphenylmethyl di-7-amino-3-[2-(5-methyl-1,2,3
,4-tetrazolyl)methyl]-Δ3-cefemu4-
Add 4.62y of carboxylate and -30 to -20 force C
and for 1 hour at -10 to 10°C. After the reaction was completed, the solvent was distilled off under reduced pressure, and 40 ml of ethyl acetate and 30 ml of water were added to the resulting residue to dissolve it, the organic layer was separated, 30 ml of water was added again, and the mixture was diluted with PHL with monohydrochloric acid under ice cooling. 5
Adjust to. Then, the organic layer was separated, 30 mt of water was added, and the pH was adjusted to 7.0 with sodium bicarbonate under ice-cooling. Adjust to O. The organic layer is separated, dried over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure, diethyl ether is added to the residue, and the resulting crystals are collected. When thoroughly washed with diethyl ether and dried, diphenylmethyl di7-[2-(2-Tert.-amyloxycarboxamidothiazol-4-yl)acetamide]-31 has a melting point of 103-105°C (decomposition). 6.52y (yield: 91.1%) of 2-(5-methyl-1,2,3,4-tetrazolyl)methyl]-Δ3-cefemu 4-carboxylate is obtained. IR(K
Br) CTrt-1; νC=01780,1720,1
675NMR (CDCl3) Ppm value; 0.90 (3H
, t, J=7Hz, gCH2? 1), (2) diphenylmethyl di7-[2-(2-Tel.-amyloxycarboxamidothiazol-4-yl)acetamide]-3-[2-(5-methyl-1, 2,3,4-
Tetrazolyl)methyl]-Δ3-cefemu 4-carboxylate (6.52y) was dissolved in a mixed solution of 32ml of trifluoroacetic acid and 10ml of anisole, and 2
Allow time to react.

After the reaction is completed, the solvent is distilled off under reduced pressure, diethyl ether is added to the residue, and the resulting crystals are distilled. If thoroughly washed with diethyl ether and dried, the melting point will be 184-18rC.
7-[2-(2-aminothiazole-4
-yl)acetamide]-3-[2-(5-methyl-1
,2,3,4-tetrazolyl)methyl]-Δ3-cefemu-4-carboxylic acid trifluoroacetate 4.61y(
Yield: 92.1%). IR(KBr)(:TA-1
;νC=01765,1655,1630NMR(D6
-DMSO)Ppm; 8.96 (1H, d, J = 8Hz, -CONH-) Example 2 (1) 2-(2-Tert.-Amyloxycarboxamidothiazol-4-yl)acetic acid 2.729 anhydrous Dissolve in 30 ml of methylene chloride, add 1.06 y of N-methylmorpholine, and cool the reaction solution to -35°C.

Then, 1.12y of ethyl chlorocarbonate was added to -35 to -2
After reacting at 5℃ for 1.5F18', the reaction solution was heated to -40℃.
Cool to ℃. On the other hand, 7-amino-3-[2-(5-methyl-1,2,3,4-tetrazolyl)methyl]-Δ3
- 2.96 y of cefemu 4-carboxylic acid was suspended in 30 ml of anhydrous methylene chloride and diluted with bis(trimethylsilyl)acetamide under ice cooling. Add 6.1y and react at 5 to 10°C for 40 minutes to form a homogeneous solution. This solution was added dropwise to the reaction solution prepared above while maintaining the temperature at -40 to -3. After dropping, the mixture is reacted for 1 hour at -30 to -20°C and for 1 hour at -10 to 10°C. After the reaction is complete, the solvent is distilled off under reduced pressure, and 40 nL of ethyl acetate and 40 mL of water are added to the resulting residue to dissolve it, and the pH is adjusted to 7.5 with sodium hydrogen carbonate under ice cooling. Separate the aqueous layer, add 40 ml of ethyl acetate, and adjust the pH to 2.0 with hydrochloric acid under ice cooling. Adjust to O. Next, separate the organic matter and add 3 parts of water.
After washing with water at 0 ml, drying over anhydrous magnesium sulfate, distilling off the solvent under reduced pressure, and drying, 7-[2-(2-Tel.-amyloxycarboxamide thiazole-4) having a melting point of 138 to 147C (decomposed) -yl)acetamide]-
3-[2-(5-methyl-1,2,3,4-tetrazolyl)methyl]-Δ3-cefemu-4-carboxylic acid 5.0
7y (yield 92.2%) is obtained. 1R (KBr) C77
! -1; νC=01775, 1720, 1675NMR
(D6-DMSO) Ppm value; 8.75 (1H, d, J = 8Hz, -CONH-) (2
) 71 obtained in (1) [2-2-(2-Tert.-amyloxycarboxamide thiazole-4-i1ha7k-7gV)-reeROfr-1,2,3, 4-
5.07 y of [tetrazolyl)methyl]-Δ3-cefemu 4-carboxylic acid is dissolved in a mixed solvent of 25 ml of trifluoroacetic acid and 8 ml of anisole, and the three powders are reacted at room temperature.

After the reaction is completed, the solvent is distilled off under reduced pressure, diethyl ether is added to the residue, and the resulting crystals are collected. If thoroughly washed with diethyl ether and dried, the melting point is 184-18rC (
7-[2-(2-aminothiazole-4-
yl)acetamide]-3-[2-(5-methyl-1
,2,3,4-tetrazolyl)methyl]-Δ3-cefemu-4-carboxylic acid trifluoroacetate 4.72y(
Yield: 93.1%). In addition, the physical properties of this compound (IR
and NMR) were consistent with those obtained in Example 1-(2).

Example 3 2.72y of 2-(2-Tert.-amyloxycarboxamidothiazol-4-yl)acetic acid was suspended in 30ml of anhydrous benzene, 2.54y of oxalyl chloride was added under ice cooling, and reacted at the same temperature for 1 hour. let

After the reaction is completed, the solvent is distilled off under reduced pressure, and the resulting residue is dissolved in 5 ml of anhydrous methylene chloride. Add this solution to -50
Diphenylmethyl di-7-amino-3-[2
-(5-methyl-1,2,3,4-tetrazolyl)methyl]-Δ3-cefemu 4-carboxylate 4.62
y and dimethylaniline 1.21y anhydrous methylene chloride 4
Add dropwise into the solution dissolved in 0ml. After dropping, -40
The reaction was carried out at 0°C for 3 minutes, at -20°C to -10°C for 3 minutes, and then at 0°C for 3 minutes. After the reaction was completed, the solvent was distilled off under reduced pressure, and the resulting residue was mixed with 40 ml of ethyl acetate and 3 ml of water.
Add 0ml of water to dissolve, separate the organic layer, and add 30ml of water again.
and PHL. with 2N monohydrochloric acid under ice-cooling. Adjust to 5. Then, the organic layer was separated, 30 ml of water was added, and the pH was adjusted to 7.0 with sodium bicarbonate under ice-cooling. Adjust to O. The organic layer was separated, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
Diethyl ether is added to the residue, and the resulting crystals are filtered. After thorough washing with diethyl ether and drying, diphenylmethyl di7-[2-(2-Tert.-amyloxycarboxamidothiazol-4-yl)acetamide]-3- exhibits a melting point of 103-105°C (decomposition). [
2-(5-methyl-1,2,3.4-tetrazolyl)methyl]-Δ3-cefemu 4-carboxylate 6.6
9V (yield 93.5%) is obtained. xThe physical properties (IR and NMR) of this compound are as shown in Example 1-(
This was consistent with that obtained in 1).

Example 4 2-(2-Tert.-amyloxycarboxamidothiazol-4-yl)acetic acid 2.72y 11-oxybenzotriazole 2.0y and diphenylmethylni-7-amino-3-[2-(5-methyl-1,2, 3
,4-tetrazolyl)methyl]-Δ3-cephemu4-
4.62y of carboxylate is dissolved in 50ml of anhydrous tetrahydrofuran and cooled to 5°C.

Then, N,N'-dicyclohexylcarbodiimide 2
．． Add 5g of the mixture and react at the same temperature for 1 hour at 25°C. After the reaction is completed, the reaction solution is filtered to remove insoluble matter.
The liquid was concentrated under reduced pressure, and the resulting residue was diluted with 4 ethyl acetate.
Add 0ml to dissolve, and remove trace amounts of insoluble matter. Add 30ml of water to the solution and add △monohydrochloric acid to PHL. under ice cooling. Adjust to 5. The organic layer was separated, 30 ml of water was added, and the pH was adjusted to pH 8. with sodium bicarbonate under ice cooling. Adjust to O. The organic layer is separated, dried over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure, diethyl ether is added to the residue, and the resulting crystals are filtered off. When thoroughly washed with diethyl ether and dried, diphenylmethyl di7-[2-(2-Tel.-amyloxycarboxamidothiazol-4-yl)acetamide]-3-[ exhibits a melting point of 103-105°C (decomposition).
2-(5-methyl-1,2,3.4-tetrazolyl)methyl]-Δ3-cefemu 4-carboxylate 6.4
6y (yield 90.3%) is obtained. The physical properties (IR and NMR) of this compound were consistent with those obtained in Example 1-(1).

Example 5 (1) 0.55 g of diketene was dissolved in 10 ml of anhydrous methylene chloride, and a solution of 5 ml of anhydrous carbon tetrachloride containing 0.46 y of chlorine was added dropwise at -30°C.
The three powders are reacted at 30°C to -20°C to obtain an acid chloride solution.

On the other hand, 7-amino-3-[2-(5-methyl-1,2,
3.4-tetrazolyl)methyl]-Δ3-cefemu4
- 1.48 g of carboxylic acid and 2.0 Tn of anhydrous methylene chloride
After suspending in L and adding 2.12y of bis(trimethylsilyl)acetamide under ice-cooling, reacting at room temperature for 1 hour,
Cool the reaction solution to -40°C. Then, the acid chloride solution prepared above is added dropwise into this at the same temperature. After the dropwise addition, the temperature is gradually raised and the reaction is carried out at 0 to 5°C for 1 hour. After the reaction is complete,
The solvent was distilled off under reduced pressure, and the resulting residue was diluted with 3 ethyl acetate.
0 ml of water was added and dissolved, and the organic layer was separated, washed successively with 20 ml of water and then with 20 ml of saturated brine, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. Diethyl ether was added to the residue, the resulting crystals were collected, washed thoroughly with diethyl ether,
When dried, it exhibits a melting point of ~10rc (decomposition). 71 (
4-chloro3-oxobutyramide)-3-[2-(
5-Methyl-1,2,3.4-tetrazolyl)methyl]
-Δ3-cefemu-4-carboxylic acid 1.85y (yield 8
9.4%).

IR(KBr)o-1; νC=01778, 1725,
1668NMR ((16-DMSO) Ppm value; 2.44 (3H, s, -CH3), 3.42 (2H, ratio, C2-H), 3.56 (2H, s, -COCH2CO-), 4. 52
(2H, s, C1CH2-), 5.08 (1H, d, J
=5Hz, C6-H), 8.99 (1H, d, J=8H
z, -CONH-) (2) 7-(4-chloro-3-oxobutyramido)-3-[2-(5-methyl-1,2,3.4-tetrazolyl)methyl]- obtained in (1) Δ3
-Cefemu 0.829f of 4-carboxylic acid and 0.167y of thiourea are dissolved in 5ml of dimethylformamide and reacted at room temperature for 2 hours.

After the reaction was completed, the reaction solution was poured into 5 ml of water, and the pH was adjusted to 5.0 with sodium hydrogen carbonate under ice cooling. Adjust to O. The precipitate was collected and washed sequentially with water, acetone and diethyl ether.
-(2-aminothiazol-4-yl)acetamide]
-3-[2-(5-methyl-1,2,3.4-tetrazolyl)methyl]-Δ3-cefemu-4-carboxylic acid 0.
77y (yield 88.3%) is obtained. IR(KBr)o-
1; νC=01760, 1650, 1625NMR(D
6-DMSO) Ppm value; 4.92 (1H, d, J=5Hz, C6-H), 5.1
8-5.80 (3H, m, C7-H, 8.68 (1H,
d, J=8Hz, -CONH-) Example 67-[2-(
2-aminothiazol-4-yl)acetamide]-3
- [2-(5-Methyl-1,2,3.4-tetrazolyl)methyl]-Δ3-cephemu 5.5y of trifluoroacetate of 4-carboxylic acid was suspended in 50ml of water, and the mixture was cooled on ice for 1 hour.
Slowly add 20 ml of N sodium monohydroxide aqueous solution and dissolve.

This reaction solution is purified by column chromatography (eluent: water) using Amperlite
Sodium salt of -[2-(2-aminothiazol-4-yl)acetamide]-3-[2-(5-methyl-1,2,3.4-tetrazolyl)methyl]-Δ3-cefemu-4-carboxylic acid4. 1y (yield 88.4%) is obtained.
IR(KBr)o-1; νC=01760, 1660,
1610NMR (D43-DMSO) Ppm value; 2.4
1 (3H, s, -CH3), 3.40 (2H, ratio, C2-H), 4.93 (1H, d, J=5Hz, C6-H), 5.2
5-6.02 (3H, m, C7-H, 8.80 (1H,
d.
-[2-(2-aminothiazol-4-yl)acetamido]-3-acetamidomethyl-Δ3-cefemu4
- Obtain trifluoroacetate of carboxylic acid.

When this compound is further reacted and treated in the same manner as in Example 6, it exhibits a melting point of 155-158°C (decomposition).
(2-aminothiazol-4-yl)acetamide]-
The sodium salt of 3-acetamidomethyl-Δ3-cefemu 4-carboxylic acid is obtained. IR(KBr)c! n-1
;νC=01755,1680,1590NMR(D2
O) Ppm value; 1.98 (3H, s, -COCH3), 3.16, 3.56 (2H,,ABq,J=16Hz,
C2-H), 3.84, 4.15 (2H,.ABq,J
=14Hz, 5.02 (1H, d, J=5Hz, C6-
H), 5.57 (1H, d, J=5Hz, C7-H),
Example 8 (1) 2.72f of 2-(2-TerL.-amyloxycarboxamidothiazol-4-yl)acetic acid was dissolved in 30ml of anhydrous methylene chloride, 1.06y of N-methylmorpholine was added, and the reaction solution was diluted to -35 Cool to ℃.

Then, 1.12y of ethyl chlorocarbonate was added to -35 to -2
1 at 5°C. After reacting for an hour, the reaction solution was cooled to -40'C. On the other hand, 7-amino-3- obtained in Reference Example n-(2)
Benzyl-Δ3-cefemu-4-carboxylic acid 2.96y
was suspended in 30 ml of anhydrous methylene chloride, and diluted with bis(
Add 6.1y of trimethylsilyl)acetamide and add 5 to 1
The four powders were reacted at 0C to form a homogeneous solution. This reaction solution was added dropwise to the reaction solution prepared above while maintaining the temperature at -40 to -3Cf'C. After dropping, at -30 to -20℃ for 1 hour, -10
React for 1 hour at ~10°C. After the reaction is complete, the solvent is distilled off under reduced pressure, and 40 ml of ethyl acetate and 40 ml of water are added to the resulting residue to dissolve it, and the pH is adjusted to 7.5 with sodium hydrogen carbonate under ice-cooling. Separate the aqueous layer and add 40ml of ethyl acetate.
1 and diluted with △monohydrochloric acid under ice cooling to pH 2. Adjust to O. The organic layer was then separated, washed with 30 ml of water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 7-[2-(2-Te
rt. -Amyloxycarboxamide thiazole-4-
yl)acetamido]-3-benzyl-Δ3-cephemu-4-carboxylic acid 5.10y (yield 93.8%). IR(KBr)Cm-1: νC=01765,171
0,1680-1660NMR(D6-DMSO)Pp
m value; 5.04 (1H, d, J=5Hz, C6-H), 5.5
8 (1H, dd, J=5Hz, J=8Hz, C7-H)
, 8.84 (1H, d, J=8Hz, -CONH-) (
2) 5.10f of 7-[2-(2-Tert.-amyloxycarboxamidothiazol-4-yl)acetamide]-3-benzyl-Δ3-cefemu-4-carboxylic acid obtained in (1) was added to 25 ml of trifluoroacetic acid and Dissolve in a mixed solvent of 8 ml of anisole and react with the three powders at room temperature.

