JP2503500B2 - Novel cefalosporin derivative and method for producing the same - Google Patents

Description

TECHNICAL FIELD The present invention relates to a novel cephalosporin derivative, a method for producing the same, and an antibacterial agent containing the compound as an active ingredient.

PRIOR ART Conventionally, a large number of compounds having a 2- (2-aminothiazol-4-yl) -2-substituted oxyiminoacetamide group at the 7-position of the cephem nucleus have been synthesized. , JP-A-52-102293,
52-116492, 53-137988, 54-9296, 54
-154786, 54-157596, 55-154980, 56-
86187, 57-59895, 57-99592, 57-19239
No. 4 and No. 58-174387 and the like, showing activity also against cephalosporin-resistant Gram-negative bacteria including Gram-positive bacteria and Pseudomonas aeruginosa.
It has been suggested to have excellent antibacterial activity and a broad antibacterial spectrum.

However, these compounds were not found in Pseudomonas aeruginosa, Pseudomonas cepacia, Pseudomonas maltophilia and Acinetobacter.
calcoaceticus) and other glucose-nonfermenting gram-negative bacilli (g
It cannot be said to be sufficient for lucose non-fermentative gram-negative rods.

A large number of compounds having a 2- (2-aminothiazol-4-yl) -2-substituted oxyiminoacetamide group at the 7-position of the cephem nucleus and an aromatic heterocyclic thiomethyl group at the 3-position of the cephem nucleus are synthesized, Examples of the disclosed technologies described therein include JP-A-51-149296 and JP-A-52-116492.
No. 53, No. 53-34795, No. 54-9296, No. 54 Steps 44695, No.
Nos. 59-128391, 59-167576 and 60-41682 are mentioned, but a cephalosporin derivative having an unsubstituted or substituted phenyl aromatic heterocyclic thiomethyl group at the 3-position of the cephem nucleus is disclosed in JP-A-54-54. No. 9296 is disclosed. JP-A-54-9296 suggests a methyl group having a nucleophilic residue or the like as a substituent at the 3-position of the cephem nucleus, such as an aromatic heterocyclic thiomethyl group which may have a substituent. Examples of the cyclic group include a thiazolyl group, an oxazolyl group, a thiadiazolyl group, and an oxadiazolyl group. It is generally described extensively that it may be present. As an aryl group which may be substituted one or more times on the heterocyclic nucleus of a heterocyclic thiomethyl group, for example, an unsubstituted or substituted phenyl group is suggested, and a large number of substituents are generally described. However, regarding the phenyl-substituted aromatic heterocyclic thiomethyl derivative, only unsubstituted or mono-substituted phenyl heterocyclic thiomethyl derivative is exemplified, and only synthesized (Examples 24 and 40 of JP-A-54-9296). , 41,187 and 199
No data on antibacterial activity of these compounds are described. Particularly, the cephalosporin derivative having a 2,3- or 3,4-di-substituted phenyl aromatic heterocyclic thiomethyl group having two hydroxyl groups or an acetoxy group adjacent to the phenyl nucleus is not only synthesized but also disclosed in the application specification. Is not done at all.

A large number of compounds having a benzene ring-condensed aromatic heterocyclic thiomethyl group at the 3-position of the cephem nucleus have also been synthesized.
Nos. 54-9296, 54-117493, 55-19267 and 55-35096, and the like.

JP-A-52-125190 discloses a heterocyclic thiomethyl group which may have an appropriate substituent at the 3-position of the cephem nucleus, for example, a benzimidazolyl group, a benzoxazolyl group, a benzothiazolyl group and the like. However, there has been no suggestion that these compounds have not been synthesized at all and may have a hydroxyl group as a substituent.

JP-A-54-9296 suggests a methyl group having a nucleophilic residue or the like as a substituent at the 3-position of the cephem nucleus, for example, a benzene ring-fused aromatic thiomethyl group which may have a substituent. Examples of the heterocyclic group include a benzothiazolyl group, a benzoxazolyl group, a benzimidazolyl group, an indolyl group, and the like, and the heterocyclic thiomethyl group may be substituted with one or more compounds over a wide range. Are generally described. However, the benzene ring of the benzene ring-fused aromatic heterocyclic thiomethyl group of the publication is suggested only for unsubstituted or mono-position, and is only synthesized (Example 58, 9 of JP-A-54-9296).
1,133,176,184,185,190,202), no antibacterial activity data of the compound is described. In particular, neither the synthesis nor the disclosure or suggestion of the cephalosporin derivative having two hydroxyl groups or acetoxy groups adjacent to the benzene ring of the benzene ring-fused heterocyclic thiomethyl group has been disclosed or suggested.

Japanese Unexamined Patent Publication (Kokai) No. 54-117493 discloses a thiadiazolylthiomethyl group, a triazolylthiomethyl group, a benzothiazolylthiomethyl group having an alkyl group having 3 to 6 carbon atoms at the 3-position, but none. Only a substituted benzothiazolylthiomethyl group has been synthesized [see Example 11 (66) in JP-A No. 54-117493], and no hydroxyl group is suggested as a substituent.

JP-A-55-19267 discloses a heterocyclic thiomethyl group which may have an appropriate substituent at the 3-position.
There is no suggestion of a hydroxyl group as a substituent, and an unsubstituted benzimidazolylthiomethyl group is merely synthesized [Examples 10 (10), 11, of JP-A-55-1926].
16 (14)].

JP-A-55-35096 only mentions a heterocyclic thiomethyl group which may have a lower alkyl group at the 3-position.

Problems to be Solved by the Invention Since β-lactam antibiotics show selective toxicity only to bacteria and have no effect on animal cells, they are widely used in the treatment of infectious diseases caused by bacteria as antibiotics with few side effects. It is a highly used drug.

However, in recent years, glucose non-fermenting Gram-negative bacilli, especially Pseudomonas aeruginosa, have often been isolated as a causative bacterium of intractable infectious diseases from patients with weakened immunity. Therefore,
Development of antibacterial agents having improved antibacterial activity against these bacteria is desired.

Means for Solving the Problems The present invention aims to provide a novel cephalosporin derivative having excellent antibacterial activity, and it is a compound of a substituted phenyl aromatic heterocyclic thiomethyl group or a substituted benzene ring condensation at the 3-position of the cephem nucleus. An aromatic heterocyclic thiomethyl group is added to 2- (2-aminothiazol-4-yl) -2 at the 7-position of the cephem nucleus.
The cephalosporin derivative having a substituted oxyiminoacetamide group was intensively studied. as a result,
A di-substituted phenyl aromatic heterocyclic thiomethyl group in which two hydroxyl groups or acetoxy groups adjacent to the phenyl nucleus are introduced,
Alternatively, the compound of the present invention having a di-substituted benzene ring-condensed aromatic heterocyclic thiomethyl group in which two hydroxyl groups or acetoxy groups adjacent to the condensed benzene nucleus are introduced is a novel compound described at the end of the literature, and is a Gram-positive bacterium or Gram-negative. It has excellent antibacterial activity against bacteria, especially Pseudomonas aeruginosa, Pseudomonas cepacia and Acinetobacter.
It has strong antibacterial activity against gram-negative bacteria including glucose non-fermenting gram-negative bacilli such as calcoaceticus, and β
-Excellent stability against β-lactamase and β-lactamase induci
The present invention was completed by finding that there is almost no bility). In particular, against gram-negative bacteria resistant to gram-negative bacteria, especially glucose non-fermenting gram-negative bacilli including Pseudomonas aeruginosa, as compared with compounds in which the phenyl nucleus is unsubstituted, monohydroxy-substituted, monoacetoxy-substituted, or dimethoxy-substituted (compounds of Reference Examples). It has been found that it has a strong antibacterial activity and is excellent in stability against β-lactamase.

Action The present invention has the general formula [I] [In the formula, R is a linear or branched lower alkyl group which may have a substituent, a cyclic lower alkyl group, a lower alkenyl group (however, 1-carboxy-1-vinyl group is excluded) , A lower alkynyl group, an aralkyl group, a phenyl group or a 2-pyrrolidon-3-yl group, and Q is a general formula. (In the formula, R ¹ is a hydrogen atom or an acetyl group, R ² is a hydrogen atom,
A carboxyl group or a carboxymethyl group, Y represents a sulfur atom or an oxygen atom, Z represents a sulfur atom, an oxygen atom or an imino group which may be substituted with a lower alkyl group)), The present invention relates to a non-toxic salt or a physiologically hydrolyzable non-toxic ester, a process for producing the same, and an antibacterial agent containing the compound as an active ingredient.

Next, the symbols and terms described in this specification will be described.

The substituent R of the compound of the general formula [I] may have a linear or branched lower alkyl group or lower alkenyl group (provided that the tricarboxy-1-vinyl group is excluded), It means a lower alkynyl group, a cyclic lower alkyl group, an aralkyl group, a phenyl group or a 2-pyrrolidone-3-yl group.

When R has a substituent, as the substituent, an alkyl group having 1 to 4 carbon atoms, a hydroxyl group, an alkoxy group having 1 to 4 carbon atoms, an acetoxy group, a carboxyl group, a carbamoyl group, a carboxymethyl group, a sulfo group, a sulfomethyl group Base,
It can have one or two or more substituents selected from the group consisting of a substituted phenyl group and a halogen atom such as a fluorine atom, a chlorine atom and a bromine atom.

The linear or branched lower alkyl group which may have a substituent means a linear or branched alkyl group having 1 to 6 carbon atoms, specifically, a methyl group, an ethyl group ,
n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, n-pentyl group, n-hexyl group, difluoromethyl group, 2-fluoroethyl group, 2,2- Examples thereof include a difluoroethyl group, a 2,2,2-trifluoroethyl group, a carboxymethyl group, a 1-carboxyethyl group, a 2-carboxyethyl group and a 1-carboxy-1-methylethyl group.

The cyclic lower alkyl group which may have a substituent means a cyclic alkyl group having a carbon number of 3 to 6, and examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group and 1-carboxy. Examples thereof include a cyclopropyl group, a 1-carboxycyclobutyl group and a 1-carboxycyclopentyl group.

The alkenyl which may have a substituent (provided that the 1-carboxy-1-vinyl group is excluded) has 2 to 6 carbon atoms.
In the case where each alkenyl group has a benzene nucleus as a substituent, it means an alkenyl group having 6 or more carbon atoms, specifically, vinyl group, 1-propenyl group, isopropenyl group, 2-methyl-1- Propenyl group, 1,3-butadienyl group, allyl group, 1,1-dimethylallyl group, 2-butenyl group, 3-butenyl group, 3-methyl-2-butenyl group,
2-carboxy-1-vinyl group, 1-carboxy-1-
Propenyl group, 2-carboxy-1-propenyl group, 3
-Carboxy-1-propenyl group, 1-carboxy-2
-Methyl-1-propenyl group, 1-carboxyallyl group, 2-carboxyallyl group, 3-carboxyallyl group, 1-carboxy-3-butenyl group, 1-carboxy-3-methyl-2-butenyl group, α- Carboxystyryl group, β-carboxystyryl group, styryl group, 1-
(Substituted phenyl) vinyl group or 2-carboxy-1
Examples thereof include a-(substituted phenyl) vinyl group.

However, the phenyl group is, for example, a hydroxyl group as a substituent,
One or the same or different substituents selected from the group of acetoxy group, methoxy group, carboxyl group, carbamoyl group, carboxymethyl group, sulfo group, sulfomethyl group and halogen atom such as fluorine atom, chlorine atom and bromine atom. You can have two or more.

Particularly preferred examples are vinyl group, isopropenyl group, 2-methyl-1-propenyl group, allyl group, 1,1-
Dimethylallyl group, 1-carboxy-2-methyl-1-
Propenyl group, 2-carboxyallyl group, styryl group,
An α-carboxystyryl group and the like can be mentioned.

The lower alkynyl group which may have a substituent means an alkynyl group having 2 to 6 carbon atoms, specifically, an ethynyl group, a 1-propynyl group, a 2-propynyl group, 1,1-dimethyl. -2-propynyl group, 2-carboxyethynyl group, 1-carboxy-2-propynyl group, 3
Examples include -carboxy-1,1-dimethyl-2-propynyl group and the like.

Examples of the phenyl group which may have a substituent include a phenyl group, a 2-hydroxyphenyl group, a 3-hydroxyphenyl group, a 4-hydroxyphenyl group, a 2-acetoxy group phenyl group, a 3-acetoxyphenyl group, Four
-Acetoxyphenyl group, 2-chlorophenyl group, 3-
Chlorophenyl group, 3-carboxyphenyl group, 4-carboxyphenyl group, 3,4-dihydroxyphenyl group,
Examples include 3,4-diacetoxyphenyl group.

As the aralkyl group which may have a substituent, for example, benzyl group, 3-hydroxybenzyl group, 4-hydroxybenzyl group, 3-acetoxybenzyl group, 4-
Acetoxybenzyl group, 2-carboxybenzyl group, 3
-Carboxybenzyl group, 4-carboxybenzyl group,
2-carboxymethylbenzyl group, 3-carboxymethylbenzyl group, 4-carboxymethylbenzyl group, 2-
Sulfobenzyl group, 3-sulfobenzyl group, 4-sulfobenzyl group, 2-sulfomethylbenzyl group, 3-sulfomethylbenzyl group, 4-sulfomethylbenzyl group, 3-
Carboxy-4-hydroxybenzyl group, 3,4-dihydroxybenzyl group, 3,4-diacetoxybenzyl group, α
-Carboxybenzyl group, α-carboxy-3-hydroxybenzyl group, α-carboxy-4-hydroxybenzyl group, α-carboxy-3-acetoxybenzyl group,
Examples thereof include α-carboxy-4-acetoxybenzyl group, α-carboxy-3,4-dihydroxybenzyl group and α-carboxy-3,4-diacetoxybenzyl group.

Group Q is a general formula (In the formula, R ¹ is a hydrogen atom or an acetyl group, R ² is a hydrogen atom,
A carboxyl group or a carboxymethyl group, Y represents a sulfur atom or an oxygen atom, and Z represents a sulfur atom, an oxygen atom, or an imino group which may be substituted with a lower alkyl group).

That is, Q means a di-substituted phenyl aromatic heterocyclic group or a di-substituted benzene ring-fused aromatic heterocyclic group having adjacent hydroxyl groups or acetoxy groups, and the aromatic heterocyclic group is a carboxy group or a carboxymethyl group. May have.

As the di-substituted phenyl group, for example, 2,3-dihydroxyphenyl group, 3,4-dihydroxyphenyl group, 2,3-
A diacetoxyphenyl group, 3,4-diacetoxyphenyl group or the like is shown, particularly a 3,4-dihydroxyphenyl group or 3,4
The -diacetoxyphenyl group is preferred.

Examples of the di-substituted phenyl aromatic heterocyclic group include:
5- (disubstituted phenyl) -1,3,4-oxadiazole-
2-yl group, 5- (disubstituted phenyl) -1,3,4-thiadiazol-2-yl group, 4- (disubstituted phenyl) thiazol-2-yl group, 4- (disubstituted phenyl) -5- A carboxythiazol-2-yl group, a 4- (disubstituted phenyl) -5-carboxymethylthiazol-2-yl group,
5- (disubstituted) phenyl-4-carboxythiazole-
2-yl group, 5- (disubstituted phenyl) -4-carboxymethylthiazol-2-yl group, 4- (disubstituted phenyl) oxazol-2-yl group, 4- (disubstituted phenyl) -5-carboxyxazole -2-yl group, 4-
(Di-substituted phenyl) -5-carboxymethyloxazol-2-yl group, 5- (di-substituted phenyl) oxazol-2-yl group, 5- (di-substituted phenyl) -4-carboxyoxazol-2-yl group, 5 -(Disubstituted phenyl)
-4-carboxymethyloxazol-2-yl group and the like, particularly 5- (dihydroxyphenyl) -1,3,4
-Oxadiazol-2-yl group, 5- (diacetoxyphenyl) -1,3,4-oxadiazol-2-yl group,
5- (dihydroxyphenyl) -1,3,4-thiadiazol-2-yl group, 5- (diacetoxyphenyl) -1,3,
4-thiadiazol-2-yl group, 4- (dihydroxyphenyl) thiazol-2-yl group, 4- (diacetoxyphenyl) thiazol-2-yl group, 4- (dihydroxyphenyl) -5-carboxymethylthiazol-2
-Yl group, 4- (diacetoxyphenyl) -5-carboxymethylthiazol-2-yl group, 5- (dihydroxyphenyl) -4-carboxythiazol-2-yl group, 5- (diacetoxyphenyl) -4- Carboxythiazol-2-yl group, 5- (dihydroxyphenyl)
An oxazol-2-yl group, a 5- (diacetoxyphenyl) oxazol-2-yl group and the like are preferable.

Examples of the aromatic heterocyclic group for the di-substituted benzene condensation include 5,6-di-substituted benzimidazol-2-yl group, 5,6
-Disubstituted-1-methylbenzimidazol-2-yl group, 5,6-disubstituted benzoxazol-2-yl group, 5,6
Examples thereof include a -disubstituted benzothiazol-2-yl group.

General formula [III] HS-Q '[III] which is a raw material compound of the compound of the present invention [wherein Q ¹ is a general formula] (In the formula, R ⁶ is a hydrogen atom or a hydroxyl group protecting group, R ⁷ is a hydrogen atom, an optionally protected carboxyl group or a carboxymethyl group, Y is a sulfur atom or an oxygen atom, Z is a sulfur atom, an oxygen atom. Or an imino group which may be substituted by a lower alkyl group)] is a novel compound described in the end of the literature, and is a compound of the cephem nucleus 3).
A cephalosporin derivative having the di-substituted phenyl aromatic heterocyclic thiomethyl group at the position or the di-substituted benzene ring-fused aromatic heterocyclic thiomethyl group has not been synthesized.

The partial structure of the oximino group of the general formula [I] is syn isomer (Z configuration) and anti isomer (E configuration).
, The syn isomer generally exhibits excellent antibacterial activity,
All substituted oximino groups in this specification are syn isomers. The E / Z nomenclature is described in Journal of the American Chemical Society (J. Am. Chem. Soc.), No. 90.
Vol. 509 (1968).

The compound of the general formula [I] can be converted into its nontoxic salt or physiologically hydrolyzable nontoxic ester by a conventional method.

The non-toxic salt of the compound of the general formula [I] means a conventional pharmaceutically acceptable salt, which includes a carboxyl group at the 4-position of the cephem nucleus, a 2-aminothiazole group at the 7-position of the cephem nucleus, and Q and Examples of the salt include an acidic residue such as a carboxyl group or a sulfo group substituted with R or R, or a basic residue such as an amino group.

Examples of the addition salt with a base include, for example, sodium salts, potassium salts, and other alkali metal salts, such as calcium salts, magnesium salts, and other alkaline earth metal salts, such as ammonium salts or trimethylamine salts, triethylamine salts, dicyclohexylamine salts, N, Basic amino acids such as N'-dibenzylethylenediamine salt, ethanolamine salt, diethanolamine salt, triethanolamine salt, procaine salt, pyrazine salt, picoline salt, quinoline salt, isoquinoline salt, and other organic amine salts, arginine salt, lysine salt, etc. Examples include salt.

Examples of the addition salt with an acid include inorganic acid salts such as hydrochloride, hydrobromide, sulfate, nitrate, phosphate, carbonate, hydrogencarbonate and perchlorate, such as acetate and propionate. , Lactate, maleate, fumarate, tartrate,
Organic acid salts such as malate and citrate, for example, methanesulfonate, isethionate, benzenesulfonate,
Examples thereof include sulfonates such as p-triene sulfonate, and amino acid salts such as aspartate and glutamate.

The non-toxic ester of the general formula [I] means a conventional pharmaceutically acceptable one at the 4-position carboxyl group of the cephem nucleus, and includes, for example, alkanoyloxymethyl groups such as acetoxymethyl group and pivaloyloxymethyl group. Base,
Alkoxycarbonyloxyalkyl groups such as 1- (ethoxycarbonyloxy) ethyl group, phthalidyl groups, eg 5-methyl-2-oxo-1,3-dioxole-4-
A 5-substituted-2-oxo-1,3-dioxol-4-ylmethyl group such as ylmethyl group can be mentioned.

Preferred examples of the compound of the general formula [I] provided by the present invention include the following.

(1) 7β- [2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamide] -3- [5-
(3,4-Dihydroxyphenyl) -1,3,4-oxadiazol-2-yl] thiomethyl-3-cephem-4-carboxylic acid (2) 3- [5- (3,4-diacetoxyphenyl) -1,
3,4-Oxadiazol-2-yl] thiomethyl-7β
-[2- (2-Aminothiazol-4-yl) -2-methoxyiminoacetamido] -3-cephem-4-carboxylic acid (3) 7β- [2- (2-aminothiazol-4-yl) -2 -Ethoxyiminoacetamide] -3- [5-
(3,4-Dihydroxyphenyl) -1,3,4-oxadiazol-2-yl] thiomethyl-3-cephem-4-carboxylic acid (4) 3- [5- (3,4-diacetoxyphenyl) -1,
3,4-Oxadiazol-2-yl] thiomethyl-7β
-[2- (2-Aminothiazol-4-yl) -2-ethoxyiminoacetamido] -3-cephem-4-carboxylic acid (5) 7β- [2- (2-aminothiazol-4-yl) -2 -Isopropoxyiminoacetamide] -3-
[5- (3,4-Dihydroxyphenyl) -1,3,4-oxadiazol-2-yl] thiomethyl-3-cephem-4
-Carboxylic acid (6) 7β- [2-allyloxyimino-2- (2-aminothiazol-4-yl) acetamide] -3- [5
-(3,4-Dihydroxyphenyl) -1,3,4-oxadiazol-2-yl] thiomethyl-3-cephem-4-carboxylic acid (7) 7β- [2- (2-aminothiazol-4- Ill) -2-propargyloxyiminoacetamide]-
3- [5- (3,4-dihydroxyphenyl) -1,3,4-oxadiazol-2-yl] thiomethyl-3-cephem-4-carboxylic acid (8) 7β- [2- (2-amino Thiazol-4-yl) -2- (carboxymethoxyimino) acetamido] -3- [5- (3,4-dihydroxyphenyl) 1,3,4
-Oxadiazol-2-yl] thiomethyl-3-cephem-4-carboxylic acid (9) 7β- [2- (2-aminothiazol-4-yl) -2- (1-carboxy-1-methylethoxyimino) ) Acetamide] -3- [5- (3,4-dihydroxyphenyl) -1,3,4-oxadiazol-2-yl] thiomethyl-3-cephem-4-carboxylic acid (10) 7β- [2- (2-Aminothiazol-4-yl) -2- (1-carboxy-1-cyclopropoxyimino) acetamido] -3- [5- (3,4-dihydroxyphenyl) -1,3,4-oxadiazole -2-yl]
Thiomethyl-3-cephem-4-carboxylic acid (11) 7β- [2- (2-aminothiazol-4-yl) -2-benzyloxyiminoacetamide] -3-
[5- (3,4-Dihydroxyphenyl) -1,3,4-oxadiazol-2-yl] thiomethyl-3-cephem-4
-Carboxylic acid (12) 7β- [2- (2-aminothiazol-4-yl) -2- (3,4-dihydroxybenzyloxyimino) acetamide] -3- [5- (3,4-dihydroxyphenyl) -1,3,4-oxadiazol-2-yl] thiomethyl-3-cephem-4-carboxylic acid (13) 7β- [2- (2-aminothiazol-4-yl) -2- (α-carboxyl Benzyloxyimino) acetamido] -3- [5- (3,4-dihydroxyphenyl) -1,3,4-oxadiazol-2-yl] thiomethyl-3-cephem-4-carboxylic acid (14) 7β- [2- (2-Aminothiazol-4-yl) -2- (α-carboxy-3,4-dihydroxybenzyloxyimino group) acetamide] -3- [5- (3,
4-Dihydroxyphenyl) -1,3,4-oxadiazol-2-yl] thiomethyl-3-cephem-4-carboxylic acid (15) 7β- [2- (2-aminothiazol-4-yl) -2 -(4-Hydroxybenzyloxyimino) acetamido] -3- [5- (3,4-dihydroxyphenyl) 1,3,4-oxadiazol-2-yl] thiomethyl-3-cephem-4-carboxylic acid ( 16) 7β- [2- (2-aminothiazol-4-yl) -2- (3-carboxy-4-hydroxybenzyloxyimino) acetamido] -3- [5- (3,4-dihydroxyphenyl) -1 , 3,4-Oxadiazole-2
-Yl] thiomethyl-3-cephem-4-carboxylic acid (17) 7β- [2- (2-aminothiazol-4-yl] -2- (4-carboxybenzyloxyimino) acetamide] -3- [5- (3,4-Dihydroxyphenyl) -1,3,4-oxadiazol-2-yl] thiomethyl-3-cephem-4-carboxylic acid (18) 7β- [2- (2-aminothiazol-4-yl) ) -2- (3-Carboxybenzyloxyimino) acetamide] -3- [5- (3,4-dihydroxyphenyl) -1,3,4-oxadiazol-2-yl] thiomethyl-3-cephem-4 -Carboxylic acid (19) 7β- [2- (2-aminothiazol-4-yl) -2- (4-carboxymethylbenzyloxyimino) acetamide] -3- [5- (3,4-dihydroxyphenyl)- 1,3,4-oxa 2-yl] thiomethyl-3-cephem-4-carboxylic acid (20) 7β- [2- (-4- 2- aminothiazol-yl) -2-phenoxyimine syn-amide] -3- [5
-(3,4-Dihydroxyphenyl) -1,3,4-oxadiazol-2-yl] thiomethyl-3-cephem-4-carboxylic acid (21) 7β- [2- (2-aminothiazol-4- 2- (2-Carboxymethylbenzyloxyimino) acetamido] -3- [5- (3,4-dihydroxyphenyl) -1,3,4-oxadiazol-2-yl] thiomethyl-3-cephem -4-carboxylic acid (22) 7β- [2- (2-aminothiazol-4-yl) -2- (1-carboxy-1-methylethoxyiminoacetamide] -3- (5,6-dihydroxybenzoxazole- 2-yl] thiomethyl-3-cephem-4
-Carboxylic acid (23) 7β- [2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamide] -3- [5-
(3,4-Dihydroxyphenyl) -1,3,4-thiadiazol-2-yl] thiomethyl-3-cephem-4-carboxylic acid (24) 3- [5- (3,4-diacetoxyphenyl) -1 ,
3,4-thiazol-2-yl] thiomethyl-7β- [2
-(2-Aminothiazol-4-yl) -2-methoxyiminoacetamido] -3-cephem-4-carboxylic acid (25) 7β- [2- (2-aminothiazol-4-yl) -2-ethoxyimino Acetamide] -3- [5-
(3,4-Dihydroxyphenyl) -1,3,4-thiadiazol-2-yl] thiomethyl-3-cephem-4-carboxylic acid (26) 3- [5- (3,4-diacetoxyphenyl) -1 ,
3,4-Thiadiazol-2-yl] thiomethyl-7β-
[2- (2-Aminothiazol-4-yl) -2--ethoxyiminoacetamido] -3-cephem-4-carboxylic acid (27) 7β- [2- (2-aminothiazol-4-yl) -2 -Isopropoxyiminoacetamide] -3-
[5- (3,4-Dihydroxyphenyl) -1,3,4-thiadiazol-2-yl] thiomethyl-3-cephem-4-
Carboxylic acid (28) 7β- [2-allyloxyimino-2- (2-aminothiazol-4-yl) acetamide] -3- [5
-(3,4-Dihydroxyphenyl) -1,3,4-thiadiazol-2-yl] thiomethyl-3-cephem-4-carboxylic acid (29) 7β- [2- (2-aminothiazol-4-yl) -2-Propargyloxyiminoacetamide]-
3- [5- (3,4-dihydroxyphenyl) -1,3,4-thiadiazol-2-yl] thiomethyl-3-cephem-
4-Carboxylic acid (30) 7β- [2- (2-aminothiazol-4-yl) -2-benzyloxyiminoacetamide] -3-
[5- (3,4-Dihydroxyphenyl) -1,3,4-thiadiazol-2-yl] thiomethyl-3-cephem-4-
Carboxylic acid (31) 7β- [2- (2-aminothiazol-4-yl) -2- (3,4-dihydroxybenzyloxyimino) acetamido] -3- [5- (3,4-dihydroxyphenyl)- 1,3,4-Thiadiazol-2-yl] thiomethyl-3-cephem-4-carboxylic acid (32) 7β- [2- (2-aminothiazol-4-yl) -2- (1-carboxy-1- Methylethoxyimino) acetamido] -3- [5- (3,4-dihydroxyphenyl) -1,3,4-thiadiazol-2-yl] thiomethyl-3-cephem-4-carboxylic acid (33) 7β- [2 -(2-Aminothiazol-4-yl) -2- (1-carboxy-1-cyclopropoxyimino) acetamido] -3- [5- (3,4-dihydroxyphenyl) -1,3,4-thiadiazole- 2-yl] thiomethyl- -Cephem-4-carboxylic acid (34) 7β- [2- (2-aminothiazol-4-yl) -2- (2-carboxymethylbenzyloxyimino) acetamide] -3- [5- (3,4- Dihydroxyphenyl) -1,3,4-thiadiazol-2-yl] thiomethyl-3-cephem-4-carboxylic acid (35) 7β- [2- (2-aminothiazol-4-yl) -2- (α- Carboxybenzyloxyimino) acetamido] -3- [5- (3,4-dihydroxyphenyl) -1,3,4-thiadiazol-2-yl] thiomethyl-3-cephem-4-carboxylic acid (36) 7β- [ 2- (2-Aminothiazol-4-yl) -2- (α-carboxy-3,4-dihydroxybenzyloxyimino) acetamide] -3- [5- (3,4
-Dihydroxyphenyl) -1,3,4-thiadiazole-
2-yl] thiomethyl-3-cephem-4-carboxylic acid (37) 7β- [2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamide] -3- [4-
(3,4-Dihydroxyphenyl) thiazol-2-yl] thiomethyl-3-cephem-4-carboxylic acid (38) 3- [4- (3,4-diacetoxyphenyl) thiazol-2-yl] thiomethyl-7β -[2- (2-Aminothiazol-4-yl) -2-methoxyiminoacetamido] -3-cephem-4-carboxylic acid (39) 7β- [2- (2-aminothiazol-4-yl) -2 -Isopropoxyiminoacetamide] -3-
[4- (3,4-dihydroxyphenyl) thiazole-2
-Yl] thiomethyl-3-cephem-4-carboxylic acid (40) 7β- [2-allyloxyimino-2- (2-aminothiazol-4-yl) acetamide] -3- [4
-(3,4-Dihydroxyphenyl) thiazol-2-yl] thiomethyl-3-cephem-4-carboxylic acid (41) 7β- [2- (2-aminothiazol-4-yl) -2- (carboxymethoxyimino ) Acetamide] -3- [4- (3,4-dihydroxyphenyl) thiazol-2-yl] thiomethyl-3-cephem-4-carboxylic acid (42) 7β- [2- (2-aminothiazol-4-yl) ) -2- (1-Carboxy-1-methylethoxyimino) acetamido] -3- [4- (3,4-dihydroxyphenyl) thiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (43) 7β- [2- (2-aminothiazol-4-yl) -2- (1-carboxy-1-cyclopropoxyimino) acetamide] -3- [4- (3,4-dihydroxyphenyl) Thiazol-2-yl] thiomethyl-3
Cephem-4-carboxylic acid (44) 7β- [2- (2-aminothiazol-4-yl) -2-benzyloxyiminoacetamide] -3-
[4- (3,4-dihydroxyphenyl) thiazole-2
-Yl] thiomethyl-3-cephem-4-carboxylic acid (45) 7β- [2- (2-aminothiazol-4-yl) -2- (3,4-dihydroxybenzyloxyimino) acetamide] -3- [ 4- (3,4-Dihydroxyphenyl) thiazol-2-yl] thiomethyl-3-cephem-4-carboxylic acid (46) 7β- [2- (2-aminothiazol-4-yl) -2-ethoxyiminoacetamide ] -3- [4-
(3,4-Dihydroxyphenyl) thiazol-2-yl] thiomethyl-3-cephem-4-carboxylic acid (47) 3- [4- (3,4-diacetoxyphenyl) thiazol-2-yl] thiomethyl-7β -[2- (2-Aminothiazol-4-yl) -2-ethoxyiminoacetamido] -3-cephem-4-carboxylic acid (48) 7β- [2- (2-aminothiazol-4-yl) -2 -(1-Carboxy-1-methylethoxyimino) acetamide] -3- [5- (3,4-dihydroxyphenyl) -4-carboxythiazol-2-yl] thiomethyl-3-cephem-4-carboxylic acid (49 ) 7β- [2- (2-Aminothiazol-4-yl) -2- (α-carboxybenzyloxyimino) acetamido] -3- [5- (3,4-dihydroxyphenyl) -4- Its pure cytidine-2-yl] thiomethyl-3-cephem-4-carboxylic acid (50) 7β- [2- (-4- 2- aminothiazol-yl) -2-methoxyiminoacetamido] -3- [5-
(3,4-Dihydroxyphenyl) -4-carboxythiazol-2-yl] thiomethyl-3-cephem-4-carboxylic acid (51) 7β- [2- (2-aminothiazol-4-yl) -2-ethoxy Iminoacetamide] -3- [5-
(3,4-Dihydroxyphenyl) -4-carboxythiazol-2-yl] thiomethyl-3-cephem-4-carboxylic acid (52) 7β- [2- (2-aminothiazol-4-yl) -2-cyclopentyl Oxyiminoacetamide]
-3- [5- (3,4-dihydroxyphenyl) 4-carboxythiazol-2-yl] thiomethyl-3-cephem-4-carboxylic acid (53) 7β- [2-allyloxyimino-2- (2- Aminothiazol-4-yl) acetamide] -3- [5
-(3,4-Dihydroxyphenyl) -4-carboxythiazol-2-yl] thiomethyl-3-cephem-4-
Carboxylic acid (54) 7β- [2- (2-aminothiazol-4-yl) -2-propargyloxyiminoacetamide]-
3- [5- (3,4-Dihydroxyphenyl) -4-carboxythiazol-2-yl] thiomethyl-3-cephem-4-carboxylic acid (55) 7β- [2- (2-aminothiazol-4-yl) ) -2-Benzyloxyiminoacetamide] -3-
[5- (3,4-Dihydroxyphenyl) -4-carboxythiazol-2-yl] thiomethyl-3-cephem-
4-Carboxylic acid (56) 7β- [2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamide] -3- [4-
(3,4-Dihydroxyphenyl) -5-carboxymethylthiazol-2-yl] thiomethyl-3-cephem-
4-Carboxylic acid (57) 7β- [2- (2-aminothiazol-4-yl) -2- (1-carboxy-1-methylethoxyimino) acetamido] -3- [4- (3,4-dihydroxy) Phenyl) -5-carboxymethylthiazol-2-yl] thiomethyl-3-cephem-4-carboxylic acid (58) 3- [4- (3,4-diacetoxyphenyl) -5
-Carboxymethylthiazol-2-yl] thiomethyl-7β- [2- (2-aminothiazol-4-yl)-
2- (1-Carboxy-1-methylethoxyimino) acetamido] -3-cephem-4-carboxylic acid (59) 7β- [2- (2-aminothiazol-4-yl) -2- (1-carboxy- 1-Cyclopropoxyimino) acetamide] -3- [4- (3,4-dihydroxyphenyl) -5-carboxymethylthiazole-2-
Il] thiomethyl-3-cephem-4-carboxylic acid (60) 3- [4- (3,4-diacetoxyphenyl) -5
-Carboxymethylthiazol-2-yl] thiomethyl-7β- [2- (2-aminothiazol-4-yl)-
2- (1-carboxy-1-cyclopropoxyimino)
Acetamide] -3-cephem-4-carboxylic acid (61) 3- [4- (3,4-diacetoxyphenyl) -5
-Carboxymethylthiazol-2-yl] thiomethyl-7β- [2- (2-aminothiazol-4-yl)-
2- (α-Carboxybenzyloxyimino) acetamide] -3-cephem-4-carboxylic acid (62) 7β- [2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamide] -3- [ 5-
(3,4-Dihydroxyphenyl) oxazol-2-yl] thiomethyl-3-cephem-4-carboxylic acid (63) 7β- [2- (2-aminothiazol-4-yl) -2-ethoxyiminoacetamide]- 3- [5-
(3,4-Dihydroxyphenyl) oxazol-2-yl] thiomethyl-3-cephem-4-carboxylic acid (64) 7β- [2- (2-aminothiazol-4-yl) -2- (1-carboxy- 1-Methylethoxyimino) acetamido] -3- [5- (3,4-dihydroxyphenyl) oxazol-2-yl] thiomethyl-3-
Cephem-4-carboxylic acid (65) 7β- {2- (2-aminothiazol-4-yl) -2-[(α-carboxy-3,4-dihydroxybenzyl) oxyimino] acetamide} -3- [5-
(3,4-Dihydroxyphenyl) oxazol-2-yl] thiomethyl-3-cephem-4-carboxylic acid (66) 7β- [2- (2-aminothiazol-4-yl) -2- (1-carboxy- 1-Cyclopropoxyimino) acetamido] -3- [5- (3,4-dihydroxyphenyl) oxazol-2-yl] thiomethyl-3
-Cephem-4-carboxylic acid (67) 3- [5- (3,4-diacetoxyphenyl) -oxazol-2-yl] -thiomethyl-7β- [2-
(2-Aminothiazol-4-yl) -2-ethoxyiminoacetamide] -3-cephem-4-carboxylic acid (68) 7β- [2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamide ] -3- [5,6
-Dihydroxybenzimidazol-2-yl] thiomethyl-3-cephem-4-carboxylic acid (69) 7β- [2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamide] -3- [5, 6
-Dihydroxy 1-methylbenzimidazol-2-yl] thiomethyl-3-cephem-4-carboxylic acid (70) 7β- [2- (2-aminothiazol-4-yl) -2-isopropoxyiminoacetamide] -3-
[5,6-dihydroxybenzimidazol-2-yl]
Thiomethyl-3-cephem-4-carboxylic acid (71) 7β- [2- (2-aminothiazol-4-yl) -2-allyloxyiminoacetamide] -3-
[5,6-dihydroxybenzimidazol-2-yl)
Thiomethyl-3-cephem-4-carboxylic acid (72) 7β- [2- (2-aminothiazol-4-yl) -2- (2-pyrrolidon-3-yl) oxyiminoacetamide] -3- (5, 6-dihydroxybenzimidazol-2-yl) thiomethyl-3-cephem-4-
Carboxylic acid (73) 7β- [2- (2-aminothiazol-4-yl) -2- (1-carboxy-1-methylethoxyimino) acetamido] -3- (5,6-dihydroxybenzimidazole-2- Il) thiomethyl-3-cephem-
4-Carboxylic acid (74) 7β- [2- (2-aminothiazol-4-yl) -2- (1-carboxy-1-cyclopentyloxyimino) acetamido) -3- (5,6-dihydroxybenzimidazole- 2-yl] thiomethyl-3-cephem-4-carboxylic acid (75) 7β- [2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamide] -3- [5,6
-Dihydroxybenzoxazol-2-yl] thiomethyl-3-cephem-4-carboxylic acid Next, a method for producing the compound of the present invention will be described.