After the reaction is complete, the solvent is distilled off under reduced pressure, diethyl ether is added to the residue, and the resulting crystals are collected. If thoroughly washed with diethyl ether and dried, the melting point is 155°C (decomposition).
4.60f of trifluoroacetate of 7-[2-aminothiazol-4-yl)acetamido]-3-benzyl-Δ3-cephemu-4-carboxylic acid (yield 90.2%)
). IR(KBr)c! n-1; νC=0176
0,1660,1630NMR(D6-CF3COOD
) Ppm value; 3.43 (2H, Me, C2-H), 5.22 (1H, d, J=5Hz, C6-H), 6.0
5 (1H, m, C7-H), Example 9 7-amino-3-benzyl-Δ3-cephemu-4-carboxylic acid obtained in Reference Example 8 instead of
-[1-(1,2,4-triazolyl)methyl]-Δ3
When reacted and treated in the same manner as in Example 8 using -cefemu-4-carboxylic acid, 7-[2-(2-aminothiazol-4-yl)acetamide]-3 exhibits a melting point of 119°C (decomposition). -[1-(1,2,4-triazolyl)methyl]-Δ3-cefemu-4-carboxylic acid trifluoroacetate is obtained.

IR(KBr)Cm-1: νC=01770,1660
, 1630NMR (D6-DMSO) Ppm value; 3.4
3 (2H, m, C2-H), 5.02-5.35 (3H, m, C6-H, 5.63 (
1H, d, J = 5 Hz, C7-H), Example 10 7-amino-3-benzyl-Δ3-cefemu Instead of 4-carboxylic acid, 7-amino-3-[ obtained in Reference Example 10]
If 1-(3-methyl-1,2,4-triazolyl)methyl]-Δ3-cefemu-4-carboxylic acid is reacted and treated in the same manner as in Example 8, the melting point is 144-146.
7-[2-(2-aminothiazol-4-yl)acetamide]3-[1-(3-methyl-1,2,4-triazolyl)methyl]-Δ3-cefemu4- showing ℃ (decomposition) The trifluoroacetate of carboxylic acid is obtained.

IR(KBr)CTn-1: νC=01765,166
5,1630 NMR (D6-DMSO) Ppm value; 2.
23(3H,s,-CH3), 3.45(2H,?,C2-H), 5.05-5.20(3H,m,C6-H,5.7O(
1H, d, J = 5 Hz, C7-H), Example 11 7-amino-3-benzyl-∆3-cefemu Instead of 4-carboxylic acid, 7-amino-3- [obtained in Reference Example 11]
Using 1-(3-methylthio-1,2,4-triazolyl)methyl]-Δ3-cefemu-4-carboxylic acid and treating in the same manner as in Example 8, the melting point was 133°C (
7-[2-(2-aminothiazole-4-
The trifluoroacetate of yl)acetamido]-3-[1-(3-methylthio-1,2,4-triazolyl)methyl]-Δ3-cefemu-4-carboxylic acid is obtained.

IR(KBr)Cm-1; νC=01765,1665
, 1630 NMR (D6-DMSO+D2O) Ppm value: 2.50 (3H, s, -CH3), 3.50 (2H,
Ratio, C2-H), 5.05 (1H, d, J=5Hz, C6-H), Example 127-Amino-3-benzyl-Δ3-cefemu-4-
Example 8 and 7-amino-3-[1-(5-chloro-1,2,4-triazolyl)methyl]-Δ3-cefemu-4-carboxylic acid obtained in Reference Example 12 were used instead of the carboxylic acid. If reacted and treated in the same way, melting point 14
(substitute) (decomposition) 7-[2-(2-aminothiazol-4-yl)acetamide]-3[1-(5-chloro1,2,4-triazolyl)methyl]-Δ3-cefemu 4 - Obtain trifluoroacetate of carboxylic acid.

IR(KBr)Crft-1; νC=01765,16
65,1630NMR(D6-DMSO+D2O)Pp
m value; 3.47 (2H, ratio, C2-H), 5.10 (1
H, d, J=5Hz, C6-H), 5.10, 5.40
(21(,ABq,J=16Hz,5.70(1H,d
, J=5Hz, C7-H), Example 13 7-Amino-3-[1-(
3-ethoxycarbonyl-1,2,4-triazolyl)
If methyl]-Δ3-cephemu-4-carboxylic acid is reacted and treated in the same manner as in Example 8, the melting point will be 155-1.
7-[2-(2-aminothiazol-4-yl)acetamide]-3-[1-(3-ethoxycarbonyl-1,2,4-triazolyl)methyl] showing 58°C (decomposition)
- Obtain trifluoroacetate of Δ3-cefemu 4-carboxylic acid.

IR(KBr)Cm-1; νC=01765,1725
, 1660, 1630 NMR (D6-DMSO) Ppm
Value; 1.34 (3H, t, J=7Hz, -CH2CH3),
3.41 (2H, ratio, C2-H), 4.38 (2H, q
, J=7Hz, -CH2CH3), 5.10(1H, d
, J=5Hz, C6-H), 5.50-5.85 (3H
, m, C7-H, Example 14 Example 1 or Example 8
The compounds shown in Table 13 are obtained by reacting and treating in the same manner as above.

Example 15 7-(4-chloro-3-oxobutyramide)-3-[2-(5-methyl-.1,2,
3,4-tetrazolyl)methyl]-Δ3-cephemu4
-carboxylic acid 4.15y and thioformamide 0.9
2y was dissolved in 40 ml of N,N-dimethylformamide and reacted at room temperature for 2 hours.

After the reaction was completed, the solvent was distilled off under reduced pressure, and the resulting residue was washed with diethyl ether, 100 ml of ethyl acetate and 50 ml of water were added, and the pH was adjusted to 3.0 with HCl under ice cooling. Adjust to O. Then, the organic layer is separated, dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure. Diethyl ether is added to the residue and the resulting crystals are collected and dried to give 7-[2-(thiazol-4-yl)acetamide]-3-[2- (5-methyl-1,2,3,4-tetrazolylmethyl]-Δ3-
Cefemu 4-carboxylic acid 3.3y (yield 78.4%)
get. 1R(KBr)c! fl-1; νC=0177
5,1720,1660NMR(D6-DMSO)Pp
m value: 2.44 (3H, s, -CH3), 3.44 (2H, ratio, C2-H), 5.06 (1H, d, J=5Hz, C6-H), 5.6
~5.8 (1H, m, C7-H), 9.00 ~ 9.25
(1H,m,-CONH-) Example 16 (1) 1.26y of diketene was dissolved in 2.0mt of anhydrous methylene chloride,
12 ml of anhydrous methylene chloride containing 1.92 f of bromine
After dropping the solution at -3(s), a three-powder reaction is carried out at -30 to -20°C.

Then, this reaction solution was converted into diphenylmethyl di-7-amino-3
-[2-(5-methyl-1,2,3,4-tetrazolyl)methyl]-Δ3-cefemu 4-carboxylate 4
．． 62f and bis(trimethylsilyl)acetamide 4y in 50 ml of anhydrous chloroform at a temperature below -30°C. After dropping, stir at -30 to -20°C and react at -10 to 0°C for 1 hour. After the reaction is complete,
The solvent was distilled off under reduced pressure, and the resulting residue was diluted with 6 ethyl acetate.
The organic layer was separated and washed with 3077.11 water and 30 ml of saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. 2 Diisopropyl ether is added to the residue and the resulting crystals are filtered to give diphenylmethyl di(4-bromo-3-oxobutyramide)-3-[2- (5-methyl-1,2,3,4
-tetrazolyl)methy3,l]-Δ3-cephemu4-
Carboxylate 5.92f (94.7% yield) is obtained.

IR(KBr)Cm-1; νC=01780,1722
, 1690-1650 NMR (CDCl3) Ppm value;
3,3.19 (2H, ratio, C2-H)
,3.62(2)1,s,-COCH2CO-),
4t3.97 (2H, s, BrC1I2-),
4.86 (1H, d, J=5Hz, C6-H), 7.9
1(1H9d, J=8Hz, -CONH-) (2) Diphenylmethyl di7-(4-bromo-3-oxobutyramide)-3-[2-(5-methyl-1,2,3,4-tetrazolyl ) Methyl]-Δ3-cefemu-4-carboxylate 6.52v and N-phenylthiourea 1.6
7y was dissolved in 30 ml of N,N-dimethylformamide and reacted at room temperature for 2 hours.

After the reaction, the solvent is distilled off under reduced pressure, and the resulting residue is washed with diethyl ether, then 100 ml of ethyl acetate and 50 ml of water are added, and the pH is adjusted to 7.5 with a saturated aqueous sodium bicarbonate solution under ice cooling. . Then, the organic layer is separated, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure to obtain diphenylmethyl di7-[2-(2-phenylaminothiazol-4-yl)acetamide]-3- [2-
5.9 f of a crude solid of (5-methyl-1,2,3,4-tetrazolyl)methyl]-Δ3-cephemu-4-carboxylate is obtained. Anisole 5 without refining this
9Tnt, then trifluoroacetic acid 59Tn
t was added dropwise and the three powders were reacted at room temperature. After the reaction is complete, the solvent is distilled off under reduced pressure, diethyl ether is added to the residue, and the resulting crystals are collected. When thoroughly washed with diethyl ether and dried, 7-[2-(2-phenylaminothiazole-4-
yl)acetamide]-3-[2-(5-methyl-1,
The trifluoroacetate of 2,3,4-tetrazolylmethyl]-Δ3-cefemu-4-carboxylic acid is obtained. IR(K
Br) Cm-1; νC=01775, 1660, 162
5NMR (D6-DMSO) Ppm value; Example 17 7-[2-(2-Tert.-Amyloxycarboxamidothiazol-4-yl)acetamide]-3-[2- (5-methyl-1,2,3,
4-tetrazolyl)methyl]-Δ3-cephemu-4-carboxylic acid 5.5y with N,N-dimethylformamide 27
ml, add triethylamine 1y1 and pivaloyloxymethyl iodide 2.9f1 under ice cooling, and react with 3 powders.

After the reaction is completed, the reaction solution is mixed with 250 nt of water and 250 nt of ethyl acetate.
ml of mixed solvent and adjust the pH to 7 with sodium hydrogen carbonate.
．． Adjust to O. Then, the organic layer is separated, washed with water, and dried over anhydrous magnesium sulfate. By distilling off the solvent under reduced pressure, pivaloyloxymethyl di7-[2-(2-Tert
．． -amyloxycarboxamidothiazol-4-yl)acetamide]-3-[2-(5-methyl-1,2,
3,4-tetrazolyl)methyl]-Δ3-cefemu 4
- 6.02y of crude solid of carboxylate are obtained. This was dissolved in 30wL1 of trifluoroacetic acid without purification, and the three powders were reacted at room temperature. After the reaction, the solvent was distilled off under reduced pressure, 80 ml of water and 80 ml of ethyl acetate were added to the resulting residue, and the pH was adjusted to 7 with sodium hydrogen carbonate under ice cooling.
．． Adjust to O. After separating the organic layer and drying it over anhydrous magnesium sulfate, 20 ml of a dry hydrogen chloride-diethyl ether solution (containing 0.8 y of hydrogen chloride) was added while stirring under ice cooling to precipitate a white powder. Offload this, wash thoroughly with diethyl ether, and then recrystallize with ethyl acetate? Then, pivaloyloxymethyl 2-[2-(2-aminothiazol-4-yl)acetamide]-3-[2-(5-methyl-1,2, 3,
4-tetrazolyl)methyl]-Δ3-cefemu 4-carboxylate hydrochloride 3.82f is obtained. Example 18 The compounds shown in Table 14 are obtained by reacting and treating in the same manner as in Example 17.

Example 19 (1) 7-amino-3-[2-(5-methyl-1,2,
3,4-tetrazolyl)methyl]-Δ3-cefemu 4
- 2.96f of carboxylic acid is suspended in 15ml of N,N-dimethylformamide, 1.34y of salicylaldehyde is added, and the mixture is allowed to react at room temperature for 1 hour.

Then, the reaction solution was cooled on ice, and 0.96 da of triethylamine was added.
Add 2.42y of pivaloyloxymethyl iodide and allow the two powders to react. After the reaction is complete, add 150ml of water to the reaction solution.
, into a mixed solvent of 150 mL of ethyl acetate. After adjusting the pH to 7.3 with sodium hydrogen carbonate, the organic layer was separated, washed twice with 100 ml of water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue is crystallized by adding isopropyl alcohol. Furthermore, if recrystallization is performed with isopropyl alcohol, the melting point is 1.
pivaloyloxymethyl di7-(2-hydroxybenzylideneamino)-3- showing 36-13TC (decomposition)
[2-(5-methyl-1,2,3,4-tetrazolyl)
Methyl]-Δ3-cefemu-4-carboxylate 2.
73y (yield 53.1%) is obtained. IR(KBr)d-
1; νC=01770,1765~NMR(CDCl3
) Ppm value; 1.23 (9H, s, -C(CH3)3)
, 3.30 (2H, s, C2-H), 5.08 (1H,
d, J = 5Hz, C6-H), 5.32 (1H, d, J
=5Hz, C7-H), 5.38, 5.82 (2H, A
Bq, J=16Hz, 5.91 (2H, ratio, -0CH2
0-), 8.49 (1H, s, -CH=N-) (2) Pivaloyloxymethyl di7 obtained in (1)
-(2-hydroxybenzylideneamino)-3-[2
-(5-methyl-1,2,3,4-tetrazolyl)methyl]-Δ3-cefemu 4-carboxylate 5.14
' was stirred for 1 hour at 10-15°C in a mixed solvent of 50ml of hydrochloric acid and 25Tnl of diethyl ether.

After that, the aqueous layer was separated, washed twice with 30 ml of diethyl ether, and 100 ml of diethyl ether was added thereto for 28 hours under ice cooling.
% ammonia water pH7. Adjust to O. The organic layer is separated and dried over anhydrous magnesium sulfate. Then, 20ml of dry hydrogen chloride-diethyl ether solution was added while stirring under ice-cooling.
1 (containing 1y hydrogen chloride), a white powder is precipitated. If this is taken out and thoroughly washed with diethyl ether and then recrystallized with chloroform, the melting point is 149-151℃ (decomposition).
pivaloyloxymethyl di-7-amino-3-[2
3.67 g (yield: 82.2%) of hydrochloride of -(5-methyl-1,2,3,4-tetrazolyl)methyl]-Δ3-cephemu 4-carboxylate is obtained. IR (KBr)
Cm-1; νC=01773, 1741, 1730NM
R(D6-DMSO)Ppm value: 1.18(9H,s,-C(CH3)3), 3.60(
2H, s, C2-H), 5.23 (2H, s, C6-H
, C7-H), 5.78-5.92 (2H, m, -0-
CH2-0-) (3) Diketene 1y was dissolved in 20ml of anhydrous methylene chloride, a solution of 9ml of anhydrous carbon tetrachloride containing 0.85y of chlorine was added dropwise at -30°C, and then -30~
React at -20°C for 3 days.

This reaction solution was then heated at -40°C to the pivaloyloxymethylni7-amino-3-[2-(5-methyl-1,2,3,4-tetrazolyl)methyl]-Δ3 obtained in (2).
-Cefemu 4-carboxylate hydrochloride 4.47f
and into a solution of 50 ml of anhydrous methylene chloride containing 2.43 g of N,N-dimethylaniline. After dropping, the temperature is gradually raised and the reaction is carried out at 0 to 5°C for 1 hour. After the reaction was completed, the solvent was distilled off under reduced pressure, and 50 ml of ethyl acetate was added to the resulting residue.
, add 30ml of water to dissolve, separate the organic layer, add water,
After washing successively with saturated brine and drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain an oil. Next, N.
Add 15 nt of N-dimethylformamide to dissolve the oil, add 0.76 y of thiourea, and react at room temperature for 2 hours. After the reaction is completed, the reaction solution is introduced into a mixed solvent of 150 ml of water and 150 ml of ethyl acetate. Sodium bicarbonate has a pH of 7. The organic layer was separated, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to a liquid volume of 50 ml. Next, 25 r1 Lt of a dry hydrogen chloride-diethyl ether solution (hydrogen chloride 1.3
When F-containing) is added, a white powder is precipitated. If this is filtered, thoroughly washed with diethyl ether, and then recrystallized with ethyl acetate, pivaloyloxymethyl 2-[2-(2-aminothiazole-4
-yl)acetamide]-3-[2-(5-methyl-1
,2,3,4-tetrazolyl)methyl]-Δ3-cefemu 4-carboxylate hydrochloride 4.4f (yield 75
．． 0%). In addition, the physical properties of this compound (IR and N
MR) was consistent with that obtained in Example 17.

Example 20 7-[2-(2-Tert.-) obtained in Example 2-(1)
amyloxycarboxamidothiazol-4-yl)acetamide]-3-[2-(5-methyl-1,2,3,
4-tetrazolyl)methyl]-Δ3-cefemu-4-carboxylic acid 5.5y with N,N-dimethylformamide 27
ml, and add 1.56y of triethylamine, 1y1, and methyl iodide under ice cooling, and react with 3 powders.

After the reaction, the reaction solution was mixed with 100ml of water and 100ml of ethyl acetate.
into a mixed solvent and adjust the pH to 7. with sodium hydrogen carbonate.
Adjust to O. Then, the organic layer is separated, washed with water, and dried over anhydrous magnesium sulfate. If the solvent is distilled off under reduced pressure,
Methyl di7-[2-(2-Tert.-amyloxycarboxamidothiazol-4-yl)acetamide]-
4.8 f of a crude solid of 3-[2-(5-methyl-1,2,3,4-tetrazolyl)methyl]-Δ3-cefemu 4-carboxylate is obtained. This was dissolved in 30 ml of trifluoroacetic acid without purification, and the three powders were reacted at room temperature. After the reaction, the solvent was distilled off under reduced pressure, 80 ml of water and 80 ml of ethyl acetate were added to the resulting residue, and the pH was adjusted to 7.0 with sodium hydrogen carbonate under ice cooling. Adjust to O. The organic layer is separated, dried over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure, diethyl ether is added to the residue, and the resulting crystals are harvested. After sufficient washing with diethyl ether and drying, methyl 27-[2-(2-aminothiazol-4-yl)acetamide]-3-[2-(5-methyl-1) having a melting point of 131-133°C (decomposition) is obtained. ,2,3,4-
Tetrazolyl)methyl]-Δ3-cefemu 4-carboxylate 3.6y (yield 80.5%) is obtained. Example 21 Example 19 is reacted and worked up similarly to give the following compound.

Phthalidilni7-[2-(2-aminothiazole-4-
yl)acetamide]-3-[2-(5-methyl-1,
Hydrochloride of 2,3,4-tetrazolyl)methyl]-Δ3-cefemu 4-carboxylate Melting point: 152-1°C (decomposition) IR (KBr)c! n-1; νC=01780,175
0,1680 NMR (D6-DMSO) Ppm value; Example 22 (1) 2-(2-chloroacetamidothiazole-4-
2.35 y of acetic acid was suspended in 40 ml of anhydrous methylene chloride, 1.06 y of N-methylmorpholine was added, and the reaction solution was cooled to -35°C.

Then, 1.12f of ethyl chlorocarbonate was added, and -35~-
After reacting at -25°C for 1.5 hours, the reaction solution was heated to -40°C.
Cool to On the other hand, 7-amino-3-[1-(5-chloro-1,2,4-triazolyl) obtained in Reference Example 12]
Methyl]-Δ3-cefemu-4-carboxylic acid 3.16y
was suspended in 30 ml of anhydrous methylene chloride, and diluted with bis(
Add 6.1y of trimethylsilyl)acetamide,
The mixture was reacted at 10° C. for 40 minutes to form a homogeneous solution. This reaction solution is added dropwise to the reaction solution prepared above while maintaining the temperature at -40 to -30°C. After dropping, at -30 to -20℃ for 1 hour, -1
React for 1 hour at 0-10°C. After the reaction was completed, the solvent was distilled off under reduced pressure, and 40 ml of ethyl acetate,
Add 40 Tnt of water to dissolve, and adjust the pH to 7.5 with sodium bicarbonate under ice-cooling. Separate the aqueous layer, add 40 ml of ethyl acetate, and adjust the pH to 2.0 with Ayuichi hydrochloric acid under ice cooling. Adjust to O. Then, the organic layer was separated, washed with 30 ml of water,
After drying with anhydrous magnesium sulfate and drying under reduced pressure,
7-[2-(2-
Chloroacetamidothiazol-4-yl)acetamido]-3-[1-(5-chloro1,2,4-triazolyl)methyl]-Δ3-cefemu-4-carboxylic acid 4.
9 Da (yield 92%) is obtained. IR(KBr)c! rl-
1; νC=01775, 1710, 1680, 1650
NMR (D6-DMSO) Ppm value; 3.43 (2H, s, C2-H), 4.32 (2) [, S, ClCH2-), 5.09 (1
H, d, J=5Hz, C6-H), 5.05-5.39
(2H, ABq, J=15Hz, 5.68 (1H, dd
, J=5Hz, J=8Hz, C7-H), 8.95(1
H, d, J = 8 Hz, -CONH-) (2) 71 obtained in (1) [2-(2-chloroacetamidothiazole-4
-yl)acetamide]-3-[1-(5-chloro1
,2,4-triazolyl)methyl]-Δ3-cefemu-4-carboxylic acid was dried in 40 ml of methylene chloride.
After suspending the mixture, 0.01y1 of p-toluenesulfonic acid pyridinium salt and 2.88V of ethyl vinyl ether were added and dissolved under reflux.

Thereafter, it was cooled to -75°C and 4.48 ml of a methanol solution of lithium methoxide (2.675rnm0e/ml) was added.
was added, and after stirring for 5 minutes, Tert. - Add 0.52y of butyl hypochloride and stir at the same temperature.

Then, after adding 0.48 V of acetic acid, the temperature was raised to -30°C. After the reaction, the solvent was distilled off under reduced pressure, and the resulting residue was mixed with 50 ml of ethyl acetate and 4,077 ml of water! Add l and cool on ice △
PHO with monohydrochloric acid. Adjust to 5.

The organic layer is separated, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. If diethyl ether is added to the residue and the resulting crystals are collected, the melting point is 145-150℃ (
7β-[2-(2-cucaroacetamidothiazol-4-yl)acetamide]-7α-methoxy3-[1-(5-chloro-1,2,4-triazolyl)methyl]-Δ3-cephemu 4-carboxylic acid 1.53
We obtain f (68%). IR(KBr)Cm-1; νC=
01775, 1720, 1685, 1635 NMR (D
6-DMSO) Ppm value: 3.34 (2H, s, C2-H), 3.38 (3H, s, -0CH3), 4.31 (2H, s, C1CH2-), 5.10-5. 30(3H,m,C6-H,9.25(
1H,s,-CONH-), (3)7β-[2-(2-
Chloroacetamidothiazol-4-yl)acetamide]-7α-methoxy3-[1-(5-chloro1,
2,4-triazolyl)methyl]-Δ3-cefemu 4
-Dissolve 1.40y of carboxylic acid in 7ml of N,N-dimethylacetamide, add 0.3y of thiourea, and add 1.40y of carboxylic acid to 7ml of N,N-dimethylacetamide.
React between C@.

After the reaction is complete, 50 ml of diethyl ether is added to the reaction solution, the supernatant liquid is decanted, 50 ml of diethyl ether is added to the residue, and the same operation is carried out. Next, water is added to the residue to loosen it well, and the crystals are taken out in an oven and dried, resulting in a melting point of 15.
7β-[2-(2-aminothiazol-4-yl)acetamide]-7α-methoxy-3-[1-(5-chloro-1,2,4-triazolyl)methyl]-1 showing 1 to 156°C (decomposition) 0.65y (yield 50%) of Δ3-cefemu-4-carboxylic acid hydrochloride is obtained. IR(KBr)c
! RL-1; νC=01765, 1660, 1610N
MR (D6-DMSO) Ppm value; 3.28 (2H, s, C2-H), 3.35 (2H, s, -0CH3), 5.05-5.30 (3H, m, C6-H, Example 23
(1) 3.15y of 2-(2-Tert.-amyloxycarboxamidothiazol-4-yl)-2-(syn)-methoxyiminoacetic acid was dissolved in 16ml of N,N-dimethylacetamide, and oxychlorinated at -200C. Phosphorus 1.6
Add 1.9' dropwise at the same temperature. Stir for an hour.

This solution was mixed with the 7-amine-3-0- obtained in Reference Example 12.
(5-chloro1,2,4-triazolyl)methyl]-
The mixture was added dropwise to a solution of 32 ml of anhydrous methylene chloride containing 3.16 y of Δ3-cefemu-4-carboxylic acid and 6.1 g of bis(trimethylsilyl)acetamide at -30 to -20°C. After dropping, the mixture was reacted for 1 hour at the same temperature, 3 times at 0 to 1 (generations), and 3 times at room temperature. After the reaction is completed, methylene chloride is distilled off under reduced pressure, and the resulting residue is introduced into a mixed solvent of 80 ml of water and 100 ml of ethyl acetate. Next, separate the organic layer, add 80 ml of water, and phosphorize with sodium hydrogen carbonate.
H7. Adjust to O. Separate the aqueous layer and add 80ml of ethyl acetate.
1 and PHL.1 with △monohydrochloric acid under ice cooling. Adjust to 5. The organic layer is separated, washed successively with 50 ml of water and 50 ml of saturated brine, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. When diethyl ether is added to the residue and the resulting crystals are collected, 7-[2-(2-Tert.-amyloxycarboxamidothiazol-4-yl)-2-] has a melting point of 198-200°C (decomposition). (syn)-methoxyiminoacetamide]-3-[1-(5-chloro1
, 2,4-triazolyl)methyl]-Δ3-cefemu-4-carboxylic acid (5.62 g (yield: 91.8%)).
IR(KBr)Cm-1; VC=01780,1720
, 1670NMR (D6-DMSO) Ppm value: 0.8
9 (3H, t, J=7Hz, -CH2,9y), 1.7
8 (2H, q, J = 7Hz, -9V2), 3.45 (2
H, bS, C2-H), 3.87 (3H, s, -0CH
3), H), 5.82 (1H, dd, J=5Hz, J=8Hz, C7
-H), 9・61 (1H9d, J=8Hz, -CONH
-), 11.79 (1H, ratio, -CONH-) (2)
7-[2-(2-Tel.-amyloxycarboxamidothiazol-4-yl)-2-(syn) obtained in (1)
-Methoxyiminoacetamide]-3-[1-(5-chloro-1,2,4-triazolyl)methyl]-Δ3-cefemu-4-carboxylic acid (5.62f) was dissolved in 30ml of trifluoroacetic acid, and 3 powders were dissolved at room temperature. Make it react.

After the reaction is completed, the solvent is distilled off under reduced pressure, diethyl ether is added to the residue, and the resulting crystals are collected. If thoroughly washed with diethyl ether and dried, the melting point is 162°C (decomposition).
7-[2-(2-aminothiazol-4-yl)]
-2-(syn)-methoxyiminoacetamide]-3-
5.23y (yield: 93.1%) of trifluoroacetate of [1-(5-chloro1,2,4-triazolyl)methyl]-Δ3-cefemu-4-carboxylic acid is obtained. R(KB
r) o-1; νC=01778, 1715, 1670,
1630NMR (↓-DMSO) Ppm value; 3.48 (2H, ratio, C2-H), 3.93 (3H, s, -0CH3), H), 5.78 (1H, dd, J = 5Hz, J =8Hz, C7
-H), Example 24 7-Amino-3-[1-(5-chloro-1,2,4-triazolyl)methyl]-Δ3-cefemu 7-amino-3- obtained in Reference Example 11 instead of 4-carboxylic acid [1-(3-methylthio 1,2,4
-Triazolyl)methyl]-Δ3-cefemu-4-carboxylic acid is reacted and treated in the same manner as in Example 231), showing a melting point of 180-183°C (decomposition).
(2-Tel.-amyloxycarboxamidothiazol-4-yl)-2-(syn)-methoxyiminoacetamide]-3-[1-(3-methylthio 1,2,4
-triazolyl)methyl]-Δ3-cefemu-4-carboxylic acid is obtained.

IR(KBr)d-1: νC=01780, 1710,
1670NMR (D6-DMSO) Ppm value; 0.87
(3H, t, J=7Hz, -CH29), 1.85 (2
H, q, J=7Hz, -Q9H3), 2.48(3H,
s, -SCH3), 3.42 (2H, 1X11-, C2
-H), 3.82 (3H, s, -0CH3), H), 5.76 (1H, dd, J=5Hz, J=8Hz, C7
-H), 9.61 (1H, d, J=8Hz, -CONH
-) Example 25 (1) Dissolved in 2-(2-chloroacetamidothiadol-4-yl)-2-(syn)-methoxyimino vinegar, and added dropwise 1.69 f of phosphorus oxychloride at -20°C. Stir at the same temperature for 1.5 hours.

This solution was mixed with the 7-amino-3-[1
-(5-chloro-1,2,4-triazolyl)methyl]
A solution containing 3.16f of -Δ3-cephemu-4-carboxylic acid and 6.1y of bis(trimethylsilyl)acetamide in 32mt of anhydrous methylene chloride is added dropwise at 30 to -20°C. After dropping, the mixture is reacted at the same temperature for 1 hour, 3 times at 0 to 10°C, and 3 times at room temperature. After the reaction is completed, methylene chloride is distilled off under reduced pressure, and the resulting residue is introduced into a mixed solvent of 80 ml of water and 100 ml of ethyl acetate. Next, separate the organic layer, add 80 ml of water, and phosphorize with sodium hydrogen carbonate.
H7. Adjust to O. Separate the aqueous layer and add 80ml of ethyl acetate.
Add PHL.1 and add hydrochloric acid to it under ice-cooling. Adjust to 5. The organic layer was separated, washed successively with 50 ml of water and 50 ml of saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. When diethyl ether is added to the residue and the resulting crystals are collected, 7-[2-(2-chloroacetamidothiazole-4
-yl)-2-(syn)-methoxyiminoacetamide]-3-[1-(5-chloro-1,2,4-triazolyl)methyl]-Δ3-cefemu-4-carboxylic acid 5.3
1y (yield 92.3%) is obtained. IR (KBr) 礪-1
;νC=01780,1720~NMR(D6-DMS
O) Ppm value; 3.50 (2H, ratio, C2-H), 3.93 (3H, s, -0CH3), 4.40 (2H, s, C1CH2-), H), 5.94 (1H , dd, J=5Hz, 8Hz, C7-H
), 9.71 (1H, d, J=8Hz, -CONH-)
Similarly, the following compound is obtained.

07-[2-(2-chloroacetamidothiazole-4
-yl)-2-(syn)-methoxyiminoacetamide]-3-acetamidomethyl-Δ3-cephemu-4-carboxylic acid Melting point: 200°C or higher IR (KBr) (3-1; νC=01780,1710
〜1赫0NMR(D6-DMSO) Ppm value; 1.83
(3H, s, -COCH3), 3.2t3.58 (2H, ABq, J=18Hz, C2
-H), 3.78 (3H, s, -0CH3), 4.33
(2H, s, CICH2-), 5.06 (1H, d, J=5Hz, C6-H), 5.7
3 (1H, dd, J=5Hz, J=8Hz, C7-H)
, 7.86-8.21 (1H, m, -NUCOCH3)
,9.57(1H,d,J=8Hz,-CONH-)(
2) 7-[2-(2-chloroacetamidothiazol-4-yl)-2-(syn)-methoxyiminoacetamide]-3-[1-(5-chloro1,2) obtained in (1)
,4-triazolyl)methyl]-Δ3-cefemu4-
5.31f of carboxylic acid is dissolved in 21ml of N,N-dimethylacetamide, 1.0y of thiourea is added, and the mixture is reacted at room temperature for 10 hours.

After the reaction is complete, 200 ml of diethyl ether is added to the reaction solution, the supernatant liquid is decanted, 100 ml of diethyl ether is added to the residue, and the same operation is carried out. Next, 40ml of water was added to the residue, and the pH was adjusted to 7.0 with sodium hydrogen carbonate. O
Adjust to. When this solution is purified by passing it through a column of Amperite XAD-2, it shows a melting point of 168°C (decomposition).
2-(syn)-methoxyiminoacetamide]-3-[
Sodium salt of 1-(5-chloro-1,2,4-triazolyl)methyl]-Δ3-cefemu-4-carboxylic acid 2
．． 5y (yield 51.9%) is obtained. IR(KBr)c!
1t-1; νC=01760, 1670, 1605NM
R(D2O)Ppm value; 3.30 (H, ratio, C2-H), 3.97 (3H, s, -0CH3), H), 5.77 (1H, d, J = 5Hz, C7-H ), Example 26 (1) 3.15 f of 2-(2-Tert.-amyloxycarboxamidothiazol-4-yl)-2-(syn)-methoxyiminoacetic acid was dissolved in 40 ml of anhydrous methylene chloride.
1.06y of N-methylmorpholine was added, and the reaction solution was cooled to -35°C.