The compound of the general formula [I] can be produced by either the production method A or the production method B shown below.

Production method A General formula [IV] [In the formula, R ³ is a hydrogen atom or an amino-protecting group, R ⁴ is a linear or branched lower alkyl group which may have a substituent, a cyclic lower alkyl group, a lower alkenyl group, a lower alkynyl. Group, aralkyl group, phenyl group or 2-pyrrolidone-3-yl group, X is a leaving group, R ⁵ is a hydrogen atom or a carboxyl protecting group (provided that the substituent of R ⁴ is optionally protected. The compound represented by general formula [III] HS-Q ¹ [III] [wherein, Q ¹ is a general formula] (In the formula, R ⁶ is a hydrogen atom or a hydroxyl group protecting group, R ⁷ is a hydrogen atom, an optionally protected carboxyl group or a carboxymethyl group, Y is a sulfur atom or an oxygen atom, Z is a sulfur atom, an oxygen atom. Or an amino group which may be substituted by a lower alkyl group)] or a salt thereof to act on the compound of the general formula [II] (Wherein R ³ , R ⁴ , R ⁵ and Q ¹ have the above-mentioned meanings), and the compound [I] of the present invention is produced by removing the protecting group if necessary. be able to.

X in the general formula [IV] represents a leaving group, and specifically, a halogen atom such as chlorine, bromine and iodine, an acetoxy group,
Examples thereof include a carbamoyloxy group, a trifluoroacetoxy group, a methanesulfonyloxy group, a trifluoromethanesulfonyloxy group and a p-toluenesulfonyloxy group, and a chlorine atom, a bromine atom, an iodine atom and an acetoxy group are particularly preferable.

Manufacturing method B General formula [VI] [In the formula, Q ⁵ is a hydrogen atom or a carboxyl protecting group, and Q ¹ is a general formula. (In the formula, R ⁶ is a hydrogen atom or a hydroxyl group protecting group, R ⁷ is a hydrogen atom, an optionally protected carboxyl group or a carboxymethyl group, Y is a sulfur atom or an oxygen atom, Z is a sulfur atom, an oxygen atom. Or an imino group which may be substituted with a lower alkyl group)] or a salt thereof is represented by the general formula [V] [In the formula, R ³ is a hydrogen atom or an amino protecting group, R ⁴ is a linear or branched lower alkyl group which may have a substituent, a cyclic lower alkyl group, a lower alkenyl group, a lower alkynyl Group, aralkyl group, phenyl group or 2-pyrrolidone-3-yl group, (provided that the substituent of R ⁴ may be optionally protected) is acylated with a carboxylic acid or a reactive derivative thereof. General formula [II] (Wherein R ³ , R ⁴ , ⁵ and Q ¹ have the above-mentioned meanings), and the compound [I] of the present invention is produced by removing the protecting group if necessary. You can

Further, the compound of the present invention in which R ¹ is an acetyl group can be produced by using the compound [III] or [VI] in which R ⁶ is an acetyl group according to the above production method A or B. ,
Compound [II] in which R ¹ is a hydrogen atom is subjected to an acetylation reaction by a conventional method to give a compound [II] having an acetyl group,
If necessary, the compound can be produced by removing the protecting group of the compound, and further can be produced by acetylating the compound [I] of the present invention in which R ¹ is a hydrogen atom by a conventional method. .

Next, the production methods A and B of the compound [I] of the present invention will be described in detail.

Production Method A The reaction of the compound of the general formula [IV] with the mercapto derivative of the general formula [III] can be carried out, for example, by water, methylene chloride, chloroform, ether, ethyl acetate, butyl acetate, tetrahydrofuran, acetonitrile, N, N-dimethylformamide. , Dimethylsulfoxide, etc., or a mixed solvent thereof.

The mercapto derivative represented by the general formula [III] includes, for example, sodium salt, potassium salt, calcium salt, magnesium salt,
It may be used as a metal salt such as a silver salt or an organic amine salt such as a triethylamine salt or an ethyldiisopropylamine salt.

The mercapto derivative [III] can also be used after being silylated with a silylating agent such as N, O-bis (trimethylsilyl) acetamide.

In the reaction, 1 to 2 mol of the mercapto derivative [III] is used with respect to 1 mol of the compound of the general formula [IV], and the reaction temperature and reaction time are 0 to 40 ° C. and 0.5 to 5 hours.

The reaction of the compound of the general formula [IV] in which X is an acetoxy group with the mercapto derivative [III] can be carried out by, for example, water, phosphate buffer, acetone, acetonitrile, methanol, ethanol, tetrahydrofuran, dioxane, N, N-dimethylformamide. , Dimethylsulfoxide, etc., or a mixed solution thereof. It is preferable to carry out the reaction near neutral, and the reaction temperature is from room temperature to 90 ° C.
The reaction time is 1 to 10 hours. In addition, this reaction is carried out with 1 to 20 mol of an iodide such as sodium iodide, a thiocyanate such as sodium thiocyanate or a quaternary ammonium salt such as trimethylbenzylammonium bromide with respect to 1 mol of the compound [IV]. Facilitated by doing in the presence. The compound [I] of the present invention has the general formula [II] if necessary.
It can be produced by removing the protecting group from the compound of.

The reaction between the compound [IV] and the mercapto derivative [III] is carried out in a solvent such as acetic acid, acetone, acetonitrile, methanol, ethanol, tetrahydrofuran, N, N-dimethylformamide, dimethylsulfoxide or a mixed solvent thereof. With respect to the compound [IV], for example, sulfuric acid, p-toluenesulfonic acid, methanesulfonic acid,
Even if Lewis acid such as trifluoromethanesulfonic acid, chlorosulfonic acid, boron trifluoride and boron trifluoride ether complex is present in the presence of 1 to 50 mol at room temperature to 60 ° C. for 1 to 10 hours, the compound [II] Can be manufactured.

As the protecting group for the carboxyl group, amino group and hydroxyl group in the above general formula, a protecting group usually used in the field of β-lactam synthesis can be appropriately selected and used.

The method of introducing and removing the protecting group depends on the type of the protecting group, for example, Protective Groups in Organic Synthesis by TWGreene, published in 1981 by Wiley. ),
JFW W McCOMY (JFW) published in 1973 by Plenum Press
Protective Groups in Organ by McOmie
ic Chemistry) and the like can be appropriately selected and performed.

Examples of the carboxyl protecting group include t-butyl group,
2,2,2-Trichloroethyl group, acetoxymethyl group, propionyloxymethyl group, pivaloyloxymethyl group, 1-acetoxyethyl group, 1-propionyloxyethyl group, 1- (ethoxycarbonyloxy) ethyl group, phthalidyl Group, benzyl group, 4-methoxybenzyl group, 3,4-dimethoxybenzyl group, 4-nitrobenzyl group, benzhydryl group, bis (4-methoxyphenyl)
Methyl group, 5-methyl-2-oxo-1,3-dioxol-4-ylmethyl group, trimethylsilyl group, t-butyldimethylsilyl group and the like can be mentioned, and benzhydryl group, t-butyl group and trimethylsilyl group are particularly preferable. .

Examples of the amino protecting group include trityl group, formyl group, chloroacetyl group, trifluoroacetyl group, t-
Examples thereof include butoxycarbonyl group, trimethylsilyl group, tert-butyldimethylsilyl group and the like.

Examples of the hydroxyl-protecting group include 2-methoxyethoxymethyl group, methoxymethyl group, methylthiomethyl group,
Tetrahydropyranyl group, phenacyl group, isopropyl group, t-butyl group, benzyl group, 4-nitrobenzyl group, acetyl group, 2,2,2-trichloroethoxycarbonyl group, benzyloxycarbonyl group, trimethylsilyl group, tert-butyl group Dimethylsilyl group, or cyclic acetal such as methylene acetal, ethylene acetal, benzylidene acetal, ortho ester such as methoxymethylidene or methoxyethylidene, cyclic ketal such as isopropylidene ketal, or cyclic ketal, which is formed by bonding protective groups to each other. Carbonate ester etc. are mentioned.

The method for removing the protective group will be described in detail. , Formic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, and other inorganic or organic acids, and trifluoroacetic acid is particularly preferable. When trifluoroacetic acid is used as the acid, the addition of anisole, thioanisole or phenol accelerates the reaction and also suppresses side reactions. The reaction can be carried out, for example, in a solvent that does not participate in the reaction, such as water, methylene chloride, chloroform, ethylene chloride, benzene, or a mixed solvent thereof. The reaction temperature and reaction time depend on the compound [I
I] and the compound [I] of the present invention are appropriately selected depending on the chemical properties and the kinds of protecting groups, and particularly preferably performed under mild conditions such as ice cooling or warming.

The starting compound [IV] of the production method A can be produced as follows.

The compound of the general formula [IV] is a 7-amino-3-chloromethyl-3-cephem-4-carboxylic acid derivative [eg,
JP-A-50-76089, JP-A-56-86187, or The Journal of Antibiotics (J. Antibiotic
s), vol. 38, page 1738 (1985)], 7
It can be produced by reacting aminocephalosporanic acid or an ester thereof with a carboxylic acid of the general formula [V] or a reactive derivative thereof (eg, acid halide, mixed acid anhydride, active ester, etc.).

The compound of [IV] in which the group X is an iodine atom is described in, for example, JP-B-51-27679 and Synth.Commun., Vol. 16, 1029-1035 (1
986), a compound of the general formula [IV] in which the group X is a chlorine atom is introduced in a solvent such as acetone, N, N-dimethylformamide, dimethylsulfoxide, or in the presence of a phase transfer catalyst. Produced by reacting with iodide such as sodium iodide or potassium iodide in a two-layer system of water and an organic solvent at ice cooling or at room temperature, or tetrahedron
Letters (Tetrahedron Lett.), Vol. 22, p. 3915 (198
1 year), the compound [IV] in which the group X is an acetoxy group is converted into, for example, methylene chloride, chloroform, diethyl ether, ethyl acetate, butyl acetate, tetrahydrofuran, acetonitrile, N, N-dimethylformamide, It can be produced by reacting iodotrimethylsilane in dimethyl sulfoxide or a mixed solvent thereof, and can be used for the next reaction without isolation or isolation.