Then, 1.12y of ethyl chloroacetate was added to -35 to -2
After reacting at 5°C for 1.5 hours, diphenylmethyl di7
-Amino-3-[2-(5-methyl-1,2,3,4-
4.62y of tetrazolyl)methyl]-Δ3-cefemu 4-carboxylate was added to -30 to -. React at 20°C for 1 hour. Then, gradually raise the temperature and keep it at room temperature for 3 more minutes.
Allow time to react. After the reaction was completed, the solvent was distilled off under reduced pressure.
50 ml of ethyl acetate and 40 ml of water were added to the resulting residue to dissolve it, the organic layer was separated, 40 ml of water was added again, and the mixture was cooled on ice. PHL. with hydrochloric acid. Adjust to 5. Then, the organic layer was separated, 40 ml of water was added, and the pH was adjusted to 7.0 with sodium bicarbonate under ice-cooling. Adjust to O. The organic layer was separated, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, diethyl ether was added to the residue, and the resulting crystals were collected. Diphenylmethyl di7-[2-(2-Tert.-amyloxycarboxamidothiazol-4-yl)-2-(syn)-methoxyiminoacetamide]-3-[2-(5-methyl-1
,2,3,4-tetrazolyl)methyl]-Δ3-cefemu 4-carboxylate 7.06f (yield 93.0%
).

[R(KBr)Cm-1; VC=01790,1725
, 1685NMR (4-DMSO) Ppm value; 0.87 (3H, t, J = 7Hz-CH2CH3), 1
．． 75 (2H, q, J = 7Hz, -CH2, CH3),
3.46 (2H, ratio, C2-H), 3.81 (3H, s
, -0CH2), 5.15 (1H, d, J=5Hz, C6-H), 5.8
7 (1H, dd, J=5Hz, J=8Hz, C7-H)
,9.61(1H,d,J=8Hz,-CONH-),
11.66 (1H, ratio, -CONH-), the following compound is obtained in the same manner.

O diphenylmethyl di7-[2-(2-Tert.-amyloxycarboxamidothiazol-4-yl)-
2-(syn)-methoxyiminoacetamide]-3-[
2-(5-ethyl-1,2,3,4-tetrazolyl)methyl]-Δ3-cephemu 4-carboxylate melting point:
104-10g'C (decomposition) IR (KBr)C7R-1; νC=01780,172
0,16800 diphenylmethyl di7-[2-(2-T
ert. -Amyloxycarboxamide thiazole-4
-yl)-2-(syn)-methoxyiminoacetamide]-3-[1-(1,2,4-tria bzolyl)methyl]-Δ3-cefemu 4-carboxylate melting point; 13
0-137C (decomposition) IR (KBr) c1-1; νC=01780,1720
, 16800 diphenylmethyl di7-[2-(2-Te
rt. l,-amyloxycarboxamidothiazol-4-yl)-2-(syn)-methoxyiminoacetamide]-3-acetamidomethyl-Δ3-cefemu4-
Carboxylate melting point: 163'C (decomposed)
11R(KBr)d-1; νC=0178
0,1720,1 Tin 0-16200 diphenylmethyl di7-[2-(2-Tert.-amyloxycarboxamidothiazol-4-yl)-2-(syn)-methoxyiminoace2doamide]-3-(furan- 2-Carboxamidomethyl)-Δ3-cefemu 4-carboxylate Melting point: 165-166°C (decomposition) IR (KBr) C77! -1; νC=01780,17
20,16802-1620○ diphenylmethyl di7-[2-(2-Tert.-amyloxycarboxamidothiazol-4-yl)-2-(syn)-methoxyiminoacetamide]-3-(4-hydroxybenzyl):
．． -Δ3-cefemu 4-carboxylate melting point; 98
~105°C (decomposition) IR (KBr)Cffl-1; νC=01780,17
23,1680○diphenylmethyl di7-[2-(2-
Tert. -Amyloxycarboxamide thiazole-4:. 1yl)-2-(syn)-methoxyiminoacetamide]-3-benzyl-Δ3-cephemu 4-carboxylate Melting point: 94-10rc (decomposition) IR(KBr)d-1; νC=01775,1720,
1670(2) Diphenylmethyl di7-[2-(2-Tert.-amyloxycarboxamidothiazol-4-yl)-2-(syn)-methoxyiminoacetamide]-3-[2] obtained in (1) -(5-methyl-1,2,
3,4-tetrazolyl)methyl]-Δ3-cephemu4
- Carboxylate 7.06f to trifluoroacetic acid 35
Dissolved in a mixed solvent of ml and anisole 12ml,
React for 2 hours at room temperature.

After the reaction is completed, the solvent is distilled off under reduced pressure, diethyl ether is added to the residue, and the resulting crystals are collected. If thoroughly washed with diethyl ether and dried, the melting point will be 123-125℃.
(decomposition) 7-[2-(2-aminothiazole-4
-yl)-2-(syn)-methoxyiminoacetamide]-3-[2-(5-methyl-1,2,3,4-tetrazolyl)methyl]-Δ3-cefemu-4-carboxylic acid trifluoroacetate 5 .07f (yield 91.9%) is obtained. IR(KBr)o-1; νC=01790,172
0 to NMR (CD3OD) Ppm value; Z. 44 (2H,
ratio, C2-H), L99(3H,s,-0CH3), . 10 (1H, d, J=5Hz, C6-H), J. 5
O, 5.8l (2H, ABq, J: 14H291.80
(1H, d, J=5Hz, C7-H), 3) Example 25
-The following compound was obtained in the same manner as in (2).

7-[2-(2-aminothiazol-4-yl)-2-
(syn)-methoxyiminoacetamide]-3-[2-
Sodium salt of (5-methyl-1,2,3,4-tetrazolyl)methyl]-Δ3-cefemu-4-carboxylic acid Melting point: 183-18TC (decomposition) IR(KBr)Crlt-1; νC=01760,16
65,1610NMR(D6-DMSO-D2O)Pp
m value; 3.30 (2H, -, C2-H), 3.91 (3
H, s, -0CH3), 5.12 (1H, d, J=5Hz, C6-H), 5.7
4 (1H, d, J=5Hz, C7-H), Example 277
-Amino-3-[1-(5-chloro-1,2,4-triazolyl)methyl]-Δ3-cephemu-4-carboxylic acid was replaced with 7-amino-3-[1-(5-chloro-1,2,4-triazolyl)methyl]-Δ3-cephemu-4-carboxylic acid obtained in Reference Example 10.
Using 1-(3-methyl-1,2,4-triazolyl)methyl]-Δ3-cefemu-4-carboxylic acid, the reaction was carried out in the same manner as in Example 23, and the melting point was 141 to 144.
7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamide]-3-[1-(3-methyl-1,2,4-triazolyl) showing °C (decomposition) [Methyl]-Δ3-cefemu-4-carboxylic acid trifluoroacetate is obtained.

IR(KBr)c! n-1; νC=01778,171
0,1670,1630 NMR (CD3OD) Ppm value; 2.39 (3H, s, -CH3), 3.56 (2H, Y:F5, C2-H), 4.03 (3
11, s, -0CH3), H), 5.86 (1H, d, J=5Hz, C7-H), Example 287-amino-3-[1-(5-chloro1,2,4
7-amino-3-[1-(3-methylthio-1,2,4-triazolyl)methyl]-Δ3-cej obtained in Reference Example 11 instead of Δ3-cephemu-4-carboxylic acid. Using femu-4-carboxylic acid, the melting point is 1 if the reaction is carried out in the same manner as in Example 23.
7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamide]-3-[1-(3-methylthio 1,2,47) showing 81°C (decomposition)
-triazolyl)methyl]-Δ3-cefemu-4-carboxylic acid trifluoroacetate is obtained.

IR(KBr)Cm-1: νC=01775,1710
, 1665, 1630H), 5.80 (1H, dd, J=5Hz, J=8Hz, C7
-H), 9.69 (1H, d, J=8Hz, -CONH
-) Example 29 7-amino-3-[1-(5-chloro-1,2,4-triazolyl)methyl]-Δ3-cefemu-4-carboxylic acid was replaced with 7 obtained in Reference Example 13.
-Amino-3-[1-(3-acetamido 1,2,4
-Triazolyl)methyl]-Δ3-cefemu-4-carboxylic acid is reacted in the same manner as in Example 23, and when treated, it exhibits a melting point of 167 to 180°C (decomposition).
2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamide]-3-[1-(3-acetamido-1,2,4-triazolyl)methyl]-Δ3-
The trifluoroacetate of cefhemu 4-carboxylic acid is obtained.

IR(KBr)Cm-1; νC=01775,1710
, 1680-1630 NMR (D6-DMSO) Ppm
Value; 9.60 (1H, d, J = 8Hz, -CONH-) Example 30 If reacted and treated in the same manner as in Example 23 or Example 26, Table-15s Table-16-a and Table-16
Compound -b is obtained.

Example 31 (1) 2.2fI of diketene was added to 25ml of anhydrous methylene chloride.
Anhydrous carbon tetrachloride containing 1.85y of chlorine dissolved in
After dropping mL of solution at -30'C, -30 to -20
React for 3 times at 0C.

Then, this reaction solution was mixed with diphenylmethylni-7-amino-3-[1-(5-chloro-1,2) obtained in Reference Example 21.
,4-triazolyl)methyl]-Δ3-cefemu4-
Anhydrous methylene chloride 100 containing carboxylate 9.63V and bis(trimethylsilyl)acetamide 4y
Drop into mt solution at -30°C or below. After dropping, -30
3 times at ~-20°C and reacted at 0-10°C for 1 hour.
After the reaction was completed, the solvent was distilled off under reduced pressure, and 100 mL of ethyl acetate and 80 mL of water were added to the resulting residue to dissolve it.
The organic layer is separated, washed successively with 50 ml of water and 50 ml of saturated brine, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. Diisopropyl ether is added to the residue and the resulting crystals are filtered to give diphenylmethyl di(4-chloro-3-oxobutylamide)-3-[1-(5- Kuroro 1,2,4-
10.7 fI (yield: 89.2%) of triazolyl)methyl]-Δ3-cefemu 4-carboxylate are obtained. I
R(KBr)d-1; νC=01780,1725,1
690-1650NMR (CDCl3-D2O)Ppm
Value; 3.19 (2H, ratio, C2-H), 3.50 (2H, s, -COCH2CO-), 4.12
(2H, s, C1CH2-), 4.88 (1H, d, J
=5Hz, C6-H), 4.82, 5.35 (2H, A
Bq, J = 15Hz, (2) diphenylmethyl 71 (
4-chloro3-oxobutyramide)-3-[1-(
5-chloro1,2,4-triazolyl)methyl]-Δ
3-cefemu 4-carboxylate 6y in acetic acid 40m
1, and a solution of 6 ml of water containing 1y of sodium nitrite was added dropwise thereto over 1 hour under water cooling, followed by reaction at room temperature for 2 hours.

After the reaction is completed, the reaction solution is introduced into 600 TfLt of water to precipitate crystals. If this is collected, thoroughly washed with water, and dried, diphenylmethyl di(4-chloro-2-hydroxyimino-3-oxobutyramide)-3-[ 1-(5-chloro1,2
,4-triazolyl)methyl]-Δ3-cefemu4-
5.24y of carboxylate (yield 83.3%) is obtained. IR(KBr)c′1;νC=01780,1720
, 1770-1650NMR(CDCl2-D2O)P
pm value: 3.20 (2H, ratio, C2-H), 4.59 (2H, s, C1CH2-), 4.93 (1H, d, J=5Hz, C6-H), 4.7
9,5.16(2H, ABq, J±16Hz, (3) diphenylmethyl di7-(4-chloro2-hydroxyimino-3-oxobutyramide)-3-[1-(5-chloro1, 2,4-tri3azolyl)methyl]-Δ3-
Cefemu 4-carboxylate 6.29y N,N-
Dissolve in 35ml of dimethylformamide, add 1.5V of sodium carbonate and 2.1y of dimethyl sulfate under ice cooling,
React for 1 hour at ~10°C.

After the reaction is completed, the reaction solution is introduced into 4,600 ml of water to precipitate crystals. If this is harvested and purified by column chromatography (Wako silica gel C-200: developing solvent: ethyl benzene diacetate 9:1), the melting point is 102 to 10.
Diphenylmethyl di7-(4-chloro-2-(syn)-methoxyimino-3-oxobutyramide)-3-[1-(5-chloro-1,2,4-triazolyl) showing 4°C (decomposition) 2.7 g (yield 42%) of methyl]-Δ3-cefemu 4-carboxylate are obtained. [R(KBr)
Cj! -1; νC=01782, 1720, 1690,
1670 NMR (CDCl3-D2O) Ppm value; 3.20 (2H, ratio, C2-H), 4.05 (3H, s, -0CH3), 4.50 (2H, s, C1CH2-), 4.95 ( 1H, d, J=5Hz, C6-H), 4.8
2,5.36 (2H, ABq, J = 15Hz, (4) diphenylmethyl di7-(4-chloro-2-(syn)-methoxyimino-3-oxobutyramide)-3-[1-
(5-chloro1,2,4-triazolyl)methyl]-
Δ3-cefemu 4-carboxylate 6.43y and thiourea 1y were converted to N,N-dimethylacetamide 48m
1 and react at room temperature for 2 hours.

After the reaction is complete, add 600ml of water and 600ml of ethyl acetate to the reaction solution.
m1 mixed solvent. Then, the pH was adjusted to 6.7 with sodium hydrogen carbonate, and the organic layer was separated. The aqueous layer is further extracted twice with 300 ml of ethyl acetate, and the organic layers are combined and washed twice with 800 ml of water, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. If diethyl ether is added to the residue and the resulting crystals are collected, the melting point is 15.
Diphenylmethyl di7-1 showing 5-15TC (decomposition)
2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamide]-3-[1-(5-
chloro1,2,4-triazolyl)methyl]-Δ3-
Cefemu 4-carboxylate 5.87y (yield 88
%). IR(KBr)Cm-1; νC=0178
1,1725,1672NMR (CDCl3-D2O)
Ppm value; 3.20 (2H, Me, C2-H), 3.86 (3H, S9-0CH3)9 4.99 (1H, d, J=5Hz, C6-H), No4.
82, 5.41 (2H, ABq, J=16Hz, (5)
Diphenylmethyl di7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamide]-3-[1-(5-chloro1,2,4-triazolyl)methyl] - 6.65y of Δ3-cefemu 4-carboxylate is dissolved in a mixed solvent of 35ml of trifluoroacetic acid and 10mL of anisole, and reacted at room temperature for 1 hour.

After the reaction is completed, the solvent is distilled off under reduced pressure, diethyl ether is added to the residue, and the resulting crystals are collected. If thoroughly washed with diethyl ether and dried, the melting point is 167C (decomposition).
7-[2-(2-aminothiazol-4-yl)]
-2-(syn)-methoxyiminoacetamide]-3-
5.71 Da (yield 93.2%) of trifluoroacetate of [1-(5-chloro1,2,4-triazolyl)methyl]-Δ3-cefemu-4-carboxylic acid is obtained. The physical properties (IR...NMR value) of this compound are as shown in Example 23-(
This was consistent with that obtained in 2).

Example 32 (1) 0.43y of diketene was dissolved in 5ml of anhydrous methylene chloride, and a solution of 3ml of anhydrous methylene chloride containing 0.81y of bromine was added dropwise at -30°C.
React the three batches at -20°C.

Then, this reaction solution was converted into diphenylmethyl di-7-amino-3
The mixture was added dropwise to a solution of 20 ml of anhydrous methylene chloride containing 2.0 y of -acetamidomethyl-Δ3-cefemu 4-carboxylate and 1.66 y of dimethylaniline at -30 DEG C. or below. After dropping, 3 times at -30 to -20℃, 0 to 1
React at 0°C for 1 hour. After the reaction, the solvent was distilled off under reduced pressure, and the resulting residue was mixed with 30 ml of ethyl acetate, 11 ml of water, and 20 ml of water.
Add m1 and dissolve. Separate the organic layer and add 20ml of water.
, and 20 ml of saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was then subjected to column chromatography (Wako silica gel C-200: developing solvent: benzene diacetate,
:1), diphenylmethyl di7-(4-bromo-3-oxobutyramide)-3-acetamidomethyl-Δ3-cefemu-4-carboxylate 2.4y
(yield 87.4%). IR(KBr)C7n-1
;νC=01775, 1720, 1690~1630N
MR (CDCl3) Ppm value: 1.81 (3H, s, -COCH3), 3.24-4.41 (4H, m, C2-H, 3.6l (
2H,s, -COCH2CO-), 3.97(2H,s
, BrCH2-), 4.85 (1H, d, J=5Hz,
C6-H), 5.76 (1H, dd, J=5Hz, J=
8Hz, C7-H), 6.12-6.55 (1H, m,
-NHCO-), 6.81 (1H, S9'l>CH-)
98.23 (1H, d, J = 8Hz, -CONH-) (
2) Dissolve 1.5y of diphenylmethyl di7-(4-bromo-3-oxobutyramide)-3-acetamidomethyl-Δ3-cephemu-4-carboxylate obtained in (1) in 7.5ml of acetic acid, A solution of 0.5 ml of water containing 0.193 fI of sodium nitrite was added dropwise to the solution over 15 minutes under ice-cooling, and the mixture was then allowed to react at room temperature for 1.5 hours.

After the reaction is completed, the solvent is distilled off under reduced pressure, and the resulting residue is dissolved in 20 ml of ethyl acetate and 15 ml of water.
The organic layer is separated, washed successively with 15 ml of water and 15 ml of saturated brine, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The resulting residue was then purified by column chromatography (Wako silica gel C-200; developing solvent: benzene ethyl diacetate 3:1) to obtain diphenylmethyl di(4-bromo-2-hydroxyimino-3-oxo). butyramide)-3-acetamidomethyl-Δ3-cefemu-4-carboxylate 1.32f
(yield 8.9%). (3) Diphenylmethyl 7
-(4-Bromo-2-hydroxyimino-3-oxobutyramide) -3-acetamidomethyl-Δ3-cephemu-4-carboxylate 0.9y and thiourea 0.9y.
131y was dissolved in 4 ml of dimethylacetamide and reacted at room temperature for 2 hours.

After the reaction is completed, 50 ml of diethyl ether is added to the reaction solution, the supernatant liquid is decanted, 50 ml of diethyl ether is added to the residue, and the same operation is performed to obtain a solid. Next, the solid was dissolved in a mixed solvent of 3.5 ml of trifluoroacetic acid and 1 ml of anisole, and the mixture was dissolved at room temperature for 1 hour.
Make it react. After the reaction is completed, the solvent is distilled off under reduced pressure, diethyl ether is added to the residue, and the resulting crystals are collected. The crystals were then dissolved in 10 ml of water and the pH was adjusted to 7.5 with sodium bicarbonate. If this solution is purified by passing it through a column of Appalite XAD-2, the melting point is 20.
7-[2-(2-aminothiazol-4-yl)-2-(syn)-hydroxyiminoacetamide]-3-acetamidomethyl-Δ3-cephemu 4 showing 00C or higher
- 0.28 fI of the sodium salt of carboxylic acid (yield 42.
4%). Example Feather (1) Diphenylmethyl di7-(4-bromo-3-oxobutyramide)-3-[2-(5-methyl-1,2) obtained in Example 16-(1)
, 3,4-tetrazolyl)methyl]-Δ3-cefemu 4-carboxylate was dissolved in 40 ml of acetic acid, and a solution of 1 g of sodium nitrite in 6 ml of water was added dropwise to this under ice-cooling over a period of 1 hour. Then, the mixture is allowed to react at room temperature for 2 hours.

After the reaction is completed, the reaction solution is introduced into 600 ml of water, and crystals are precipitated. If this is collected, washed thoroughly with water, and dried, diphenylmethyl di(4-
Bromo 2-hydroxyimino 3-oxobutyramide)-3-[2-(5-methyl-1,2,3,4-tetrazolyl)methyl]-Δ3-cefemu 4-carboxylate 5.43y (yield 83. 0%). (2) Diphenylmethyl di7-(4-bromo-2-hydroxyimino-3-oxobutyramide)-3-[2-(5-methyl-1,2,3,4-tetrazolyl)methyl]-Δ3
- Cefemu 4-carboxylate 6.54f and thiourea 1y are dissolved in 35mt of N,N-dimethylacetamide and reacted for 2 hours at room temperature.

After the reaction, the reaction solution was mixed with 500ml of water and 500ml of ethyl acetate.
m1 mixed solvent. Then adjust the pH to 7 with sodium carbonate. Adjust to O and separate the organic layer. The aqueous layer is further extracted twice with 200 ml of ethyl acetate, the organic layers are combined and dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure. The residue was purified by column chromatography (Wako silica gel C-200; developing solvent: chloroform; methanol
0:1), diphenylmethyl di7-[2-(2-aminothiazol-4-yl)-2-(syn)-hydroxyiminoacetamide]-3- exhibits a melting point of 164°C (decomposition). [2-(5-Methyl-1,2,3,4-tetrazolyl)methyl]-Δ3-cefemu 4-carboxylate 3.2y (yield 50.7%) is obtained. (3) Diphenylmethyl di7-[2-(2-aminothiazol-4-yl)-2-(syn)-hydroxyiminoacetamide]-3-[2-(5-methyl-1,2,3,4- 6.31y of [tetrazolyl)methyl]-Δ3-cefemu 4-carboxylate was dissolved in a mixed solvent of 32 ml of trifluoroacetic acid and 10 ml of anisole, and 1.
Allow to react for 5 hours.

After the reaction is completed, the solvent is distilled off under reduced pressure, diethyl ether is added to the residue, and the resulting crystals are collected. If thoroughly washed with diethyl ether and dried, the melting point is 175°C (decomposition).
shows. 7-[2-(2-aminothiazol-4-yl)-2-(syn)-hydroxyiminoacedeamide]-
5.33y (yield: 92.1%) of trifluoroacetate of 3-[2-(5-methyl-1,2,3,4-tetrazolyl)methyl]-Δ3-cefemu-4-carboxylic acid is obtained.

The following compound is obtained in the same manner.

07-[2-(2-aminothiazol-4-yl)-2
-(Syn)-Hydroxyiminoacetamide]-3-benzyl-Δ3-cefemu-4-carboxylic acid trifluoroacetate Melting point; 139°C (decomposition) Example ((1) 2-[2-(benzyloxycarboxamide 5
-Chlorothiazol-4-yl]-2-(syn)-methoxyiminoacetic acid 3.70y in anhydrous methylene chloride 50ml
1, 1.06y of N-methylmorpholine was added, and the reaction solution was cooled to -35°C.

Then add 1.12y of ethyl chlorocarbonate to -30 to -12
After reacting at 0°C for 2 hours, diphenylmethylni-7-amino-3-acetamidomethyl-Δ3-cephemu4-
Anhydrous chloroform 5 containing 4.37y carboxylate
Add 0 ml of the solution dropwise and react at -20 to -10°C for 1 hour and at room temperature for 3 hours. After the reaction, the solvent was distilled off under reduced pressure, and the resulting residue was mixed with 50 mt of ethyl acetate and 40 m of water.
Add and dissolve 1, separate the organic layer, and add 40ml of water again.
and PHL. under ice-cooling with △monohydrochloric acid. Adjust to 5. Then, the organic layer was separated, 40 ml of water was added, and the pH was adjusted to 7.0 with sodium bicarbonate under ice cooling. Adjust to O. The organic layer was separated, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
When diethyl ether is added to the residue and the resulting crystals are distilled, diphenylmethyl di[2-(2-(benzyloxycarboxamide)-5-chlorothiazole]) has a melting point of 132-136°C (decomposition). 4-yl)-2-(syn)-methoxyiminoacetamide]-3-acetamidomethyl-Δ3-cefemu 4-carboxylate6.
50y (yield 82.4%) is obtained. IR(c!n-ri)
; VC=01780,1720,1680~(2) diphenylmethyl di7-[2-(2-(benzyloxycarboxamide)-5-chlorothiazol-4-yl)-
0.79 da of 2-(syn)-methoxyiminoacetamide]-3-acetamidomethyl-Δ3-cephemu 4-carboxylate was dissolved in 15 ml of anisole, and 1.33 f of aluminum chloride was added under ice cooling, and the mixture was heated at 5 to 10°C. 2
Allow time to react. After the reaction is completed, the reaction solution is added to 30 ml of ice water, the pH is adjusted to 7.5 with sodium hydrogen carbonate, and insoluble materials are separated. Next, after washing the honeycomb solution with 30 ml of ethyl acetate, 50 ml of methyl ethyl ketone was added, and the pH was adjusted to 2.0 with monohydrochloric acid. Adjust to O. The organic layer is separated, washed with 30 ml of saturated brine, dried over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure, diethyl ether is added to the residue, and the resulting crystals are collected. 7-[2-(2-amino-5-chlorothiazol-4-yl)-2-(syn)-methoxyiminoacetamide]-3-acetamidomethyl-Δ3-cefemu-4-carvone showing 152'C (decomposition) 0.37y of acid (yield 75.7%) is obtained. Example 35 (1) 2-(thiazol-4-yl)-2-(syn)-
1.58 fI of methoxyiminoacetic acid in anhydrous methylene chloride 4
1.06 f of N-methylmorpholine was added, and the reaction solution was cooled to -35°C.

Then, 1.12y of ethyl chloroacetate was added to -35 to -2
After reacting at 5°C for 1.5 hours, the diphenylmethyl di-7-amino-3-[1-(5-chloro-1,2,4-triazolyl)methyl]-Δ3-cefemu-4-carboxy obtained in Reference Example 21 Add rate 4.82y and -30~-
1 hour at 200C, 1 hour at -10~5℃, 1m at 5℃
Let it react for a while. After the reaction is complete, the solvent is distilled off under reduced pressure, and the resulting residue is mixed with ethyl acetate 507F! t1 Add 40 ml of water to dissolve, separate the organic layer, add 40 ml of water again, and add PHL with hydrochloric acid under ice cooling. Adjust to 5. Then, the organic layer was separated, 40 mL of water was added, and the pH was adjusted to 7.0 with sodium bicarbonate under ice cooling. Adjust to O. The organic layer is separated, dried over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure, diethyl ether is added to the residue, and the resulting crystals are collected.
Diphenylmethyl di7-[2-(thiazol-4-yl)-2-(syn)-methoxyiminoacetamide]-3-[1-(5-chloro1,2) showing 02-104°C (decomposition) ,4-triazolyl)methyl]-Δ3-cefemu 4-carboxylate 5.77y (yield 92.8%)
get. The following compound is obtained in the same manner.

O diphenylmethyl di7-[2-(thiazole-4-
yl)-2-(syn)-methoxyiminoacetamide]
-3-[2-(5-methyl-1,2,3,4-tetrazolyl)methyl]-Δ3-cefemu 4-carboxylate Melting point: 106-10 CfC (decomposition) IR (KBr) (1-1; νC=01780 ,1730
, 1630 NMR (CDCl3) Ppm value: (2) (1
) Diphenylmethyl di7-[2-(thiazol-4-yl)-2-(syn)-methoxyiminoacetamide]-3-[1-(5-cucaro-1,2,4-triazolyl) 5.77 g of [methyl]-Δ3-cefemu-4-carboxylate was dissolved in a mixed solvent of 29 ml of trifluoroacetic acid and 10 ml of anisole, and reacted at room temperature for 2 hours.

After the reaction is completed, the solvent is distilled off under reduced pressure, diethyl ether is added to the residue, and the resulting crystals are collected. If thoroughly washed with diethyl ether and dried, the melting point will be 130-140℃.
(decomposition) 7-[2-(thiazol-4-yl)-
2-(syn)-methoxyiminoacetamide]-31[
3.86y (yield: 91.5%) of 1-(5-chloro1,2,4-triazolyl)methyl]-Δ3-cefemu-4-carboxylic acid is obtained. The following compound is obtained in the same manner.

07-[2-(thiazol-4-yl)-2-(syn)
-methoxyiminoacetamide]-3-[2-(5-methyl-1,2,3,4-tetrazolyl)methyl]-Δ3
-Cefemu 4-carboxylic acid Melting point: 129-134°C (
Disassembly) u●νν 〜53Sw＆▼JV▼Vゑ1Ua Example 3
6(1) 7-[2-(2-T) obtained in Example 23-(1)
ert. Monoamyloxycarboxamide thiazole-4
6.1
3f was dissolved in 30 ml of N,N-dimethylformamide, and under ice-cooling, 1y1 of triethylamine and 2.9y of pivaloyloxymethyl iodide were added to react the 3 powders.

After the reaction is complete, add 300ml of water to 300ml of ethyl acetate.
ml of mixed solvent and adjust the pH to 7 with sodium hydrogen carbonate.
．． Adjust to O. Then, separate the organic layer and add 100ml of water.
After sequentially washing with 100 ml of saturated brine, drying over anhydrous magnesium sulfate, and distilling off the solvent under reduced pressure. Add diisopropyl ether to the residue, collect the resulting crystals,
After thorough washing with diisopropyl ether and drying, pivaloyloxymethyl di7-[2-(2-Tert.-amyloxycarboxamidothiazol-4-yl)-2]
-(syn)-methoxyiminoacetamide]-3-[1
-(5-chloro1,2,4-triazolyl)methyl]
-Δ3-cefemu 4-carboxylate 6.6y (yield 90.8%) is obtained. (2) Pivaloyloxymethyl di7-[2-Tert.-amyloxycarboxamidothiazol-4-yl)-2-(syn)-methoxyiminoacetamide]-3-[2-Tert.-amyloxycarboxamidothiazol-4-yl)-2-(syn)-methoxyiminoacetamide]-3-[ 1-(5
-chloro1,2,4-triazolyl)methyl]-Δ3
-Cefemu 4-carboxylate 6.6f is dissolved in ml of trifluoroacetic acid and reacted between 3C@ at room temperature. After the reaction is complete, the solvent is distilled off under reduced pressure, and 80 ml of water and 80 ml of ethyl acetate are added to the resulting residue, and the pH is adjusted to 7.0 with sodium hydrogen carbonate under ice cooling. The organic layer is separated, dried over anhydrous magnesium sulfate, and then 20 ml of a dry hydrogen chloride-diethyl ether solution (containing 1y of hydrogen chloride) is added while stirring under ice cooling to precipitate a white powder. If this is taken, thoroughly washed with diethyl ether and dried, the melting point is 1.
pivaloyloxymethyl di7-[2-(2-aminothiazol-4-yl)-2] showing 34-136°C (decomposition)
-(syn)-methoxyiminoacetamide]-3-[1
-(5-chloro1,2,4-triazolyl)methyl]
-Δ3-cefemu 4-carboxylate hydrochloride 5.
2y (yield 88.2%) is obtained. Example 37 The compound shown in Table 17 is obtained by reacting and treating in the same manner as in Example 36.

Example 7-Amino-3- obtained in Reference Example 10 instead of J-Me[amino-3-[1-(5-chloro-1,2,4-triazolyl)methyl]-Δ3-cefemu-4-carboxylic acid [1-(
3-Methyl-1,2,4-triazolyl)methyl]-Δ
Example 23-(1) using 3-cefemu-4-carboxylic acid
) and treated in the same manner as 7-[2-(2-Te
rt. -Amyloxycarboxamide thiazole-4-
yl)-2-(syn)-methoxyiminoacetamide]
-3-[1-(3-methyl-1,2,4-triazolyl)methyl]-Δ3-cefemu-4-carboxylic acid is obtained.

When this compound is reacted and treated in the same manner as in Example 36, it exhibits a melting point of 144-146°C (decomposition). (Syn)-Methoxyiminoacetamide]-
3-[1-(3-methyl-1,2,4-triazolyl)
[Methyl]-Δ3-cefemu 4-carboxylate hydrochloride is obtained. Example 39 7-amino-3-[1-(5-chloro-1,2,4-triazolyl)methyl]-Δ3-cefemu-4-carboxylic acid obtained in Reference Example 11 instead of 7-amino-3-[1-(5-chloro-1,2,4-triazolyl)methyl]-
7-[2-
(2-Tert.-amyloxycarboxamidothiazol l-4-yl)-2-(syn)-methoxyiminoacetamide]-3-[1-(3-methylthio 1,2,
4-triazolyl)methyl]-Δ3-cefemu 4-carboxylic acid is obtained.

When this compound is reacted and treated in the same manner as in Example 36, it exhibits a melting point of 135.about.13TC (decomposition).
The hydrochloride of -yl)-2-(syn)-methoxyiminoacetamide]-3-[1-(3-methylthio 1,2,4-triazolyl)methyl]-Δ3-cefemu 4-nocarboxylate is obtained. u◆υυ \1A＆9U9J1
011L9νVilA1-1 Example 40(1)7-[2
-(2-chloroacetamidothiazol-4-yl)-
2-(syn)-methoxyiminoacetamide]-3-acetamidomethyl-Δ3-cephemu 4-carboxylic acid 5
．． 31y was dissolved in 26 ml of N,N-dimethylformamide, and under ice-cooling, 1y1 of triethylamine and 2.9y of pivaloyloxymethyl iodide were added thereto for a three-powder reaction.