The mercapto derivative having two adjacent hydroxyl groups or acetoxy groups represented by the general formula [III] is a novel compound described in the end of the literature. The compound can be produced by the following method.

2-mercapto-5- (3,4-disubstituted phenyl) -1,
The 3,4-oxadiazole derivative can be produced by reacting a benzoic acid hydrazide derivative with carbon disulfide in the presence of potassium hydroxide in an ethanol solvent.

2-mercapto-5- (3,4-disubstituted phenyl) -1,
The 3,4-thiazole derivative can be produced by the following method (i) or (ii).

(I) 3,4-disubstituted thiobenzamide is produced by reacting hydrogen sulfide in the presence of triethylamine in a pyridine solvent.

(Ii) It is produced by reacting potassium 3- (3,4-disubstituted benzoyl) dithiocarbazate with concentrated sulfuric acid.

The 2-mercapto-4- (3,4-disubstituted phenyl) thiazole derivative is available from Chemical Abstracts (Chem. Abst
r.), 84-43639s (1976), and 2-chloro-3 ', 4'-dihydroxyacetophenone synthesized by a method described above, and ammonium dithiocarbamate in a methanol solvent.

4-carboxy-5- (3,4-disubstituted phenyl) -2
-The mercaptothiazole derivative is produced by using piperonal as a starting material for organic synthes (Org.Synth.), Co
ll. Vol. 11, pp. 11 to 12, pp. 1 to 3 and pp. 519 to 520, to give 3- (3,4-disubstituted phenyl) pyruvic acid, and brominate the compound to give 3- (3,4-disubstitutedphenyl) pyruvic acid. Bromo-3- (3,
4-di-substituted phenyl) pyruvic acid, and the compound can be further reacted with ammonium dithiocarbamate to produce the compound.

5-Carboxymethyl-4- (3,4-disubstituted phenyl) -2-mercaptothiazole derivative is prepared by reacting veratrol with succinic anhydride in the presence of anhydrous aluminum chloride to give 3- (3,4-dimethoxybenzoyl). ) Propionic acid, then demethylated with hydrobromic acid,
3- (3,4-dihydroxybenzoyl) propionic acid was prepared, and the compound was added in the presence of acetic anhydride and sodium acetate.
After enol lactonization, N-bromosuccinimide and then diphenyldiazomethane were reacted to give 3-
(3,4-diacetoxybenzoyl) -3-bromopropionic acid ester can be prepared, and the compound can be further reacted with ammonium dithiocarbamate to produce the compound.

2-Mercapto-5- (3,4-disubstituted phenyl) oxazole derivatives are commercially available from Chemical Abstracts (Chem.Abs
tr.), 84-43639s (1976), 2-chloro-3 ′, 4′-dihydroxyacetophenone synthesized by the method described above is treated with sodium azide to give an azide compound,
The compound is derivatized to 2-amino-3 ′, 4′-dihydroxyacetophenone by catalytic reduction, and further in an ethanol solvent according to the method described in Chemical Abstracts (Chem. Abstr.), 67-43806t (1967). It can be produced by reacting carbon disulfide in the presence of sodium ethoxide.

The 2-mercaptobenzimidazole derivative is prepared by using veratrol as a starting material in the synthesis, 1033.
Page (1974) and Organic Synths (Org.Synt)
h.), Coll. Voll. IV, page 56 (1963).

The 2-mercaptobenzoxazole derivative is prepared from veratrol aldehyde as a starting material, Journal of the Society Perkin Transactions (J.
Chem.Perkin Trans.1), p. 1353 (1974), Canadian Journal of Chemistry (Can.j.Che)
m.), Vol. 44, p. 1879 (1966) and Journal of Pharmaceutical Sciences (J.Pharm.Soc.
Jpn.), Vol. 76, p. 1002 (1956).

The 2-mercaptobenzothiazole derivative uses veratrol as a starting material and is subjected to nitration and catalytic reduction to give 3,4
-Dimethoxy-6-nitroaniline was prepared, and the compound was converted to a diazonium salt.
6-Nitrophenyldithiocarbonate can be produced by further performing a reductive ring closure reaction with stannous chloride in an ethanol solvent.

The 2- (2-aminothiazol-4-yl) -2-substituted oximinoacetic acid derivative of the general formula [V] is a chemical compound
And Pharmaceutical Bulletin (Chem.Pha
rm.Bull.), Vol. 25, pp. 3115-3119 (1977), Journal of the Chemical Society of Japan, pp. 785-801 (1981), and the like, 2- (2-aminothiazol-4-yl) ) Glyoxylic acid derivative or 2- (2-aminothiazol-4-yl)
It can be produced using a 2-hydroxyiminoacetic acid derivative.

Production Method B The compound of the general formula [II] is the compound of the general formula [VI], for example, water, acetone, dioxane, acetonitrile, tetrahydrofuran, methylene chloride, chloroform, ethylene chloride, benzene, ethyl acetate, N, N-dimethylformamide. In a solvent that does not adversely affect the reaction such as dimethyl sulfoxide, or a mixed solvent thereof, the compound represented by the general formula [V]
The carboxylic acid or its reactive derivative (for example, acid halide, mixed anhydride, active ester, etc.) can be reacted for production.

In the reaction, 1 to 1.5 mol of the carboxylic acid of the general formula [V] or its reactive derivative is used per 1 mol of the compound of the general formula [VI], and the reaction temperature is -40 to 40 ° C. When an acid halide is used as the reactive derivative of the general formula [V], for example, triethylamine, N-methylmorpholine, N, N-
It is preferably carried out in the presence of a deoxidizing agent such as dimethylaniline or pyridine.

In the acid halide forming reaction, 1 mol of a halogenating agent such as thionyl chloride, phosphorus trichloride, phosphorus tribromide, phosphorus pentachloride, phosphorus oxychloride, oxalyl chloride or phosgene is added to 1 mol of carboxylic acid [V]. 10 moles, preferably 1 to 1.5 moles are used, the reaction temperature is −40 to 100 ° C., preferably −20 to 20 ° C., and the reaction time is 10 to 120 minutes.

The mixed acid anhydride forming reaction is carried out by using 1 to 1 mol of the carboxylic acid [V] as a deoxidizing agent such as triethylamine, N-methylmorpholine, N, N-dimethylaniline or pyridine.
In the presence of 1.2 mol, 1-1.2 mol of chloroformate such as methyl chloroformate, ethyl chloroformate, isobutyl chloroformate, etc. is used, and the reaction temperature is -40 to 20 ° C, preferably -20 to 5 ° C. And the reaction time is 10 ~
60 minutes.

The active ester formation reaction is carried out by reacting 1 mol of carboxylic acid [V] with an N-hydroxy compound (for example, N-hydroxysuccinimide, 1-hydroxybenzotriazole, etc.) or a phenol compound (for example, 4-nitrophenol, 2, 4-dinitrophenol, 2,4,5-trichlorophenol, etc.) is used in an amount of 1 to 1.2 mol and N, N'-dicyclohexylcarbodiimide in an amount of 1 to 1.4 mol, and the reaction temperature is -1.
The reaction time is 0 to 50 ° C and the reaction time is 0.5 to 2 hours.

When the carboxylic acid of the general formula [V] is used in the free acid form in the acylation reaction, carbodiimides such as N, N'-dicyclohexylcarbodiimide, N, N-dimethylformamide / phosphorus oxychloride adduct, etc. The compound of the general formula [II] can be produced even in the presence of the condensing agent. The production of the compound [I] of the present invention from the compound of the general formula [II] is the same as the production method A.

The compound [IV] of the production method B is a cephalosporins and penicillins by Flynn, Academic Press (Cephalosporins and Penicilins, Academic Press),
It can be produced according to the method described on pages 151 to 171 (1972). For example, a 7-acylamino-3-halomethyl-3-cephem-4-carboxylic acid derivative (JP-A-58)
-72590 and 58-154588), a 7-acylaminocephalosporanic acid derivative or 7-acylcephalosporanic acid is reacted with a mercapto derivative [III] to give a compound of the general formula [Wherein R ⁵ and Q ¹ have the above-mentioned meanings and R ⁸ represents a hydrogen atom or an acyl group), and can be produced by deacylation, if necessary.

The deacylation reaction is already known in the art, and in the compound represented by the general formula, when R ⁸ is, for example, a phenylacetyl group, a phenoxyacetyl group or an aminoadipyl group, JP-B-49-20319. Alternatively, it can be removed according to the method described in Japanese Patent Application No. 60-291431 by the present inventors. For example, the compound may be added with phosphorus pentachloride or phosphorus pentachloride in the presence of a deoxidizing agent such as pyridine, triethylamine, sodium bicarbonate or potassium bicarbonate in benzene, toluene, ethyl acetate, methylene chloride, ethylene chloride or a mixed solvent thereof. -80 to 50 phosphorus oxychloride
After reacting at 0.5 ° C., preferably −65 to 0 ° C. for 0.5 to 2 hours, it is treated with a lower alcohol such as methanol, ethanol or propanol, and then hydrolyzed to chemically remove the R ⁸ group. can do. Alternatively, the compound is added to water or water and an organic solvent such as acetone, acetonitrile, methanol, ethanol, or tetrahydrofuran at room temperature to give penicillin G acylase or immobilized penicillin G acylase at pH 7 to 8, preferably pH 7.5 to
The R ⁸ group can also be enzymatically removed by acting at 7.8. The enzymatic reaction is preferably carried out by adding a base such as lithium hydroxide, sodium hydroxide, potassium hydroxide, triethylamine, tripropylamine or pyridine to keep the pH constant.

Next, the in vitro antibacterial activity of the compound of the present invention against various bacteria was measured by the following agar plate dilution method. One platinum loop of each test strain cultured overnight in Mueller Hinton broth (inoculum: 10 ⁶ CFU / m
l) was inoculated into Mueller Hinton agar (MH agar). This medium contains antibacterial agents at various concentrations.
After culturing at ℃ for 16 hours, the minimum inhibitory concentration (MIC; μg / m
l) was measured. As a comparative compound cefotaxime (cef
otaxime), ceftazidme and a compound having an unsubstituted, monohydroxy-substituted, monoacetoxy-substituted or dimethoxy-substituted phenyl aromatic heterocyclic thiomethyl group at the 3-position (the compounds of Reference Examples 1 to 24) were used. The results are shown in the table below.

The compounds of the present invention have excellent antibacterial activity against susceptible and resistant Gram-positive and Gram-negative bacteria, particularly against glucose non-fermenting Gram-negative bacilli such as Pseudomonas aeruginosa, Pseudomonas cepacia, Pseudomonas maltophilia and Acinetobacter calcoaceticus. Indicated.

In addition, for the compounds of Examples 11, 34, 44, 59, 64 and 76, Enterobacter clogae (Enterobacter c
As a result of measuring the β-lactamase inducing ability against loacae) GN5797, the β-lactamase inducing ability was hardly recognized.

β-lactamase inducibility measurement method Muller Hinton brot
h) 10 ml test strain Enterobacter cloacae (Enter
bacterium cloacae) GN5797 is planted and shaken at 37 ° C overnight. Add the bacterial solution so that it will be diluted 10 times with Mueller Hinton Broth, mix, and pipette 20 ml into an L-shaped tube. After shaking at 37 ° C. for 2 hours, 1 ml of each concentration drug (final concentration; 50 g / ml, 10 μg / ml, 1 μg / ml) is aseptically added. After adding the drug, take a 5 ml sample from each L-shaped tube every hour and add 0.1m of 50mM sodium azide aqueous solution to it.
Add l and centrifuge (5500G) at 4 ° C for 10 minutes to collect the cells. The supernatant is discarded, 5 ml of 50 mM phosphate buffer (pH 7.0) is added to disperse the cells, and then the cells are collected by centrifugation as described above. Discard the supernatant, add 5 ml of 50 mM phosphate buffer (pH 7.0) to disperse, and sonicate under ice cooling. The liquid at 4 ° C
Centrifuge for 40 minutes (16500G) and measure the β-lactamase activity of the supernatant. The β-lactamase activity was measured by a spectroscopic method [Antimicrob. Agents Chemother., 17: 355-358 (198) using 100 μM of cephaloridine as a substrate.
0)]. Lowry method [J.Biol / Chem., 193,265-275] using phenol reagent for protein measurement
(1951)].

Results of β-lactamase inducibility measurement against Enterobacter cloacae GN5797 Substrate: Cephaloridine 100 μM Inducer concentration: 50 μg / ml Incubation time: 3 hr Further, the compound of the present invention is a compound having good pharmacokinetics.
Using the compound of Example 50 as a representative example, the blood concentration when subcutaneously administered to mice was measured.

A group of five 4-week-old ddY male mice (body weight 19 to 22 g) is prepared, and the test compound is dissolved in physiological saline to prepare a drug at a concentration of 2 mg / ml. The drug is subcutaneously administered in an amount of 0.1 ml per 10 g of mouse body weight. 7.5 minutes, 15 minutes, 30 minutes, 60 minutes, 1 after drug administration
After 20 and 240 minutes, blood is collected from the heart of the mouse with a heparin-treated syringe. The blood concentration at each measurement is shown in the table below. In addition, ceftazidime was used as a control compound. The antibacterial activity of the sample diluted with plasma to an appropriate concentration was measured by the paper disk method using Morganella morganii IF03843 as an assay bacterium.

As is clear from the results in the above table, the compound of the present invention rapidly provides a high blood concentration, and is highly superior to that of ceftazidime.

Therefore, the compound of general formula [I], its non-toxic salts and physiologically hydrolyzable non-toxic esters are useful as antibacterial agents.

The compound of the present invention can be mixed with a carrier of a solid or liquid excipient known in the art, and used in the form of a pharmaceutical preparation suitable for parenteral administration, oral administration or external administration.

Examples of the pharmaceutical preparation include liquid preparations such as injections, syrups and emulsions, solid preparations such as tablets, capsules and granules, and external preparations such as ointments and suppositories.

In addition, auxiliary agents, stabilizers, and
Additives that are commonly used, such as wetting agents, emulsifying agents, absorption promoters, and surfactants may be included.

Examples of the additive include distilled water for injection, Ringer's solution, glucose, sucrose syrup, gelatin, edible oil, cacao oil, ethylene glycol, sucrose, corn starch, magnesium stearate, talc and the like.

Further, the compound of the present invention is an antibacterial agent containing Gram-positive and Gram-negative bacteria, which are sensitive and resistant, particularly glucose non-fermenting Gram-negative bacilli such as Pseudomonas aeruginosa, Pseudomonas cepacia, Pseudomonas maltophilia and Acinetobacter calcoaceticus. It can be used for the treatment of human bacterial infections in which a negative bacterium is the causative agent. The dose varies depending on the patient's age, sex, etc., but usually 1 to 100 mg / kg per day
It is preferably used in the range of 5 to 30 mg / kg and administered in 2 to 4 divided doses per day.

Examples Example 1 7β- [2- (2-aminothiazol-4-yl)-
2-Methoxyiminoacetamide] -3- [5- (3,4
-Dihydroxyphenyl) -1,3,4-oxadiazol-2-yl] thiomethyl-3-cephem-4-carboxylate sodium salt (syn isomer) (A) Benzhydryl 3-iodomethyl-7β- [ 2-
1.0 g (1.1 mmol) of methoxyimino-2- (2-tritylaminothiazol-4-yl) acetamido] -3-cephem-4-carboxylate (syn isomer) was dissolved in 10 ml of N, N-dimethylformamide, 2-mercapto-5
0.34 g (1.1 mmol) of-[3,4, -di (2-methoxyethoxymethoxy) phenyl] -1,3,4-oxazole was added,
Stir at room temperature for 2 hours. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (Wako gel C-300), and the elution fraction containing the desired product (ethyl acetate / hexane = 3: 1) was concentrated, Benzhydryl 3- {5- [3,4-di (2-methoxyethoxymethoxy) phenyl] -1,3,4-oxadiazole-2
-Yl} thiomethyl-7β- [2-methoxyimino-2
0.73 g (61% yield) of-(2-tritylaminothiazol-4-yl) acetamido] -3-cephem-4-carboxylate (syn isomer) is obtained as a foam.

NMR (DMSO-d ₆ ) δ: 3.23 (6H, s), 3.50 (6H, m), 3.80
(4H, m), 4.30 (2H, m), 5.23 (1H, d, J = 5Hz), 5.25 (4
H, m), 5.82 (1H, dd, J = 5 and 7Hz), 6.80 (1H, s), 6.88 (1H, s), 7.00 to 7.90 (28H, m), 9.00
(1H, br s), 9.62 (1H, br d, J = 7Hz) (B) 0.73 g (0.65 mmol) of the compound obtained in the above reaction (A)
Dissolved in 3.6 ml of methylene chloride and 0.7 ml of anisole,
Then, add 3.6 ml of trifluoroacetic acid dropwise, then 1 at room temperature.
Stir for hours. After distilling off the solvent under reduced pressure, diethyl ether is added under ice cooling, and the formed precipitate is collected by filtration. This precipitate was suspended in water and adjusted to pH 6.5 with saturated aqueous sodium hydrogen carbonate,
After dissolution, the insoluble material is filtered off. This filtrate was subjected to ODS silica gel column chromatography (LC-Sorb RP-18, Chemco), and the eluate fraction containing the desired product (10% aqueous methanol solution) was concentrated under reduced pressure and then freeze-dried to give the title compound 15
6 mg (40% yield) are obtained.

MP: 175 ℃ (decomposition) NMR (DMSO-d ₆ ) δ: 3.53 (2H, m), 3.83 (3H, s) 4.37
(2H, m), 5.00 (1H, d, J = 5Hz), 5.58 (1H, m), 6.72 (1
H, s), 6.74 (1H, d, J = 7Hz), 7.18 (1H, br d, J = 7Hz),
7.22 (1H, br s) Example 2 7β- [2- (2-aminothiazol-4-yl)-
2-Methoxyiminoacetamide] -3- [5- (3,4
-Dihydroxyphenyl) -1,3,4-oxadiazol-2-yl] thiomethyl-3-cephem-4-carboxylate sodium salt (syn isomer) 7β- [2- (2-aminothiazole- 4-yl)-
2-methoxyiminoacetamide] cephalosporanic acid formate (syn isomer) 1.25 g (2.50 mmol) and 5- (3,4
-Dihydroxyphenyl) -2-mercapto-1,3,4-
0.63 g (3.00 mmol) of oxadiazole is suspended in 25 ml of water and adjusted to pH 6.5 with sodium bicarbonate. Acetone 2 in this solution
Add 5 ml and stir at 65-70 ° C for 4 hours. The reaction solution was concentrated under reduced pressure, the concentrated aqueous solution was purified by ODS column chromatography (LC-Sorb RP-18, Chemco), and the elution fraction containing the desired product (40% methanol aqueous solution) was concentrated, 119 mg (7.9% yield) of the title compound are obtained. The IR absorption spectrum and NMR absorption spectrum of this product are exactly the same as those of the compound of Example 1.

Example 3 7β- [2- (2-aminothiazol-4-yl)-
2-Methoxyiminoacetamide] -3- [5- (3,4
-Dihydroxyphenyl) -1,3,4-oxadiazol-2-yl] thiomethyl-3-cephem-4-carboxylate sodium salt (syn isomer) (A) a) 7β-amino-3- [5- (3,4-dihydroxyphenyl) -1,3,4-oxadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid 1.48 g
(3.5 mmol) is suspended in 12 ml of methylene chloride, 3.46 ml (14 mmol) of N, O-bis (trimethylsilyl) acetamide is added, the mixture is refluxed for 45 minutes, and then cooled to -10 ° C.

b) 0.42 ml of phosphorus oxychloride at room temperature in 1.3 ml of ethyl acetate
(4.5 mmol) and 0.35 ml of N, N-dimethylformamide (4.
(5 mmol), and the mixture is stirred at the same temperature for 30 minutes, 12 ml of methylene chloride is added, and the mixture is cooled to 5 ° C. 2-Methoxyimino-2- (2-tritylaminothiazole-
1.77 g (4 mmol) of 4-yl) acetic acid (syn isomer) was added,
Stir for 20 minutes at 5 ° C. This solution is added at once to the solution prepared in a) and stirred at the same temperature for 1 hour. The reaction solution is poured into 20 ml of cold water, the organic layer is separated, washed with saturated brine and dried over anhydrous magnesium sulfate. The mixture was concentrated under reduced pressure, ether was added to the oily residue, and the mixture was stirred for 30 minutes under ice cooling to give powdery 3- [5- (3,4-dihydroxyphenyl) -1,3,4-oxadiazole- 2-yl] thiomethyl-7β- [2- (methoxyimino-2- (2-tritylaminothiazol-4-yl) acetamide] -3-
2.88 g of cephem-4-carboxylic acid (syn isomer) (yield 9
7%).

_{NMR (DMOSO-d 6) δ} : 3.70 (2H, ABq), 3.94 (3H, s),
4.35 (2H, ABq), 5.15 (1H, d, J = 4.5Hz), 5.73 (1H, dd, J
= 4.5 and 9Hz), 6.87 (1H, s), 7.04 (1H, d, J = 1OHz),
7.15 ~ 7.70 (17H, m), 9.68 (1H, d, J = 9Hz) 10.40 (1H, b
rs), 11.85 (3H, br s) (B) 1.48 g (1.75 mmol) of the compound obtained in the above reaction (A)
At room temperature, 9 ml of 99% formic acid and 0.71 ml of concentrated hydrochloric acid are added, and the mixture is stirred at the same temperature for 2.5 hours (from a gum-like insoluble matter, gradually becomes a yellow suspension). The insoluble matter is filtered off, washed with 1 ml of 99% formic acid and the filtrate is added to 150 ml of diisopropyl ether. The mixture was stirred at room temperature for 30 minutes, the precipitate was collected by filtration, washed with diisopropyl ether (20 ml, twice), and 7β- [2-
(2-Aminothiazol-4-yl) -2-methoxyiminoacetamido] -3- [5- (3,4-dihydroxyphenyl) -1,3,4-oxadiazol-2-yl] thiomethyl-3- 0.9 g (yield 80%) of cephem-4-carboxylic acid / hydrochloride (syn isomer) is obtained.

_{NMR (DMSO-d 6) δ} : 3.73 (2H, ABq), 3.97 (3H, s), 4.
35 (2H, ABq), 5.17 (1H, d, J = 4.5Hz), 5.77 (1H, dd, J =
4.5 and 9Hz), 6.93 (1H, d, J = 9Hz), 6.97 (1H, s), 7.10
~ 7.40 (2H, m), 9.80 (6H, br s) (C) Compound obtained in the above reaction (B) 670mg (1.04mmol)
Is suspended in 27 ml of water, adjusted to pH 7 with saturated aqueous sodium hydrogen carbonate, and then filtered. The filtrate was adjusted to pH 3 with 6N hydrochloric acid under ice cooling and stirred for 1 hour, and then the precipitate was collected by filtration, washed with water (6 ml, twice), and dried under reduced pressure to obtain 7β- [2- (white powder). 2-Aminothiazol-4-yl) -2-methoxyiminoacetamido] -3- [5- (3,4-dihydroxyphenyl) -1,
3,4-Oxadiazol-2-yl] thiomethyl-3-
Cephem-4-carboxylic acid (syn isomer) 510 mg (yield 8
1%).

MP: 175-180 ℃ (decomposition) NMR (DMSO-d ₆ ) δ: 3.73 (2H, ABq), 3.86 (3H, s), 4.34
(2H, ABq), 5.15 (1H, d, J = 4.5Hz), 5.78 (1H, dd, J = 4.
5 and 9Hz), 6.75 (1H, s), 6.90 (1H, d, J = 9Hz), 7.20〜
7.50 (2H, m), 9.20 to 10.00 (2H, br s) (D) 121 mg (0.2 mmol) of the compound obtained in the above reaction (C) was suspended in 1.21 ml of water, and 25.2 mg (0.3 mmo of sodium hydrogen carbonate).
l) is added and filtered. The filtrate is left at room temperature for 1 hour, then the precipitate is collected by filtration, washed with 0.5 ml of water and dried under reduced pressure to obtain 40 mg (yield 32%) of the title compound as a white powder. The IR absorption spectrum and NMP absorption spectrum of this product are exactly the same as those of the compound of Example 1.

Example 4 3- [5- (3,4-diacetoxyphenyl) -1,3,4-
Oxodiazol-2-yl] thiomethyl-7β- [2
-(2-Aminothiazol-4-yl) -2-methoxyiminoacetamide] -3-cephem-4-carboxylate sodium salt (syn isomer) (A) Benzhydryl 3-iodomethyl-7β- [2-
Methoxyimino-2- (2-tritylaminothiazol-4-yl) acetamido] -3-cephem-4-carboxylate (syn isomer) (1.0 g, 1.1 mmol) was added to N, N-
It is dissolved in 10 ml of dimethylformamide, 0.34 g (1.1 mmol) of 5- (3,4-dihydroxyphenyl) -2-mercapto-1,3,4-oxadiazole is added, and the mixture is stirred at room temperature for 2 hours. 2.5 ml of acetic anhydride and 2.5 ml of pyridine are dissolved in the residue obtained by distilling off the solvent under reduced pressure, and the mixture is left at room temperature for 1 hour. The solvent was distilled off again under reduced pressure, and the resulting residue was purified by silica gel column chromatography (Wako Gel).
C-300) and the elution fraction containing the desired product (ethyl acetate / hexane = 1: 1) was concentrated to give benzhydryl 3-
[5-3,4-diacetoxyphenyl) -1,3,4-oxadiazol-2-yl] thiomethyl-7β- [2-methoxyimino 2- (2-tritylaminothiazole-4-]
Yield) acetamido] -3-cephem-4-carboxylate (syn isomer) 0.74 (63% yield) is obtained as a foam.

NMR (DMSO-d ₆ ) δ: 2.36 (6H, s), 3.80 (2H, m), 3.86
(3H, s), 4.10 to 4.60 (2H, m), 5.22 (1H, d, J = 5Hz), 5.
80 (1H, m), 6.77 (1H, s), 6.90 (1H, s), 7.10 ~ 7.70 (2
8H, m), 8.80 (1H, br s), 9.60 (1H, br d, J = 8Hz) (B) Compound obtained in the above reaction (A) 0.74 g (0.67 mmol)
Was dissolved in a solution of 4.0 ml of methylene chloride and 0.8 ml of anisole, 4.0 ml of trifluoroacetic acid was added dropwise at 0 ° C., and the mixture was stirred at room temperature for 1 hour. After distilling off the solvent under reduced pressure, diethyl ether is added under ice cooling, and the formed precipitate is collected by filtration. The precipitate is suspended in water, adjusted to pH 6.5 with saturated aqueous sodium hydrogen carbonate, and the insoluble solution is filtered off. This filtrate was subjected to ODS column chromatography (LC-Sorb RP-18, Chemco), and the elution fraction containing the target substance (40% methanol aqueous solution) was concentrated under reduced pressure and freeze-dried to give 142 mg of the title compound (yield. 30
%).

MP: 170 ℃ (decomposition) NMR (DMSO-d ₆ ) δ: 2.33 (6H, s), 3.56 (2H, m) 3.83
(3H, s), 4.40 (2H, m), 5.00 (1H, d, J = 5Hz), 5.60 (1
H, dd, J = 5 and 8Hz), 6.72 (1H, s), 7.50 (1H, d, J = 8H)
z), 7.89 (1H, br, s), 7.90 (1H, br d, J = 8Hz), 9.50 (1
H, br d, J = 8 Hz) Example 5 7β- [2- (2-aminothiazol-4-yl)-
2-Ethoxyiminoacetamide] -3- [5- (3,4
-Dihydroxyphenyl) -1,3,4-oxadiazol-2-yl] thiomethyl-3-cephem-4-carboxylate sodium salt (syn isomer) Benzhydryl 7β- [2-ethoxyimino-2-
(2-Tritylaminothiazol-4-yl) acetamido] -3-iodomethyl-3-cephem-4-carboxylate (syn isomer) 1.0 g (1.1 mmol) and 2-mercapto-5- [3,4-di (2-Methoxyiethoxymethoxy) phenyl] -1,3,4-oxazole 0.34 g (1.1 mmo
l) was used and the same procedure as in Example 1 was conducted to obtain the title compound 9
5 mg (13.5% yield) are obtained.

MP: 165 ℃ (decomposition) NMR (DMSO-d ₆ ) δ: 1.25 (3H, t, J = 8Hz), 3.20-3.90
(2H, m), 4.10 (2H, q, J = 8Hz), 5.00 (1H, d, J = 5Hz),
5.62 (1H, m), 6.72 (1H, s), 6.85 (1H, d, J = 8Hz), 7.20
(1H, br d, J = 8 Hz), 7.28 (1H, br s) Example 6 3 [5- (3,4-diacetoxyphenyl) -1,3,4-oxadiazol-2-yl] thiomethyl -7β- [2-
Preparation of (2-aminothiazol-4-yl) -2-ethoxyiminoacetamide] -3-cephem-4-carboxylate sodium salt (syn isomer) Benzhydryl 7β- [2-ethoxyimino-2-
(2-Tritylaminothiazol-4-yl) acetamido] -3-iodomethyl-3-cephem-4-carboxylate (syn isomer) 2.0 g (2.11 mmol) and 5-
(3,4-dihydroxyphenyl) -2-mercapto-1,
The same operation as in Example 4 was carried out using 0.89 g (4.22 mmol) of 3,4-oxadiazole to give 291 mg of the title compound (yield: 21.4
%).

MP: 175 ℃ (decomposition) NMR (DMSO-d ₆ ) δ: 1.23 (3H, t, J = 8Hz), 2.33 (6H,
s), 3.60 (2H, m), 4.12 (2H, q, J = 8Hz), 4.43 (2H, m),
5.04 (1H, d, J = 8Hz), 4.43 (2H, m), 5.04 (1H, d, J = 5H
z), 5.60 (1H, dd, J = 5 and 8Hz), 6.70 (1H, s), 7.28
(2H, br s), 7.50 (1H, d, J = 14Hz), 7.88 (1H, s), 7.89
(1H, br d, J = 14 Hz), 9.44 (1H, br d, J = 8 Hz) Example 7 7β- [2- (2-aminothiazol-4-yl)-
2-Isopropoxyiminoacetamide] -3- [5-
Preparation of (3,4-dihydroxyphenyl) -1,3,4-oxazol-2-yl] thiomethyl-3-cephem-4-carboxylate sodium salt (syn isomer) Benzhydryl 3-iodomethyl-7β- [2 -Isopropoxyimino-2- (2-tritylaminothiazol-4-yl) acetamido] -3-cephem-4-carboxylate (syn isomer) 1.0 g (1.0 mmol) and 2-mercapto-5- [3, 4-di (2-methoxyethoxymethoxy) phenyl] -1,3,4-oxadiazole 0.40 g (1.
The same procedure as in Example 1 is carried out using 2 mmol) to obtain 56 mg (yield 8.2%) of the title compound.

MP: 195 ℃ (decomposition) NMR (DMSO-d ₆ ) δ: 1.22 (6H, t, J = 6Hz), 3.53 (2H,
s), 4.15 to 4.50 (3H, m), 5.01 (1H, d, J = 5Hz), 5.62 (1
H, m), 6.69 (1H, s), 6.92 (1H, d, J = 8Hz), 7.20 ~ 7.40
(3H, m) Example 8 7β- [2-allyloxyimino-2- (2-aminothiazol-4-yl) acetamide] -3- [5-
Preparation of (3,4-dihydroxyphenyl) -1,3,4-oxadiazol-2-yl] thiomethyl-3-cephem-4-carboxylate sodium salt (syn isomer) Benzhydryl 7β- [2-allyl Oxyimino-2
-(2-Tritylaminothiazol-4-yl) acetamido] -3-iodomethyl-3-cephem-4-carboxylate (syn isomer) 1.0 g (1.0 mmol) and 2-
Mercapto-5- [3,4-di (2-methoxyethoxymethoxy) phenyl] -1,3,4-oxadiazole 0.40 g
Using (1.2 mmol), the same operation as in Example 1 was carried out,
150 mg (yield 18.2%) of the title compound are obtained.