After the reaction is complete, add 25077!11 ethyl acetate to the reaction solution.
It was introduced into 50 ml of mixed solvent, and the pH was adjusted to 7.0 with sodium hydrogen carbonate. Adjust to O. Then, separate the organic layer and add 80% water
After sequentially washing with m1 and 80 TrL1 of saturated saline, drying over anhydrous magnesium sulfate, and distilling off the solvent under reduced pressure.
What about the crystals obtained by adding diethyl ether to the residue? If taken, thoroughly washed with diethyl ether and dried, the melting point is 12.
Pivaloyloxymethyl 7-5 showing 4°C (decomposition)
2-(2-chloroacetamidothiazol-4-yl)
-2-(syn)-methoxyiminoacetamide]-3-
5.86y of acetamidomethyl-Δ3-cephemu-4-carboxylate (yield 90.9%) is obtained. (2)(
pivaloyloxymethyl di7-[2-(2-
Chloroacetamidothiazol-4-yl)-2-(syn)-methoxyiminoacetamide]-3-acetamidomethyl-Δ3-cefemu-4-carboxylate5.
86f was dissolved in 25 ml of N,N-dimethylacetamide, 1.04 y of thiourea was added, and the mixture was allowed to react at room temperature for 1 hour.

After the reaction is complete, add 300ml of water and 300ml of ethyl acetate to the reaction solution.
ml of mixed solvent, and pH was adjusted with sodium hydrogen carbonate.
7. Adjust to O. Then, separate the organic layer and add 100ml of water.
1. After sequentially washing with 100 ml of saturated brine, drying over anhydrous magnesium sulfate, and distilling off the solvent under reduced pressure. Diethyl ether is added to the residue, the resulting crystals are collected, thoroughly washed with diethyl ether, and dried to give a melting point of 133 to 1.
Pivaloyloxymethyl 271 showing 35°C (decomposition)
2-(2-Aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamide]-3-acetamidomethyl-Δ3-cefemu 4-carboxylate 4.2
0y (yield 81.3%). The following compound is obtained in the same manner. O pivaloyloxymethyl di7-[2-(2
-aminothiazol-4-yl)-2-(syn)1-methoxyiminoacetamide]-3-[1-(1,2,4
-triazolyl)methyl]-Δ3-cefemu-4-carboxylate melting point; 130-137C (decomposition) Example 41 (1)7-[2-(2-chloroacetamidothiazol-4-yl)-2-(syn)- 5.55 f of methoxyiminoacetamide]-3-[2-(5-methyl-1,2,3,4-tetrazolyl)methyl]-Δ3-cephemu-4-carboxylic acid and 27 ml of N,N-dimethylformamide
After dissolving the mixture, 2.3f of triethylamine 1y1 phthalidyl bromide was added under ice cooling, and the mixture was allowed to react for 6 hours.

After the reaction is complete, add 250ml of water and 250ml of ethyl acetate to the reaction solution.
ml of mixed solvent, and pH was adjusted with sodium hydrogen carbonate.
7. Adjust to O. The organic layer is then separated, washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 6.05f of a crude solid. If this was purified by column chromatography (Wako silica gel C-200; developing solvent: benzene; ethyl acetate 2:1), the melting point was 156.
~15rc (decomposition)
-chloroacetamidothiazol-4-yl)-2-(
syn)-methoxyiminoacetamide]-3-[2-(
5-Methyl-1,2,3,4-tetrazolyl)methyl]
-Δ3-cefemu 4-carboxylate 2.78V (
Yield: 40.5%).

(2) Phthalidyl di7-[2-(2-chloroacetamidothiazol-4-yl)-2-(syn)-methoxyiminoacetamide]-3-[2-(5-
Methyl-1,2,3,4-tetrazolyl)methyl]-Δ
3-cefemu 4-carboxylate 2.5y N,N
-Dissolve in 10TfL1 of dimethylacetamide, add 0.42y of thiourea at room temperature, and react for a specific time. After the reaction was completed, the reaction solution was introduced into a mixed solvent of 250 ml of water and 250 ml of ethyl acetate, and the pH was adjusted to 7.0 with sodium hydrogen carbonate. O
Adjust to. The organic layer was then separated, washed successively with 100 ml of water and 100 ml of saturated brine, dried over anhydrous magnesium sulfate, and added with a dry hydrogen chloride-diethyl ether solution while stirring under ice cooling to precipitate white crystals. If this is taken out and thoroughly washed with diethyl ether, the melting point is 16.
Phthalidylni7-[2-(
2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamide]-3-[2-(5-methyl-1,2,3,4-tetrazolyl)methyl]-Δ3-cefemu 4-carboxylate 1.8V (yield 76.5%) of the hydrochloride of is obtained. Similarly, the following compound is obtained.

○ Methyl di7-[2-(2-chloroacetamidothiazol-4-yl)-2-(syn)-methoxyiminoacetamide]-3-[2-(5-methyl-1,2,3,
4-tetrazolyl)methyl]-Δ3-cephemu 4-carboxylate melting point; 189-191°C (decomposition) O Methyl 7-[2-(2-aminothiazole-4-
yl)-2-(syn)-methoxyiminoacetamide]
-3-[2-(5-Methyl-1,2,3,4-tetrazolyl)methyl]-Δ3-cefemu 4-carboxylate hydrochloride melting point; 154°C (decomposition) Example 42 In Example 35-(2) Obtained 71 [2-(thiazole-4-
yl)-2-(syn)-methoxyiminoacetamide]
-3-(3-chloro1,2,4-triazolyl)methyl-Δ3-cefemu-4-carboxylic acid 4.55yf! −
Dissolve in 25 ml of N,N-dimethylformamide, add 2.9 da of triethylamine 1y1 pivaloyloxymethyl iodide under ice cooling, and react for 30 minutes.

After the reaction is complete, add 300ml of water and 300ml of ethyl acetate to the reaction solution.
ml of mixed solvent, and pH was adjusted with sodium hydrogen carbonate.
7. Adjust to O. Then, separate the organic layer and add 100ml of water.
1. After sequentially washing with 100 ml of saturated brine, drying over anhydrous magnesium sulfate, and distilling off the solvent under reduced pressure. Diisopropyl ether is added to the residue, and the resulting crystals are collected, thoroughly washed with diisopropyl ether, and dried to give pivaloyloxymethyl 2-[2-(thiazo- Lou 4-il)-2-(shin)
-methoxyiminoacetamide]-3-(3-chloro-1,2,4-triazolyl)methyl-Δ3-cefemu-4-carboxylate 5.07y (yield 89.0%λ
−≦! - Obtain the following compound in the same manner.

O pivaloyloxymethyl di7-[2-(thiazol-4-yl)-2-(syn)-methoxyiminoacetamide]-3-[2-(5-methyl-1,2,3,4-tetrazolyl) ) methyl] -Δ3-cefemu 4-carboxylate melting point; 71-8rC (decomposition) Example 43 7-[2-(2-aminothiazol-4-yl)-2-
(syn)-methoxyiminoacetamide]-3-[1-
(5-chloro1,2,4-triazolyl)methyl]-
Δ3-cefemu 4-carboxylic acid trifluoroacetate 6
．． 13f is suspended in 25 ml of water, the pH is adjusted to 80 with sodium bicarbonate under ice cooling, and the suspension is dissolved.

Then, by adjusting the pH to 2.5 with concentrated hydrochloric acid at the same temperature, crystals will crystallize. If you take it out, wash it thoroughly with water and then acetone, and dry it, it will show a melting point of 200°C or higher.
2-Aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamide]-3-[1-(5-chloro1,2,4-triazolyl)methyl]-Δ3-cefemu-4-carboxylic acid4. 71f (yield 94.5%) is obtained. - - - - J Yok2- (2-aminothiazole-4-
yl)-2-(syn)-methoxyiminoacetamide]
-3-[2-(5-methyl-1,2,3,4-tetrazolyl)methyl]-Δ3-cephemu-4-carboxylic acid Melting point>200°C Example 44 4-bromo-3-oxo-2-methoxyiminobutyric acid 2
．． 2.0 V of 24y11-oxybenztriazole and 4.62 V of diphenylmethyl di-7-amino-3-[1-(5-chloro-1,2,4-triazolyl)methyl]-Δ3-cefemu-4-carboxylate were added to 50 ml of anhydrous tetrahydrofuran. Dissolution: Dissolve and cool to 5°C.

Then N,N″-dicyclohexylcarbodiimide 2.
Add 5y and react at the same temperature for 3 minutes and at room temperature for 5 hours. After the reaction is completed, insoluble matter is removed, and the solvent is distilled off from the suspension under reduced pressure. After adding 40 ml of ethyl acetate to the residue and removing a small amount of insoluble matter in an oven, the residue was washed with a 5% aqueous sodium bicarbonate solution and then with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by column chromatography (Wako silica gel C-200; developing solvent: benzene; ethyl acetate 9:1) to give a melting point of 91-?
℃ (decomposition) of diphenylmethyl Jyoiroi 4-bromo 2-methoxyimino 3-oxobutyramide 3-[
1-(5-chloro-1,2,4-triazolyl)methyl]-Δ3-cefemu 4-carboxylate 3.65f
(yield 54.6%). Similarly, the following compound was obtained.

Diphenylmethyl 4-bromo-2-methoxyimino-3-oxobutyramide)-3-[2-(5-methyl-1,2,3,4-tetrazolyl)methyl]-Δ3-
Cefemu 4-carboxylate melting point; 80-87C (
Disassembly) IR (KBr) C77! -1; νC=01780,17
20,1680 NMR (CDCl3) Ppm value; Example 45 3-oxo 2-methoxyiminobutyric acid 1.459, 1-
Oxybenztriazole 2.0y and diphenylmethylni7-amino-3-[1-(5-chloro1,2,
4-triazolyl)methyl]-Δ3-cefemu 4-carboxylate 4.62f in anhydrous tetrahydrofuran 5
Dissolve in 0ml and cool to 5°C.

Then N,N″-dicyclohexylcarbodiimide 2.
Add 5f and react at the same temperature for 3 minutes and at room temperature for 5 hours.
After the reaction is completed, insoluble materials are removed and the solvent is distilled off from the resulting solution under reduced pressure. After adding 40 mL of ethyl acetate to the residue to remove a small amount of insoluble matter, the residue was washed with a 5% aqueous sodium hydrogen carbonate solution and then with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. If the obtained residue is purified by column chromatography (Wako silica gel C-200; developing solvent: benzene; ethyl acetate 8:1), the melting point is 102-103°C.
Diphenylmethyl di7-(2-methoxyimino-3-oxobutyramide)-3-[1-(5-
chloro1,2,4-triazolyl)methyl]-Δ3-
Cefemu 4-carboxylate 3.7y (yield 62.
8%). IR(KBr)Cm-1; νC=017
75,1740,1670NMR(D6-DMSO)P
pm value; Example 46 (1) 7-amino-3-[1-(5-chloro1,2,
2.96 g of 4-triazolyl)methyl]-Δ3-cefemu-4-carboxylic acid was suspended in 90 ml of anhydrous methylene chloride, and 2.02 g of triethylamine and 1.7 y of diketene were added under ice cooling, and the mixture was heated at 5 to 10°C for 4 hours. Make it react.

After the reaction is completed, 100 ml of water is added to the reaction solution and the aqueous layer is separated. Next, add 100ml of ethyl acetate, and add P with △monohydrochloric acid.
Hl. Adjust to O. After removing the horsetail precipitate, the organic layer is separated and dried over anhydrous magnesium sulfate. About 1.6 y of diphenyldiazomethane was slowly added to the mixture while stirring, and the mixture was reacted with three powders. The solvent of the reaction mixture was distilled off under reduced pressure, and isopropyl ether was added to the residue to collect the crystals. After thorough washing with isopropyl ether and drying, diphenylmethyl di(3-oxobutylamide 3-[1-(5-chloro.1,2,4-triazolyl) having a melting point of 75-77°C (decomposition) ) methyl]-Δ3-cephemu 4-carboxylate 3.3 g (yield 60.4%
). v▼Recruitment-uwoJVlAB9νV
The following compound was obtained in the same manner.

Diphenylmethyl di7-(oxobutyramide)-3-
[2-(5-methyl-1,2,3,4-tetrazolyl)
Methyl]-Δ3-cefemu 4-carboxylate)
Melting point: 84-86°C (decomposition) (2) Diphenylmethyl di7-(3-oxobutyramide 3-[1-(5-chloro1,2,4) obtained in (1)
-Triazolyl)methyl]-Δ3-Cefemul-Carbohon-NlehKf-Sora#. Diphenylmethyl di(2-hydroxyimino-3-oxobutyramide)-3-[1-(5- Kuroro 1,2,4-
Triazolyl)methyl]-Δ3-cefemu-4-carboxylate was obtained.

Similarly, the following compound was obtained.

Diphenylmethyl di7-(2-hydroxyimino-3-
oxobutyramide)-3-[2-(5-methyl-1,
2,3,4-Tetrazolyl)methyl]-Δ3-cephemu 4-carboxylate Melting point: 102-105°C (decomposition) (3) Diphenylmethyl di7-(2-hydroxyimino 3- oxobutyramide)-3-[1
-(5-chloro1,2,4-triazolyl)methyl]
-Δ3-cefemu 4-carboxylate and diphenylmethyl di7-(2-hydroxyimino-3-oxobutyramide)-3-[2-(5-methyl-1,2,
3,4-tetrazolyl)methyl]-Δ3-cephemu4
-carboxylate was reacted in the same manner as in Example 31-(3), and the diphenylmethyl di(2-methoxyimino-3-oxobutyramide)-3-[ exhibiting a melting point of 102-103°C (decomposition)] 1-(5-chloro-1,2,4-triazolyl)methyl]-Δ3-cephemu-4-carboxylate and diphenylmethyl di(2-methoxyimino-3-carboxylate) with a melting point of 88-90'C (decomposition). oxobutyramide)-3-[2-(5-methyl-1,2,
3,4-tetrazolyl)methyl]-Δ3-cephemu4
-carboxylate was obtained.

The physical properties (IR, NMR) of this compound were consistent with those obtained in Example 45.

Example 47 Diphenylmethyl di7-(2-methoxyimino-3-oxobutyramide)-3-[2-(5-methyl-1,2
, 3,4-tetrazolyl)methyl]-Δ3-cephemu-4-carboxylate and 120 ml of dry tetrahydrofuran were dissolved, and 1 ml of aluminum chloride was dissolved in this.
．． Add 34y.

Add 5.00 f of pyridinium hydrobromide perbromide to this solution at room temperature, and stir at the same temperature for three times. After the reaction is complete, the solvent is distilled off under reduced pressure, and 50 ml of ethyl acetate and 50 ml of water are added to the distillate to remove a small amount of insoluble material, and the organic layer is separated. This is washed with water, dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure. The obtained residue was subjected to column chromatography (Wako silica gel C-200: developing solvent: ethyl benzene diacetate 9:1).
If purified with ,4-tetrazolyl)methyl]-Δ3-cefemu 4-carboxylate 4.13y (yield 61.8
%). The physical properties (IR, NMR) of this compound were consistent with those obtained in Example 44.

Similarly, the following compound was obtained.

Diphenylmethyl di7-(4-bromo-2-methoxyimino-3-oxobutyramide)-3-[1-(5-chloro-1,2,4-triazolyl)methyl]-Δ3-cephemu-4-carboxylate , the physical properties of this compound (
The melting point, IR, NMR) were consistent with those obtained in Example 44.

Example 48 (1) 2-(2-chloroacetamidothiazol-4-yl)glyoxylic acid 2.49f1 in N,N
-Dissolved in 13ml of dimethylacetamide, -20-
Add 3.07y of phosphorus oxychloride dropwise at C to -20 to -10
After reacting at ℃ for 1 hour, 4.62y of diphenylmethyl di-7-amino-3-[2-(5-methyl-1,2,3,4-tetrazolyl)methyl]-Δ3-cefemu-4-carboxylate was added. The mixture is reacted for 3 times at 20°C to -10°C for 30 minutes at room temperature.

After the reaction is complete, add 40ml of water and 60ml of ethyl acetate to the reaction solution.
into a mixed solvent. Then adjust the pH to 7 with sodium hydrogen carbonate. Adjust to O and separate the organic layer. Ru. 30m1 water
After washing with water, it is dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. Add diethyl ether to the residue,
The obtained crystals were collected and obtained as diphenylmethyl di7-[2-(2-chloroacetamidothia.zol-4-yl)glyoxylamide]-3 having a melting point of 115-119°C.
-[2-(5-methyl-1,2,3,4-tetrazolyl)methyl]-Δ3-cefemu 4-carboxylate 6
．． 35y (yield 91.6%) is obtained. Similarly, the following compound was obtained. Diphenylmethyl di7-[2-(2-chloroacetamidothiazol-4-yl)glyoxylamide 3-[1-(5-chloro-1,2,4-triazolyl)methyl]-Δ3-cefemu-4-carboxylate '(2) Dissolve 0.84y of hydrochloride in 30ml of methanol, and dissolve 0.76y of triethylamine.
was added, and then the diphenylmethyl di7i obtained in (1) [
2-(2-chloroacetamidothiazol-4-yl)
-glyoxylamide]-3-[2-(5-methyl-1
,2,3,4-tetrazolyl)methyl]-Δ3-cefemu 4-carboxylate was added, and 3.46y of
Allow time to react.