MP: 180 ℃ (decomposition) NMR (DMSO-d ₆ ) δ: 3.54 (2H, m), 4.38 (2H, m), 4.60
(2H, br d, J = 5Hz), 5.00 (1H, d, J = 5Hz), 5.05 to 5.50
(2H, m), 5.60 (1H, d, J = 5Hz), 5.70 ~ 6.10 (1H, m), 6.
72 (1H, s), 6.83 (1H, d, J = 9Hz), 7.22 (1H, d, J = 9H
z), 7.29 (1H, s) Example 9 7β- [2- (2-aminothiazol-4-yl)-
2- (2-propynyloxyimino) acetamide]-
3- [5- (3,4-Dihydroxyphenyl) -1,3,4-oxadiazol-2-yl] thiomethyl-3-cephem-4-carboxylate sodium salt (syn isomer)
Production of benzhydryl 3-iodomethyl-7β- [2- (2
-Propinyloxyimino) -2- (2-tritylaminothiazol-4-yl) acetamido] -3-cephem-4-carboxylate (syn isomer) 1.0 g (1.0 m
mol) and 2-mercapto-5- [3,4-di (2-methoxyethoxymethoxy) phenyl] -1,3,4-oxadiazole (0.40 g, 1.2 mmol) were used in the same manner as in Example 1. By operation, 113 mg (yield 16.6%) of the title compound is obtained.

MP: 155 ℃ (decomposition) NMR (DMSO-d ₆ ) δ: 2.50 (1H, br s), 3.50 (2H, m),
4.36 (2H, m), 4.67 (2H, br s), 5.00 (1H, d, J = 5Hz),
5.60 (1H, m), 6.73 (1H, s), 6.92 (1H, d, J = 7Hz), 7.24
(1H, br d, J = 7Hz), 7.35 (1H, br.s), 9.58 (1H, br d, J
= 8 Hz) Example 10 7β- [2- (2-aminothiazol-4-yl)-
2-carboxylate methoxyiminoacetamide]-
Preparation of 3- [5- (3,4-dihydroxyphenyl) -1,3,4-oxadiazol-2-yl] thiomethyl-3-cephem-4-carboxylate disodium salt (syn isomer) Benzhydryl 7β- [2-benzhydryloxycarbonylmethoxyimino-2- (2-tritylaminothiazol-4-yl) acetamido] -3-iodomethyl-3-cephem-4-carboxylate (syn isomer) 1.0 g (0.88) mmol) and 2-mercapto-5- [3,4-
Di (2-methoxyethoxymethoxy) phenyl] -1,3,
Using 0.28 g (0.88 mmol) of 4-oxadiazole and following the same procedure as in Example 1, 172 mg of the title compound (yield: 29.9
%).

MP: 180 ℃ (decomposition) NMR (DMSO-d ₆ ) δ: 3.55 (2H, m), 3.90-4.60 (3H,
m), 5.02 (1H, d, J = 5Hz), 5.65 (1H, m), 6.85 (1H, s),
6.86 (1H, d, J = 7Hz), 7.30 (3H, m) Example 11 7β- [2- (2-aminothiazol-4-yl)-
2- (1-carboxylate-1-methylethoxyimino) acetamide] -3- [5- (3,4-dihydroxyphenyl) -1,3,4-oxadiazol-2-yl] thiomethyl-3-cephem Preparation of 4-carboxylate disodium salt (syn isomer) Benzhydryl 7β- [2- (1-benzhydryloxycarbonyl-1-methylethoxyimino) -2- (2
-Tritylaminothiazol-4-yl) acetamido] -3-iodomethyl-3-cephem-4-carboxylate (syn isomer) 1.2 g (1.0 mmol) and 2-mercapto-5- [3,4-di (2 -Methoxyethoxymethoxy) phenyl] -1,3,4-oxadiazole 0.33 g (1.1 m
(mol) in the same manner as in Example 1 to obtain 238 mg (yield 34.4%) of the title compound.

MP: 185 ℃ (decomposition) NMR (DMSO-d ₆ ) δ: 1.39 (3H, br s), 1.47 (3H, br
s), 3.54 (2H, m), 4.08 (1H, br d, J = 12Hz), 4.50 (1H,
br d, J = 12Hz), 5.08 (1H, d, J = 6Hz), 5.70 (1H, m), 6.
69 (1H, s), 6.77 (1H, d, J = 7Hz), 7.20 (1H, br d, J = 7H
z), 7.27 (1H, br s) Example 12 7β- [2- (2-aminothiazol-4-yl)-
2- (1-carboxylate-1-cycloproxyimino) acetamide] -3- [5- (3,4-dihydroxyphenyl) -1,3,4-oxadiazol-2-yl] thiomethyl-3-cephem Production of 4-carboxylate disodium salt (syn isomer) Benzhydryl 7β- [2- (1-tert-butoxycarbonyl-1-cyclopropoxyimino) -2- (2-
Tritylaminothiazol-4-yl) acetamide]
1.0 g (0.96 mmol) of 3--3-iodomethyl-3-cephem-4-carboxylate (syn isomer) and 2-mercapto-5- [3,4-di (2-methoxyethoxymethoxy) phenyl] -1,3 0.30 g (1.0 mmol) of 4,4-oxadiazole
And the title compound 14 in the same manner as in Example 1
6 mg (yield 21.7%) are obtained.

MP: 155 ℃ (decomposition) NMR (DMSO-d ₆ ) δ: 1.16 (4H, m), 3.58 (2H, m), 4.18
(1H, d, J = 12Hz), 4.45 (1H, d, J = 12Hz), 5.05 (1H, d, J
= 4Hz), 5.65 (1H, m), 6.75 (1H, d, J = 10Hz), 6.83 (1
H, s), 7.22 (3H, m) Example 13 7β- [2- (2-aminothiazol-4-yl)-
2-Benzyloxyiminoacetamide] -3- [5-
Preparation of (3,4-dihydroxyphenyl) -1,3,4-oxadiazol-2-yl] thiomethyl-3-cephem-4-carboxylate sodium salt (syn isomer) Benzhydryl 7β- [2- ( Benzyloxyimino-
2- (2-Tritylaminothiazol-4-yl) acetamido] -3-chloromethyl-3-cephem-4-carboxylate (syn isomer) 0.65 g (0.67 mmol) and 2
-Mercapto-5- [3,4-di (2-methoxyethoxymethoxy) phenyl] -1,3,4-oxadiazole 0.41 g
Using (1.34 mmol) and the same procedure as in Example 1, 30 mg (yield 12.4%) of the title compound is obtained.

MP: 170 ℃ (decomposition) _{NMR (DMSO-d 6) δ} : 3.40 (1H, br d, J = 18Hz), 3.65
(1H, br d, J = 18Hz), 4.39 (2H, m), 5.00 (1H, d, J = 6H
z), 5.13 (2H, br s), 5.68 (1H, m), 6.74 (1H, s), 6.90
(1H, d, J = 8Hz), 7.33 (7H, m). Example 14 7β- [2- (2-Aminothiazol-4-yl)-
2- (3,4-Dihydroxybenzyloxyimino) acetamido] -3- [5- (3,4-dihydroxyphenyl) -1,3,4-oxadiazol-2-yl] thiomethyl-3-cephem-4 -Production of sodium salt of carboxylate (syn isomer) Benzhydryl 3-iodomethyl-7β- {2- [3,
4-Di (2-methoxyethoxymethoxy) benzyloxyimino] -2- (2-tritylaminothiazole-4
-Yl) acetamido} -3-cephem-4-carboxylate (syn isomer) 1.0 g (0.82 mmol) and 5- (3,4
-Dihydroxyphenyl) -2-mercapto-1,3,4-
Using 0.25 g (1.1 mmol) of oxadiazole and by the same procedure as in Example 1, 345 mg of the title compound (yield 52%) is obtained.

MP: 170 ℃ (decomposition) NMR (DMSO-d ₆ ) δ: 3.60 (2H, m), 4.39 (2H, m), 5.03
(3H, m), 5.65 (1H, m), 6.70 (1H, s), 6.75 (3H, m), 7.
20 (3H, m), 7.42 (1H, d, J = 9Hz).

Example 15 7β- [2- (2-aminothiazol-4-yl)-
2- (α-carboxylate benzyloxyimino) acetamido] -3- [5- (3,4-dihydroxyphenyl) -1,3,4-oxadiazol-2-yl] thiomethyl-3-cephem-4- Production of carboxylate disodium salt (syn isomer) (A) 2- (α-benzhydryloxycarbonylbenzyloxyimino) -2- (2-tritylaminothiazol-4-yl) acetic acid (syn isomer) 730 mg (1 mmol) is dissolved in 10 ml of methylene chloride, benzhydryl 7β-amino-3-chloromethyl-3-cephem-4-carboxylate (415 mg) is added, and the mixture is cooled to 0 ° C. N, N-
After adding 0.57 ml (4.5 mmol) of dimethylaniline, 0.11 ml (1.2 mmol) of phosphorus oxychloride is added dropwise and stirred for 1 hour. The reaction solution is washed successively with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine. The organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and ether was added to the residue to give benzhydryl 3-chloromethyl-7β- [2-
(Α-Benzhydryloxycarbonylbenzyloxyimino) -2- (2-tritylaminothiazole-4-
1.12 g of (yl) acetamido] -3-cephem-4-carboxylate (syn isomer) is obtained, which is then used in the next reaction without purification.

(B) 500 mg (0.44 mmol) of the compound obtained in the above reaction (A)
Was dissolved in 5 ml of N, N-dimethylformamide, 333 mg (2.22 mmol) of sodium iodide was added, and after stirring for 50 minutes, 2-
Mercapto-5- [3,4-di (2-methoxyethoxymethoxy) phenyl] -1,3,4-oxadiazole 172 mg
Add (0.44 mmol) and stir for 2 hours. Ethyl acetate (30 ml) was added to the reaction solution, and the mixture was washed with water and saturated brine successively,
Dry over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and benzhydryl 7β- [2- {2-[[α-benzhydryloxycarbonyl-3,4-di (2-methoxyethoxymethoxy) benzyl] oxyimino] -2- (2
-Tritylaminothiazol-4-yl) acetamido} -3- {5- [3,4-di (2-methoxyethoxymethoxy) phenyl] -1,3,4-oxadiazole-2-
Yield} thiomethyl-3-cephem-4-carboxylate (syn isomer) (420 mg) was used in the next reaction without purification.

(C) 400 mg (0.27 mmol) of the compound obtained in the above reaction (B)
Was carried out in the same manner as in Example 1 (B) to give 115 m of the title compound.
g (55% yield) are obtained.

MP: 170 ℃ (decomposition) NMR (D ₂ O) δ: 3.60 (2H, br s), 4.35 (2H, br s), 4.9
8 (0.5H, d, J = 4.5Hz), 5.06 (0.5H, d, J = 4.5Hz), 5.36
(0.5, H, s), 5.40 (0.5H, s), 5.51 (0.5H, d, J = 4.5H
z), 5.72 (0.5H, d, J = 4.5Hz), 6.76 (0.5H, s), 6.86
(0.5H, s), 7.10 to 7.30 (5H, m), 7.45 to 7.65 (3H, m) Example 16 7β- {2- (2-aminothiazol-4-yl)-
2- [α-carboxylate-3,4-dihydroxybenzyl) oxyimino] acetamide} -3- [5- (3,
Preparation of 4-dihydroxyphenyl) -1,3,4-oxadiazol-2-yl] thiomethyl-3-cephem-4-carboxylate disodium salt (syn isomer) 2-{[α-benzhydryl Oxycarbonyl-3,4
-Di (2-methoxyethoxymethoxy) benzyl] oxyimino} -2- (2-tritylaminothiazole-
4-yl) acetic acid (syn isomer) (4.87 g, 5.19 mmol) and benzhydryl 7β-amino-3-chloromethyl-3-cephem-4-carboxylate (2.34 g, 5.64 mmol) were treated in the same manner as in Example 16. , 184 mg of the title compound are obtained.

MP: 170 ℃ NMR (DMSO-d ₆ ) δ: 3.60 (2H, m), 4.40 (2H, m), 4.95
(0.5H, d, J = 5Hz), 5.06 (0.5H, d, J = 5Hz), 5.15 (0.5
H, s), 5.21 (0.5H, s), 5.51 (0.5H, d, J = 5Hz), 5.57
(0.5H, d, J = 5Hz), 6.50 ~ 7.00 (5H, m), 7.25 (2H,
m).

Example 17 7β- [2- (2-aminothiazol-4-yl)-
2- (4-Hydroxybenzyloxyimino) acetamide] -3- [5- (3,4-dihydroxyphenyl)-
1,3,4-Oxadiazol-2-yl] thiomethyl-3
-Preparation of cephem-4-carboxylic acid (syn isomer) Benzhydryl 3-chloromethyl-7β- {2- [4
2.04 g (2 mmol) of 2- (2-methoxyethoxymethoxy) benzyloxyimino] -2- (2-tritylaminothiazol-4-yl) acetamido} -3-cephem-4-carboxylate (syn isomer) and 2- Mercapto-
Using the same procedure as in Example 1, using 5- [3,4-di (2-methoxyethoxymethoxy) phenyl] -1,3,4-oxadiazole (773 mg, 2 mmol), the title compound (530 g, yield 38.0%).

MP: 170 ℃ _{NMR (DMSO-d 6) δ} : 3.70 (2H, br s), 4.25 (1H, d, J =
14Hz), 4.45 (1H, d, J = 14Hz), 5.00 (2H, s), 5.13 (1H,
d, J = 5Hz), 5.77 (1H, dd, J = 5 and 8Hz), 6.70 (1H,
s), 6.72 (2H, d, J = 8Hz), 6.88 (1H, d, J = 8Hz), 7.28
(1H, d, J = 8Hz), 7.38 (2H, d, J = 8Hz), 7.40 (1H, s),
9.60 (1H, d, J = 8Hz).

Example 18 7β- [2- (2-Aminothiazol-4-yl)-
2- (3-carboxylate-4-hydroxybenzyloxyimino) acetamido] -3- [5- (3,4-dihydroxyphenyl) -1,3,4-oxadiazole-2
-Yl] thiomethyl-3-cephem-4-carboxylate disodium salt (syn isomer) Benzhydryl 7β- {2- [3-benzhydryloxycarbonyl-4- (2-methoxyethoxymethoxy) benzyloxy] Imino] -2- (2-tritylaminothiazol-4-yl) acetamido} -3-chloromethyl-3-cephem-4-carboxylate (syn isomer) 1.23 g (1 mmol) and 2-mercapto-5- [ 3,4-
Di (2-methoxyethoxymethoxy) phenyl] -1,3,
Using 386 mg (1 mmol) of 4-oxadiazole, Example 1
Perform the same operation as above to obtain 230 mg of the title compound (yield 29.3%).
Get.

MP: 180 ℃ (decomposition) NMR (DMSO-d ₆ ) δ: 3.40 (1H, d, J = 18Hz), 3.68 (1H,
d, J = 18Hz), 4.40 (2H, br s), 4.98 (2H, s), 5.00 (1H,
d, J = 5Hz), 5.60 (1H, d, J = 5Hz), 6.60 (1H, d, J = 8H)
z), 6.83 (1H, d, J = 8Hz), 7.20 (1H, d, J = 8Hz), 7.22
(1H, d, J = 8Hz), 7.30 (1H, s), 7.70 (1H, s).

Example 19 7β- [2- (2-aminothiazol-4-yl)-
2- (4-carboxylate benzyloxyimino) acetamido] -3- [5- (3,4-dihydroxyphenyl) -1,3,4-oxadiazol-2-yl] thiomethyl-3-cephem-4- Production of carboxylate disodium salt (syn isomer) Benzhydryl 7β- [2- (4-benzhydryloxycarbonylbenzyloxyimino) -2- (2-tritylaminothiazol-4-yl) acetamide]
550 mg (0.46 mmol) of 3-iodomethyl-3-cephem-4-carboxylate (syn isomer) and 2-mercapto-5- [3,4-di (2-methoxyethoxymethoxy)]
Phenyl] -1,3,4-oxadiazole 176 mg (0.46 mmo
l) was used and the same operation as in Example 1 was carried out to give the title compound 5
4 mg (16% yield) are obtained.

MP: 165 ℃ (decomposition) NMR (DMSO-d ₆ ) δ: 3.35 (1H, d, J = 18Hz), 3.63 (1H,
d, J = 18Hz), 4.30 (2H, br s), 4.98 (1H, d, J = 5Hz), 5.
12 (2H, s), 5.60 (1H, d, J = 5Hz), 6.70 (1H, s), 6.77
(1H, d, J = 8Hz), 7.20 (1H, d, J = 8Hz), 7.25 (1H, s),
7.27 (2H, d, J = 8Hz), 7.80 (2H, d, J = 8Hz).