After the reaction, the solvent was distilled off under reduced pressure, and the residue was mixed with 30ml of water.
1. Add 30ml of ethyl acetate, separate the organic layer, and add 2.0ml of water.
After washing with 0 ml of water, it was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. When diethyl ether is added to the residue and the resulting crystals are collected, the melting point is 129-1377C.
Diphenylmethyl di7-[2-(2-chloroacetamidothiazol-4-yl)-2-(syn)-methoxyiminoacetamide]-3-[2-(5
-Methyl-1,2,3,4-tetrazolyl)methyl]-
Δ3-cefemu 4-carboxylate 2.80' (yield 77.6%) is obtained. Similarly, the following compound was obtained. diphenylmethyl di7-[2-(2-chloroacetamidothiazol-4-yl)-2-(syn)-methoxyiminoacetamide]-3-[1-(5-chloro1,
2,4-triazolyl)methyl]-Δ3-cefemu 4
- Carboxylate melting point: 120-124°C (decomposed) (
3) Diphenylmethyl di7-[2-(2-
Chloroacetamidothiazol-4-yl)-2-(syn)-methoxyiminoacetamide]-3-[2-(5
-Methyl-1,2,3,4-tetrazolyl)methyl]-
Δ3-cefemu 4-carboxylate 2.0f in N,
Dissolve in 10 ml of N-dimethylformamide, add 0.27 y of thiourea, and react at room temperature for 3 hours.

After the reaction is complete, add the reaction solution to 20 ml of water and 30 ml of ethyl acetate.
into a mixed solvent. Then adjust the pH to 7 with sodium hydrogen carbonate. The organic layer was separated and washed with 15 ml of water and 15 ml of saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. If diethyl ether is added to the residue and the resulting crystals are collected, the melting point is 10.
Diphenylmethyl di7-1 exhibiting a temperature of 2 to 105°C (decomposition)
2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamide]-3-[2-(5-
Methyl-1,2,3,4-tetrazolyl)methyl]-Δ
1.45y of 3-cefemu 4-carboxylate (yield 81.0%) is obtained. Similarly, the following compound was obtained.

Diphenylmethyl di7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamide]-3-[1-(5-chloro1,2,4-triazolyl)methyl] -Δ3-Cefemu4-Carboxylate Ya・? Y4lA~127C (Bonkai ≧ - - -
--- (4) The compound obtained in (3) was used as Example 26-(2)
The reaction treatment was carried out in the same manner as above to obtain the compounds shown in Table 18.

Example 49 (1) 7-amino-3-[2-(5-methyl-1,2,
3,4-tetrazolyl)methyl]-Δ3-fu〒′--A-+J! Suspend in 20 ml of 71 V solute 90 ml of N-N-S chloroformamide, and add 1.1 y of triethylamine to dissolve under ice-cooling.

Then, 2.7y of pivaloyloxymethyl iodide
and react at 0 to 5°C for 1 hour. After the reaction was completed, the reaction solution was introduced into a mixed solvent of 250 ml of water and 200 ml of ethyl acetate, and the pH was adjusted to 7.0 with sodium hydrogen carbonate. Adjust to O. After removing insoluble matter, the organic layer is separated, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. Next, the residue was washed with diethyl ether, dissolved in 30 ml of ethyl acetate, and 30 ml of a dry hydrogen chloride-diethyl ether solution (containing 1y of hydrogen chloride) was added while stirring under ice cooling.
194) is added.

If the precipitated crystals are collected in a furnace, thoroughly washed with diethyl ether, and then recrystallized with chloroform, the melting point is 149-151°C.
2.72f of the hydrochloride of pivaloyloxymethyl di-7-amino-3-[2-(5-methyl-1,2,3,4-tetrazolyl)methyl]-Δ3-cefemu-4-carboxylate (decomposition) 60.9%). The physical properties (IR and NMR) of this compound are as shown in Example 19-
This was consistent with what was obtained in (2).

By similar reaction, Table-19 and Table-1 can be obtained from any raw material.
The corresponding compound shown in 20 was obtained. Example 50 Anhydrous methylene chloride 8 ml. ．． Add 3.7 y of phosphorus oxychloride to a mixed solvent of 2.3 ml of N,N-dimethylacetamide at 0 to 5°C, react with 3 powders at the same temperature, and then cool the reaction solution to -15 to -10°C. Then, 2.4y of 2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetic acid was added, and the mixture was allowed to react at the same temperature for 20 minutes.

Then, pivaloyloxymethyl di-7-amino-3-[2-(5-methyl-1,2,3,
A solution of 20 ml of anhydrous methylene chloride containing 4.47 y of 4-tetrazolyl)methyl]-Δ3-cefemu 4-carboxylate hydrochloride and 1.01 y of triethylamine is added dropwise. After dropping, 3 times at -1 (temperature), 3 times at 0℃,
React in three batches at room temperature. After the reaction, the solvent was distilled off under reduced pressure, 50 ml of water and 50 ml of ethyl acetate were added to the residue, and the pH was adjusted to 7.0 with sodium hydrogen carbonate. Adjust to O. The organic layer is separated, sequentially washed with 30 ml of water and 30 WLt of saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, diethyl ether was added to the residue, and the crystals were collected. -4-yl)-2-(syn)-methoxyiminoacetamide]-3-[2-(5-methyl-1,2,3,4-tetrazolyl)methyl]-Δ3-cefemu 4-carboxylate 5.1 g ( Yield: 86%). IR (KBr
) d-1; νC=01780, 1743, 1675 Table-21 and Table-22 from any raw material by a similar reaction
The corresponding compound shown in was obtained.

Example 51 pivaloyloxymethyl di-7-amino-3-
Example 16-(1) and Example 1(1), (
2), and pivaloyloxymethyl di7
-[2-(2-aminothiazol-4-yl)-2
-(syn)-hydroxyiminoacetamide]-3-[
2-(5-Methyl-1,2,3,4-tetrazolyl)methyl]-Δa-cefemucarboxylate was obtained.

This compound was further treated with a dry hydrogen chloride-diethyl ether solution in ethyl acetate to give a melting point of 142-145°C (decomposition).
-aminothiazol-4-yl)-2-(syn)-hydroxyiminoacetamide]-3-[2-(5-
Methyl-1,2,3,4-tetrazolyl)methyl]-Δ
The hydrochloride of 3-cefemu 4-carboxylate was obtained.

IR(KBr)An-”; νC=01785,1750
, 1675NMB (D6-DMSO) Ppm value; 1.2
0(9H,s,-C(CH3)3),2.49(3H,
s, ゛)! ? ), K" 3.55 (2H, 卜, C2-H), 5.26 (IH, d, J=5Hz, C6-H), 5.6
3(2H, ", /LcH.

), 5.78 to 5.95 (3H, m, C7-H, -
COOCH2O-), 6.84 (IH, s,, husband), 9.76 (IH, d, J=7Hz, -CONH-) Example 52 Pivaloyloxymethyl 7-[2-(2-
aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamide]-3-[2-(5-methyl-1
, 2,3,4-tetrazolyl)methyl]-Δa-cefemucarboxylate 5.93 g was added to 50 n1 of ethyl acetate.
To this solution, a solution of 20 ml of ethyl acetate containing 2.5 d of hemedylene sulfonic acid dihydrate was added.

If the precipitate is collected in a furnace, washed with ethyl acetate and dried, pivaloyloxymethyl ni-7-[2-(2-aminothiazol-4-yl)-] has a melting point of 218-220°C (decomposition).
2-(syn)-methoxyiminoacetamide]-3-[
2-(5-Methyl-1,2,3,4-tetrazolyl)methyl]-Δ3-cefemucarboxylate meditylene sulfonate salt 7.39f1 (yield 93.2%) is obtained. IR(KBr)CE-1; νC=01782,174
5,1680 NMR (D6-DMSO) Ppm value; 1.
15(9H,s,-C(CH3).

), 2.14 (3H, s palanquin - X○ only), 2.43 (3H
, s, "[), N 2.53 (6H, s, be〇sho), 3.52 (bile, 卜, C.

-H), 3.93 (3H, s, -0CH3), 5.20 (IH, d, J=5Hz, C6-H), 5.5
6 (2H, B, Ren H,.1), 5.78 (IH, d
d, J=5Hz, J=8Hz, C7-H), 5.85(
2H,s, -COOCH2O-), 6.50(3H,F
f5, H3N-), 6.75 (2H, s, 〇 catty SOΓ
), 6.93 (IH, s, c.y..), 9.81 (IH, d, J=8Hz, -CONH-) Example 81) 2-(2-formamidothiazole-4-
yl)-2-(syn)methoxyiminoacetic acid 2.4f with N
, dissolved in 5 mι of N-dimethylacetamide, -10
~ Drop 1.7f of phosphorus oxychloride at -5°C, -5 to 0
Incubate at ℃ for 1 hour.

On the other hand, bivaloyloxymethyl di-7-amino-3-[2-(5-methyl-1,2,3,4-tetrazolyl)methyl]-Δ3-cefemu-4-carboxylate oxalate 5
y was suspended in 35 ml of ethyl acetate, and 1.01 g of triethylamine was added at -30°C. The above reaction solution is added dropwise to this at -30 to -20°C, and the mixture is reacted at the same temperature for 1 hour. After the reaction is complete, 12 ml of water is added and the organic layer is separated. Next, add 12 ml of water and adjust the pH to 4.0 with sodium hydrogen carbonate. O
Adjust to. The organic layer is separated, dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure.

If diethyl ether is added to the residue and the crystals are collected, pivaloyloxymethyl ni7 has a melting point of 132-135°C.
-[2-(2-formamidothiazol-4-yl)-2-(syn)-methoxyiminoacetamide]-3
-[2-(5-Methyl-1,2,3,4-tetrazolyl)methyl]-Δ3-cefemu-4-carboxylate 5.65 da (yield 91%) is obtained. IR(KBr)C
wL-”; νC=01785, 1752, 1680NM
R((36-DMSO)Ppm value; 1.20(9H,s
, -C(CH3).

), 2.51 (3H, s, N, > TH3), 3.61 (
2H, 卜, C, -H), 3.97N'(3H, s, -0
CH.

), 5.38 (IH, d, J=5Hz, C.-H), 5
．． 77 (2H, bS, LH.1), 6.05 (2H, s
, -0CH. 0-), 6.11 (IH, dd, = 5Hz
, J=8Hz, C7-H), 7.60(IH,s,-1
), 8.73 (IH,s,,l,), 10.00(I
H, d, J = 8 Hz, -CONH-), 12.63 (I
H, 卜, -CONH-) The following compound is obtained in the same manner.

o11-pivaloyloxyethyl di-7-[2-(2-formamidothiazol-4-yl)-2-(syn)-methoxyiminoacetamide]-3-[1-(5-chloro1,2,4- triazolyl)methyl]-Δ3-cefemucarboxylate (crystallized from methanol) Melting point 151-154°C IR(KBr)Cm-1; νC=01785,1745
, 1680NMR (D6-DMSO) Ppm value: 1.1
7(9H,s,-C(CH.

). ), 1.53 (3H, d, 1℃H-d6Hz, 1)
, 3.50 (2H, Yf5.C2-CHaH), 3.9
0 (3H, s, -α■3), 4.93-5.46 (3H
, m, C6-H, -H, 1), 5.92 (IH, dd,
J=5Hz, J=8Hz, C7-H), 6.83-7.
08 (IH, m, I-), 7.40 (IH, s,.

y. ．． ), 8.04 (IH, S, M/±), 8.50 (
IH, s, ; 1 ), 9.75 (IH, d, J = 8Hz
, Her CONH-), 12.64 (IH, -CONH-) 〇1-pivaloyloxyethyl di-7-[2-(2-formamidothiazol-4-yl)-2-(syn)-methoxy iminoacetamide]-3-[2-(5-methyl-1,2,3,4-tetrazolyl)methyl]-Δ3-
Cefemu carboxylate (crystallized from methanol) Melting point 203-205°C (decomposition) IR (KBr) a-1
;νC=01790, 1750, 1725, 1680
NMR (D6-DMSO) PPm value; 1.18 (9H, s, -C(Cl)3), 1.53 (3
H, d, = 6Hz, 1), 2.50 (3H, s, CH, ゛”.et al.-CH3), 3.71 (2H, bS, C2-H), 4.00N'
(3H, s, -0CH.

), 5.35 (3H, d, J=6Hz, C6-H), 5
．． 68 (Fuchi, BS, xlcH.--), 6.02 (I
H, dd, J=6Hz, J=9Hz, C7-H), 7.
08 (IH, m, l-), 7.58 (IH, s,, U,
, - -), 8.70 (IH, s, HC-), 9.99
(IH, d, J=9Hz, -CONH-), 12.70
(IH, 卜, -CONH-) (2) 1 obtained in (1)
-pivaloyloxyethyl di-7-[2-(2-formamidothiazol-4-yl)-2-(syn)-methoxyiminoacetamide]-3-[1-(5-chloro1,2,4-triazolyl) ) Methyl]-Δ3-cefemu 4-carboxylate 6.55y in methanol 66
12N-hydrochloric acid was added under ice cooling, and the mixture was reacted at 5 to 10°C for 2 hours.

After the reaction is completed, the reaction solution is introduced into 660 ml of water. Next, add sodium bicarbonate to pH 5. If the temperature is adjusted to -methoxyiminoacetamide]-3-[1-(5-chloro1,2,4
-triazolyl)methyl]-Δ3-cefemu 4-carboxylate 5.73y (yield 91.4%) is obtained. Similarly, the following compound is obtained.

. pivaloyloxymethyl-7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamide]-3-[2-(5-methyl-1,2
,3,4-tetrazolyl)methyl]-Δ3-cefemu-4-carboxylate Melting point 127-128°C (decomposition) 〇1-pivaloyloxyethylni-7-[2-(2-aminothiazol-4-yl)- 2-(syn)-methoxyiminoacetamide]-3-[2-(5-methyl-1
,2,3,4-tetrazolyl)methyl]-Δ3-cefemu 4-carboxylate Melting point: 127-130°C (decomposition) The physical properties (IR, NMR) of these compounds are the same as those obtained in Example 50. Agreed.

Example 54 (1) 1.72 da of 2-aminothiazol-4-ylglyoxylic acid was suspended in 6 ml of N,N-dimethylacetamide, and 3.39 d of phosphorus oxychloride was added dropwise at -10°C.
React at -5°C for 3 hours.

On the other hand, pivaloyloxymethyl di-7-amino-3-[2-
5 das of oxalate of (5-methyl-1,2,3,4-tetrazolyl)methyl]-Δ3-cefemu 4-carboxylate was suspended in 20 mι of anhydrous methylene chloride, and the mixture was heated at -30°C.
Add 1.01y of triethylamine. This was added dropwise to the above reaction solution at -30 to -20°C and kept at the same temperature for -
A three-powder reaction is carried out at 10 to 0°C. After the reaction, methylene chloride was distilled off under reduced pressure, and the residue was mixed with 60 ml of water (1) 60 ml of ethyl acetate.
Add m1. Then adjust the pH to 4 with sodium hydrogen carbonate. O
After the insoluble matter is separated in a furnace, the organic layer is separated. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (Wako silica gel C-2).
Pivaloyloxymethyl di-7-[(2-aminothiazol-4-yl)-glyoxylamide] exhibits a melting point of 99 to 10 degrees (decomposition) when purified with 00: developing solvent; benzene-ethyl diacetate 2:1). -3-[2-(5-methyl-1,2,3,4-tetrazolyl)methyl]-Δ3
- Cefemu 4-carboxylate 3.5 g (yield 62
．． 1%). IR(KBr)Cln-”: νC=0
1785, 1745, 1685, 1660NMR (D6
-DMSO) Ppm value; 1.21 (9H, s, -C(CH3)a), 2.54 (
3H, s, cn°), 3.65 (2H, 卜, C.

-H), 5.40 (out, D, J=5Hz, C6-H),
5.81 (2H, .."NH-), 5.88-6.25
(3H, m, C7-H, -0CH20-), 7.59(
2H,bS,NH2-),8.07(IH,s,,)I
N), 10.10 (IH, d, = 9HZ, -CONH-
) The following compound is obtained in the same manner.