Example 20 (A) 7β- [2- (2-Aminothiazol-4-yl) -2- (3-carboxylatebenzyloxyimino) acetamido] -3- [5- (3,4-dihydroxyphenyl)- Preparation of 1,3,5-oxadiazol-2-yl] thiomethyl-3-cephem-4-carboxylate disodium salt (syn isomer) a) 7β-amino-3- [5- (3,4 -Dihydroxyphenyl) -1,3,4-oxadiazol-2-yl] thiomethyl-3-cephem-4-carboxylic acid 465 mg (1.1 mmo
l) was suspended in 5 ml of methylene chloride, 1.08 ml (4.4 mmol) of N, O-bis (trimethylsilyl) acetamide was added, and 1)
After refluxing for a period of time to dissolve, the mixture was cooled to −15 ° C., 0.95 ml (7.5 mmol) of N, N-dimethylaniline was added, and the temperature was maintained at the same.

b) 10 ml of a methylene chloride solution containing 229 mg (1.1 mmol) of phosphorus pentachloride was cooled to -10 ° C, and 2- (3-benzhydryloxycarbonylbenzyloxyimino) -2- (2-
730 mg (1 mmol) of tritylaminothiazol-4-yl) acetic acid (syn isomer) is added, and the mixture is stirred at -5 ° C for 30 minutes. This methylene chloride solution is added dropwise to the solution prepared in a) and stirred at -10 to 0 ° C for 3 hours. The reaction mixture is concentrated under reduced pressure, ethyl acetate and water are added to the residue, the insoluble matter is filtered off, and the layers are separated. The ethyl acetate layer is washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated.
The residue was separated and purified by silica gel flash column chromatography (Wakogel C-300, eluted with 20% acetone / methylene chloride), and 7β- [2- (3-benzhydryloxycarbonylbenzyloxyimino) -2-
(2-Tritylaminothiazol-4-yl) acetamido] -3- [5- (3,4-dihydroxyphenyl)-
1,3,4-Oxadiazol-2-yl] thiomethyl-3
870 mg (76.7% yield) of cephem-4-carboxylic acid (syn isomer) are obtained as a foam.

(B) To 870 mg of the compound obtained in the above reaction (A), 8 ml of methylene chloride and 0.8 ml of anisole were added, and the mixture was ice-cooled, 8 ml of trifluoroacetic acid cooled in advance was added, and the mixture was stirred at room temperature for 2 hours. 80 ml of ether is added to the reaction solution and the precipitate is collected by filtration.
This precipitate was suspended in 100 ml of water, adjusted to pH 7.2 with a saturated aqueous sodium hydrogen carbonate solution, and subjected to reverse phase chromatography (LC
-Sorb RP-18, 100 ml: 5 to 10% after passing 400 ml of water
250 mg of the title compound (yield: 42.3%), and the elution fraction containing the desired product was concentrated and freeze-dried.
%).

MP: 170 ℃ (decomposition) NMR (DMSO-d ₆ ) δ: 3.45 (1H, d, J = 18Hz), 3.72 (1H,
d, J = 18Hz), 4.35 (2H, br s), 5.00 (1H, d, J = 5Hz), 5.
15 (2H, s), 5.64 (1H, d, J = 5Hz), 6.58 (1H, d, J = 8H
z), 6.72 (1H, s), 7.10 ~ 7.40 (4H, m), 7.70 ~ 7.90 (2
H, m) Example 21 7β- [2- (2-aminothiazol-4-yl)-
2- (4-carboxylate methylbenzyloxyimino) acetamido] -3- [5- (3,4-dihydroxyphenyl) -1,3,4-oxadiazol-2-yl] thiomethyl-3-cephem-4 -Production of carboxylate disodium salt (syn isomer).

372 mg (0.5 mmol) of 2- (4-benzhydryloxycarbonylmethylbenzyloxyimino) -2- (2-tritylaminothiazol-4-yl) acetic acid (syn isomer)
And 7β-amino-3- [5- (3,4-dihydroxyphenyl) -1,3,4-oxadiazol-2-yl] thiomethyl-3-cephem-4-carboxylic acid 211 mg (0.5 mmo
l) was used and the same operation as in Example 20 was carried out to give the title compound 6
7 mg (yield 17.1%) are obtained.

MP: 170 ℃ (decomposition) NMR (DMSO-d ₆ ) δ: 3.26 (2H, s), 3.40 (1H, d, J = 18H
z), 3.70 (1H, d, J = 18Hz), 4.35 (2H, br s), 5.00 (1H,
d, J = 5Hz), 5.06 (2H, s), 5.60 (1H, d, J = 5Hz), 6.68
(1H, s), 6.72 (1H, d, J = 8Hz), 7.00 to 7.30 (6H, m).

Example 22 7β- [2- (2-Aminothiazol-4-yl)-
2-phenoxyiminoacetamide] -3- [5- (3,
Preparation of 4-dihydroxyphenyl) -1,3,4-oxadiazol-2-yl] thiomethyl-3-cephem-4-carboxylate sodium salt (syn isomer).

Benzhydryl 3-chloromethyl-7β- [2-phenoxyimino-2- (2-tritylaminothiazole-
4-yl) acetamido] -3-cephem-4-carboxylate (syn isomer) 350 mg (0.5 mmol) and 5
-(3,4-Dihydroxyphenyl) -2-mercapto-
The same operation as in Example 1 was carried out using 105 mg (0.5 mmol) of 1,3,4-oxadiazole to obtain 42 mg (yield 26.8%) of the title compound.

MP: 160 ℃ (decomposition) _{NMR (DMSO-d 6) δ} : 3.60 (2H, ABq), 4.70 (2H, m), 5.
20 (2H, d, J = 4.5Hz), 5.76 (1H, d, J = 4.5Hz), 7.08 (1
H, s), 7.20 to 7.40 (8H, m) Example 23 7β- {2- (2-aminothiazol-4-yl)-
2- [2- (carboxylatemethyl) benzyloxyimino] acetamido} -3- [5- (3,4-dihydroxyphenyl) -1,3,4-oxadiazol-2-yl] thiomethyl-3-cephem Preparation of 4-carboxylate disodium salt (syn isomer) 2- [2- (benzhydryloxycarbonylmethyl) benzyloxyimino] -2- (2-tritylaminothiazol-4-yl) acetic acid (syn Isomer) 744mg
(1.0 mmol) and 7β-amino-3- [5- (3,4-dihydroxyphenyl) -1,3,4-oxadiazole-2
-Yl] thiomethyl-3-cephem-4-carboxylic acid 42
The same operation as in Example 20 is performed using 2 mg (1.0 mmol) to obtain 234 mg of the title compound (yield 30%).

MP: 170 ℃ (decomposition) NMR (DMSO-d ₆ ) δ: 3.40 (2H, s), 3.50 (2H, br s),
4.30 (2H, br s), 5.00 (1H, d, J = 5Hz), 5.27 (2H, s),
5.60 (1H, d, J = 5Hz), 6.70 (1H, s), 6.73 (1H, d, J = 8)
Hz), 7.00 to 7.30 (5H, m) Example 24 7β- {2- (2-aminothiazol-4-yl)-
2-[(α- (carboxylatebenzyl) oxyimino)] acetamido} -3- [5- (3,4-dihydroxyphenyl) -1,3,4-oxadiazol-2-yl]
Thiomethyl-3-cephem-4-carboxylate disodium salt (diastereomer A and B, syn isomer)
7β-Amino-3- [5- (3,4-dihydroxyphenyl) -1,3,4-oxadiazole-2 obtained in Reference Example 26
-Yl] thiomethyl-3-cephem-4-carboxylic acid 9.
8 g (23.2 mmol) and 2-α-benzhydryloxycarbonylbenzyloxyimino) -2- (2-tritylaminothiazol-4-yl) acetic acid (syn isomer) 18.6
The same operation as in Example 20 was carried out using g (25.5 mmol), and in ODS column chromatography, diastereomer A was eluted with 5% aqueous methanol solution and diastereomer B was eluted with 10% aqueous methanol solution to give the desired product. The elution fractions containing are concentrated and lyophilized to give 620 mg (yield 3.5
%) And 400 mg (yield 2.2%).

High-performance liquid chromatography analysis Column: ODS (YMC-PACK A-302) 4.6 x 150 mm Mobile phase: 45% MeOH-0.01M Phosphate buffer (pH3.0) Flow rate: 1.2 ml / min Detection: UV 280 nm Diastereomer A: 5.9 minutes Diastereomer B: 8.3 minutes Diastereomer A MP: 195 ℃ (decomposition) NMR (D ₂ O / DSS) δ: 3.40 (2H, ABq) 4.08 (2H, ABq) 5.0
7 (1H, d, J = 4.5Hz), 5.55 (1H, s), 5.68 (1H, d, J = 4.5H)
z), 6.95 (1H, s), 7.1 ~ 7.6 (8H, m) Diastereomer B MP: 180 ℃ (decomposition) NMR (D ₂ O / DSS) δ: 3.30 (2H, ABq), 4.15 (2H, br s),
5.00 (1H, d, J = 4.5Hz), 5.54 (1H, s), 5.63 (1H, d, J =
4.5 Hz), 6.90 (1H, s), 7.1 to 7.6 (8H, m) Example 25 7β- [2- (2-aminothiazol-4-yl) -2
-Methoxyiminoacetamide] -3- [5- (3,4-
Dihydroxyphenyl) -1,3,4-thiadiazole-2
-Yl] thiomethyl-3-cephem-4-carboxylate sodium salt (syn isomer) Benzhydryl 3-iodomethyl-7β- [2-methoxyimino-2- (2-tritylaminothiazole-4)
-Yl) acetamido] -3-cephem-4-carboxylate (syn isomer) 1.0 g (1.07 mmol) and 2-mercapto-5- [3,4-di (2-methoxyethoxymethoxy) phenyl] -1, 3,4-thiadiazole 0.43 g (1.07 mm
The trifluoroacetate salt obtained by the same procedure as in Example 1 was suspended in water and adjusted to pH 6.5 with saturated aqueous sodium hydrogen carbonate, and then ODS column chromatography (LC-Sorb RP).
-18, Kecom Co., Ltd.) and elute with 20% methanol / water solution. The eluted fraction containing the desired product is concentrated and freeze-dried to obtain 168 mg of the title compound (yield 24.3%).

mp: 195 ℃ (decomposition) NMR (DMSO-d ₆ ) δ: 3.55 (2H, m), 3.87 (3H, s), 4.50
(2H, m), 5.03 (1H, d, J = 5Hz), 5.60 (1H, m), 6.75 (2
H, m), 7.08 (1H, m), 7.23 (1H, br s) Example 26 7β- [2- (2-aminothiazol-4-yl]-
2-Methoxyiminoacetamide] -3- [5- (3,4
-Diacetoxyphenyl) -1,3,4-thiadiazole-
Preparation of 2-yl] thiomethyl-3-cephem-4-carboxylate sodium salt (syn isomer) (A) Benzhydryl 3-iodomethyl-7β- [2
-Methoxyimino-2- (2-tritylaminothiazol-4-yl) acetamido] -3-cephem-4-carboxylate (syn isomer) 1.0 g (1.09 mmol) N, N
-Dissolved in 10.0 ml of dimethylformamide, 5- (3,4-
Dihydroxyphenyl) -2-mercapto-1,3,4-thiadiazole (0.30 g, 1.33 mmol) was added, and the mixture was allowed to stand at room temperature for 2 minutes.
Stir for hours. To the reaction solution, 1.0 ml of acetic anhydride and 0.8 of pyridine
Add ml and stir at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (Wakogel-C-300; ethyl acetate-hexane = 3: 1) to give benzhydryl 3- [5- (3,4-diacetoxyphenyl). ) -1,3,4-Thiadiazol-2-yl] thiomethyl-7β- [2-methoxyimino-2- (2-tritylaminothiazol-4-yl) acetamido]-
3-Cephem-4-carboxylate (syn isomer) 0.
73 g (60% yield) are obtained as a foam.

NMR (DMSO-d ₆ ) δ: 2.32 (6H, s), 3.80 (2H, m), 3.82
(3H, s), 4.10 to 4.70 (2H, m), 5.20 (1H, d, J = 5Hz), 5.
72 (1H, m), 6.72 (1H, s), 6.09 (1H, s), 7.00 ~ 7.60 (2
6H, m), 7.76 (1H, m), 7.80 (1H, s), 8.75 (1H, m), 9.55
(1H, m) (B) 724 mg (0.66 mmol) of the compound obtained in the above reaction (A)
Is dissolved in 3.5 ml of methylene chloride and 0.7 ml of anisole, 3.5 ml of trifluoroacetic acid is added under ice cooling, and the mixture is stirred for 1 hour.
The solvent is distilled off under reduced pressure, ether is added to the residue, and the precipitate is collected by filtration. Suspend this precipitate in water and adjust the pH with saturated aqueous sodium hydrogen carbonate.
After adjusting to 6.5, ODS column chromatography (LC-
Sorb RP-18, Chemco), and elute with a 40% aqueous methanol solution. The elution fraction containing the desired product is concentrated and lyophilized to give 191 mg (yield 40%) of the title compound.

mp: 180 ℃ (decomposition) NMR (DMSO-d ₆ ) δ: 2.35 (6H, s), 3.60 (2H, m), 3.90
(3H, s), 4.40 ~ 4.80 (2H, m), 5.08 (1H, d, J = 5Hz), 5.
66 (1H, dd, J = 5 and 8Hz), 6.76 (1H, s), 7.46 (1H, d, J
= 9Hz), 7.82 (1H, m), 7.88 (1H, br s), 9.54 (1H, d, J
= 8 Hz) Example 27 7β- [2- (2-aminothiazol-4-yl)-
2-Ethoxyiminoacetamide] -3- [5- (3,4
-Dihydroxyphenyl) -1,3,4-thiadiazole-
Preparation of 2-yl] thiomethyl-3-cephem-4-carboxylate sodium salt (syn isomer) Benzhydryl 3-iodomethyl-7β- [2-ethoxyimino-2- (2-tritylaminothiazole-
4-yl) acetamido] -3-cephem-4-carboxylate (syn isomer) 800 mg (0.86 mmol) and 5-
[3,4-di (2-methoxyethoxymethoxy) phenyl] -2-mercapto-1,3,4-thiadiazole 0.50 g
(1.24 mmol), the trifluoroacetic acid salt obtained by the same operation as in Example 1 was suspended in water, and the pH was adjusted to saturated sodium bicarbonate water.
After adjusting to 6.5, ODS column chromatography (LC-
Sorb RP-18, Chemco) and eluted with a 30% aqueous methanol solution. The eluted fraction containing the desired product is concentrated and lyophilized to give 61 mg of the title compound (yield 10.8%).

mp: 195 ℃ (decomposition) NMR (DMSO-d ₆ ) δ: 1.23 (3H, q, J = 6Hz), 3.55 (2H,
m), 4.13 (2H, q, J = 6Hz), 4.46 (2H, m), 5.05 (1H, d, J
= 5Hz), 5.62 (1H, m), 6.70 (1H, m), 6.72 (1H, s), 7.2
0 (1H, br s) Example 28 7β- [2- (2-aminothiazol-4-yl]-
2-Ethoxyiminoacetamide] -3- [5- (3,4
-Diacetoxyphenyl) -1,3,4-thiadiazole-
Preparation of 2-yl] thiomethyl-3-cephem-4-carboxylate sodium salt (syn isomer) Benzhydryl 3-iodomethyl-7β- [2-ethoxyimino-2- (2-tritylaminothiazole-
4-yl) acetamido] -3-cephem-4-carboxylate (syn isomer) 800 mg (0.86 mmol) and 2-mercapto-5- (3,4-dihydroxyphenyl) 1,3,4-
Thiadiazole 300 mg (1.33 mmol) was used to suspend the trifluoroacetate salt obtained by the same operation as in Example 26 in water, and the pH was adjusted to 6.5 with saturated aqueous sodium hydrogen carbonate, followed by ODS column chromatography (LC-Sorb RP -18, Chemco),
Elute with a 40% aqueous methanol solution, concentrate the elution fraction containing the desired product, and lyophilize to give 106 mg of the title compound (yield 16.6).
%).