〇1-pivaloyloxyethyl di-7-[(2-aminothiazol-4-yl)-glyoxylamide]-3-[
2-(5-methyl-1,2,3,4-tetrazolyl)methyl]-Δ3-cefemu 4-carboxylate melting point 1
06-109℃ (decomposition) IR (KBr)Cm-1; νC=01780,1740
, 1680, 1660 NMR (D6-DMSO) Ppm
Value; 1.18 (9H, s, -C(CH.

). ), 1.56 (3H, d, J=6Hz, 1), 2.
51 (3H, sru, ?-CH゜), 3.61 (2H
, 卜, D, "H), 5.38 (IH, d, J = 5Hz,
C. -H), 5.74 (2H, bS,, A.cH9-)
, 5.80-6.15 (IH, m, C7-H), 6.9
0 to 7.25 (IH, m, l-), 7.54 (2H,
Yf=, -NH. ), 8.03 (IH, s, c included...)
, 10.07 (IH, d, J=9Hz, -CONH-)
〇1-Bivaloyloxyethyl di-7-[(2-aminothiazol-4-yl)-glyoxylamide]-3-[
1-(5-chloro1,2,4-triazolyl)methyl]-Δ3-cefemu 4-carboxylate melting point 11
1-114℃ (decomposition) IR (KBr)Cm-1; νC=01780,174
0,1680,1660NMR(D6-DMSO)Pp
m value; 1.19 (9H, s, -C (Cll.).

), 1.56 (3H, d, = 6Hz, 1), 3.57 (
2H, 卜, C2-RuH), 5.17-5.52 (3H
, m, C6-H, -H. ,-), 5.77-6.18(
IH, m, C7-H), 6.85-7.28 (IH, m
, l-), 7.55 (2H, bs, -NH2), 8.0
3(IH,s,,y--),8.24(IH,s,''
．． '． ．． >”), 9.85 (IH, d, J=9Hz,
-CONH-) (2) pivaloyloxymethyl di7-
[(2-aminothiazol-4-yl)-glyoxylamide]-3-[2-(5-methyl-1,2,3,
5.64 f1 of 4-tetrazolyl)methyl]-Δ3-cefemu 4-carboxylate was dissolved in 25 mL of N,N-dimethylacetamide, and 1.67 mL of methoxyamine hydrochloride was added under ice cooling, and the mixture was heated at 15 to 20°C for 12 hours. Make it react.

After the reaction was completed, the reaction solution was mixed with 250ml of water and 25ml of ethyl acetate.
into 0ml of mixed solvent, and remove P with sodium hydrogen carbonate.
H4. After adjusting to O, separate the organic layer. After drying over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure, diethyl ether is added to the residue, and the crystals are collected.
pivaloyloxymethyl di7-[2
-(2-aminothiazol-4-yl)-2 -(
Syn)-methoxyiminoacetamide]-3-[2-
(5-Methyl-1,2,3,4-tetrazolyl)methyl]-Δ3-cefemu 4-carboxylate 4.7y
(yield 84.7%). The following compound is obtained in the same manner.

〇1-pivaloyloxyethyl di-7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamide]-3-[2-(5-methyl-1
, 2,3,4-tetrazolyl)methyl]-Δ3-cefemu 4-carboxylate 1 - melting point 127-130°C (
decomposition) 1-pivaloyloxyethyl di-7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamide]-3-[1-(5-chloro1,2
,4-triazolyl)methyl]-Δ3-cefemu4-
Carboxylate melting point: 145-IU°C Physical properties (IR, NMR) of these compounds are as shown in Example 5.
This was consistent with that obtained with 0.

Example 55 (1) 2.2y of 2-formamidothiazole-4-ylglyoxylic acid was converted to 6.2y of N,N-dimethylacetamide.
Suspended in 6wL1, phosphorus oxychloride 1.8 at -200C
g was added dropwise and reacted at the same temperature for 2 hours.

On the other hand, pivaloyloxymethyl di-7-amino-3-[2
-(5-Methyl-1,2,3,4-tetrazolyl)methyl]-Δ3-cefemu 4-carboxylate oxalate 5f was suspended in 20 mι of anhydrous methylene chloride, and -30
1.01y of triethylamine is added at °C. This was added dropwise to the above reaction solution at -30 to -20°C and allowed to react at the same temperature for 1 hour. After the reaction is completed, methylene chloride is distilled off under reduced pressure, and 70 mι of water and 70 mι of ethyl acetate are added to the residue.
Then, the pH was adjusted to 3.5 with sodium hydrogen carbonate, and after removing insoluble matter, the organic layer was separated. After sequentially washing with water and saturated brine and drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. When diethyl ether is added to the residue and the crystals are separated, pivaloyloxymethyl di-7-[(2-formamidothiazol-4-yl)-glyoxylamide]-3- exhibits a melting point of 129-13 (decomposition). [2-
(5-Methyl-1,2,3,4-tetrazolyl)methyl]-Δ3-cefemu 4-carboxylate 4.74
f1 (yield 80.1%) is obtained. IR(KBr)CE-
1; νC=01785, 1755, 1695, 167
0NMR (D6-DMSO) Ppm value; 1.16 (9H,s,-C(CH,).

), 2.47 (3H, s, .rnΠ3), 3.57 (2
H, 卜, C2-H), 5.29M'(IH, d, J=5
Hz, C6-H), 5.65 (2H, bS,,) Ichimachi), 5.75-6.10 (3H, m, C7-H, -0C
H20-), 8.44 (IH, s, l-I), -/
\&59 (IH, s, ll), 9.95 (IH, d, J
=9Hz, -CONH-), 12.87(IH, ',
-CONH-) The following compound is obtained in the same manner.

o11-pivaloyloxyethyl di-7-[(2-formamidothiazol-4-yl)-glyoxylamide]
-3-[2-(5-methyl-1,2,3,4-tetrazolyl)methyl]-Δ3-cefemu 4-carboxylate melting point 136-13CfC (decomposition) IR(KBr)C7R-1; νC=01785,17
40,1690,1665NMR(D6-DMSO)P
pm value; 1.19 (9H, s, -C(CH3).

), 1.56 (3H, d, = 6Hz, I), 2.53 (
3H, s, CH,, cn°), 3.67 (2H, Yf-, C2-H), 5.
42 (IH, d, J=5Hz, C?-H), 5.75 (
2H, bs, /Sakai-), 6.06 (IH, dd, J=
5Hz, J=9Hz, C7-H), 6.95-7.35
(IH, m, skin), &68 (IH, S, Q/V,,,)
, 8.83 (IH, s, ll), 10.03 (IH, d
, J=9Hz, H CONH-), 12.82 (IH,
bs, -NHCO-)〇1-pivaloyloxyethyl di-7-[(2-formamidothiazol-4-yl)-glyoxylamide]-3-[1-(5-chloro1,
2,4-triazolyl)methyl]-Δ3-cephemu 4
-Carboxylate melting point 141-143 BoC (decomposition) IR (KBr)c! ! t-1; νC=01785,17
45,1690,1665NMR(D6-DMSO)P
PM value; 1.20 (9H, s, -C (C).

), 1.56 (3H, d, = 6Hz, upper... ), 3.
61 (2H, Yf!,,C2-H), 5.17-5.5
0 (3H, m, C6-H, → one), 5.83 to 6.18
(IH, m, C7-H), 6.93-7.30 (IH,
m, l-), 8.26 (IH, ruS, Kzu), 8.6
4 (IH, s, c./IIN..), 8.81 (IH, s, 8), 1
0.18 (IH, d, J=9Hz, -CONH-), 1
2.97 (IH, ratio, -NHCO-) (2) pivaloyloxymethyl di-7-[(2-formamidothiazol-4-yl)-glyoxylamide]-3-[2-(5-
Methyl-1,2,3,4-tetrazolyl)methyl]-Δ
3-cephemu 4-carboxylate 5.92 daN,
Dissolve in 25WLt of N-dimethylacetamide, add 1.679% of methoxyamine hydrochloride under ice cooling,
React at ℃ for 3 hours.

After the reaction is complete, add 250 ml of water to the reaction solution (1) 250 ml of ethyl acetate.
nι into a mixed solvent and separate the organic layer. After sequentially washing with water and saturated brine and drying anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. When diethyl ether is added to the residue and the crystals are collected, pivaloyloxymethyl di-7-[2-(2-formamidothiazol-4-yl)-2-(syn)-] has a melting point of 132-135°C. methoxyiminoacetamide]-3-[2-(5-methyl-1,
2,3,4-tetrazolyl)methyl]-Δ3-cefemu 4-carboxylate 5.27f (yield 84.9%)
get. The following compound is obtained in the same manner. o11-pivaloyloxymethyl-7-[2-(2-formamidothiazol-4-yl)-2-(syn)-methoxyiminoacetamide]-3-[1-(5-chloro1,2,4
-triazolyl)methyl]-Δ3-cefemu 4-carboxylate melting point 151-154°C.

1-pivaloyloxyethyl-7-[2-(2-formamidothiazol-4-yl)-2-(syn)-methoxyiminoacetamide]-3-[2-(5-methyl-1,2,3, 4-tetrazolyl)methyl]-Δ3-cefemu 4-carboxylate Melting point 203-205℃ (
Decomposition) The physical properties (IR, NrVlR) of these compounds were consistent with those obtained in Example B-T.

Example 56 1) Using 2-(2-Tert.-amyloxycarboxamidothiazol-4-yl)acetic acid, the reaction is carried out in the same manner as in Example 1 to obtain the following compound.

07-[2-(2-aminothiazol-4-yl)
-2-(syn)monoethoxyiminoacetamide]-3-
Trifluoroacetate of [2-(5-methyl-1,2,3,4-tetrazolyl)methyl]-Δ3-cefemu-4-carboxylic acid Melting point 180.5-181°C (decomposition) IR
(KBr)Cm-1; νC=01775,1665,
1630(2) Using 2-(2-aminothiazol-4-yl)-2-(syn)-1ethoxyiminoacetic acid, the reaction is carried out in the same manner as in Example 50 to obtain the following compound.

. pivaloyloxymethyl di7-[2-(2-aminothiazol-4-yl)-2-(syn)monoethoxyiminoacetamide]-3-[2-(5-methyl-1,2
,3,4-tetrazolyl)methyl]-Δ3-cephemu 4-carboxylate Melting point 99-10 (decomposition) IR(KBr)Cm-1; νC=01785,1745
, 1675, 1615 (3) The compound obtained in (2) is reacted in the same manner as in Example 52 to obtain the following compound.

〇 Pivaloyloxymethyl di-7-[2-(2-aminothiazol-4-yl)-2-(syn)monoethoxyiminoacetamide]-3-[2-(5-methyl-1,
Mesitylene sulfonate of 2,3,4-tetrazolyl)methyl]-Δa-cefemu 4-carboxylate Melting point >190°C

Claims (1)

[Claims] 1 Formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R^1 is a hydrogen atom or a carboxyl protecting group, and R^2 is an aromatic hydrocarbon with or without a substituent. R^3 is a hydrogen atom or an alkoxy group; R^4 is a hydrogen atom or a halogen atom, R^5 is a hydrogen atom or an optionally protected or substituted amino group, A is a formula -CH_2- or a formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ group ( In the formula, R^6 represents a hydrogen atom or an alkyl group, - may be a syn or anti isomer, or a mixture thereof), and ▲ a mathematical formula, a chemical formula,
There are tables, etc. ▼ is shown, and the dotted lines in the Cefem ring are 2 to 3
It means that there is a double bond between positions or between positions 3 and 4. ] Cephalosporins and their salts. 2. The cephalosporin and its salts according to claim 1, wherein ▲There are mathematical formulas, chemical formulas, tables, etc.▼ is ▲There are mathematical formulas, chemical formulas, tables, etc.▼. 3. The cephalosporin and its salts according to claim 2, wherein the cefem ring is a Δ^3-cephem ring. 4. The cephalosporin and its salts according to claim 3, wherein R^2 is an aromatic hydrocarbon group with or without a substituent. 5. The cephalosporin and its salts according to claim 3, wherein R^2 is an acylamino group with or without a substituent. 6. The cephalosporin and its salts according to claim 3, wherein R^2 is an aromatic heterocyclic group with or without a substituent that forms a carbon-carbon bond with the exomethylene at the 3-position. 7. The cephalosporin and its salts according to claim 3, wherein R^2 is a triazolyl or tetrazolyl group with or without a substituent that forms a carbon-nitrogen bond with the exomethylene at the 3-position. 8. The cephalosporin and its salts according to any one of claims 1 to 7, wherein A is represented by the formula -CH_2-. 9 A is a formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula,
R^6 represents a hydrogen atom or an alkyl group, and {circle around (2)} may be a syn or anti isomer, or a mixture thereof. Phosphorus and its salts. 10 The cephalosporin and the cephalosporin according to any one of claims 1 to 7, wherein A is a group represented by the formula ▲ has a numerical formula, chemical formula, table, etc. ▼ (in the formula, it is a syn isomer); The salts. 11 Claims 1 to 1 in which R^3 is a hydrogen atom
The cephalosporin and its salts according to any of item 0. 12 Claims 1 to 3 in which R^3 is a methoxy group
The cephalosporin and its salts according to any one of item 10. 13 Claims 1 to 1 in which R^4 is a hydrogen atom
The cephalosporin and its salts according to any one of Item 2. 14 Claims 1 to 1 in which R^5 is an amino group
The cephalosporin and its salts according to any one of item 3. 15 7-[2-(2-aminothiazol-4-yl)
acetamido]-3-[2-(5-acetamido-1,
8. The compound according to claim 7, which is 2,3,4-tetrazolyl)methyl]-Δ^3-cephem-4-carboxylic acid, an ester thereof, or a salt thereof. 16 7-[2-(2-aminothiazol-4-yl)
Acetamide]-3-[2-(1,2,3,4-tetrazolyl)methyl]-Δ^3-cephem-4-carboxylic acid, an ester thereof, or a salt thereof, according to claim 7. Compound. 17 7-[2-(2-aminothiazol-4-yl)
-2-2(syn)-methoxyiminoacetamide]-3
-[2-(5-acetamido-1,2,3,4-tetrazolyl)methyl]-Δ^3-cephem-4-carboxylic acid, an ester thereof, or a salt thereof; Compound. 18 7-[2-(2-aminothiazol-4-yl)
-2-(syn)-methoxyiminoacetamide]-3-
[2-(5-methyl-1,2,3,4-tetrazolyl)
8. The compound according to claim 7, which is methyl]-Δ^3cefem-4-carboxylic acid, an ester thereof, or a salt thereof. 19 7-[2-(2-aminothiazol-4-yl)
-2-(syn)-methoxyiminoacetamide]-3-
[2-(5-ethyl-1,2,3,4-tetrazolyl)
8. The compound according to claim 7, which is methyl]-Δ^3-cefem-4-carboxylic acid, an ester thereof, or a salt thereof. 20 7-[2-(2-aminothiazol-4-yl)
-2-(syn)-methoxyiminoacetamide]-3-
6. The compound according to claim 5, which is (furan-2-carboxamide)methyl-Δ^3-cephem-4-carboxylic acid, an ester thereof, or a salt thereof. 21 7-[2-(2-aminothiazol-4-yl)
-2-(syn)-methoxyiminoacetamide]-3-
6. The compound according to claim 5, which is acetamidomethyl-Δ^3-cephem-4-carboxylic acid, an ester thereof, or a salt thereof. 22 7-[2-(2-aminothiazol-4-yl)
-2-(syn)-methoxyiminoacetamide]-3-
(4-hydroxybenzyl)-Δ^3-cephem-4-
5. The compound according to claim 4, which is a carboxylic acid, an ester thereof, or a salt thereof. 23 7-[2-(2-aminothiazol-4-yl)
-2-(syn)-methoxyiminoacetamide]-3-
The compound according to claim 7, which is [1-(5-chloro-1,2,4-triazolyl)methyl]-Δ^3-cephem-4-carboxylic acid, an ester thereof, or a salt thereof. 24 7-[2-(2-aminothiazol-4-yl)
-2-(syn)-methoxyiminoacetamide]-3-
The compound according to claim 7, which is [1-(3-acetamido-1,2,4-triazolyl)methyl]-Δ^3-cephem-4-carboxylic acid, an ester thereof, or a salt thereof. 25 7-[2-(2-aminothiazol-4-yl)
-2-(syn)-hydroxyiminoacetamide]-3
-[2-(5-methyl-1,2,3,4-tetrazolyl)methyl]-Δ^3-cephem-4-carboxylic acid, an ester thereof, or a salt thereof; Compound.