mp: 180 ℃ (decomposition) NMR (DMSO-d ₆ ) δ: 1.22 (3H, t, J = 6Hz), 2.32 (6H,
s), 3.50 (2H, m), 4.12 (2H, q, J = 6Hz), 4.20 to 4.70 (2
H, m), 5.06 (1H, d, J = 5Hz), 5.65 (1H, m), 6.72 (161,
5), 7.46 (1H, d, J = 5Hz), 7.82 (1H, m), 7.87 (1H, br
s), 9.48 (1H, m) Example 29 7β- [2- (2-aminothiazol-4-yl]-
2-Isopropoxyiminoacetamide] 3- [5-
Preparation of (3,4-dihydroxyphenyl) -1,3,4-thiadiazol-2-yl] thiomethyl-3-cephem-4-carboxylate sodium salt (syn isomer) Benzhydryl 3-iodomethyl-7β- [2 -Isopropoxyimino-2- (2-tritylaminothiazol-4-yl) acetamido] -3-cephem-4-
The same procedure as in Example 1 was performed using 800 mg (0.83 mmol) of carboxylate (syn isomer) and 200 mg (1.07 mmol) of 5- (3,4-dihydroxyphenyl) -2-mercapto-1,3,4-thiadiazole. The trifluoroacetic acid salt obtained by was suspended in water and adjusted to pH 6.5 with saturated aqueous sodium hydrogen carbonate, and then ODS column chromatography (LC-Sorb RP-18, Chemco).
And elute with a 20% aqueous methanol solution, concentrate the elution fraction containing the desired product and freeze-dry to give 39 mg (yield) of the title compound.
6.75%).

mp: 185 ℃ (decomposition) NMR (DMSO-d ₆ ) δ: 1.22 (6H, t, J = 6Hz), 3.52 (2H,
m), 4.10 to 4.70 (3H, m), 5.08 (1H, d, J = 5Hz), 5.60 (1
H, m), 6.70 (1H, s), 6.75 ~ 7.26 (2H, m), 7.32 (1H, br
s) Example 30 7β- [2-allyloxyimino-2- (2-aminothiazol-4-yl) -acetamido] -3- [5-
Preparation of (3,4-dihydroxyphenyl) -1,3,4-thiadiazol-2-yl] thiomethyl-3-cephem-4-carboxylate sodium salt (syn isomer) Benzhydryl 7β- [2-allylokiimino-2
-(2-Tritylaminothiazol-4-yl) acetamido] -3-iodomethyl-3-cephem-4-carboxylate (syn isomer) 800 mg (0.83 mmol) and 2
-Mercapto-5- [3,4-di (methoxyethoxymethoxy) phenyl] -1,3,4-thiadiazole 340 mg (0.83
120 mg (yield 21.6%) of the title compound by the same procedure as in Example 1 using (mmol).

mp: 190 ℃ (decomposition) _{NMR (DMSO-d 6) δ} : 3.55 (2H, m), 4.30~4.70 (2H,
m), 5.10 (1H, d, J = 5Hz), 5.25 (1H, br s), 5.43 (1H, b
rs), 5.64 (1H, d, J = 5Hz), 5.80-6.20 (1H, m), 6.60
-7.20 (2H.m), 6.74 (1H, s) 7.26 (1H, br s) Example 31 7β- [2- (2-aminothiazol-4-yl]-
2-Propargyloxyiminoacetamide] -3-
[5- (3,4-Dihydroxyphenyl) -1,3,4-thiadiazol-2-yl] thiomethyl-3-cephem-4-
Production of carboxylate sodium salt (syn isomer) Benzhydryl 3-iodomethyl-7β- [2-propargyloxyimino-2- (2-tritylaminothiazol-4-yl) acetamido] -3-cephem-
4-carboxylate (syn isomer) 800mg (0.84mmo
l) and 5- (3,4-dihydroxyphenyl) -2-mercapto-1,3,4-thiadiazole 200 mg (0.88 mmol) were used to carry out the same procedure as in Example 1 to obtain 114 mg of the title compound.
(Yield 20.2%) is obtained.

mp: 165 ℃ (decomposition) NMR (DMSO-d ₆ ) δ: 3.43 (1H, br s), 3.60 (2H, m),
4.50 (2H, m), 4.75 (2H, br s), 5.06 (1H, d, J = 5Hz),
5.60 (1H, d, J = 5Hz), 6.60 ~ 7.20 (1H, m), 6.78 (1H,
s), 7.22 (1H, br s) Example 32 7β- [2- (2-aminothiazol-4-yl)-
2-Benzyloxyiminoacetamide] -3- [5-
Preparation of (3,4-dihydroxyphenyl) -1,3,4-thiadiazol-2-yl] thiomethyl-3-cephem-4-carboxylic acid / trifluoroacetic acid salt (syn isomer) (A) Benzhydryl 7β- [ 2-benzyloxyimino-2- (2-tritylaminothiazol-4-yl) acetamido] -3-iodomethyl-3-cephem-4-carboxylate (syn isomer) 800 mg (0.79 mmo
l) and 2-mercapto-5- [3,4-di (2-methoxyethoxymethoxy) phenyl] -1,3,4-thiadiazole 318 mg (0.79 mmol) were used, and the same procedure as in Example 1 was conducted. Benzhydryl 7β- [2-benzyloxyimino-2 (2-tritylaminothiazol-4-yl) acetamido] -3- {5- [3,4-di (2-methoxyethoxymethoxy) phenyl] -1,3, 278 mg (27% yield) of 4-thiadiazol-2-yl} thiomethyl-3-cephem-4-carboxylate (syn isomer) are obtained as a foam.

NMR (DMSO-d ₆ ) δ: 3.23 (6H, s), 3.5 (4H, m), 3.78
(6H, m), 4.10 to 4.60 (2H, m), 5.21 (1H, d, J = 5Hz), 5.22 (2H, br s), 5.32 (4H, br s), 5.
82 (1H, m), 6.74 (1H, s), 6.91 (1H, s), 7.00 to 7.60 (33H, m), 8.77 (1H, br s), 9.65 (1H, br d, J = 8Hz) ( B) 278 mg (0.22 mmol) of the compound obtained in the above reaction (A)
Is dissolved in 1.5 ml of methylene chloride and 0.3 ml of anisole, 1.5 ml of trifluoroacetic acid is added under ice cooling, and the mixture is stirred for 1 hour.
The solvent was distilled off under reduced pressure, ether was added to the residue, and the precipitate was collected by filtration to obtain 148 mg of the title compound (yield 98%).

mp: 170 ℃ (decomposition) NMR (DMSO-d ₆ ) δ: 3.72 (2H, m), 4.26 (2H, br d, J =
12Hz), 4.68 (1H, d, J = 12Hz), 5.16 (1H, d, J = 5Hz), 5.
22 (2H, br s), 5.74 (1H, m), 6.80 to 7.50 (9H, m), 9.72 (1H, m) Example 33 7β- [2- (2-aminothiazol-4-yl)-
2- (3,4-Dihydroxybenzyloxyimino) acetamido] -3- [5- (3,5-dihydroxyphenyl) -1,3,4-thiadiazol-2-yl] thiomethyl-3-cephem-4-carboxylic Production of acid / trifluoroacetate Benzhydryl 3-iodomethyl-7β- {2-
[3,4-Di (2-methoxyethoxymethoxy) benzyloxyimino] -2- (2-tritylaminothiazol-4-yl) acetamido} -3-cephem-4-carboxylate (syn isomer) 800 mg (0.65 mmol) and 5
-(3,4-Dihydroxyphenyl) -2-mercapto-
Using 148 mg (0.35 mmol) of 1,3,4-thiadiazole and by the same procedure as in Example 32, the title compound (syn isomer) was obtained.
214 mg (96% yield) are obtained.

mp: 165 ℃ (decomposition) NMR (DMSO-d ₆ ) δ: 3.75 (2H, m), 4.28 (1H, br d, J = 12Hz), 4.60 (1H, br d, J = 12Hz), 5.00 (2H, br s), 5.18 ( 1H, d, J = 5Hz), 5,80 (1H, m), 6.60 to 7.40 (7H, m) 9.70 (1H, m) Example 34 7β- [2- (2-aminothiazol-4-yl) −
2- (1-carboxylate-1-methylethoxyimino) acetamide] -3- [5- (3,4-dihydroxyphenyl) -1,3,4-thiadiazol-2-yl] thiomethyl-3-cephem-4 -Production of carboxylate disodium salt (syn isomer) Benzhydryl 7β- [2- (1-benzhydryloxycarbonyl-1-methylethoxyimino) -2-
(2-Tritylaminothiazol-4-yl) acetamido] -3-iodomethyl-3-cephem-4-carboxylate (syn isomer) 1.0 g (0.85 mmol) and 2-mercapto-5- [3,4-di] (2-Methoxyethoxymethoxy) phenyl] -1,3,4-thiadiazole 0.34 g (0.84
mmol) was used to suspend the trifluoroacetic acid salt obtained by the same operation as in Example 1, and the suspension was added to saturated aqueous sodium hydrogen carbonate to adjust the pH to 6.5.
After adjusting to, ODS column chromitography (LC-S
orb RP-18, Kecom Co., Ltd.) and eluted with 10% aqueous methanol solution, and the eluted fraction containing the desired product is concentrated and lyophilized to give 148 mg of the title compound (yield 41.1%).

mp: 185 ℃ (decomposition) NMR (DMSO-d ₆ ) δ: 1.44 (3H, br s), 1.50 (3H, br
s), 3.53 (2H, m), 4.42 (2H, m), 5.06 (1H, d, J = 5Hz),
5.70 (1H, m), 6.72 (1H, m), 6.75 (1H, s), 7.15 (1H, m
m), 7.20 (1H, br s) Example 35 7β- [2- (2-aminothiazol-4-yl)-
2- (1-carboxylate-1-cyclopropoxyimino) acetamide] -3- [5- (3,4-dihydroxyphenyl) -1,3,4-thiadiazol-2-yl] thiomethyl-3-cephem-4 -Preparation of carboxylate disodium salt (syn isomer) Benzhydryl 7β- [2- (1-tert-butoxycarbonyl-1-cyclopropoxyimino) -2- (2
-Tritylaminothiazol-4-yl) acetamido] -3-iodomethyl-3-cephem-4-carboxylate (syn isomer) 1.0 g (0.96 mmol) and 2-mercapto-5- [3.4-di (2-methoxy) Ethoxymethoxy) phenyl] -1,3,4-thiadiazole 0.38 g (0.94 mm
The title compound (130 mg, yield 29.4%) is obtained by the same procedure as in Example 1 using ol).

mp: 170 ℃ (decomposition) NMR (DMSO-d ₆ ) δ: 0.90 to 1.40 (4H, m), 3.20 to 3.80
(2H, m), 4.42 (2H, m), 5.05 (1H, d, J = 5Hz), 5.66 (1H, m), 6.73 (1H, d, J = 9Hz),
6.85 (1H, s), 7.13 (1H, m), 7.23 (1H, br s) Example 36 7β- {2- (2-aminothiazol-4-yl)-
2- [2- (carboxylate methyl) benzyloxyimino] acetamido} -3- [5- (3,4-dihydroxyphenyl) -1,3,4-thiadiazol-2-yl]
Production of thiomethyl-3-cephem-4-carboxylate disodium salt (syn isomer) Benzhydryl 7β- {2- [2- (benzhydryloxycarbonylmethyl) benzyloxyimino]-
2- (2-totylaminothiazol-4-yl) acetamido} -3-iodomethyl-3-cephem-4-carboxylate (syn isomer) 1.23 g (1.0 mmol) and 5
-(3,4-Dihydroxyphenyl) -2-mercapto-
Using 270 mg (1.2 mmol) of 1,3,4-thiadiazole, the trifluoroacetic acid salt obtained by the same operation as in Example 1 was suspended in water and adjusted to pH 6.5 with saturated aqueous sodium hydrogen carbonate, and then ODS column chromite. Graphography (LC-Sorb RP-18, Chemco), eluting with 10% aqueous methanol solution, concentrating the elution fraction containing the desired product and freeze-drying to give 145 mg of the title compound (yield 1
8%).

mp: 185 ℃ (decomposition) NMR (D ₂ O) δ: 3.20 (1H, d, J = 15Hz), 3.60 (2H, s), 3.67 (1H, d, J = 15Hz), 5.02 (1H, d, J = 5Hz) 5.30 (2H , s), 5.65 (1H, d, J = 15Hz), 6.93 (1H, s), 7.1
0-7.40 (7H, m) Example 37 7β- {2- (2-aminothiazol-4-yl)-
2-[(α-carboxylate benzyl) oxyimino] acetamido} -3- [5- (3,4-dihydroxyphenyl) -1,3,4-thiadiazol-2-yl] thiomethyl-3-cephem-4-carboxy Preparation of rate disodium salt (diastereomer A and B, syn isomer) (A) Benzhydryl 7β- {2-[(α-benzhydryloxycarbonylbenzyl) oxyimino] -2
-(2-Tritylaminothiazol-4-yl) acetamido]}-3-iodomethyl-3-cephem-4-carboxylate (syn isomer) 800 mg (0.64 mmol) and 2-mercapto-5- [3,4- Di (2-methoxyethoxymethoxy) phenyl) -1,3,4-thiadiazole 0.32 g
(0.80 mmol) and by the same operation as in Example 1,
Benzhydryl 7β- {2-[(α-benzhydryloxycarbonylbenzyl) oxyimino] -2- (2
-Tritylaminothiazol-4-yl) acetamido} -3- {5- [3,4-di (2-methoxyethoxymethoxy) phenyl] -1,3,4-thiadiazol-2-yl} thiomethyl-3-cephem -4-Carboxylate (syn isomer) is obtained as a crude product.

NMR (DMSO-d ₆ ) δ: 3.25 (6H, s), 3.50 (4H, m), 3.80
(6H, m), 4.10 ~ 4.80 (2H, m), 5.00 ~ 6.00 (7H, m), 6,8
0 to 7.70 (36H, m) (B) The crude product obtained in the above reaction (A) was methylene chloride 5.
Dissolve in 0 ml and 1.0 ml of anisole, add 5.0 ml of trifluoroacetic acid under ice cooling, and stir for 1 hour. The solvent is distilled off under reduced pressure, ether is added to the residue, and the precipitate is collected by filtration. This precipitate was suspended in water and adjusted to pH 6.5 with saturated aqueous sodium hydrogen carbonate, and then ODS column chromatography (LC-Sorb RP-18,
Chemco), diastereomer A was eluted with 5% aqueous methanol solution, diastereomer B was eluted with 10% aqueous methanol solution, concentrated and freeze-dried to 100 m each.
g (20% yield) and 98 mg (19% yield) are obtained.

High performance liquid chromatography analysis Column: ODS (YMC-PACK AM-312) 6 x 150 mm Mobile phase: 60% MeOH-0.01M phosphate buffer (PH3.0) Flow rate: 1 ml / min Detection: UV 254 nm Diastereomer A : 3.3 minutes Diastereomer B: 3.6 minutes Diastereomer A mp: 190 ℃ (decomposition) NMR (DMSO-d ₆ ) δ: 3.52 (2H, m), 4.10 to 4.80 (2H, m), 5.06 (1H, d, J = 5Hz), 5.36 (1H, s), 5.42 (1H, m), 6.50 (H, m), 6.82 (1H, s), 6.90 ~ 7.70 (7H,
m) Diastereomer B mp: 190 ℃ (decomposition) NMR (DMSO-d ₆ ) δ: 3.40 (2H, m), 4.10 to 4.70 (2H, m), 4.98 (1H, d, J = 5Hz), 5.42 (1H, s), 5.45 (1H, m), 6.70 (H, m), 6.90 (1H, s), 7.00 ~ 7.70 (7H,
m) Example 38 7β- {2- (2-aminothiazol-4-yl)-
2-[(α-carboxylate-3,4-dihydroxybenzyl) oxyimino] acetamide} -3- [5-
(3,4-Dihydroxyphenyl) -1,3,4-thiadiazol-2-yl] thiomethyl-3-cephem-4-carboxylate disodium salt (diastereomer A and diastereomer B, syn isomer) Preparation of benzhydryl 7β- {2-[[α-benzhydryloxycarbonyl-3,4-di (2-methoxyethoxymethoxy) benzyl] oxyimino] -2- (2-tritylaminothiazol-4-yl) acetamide} -3
800 mg (0.56 mmol) of iodomethyl-3-cephem-4-carboxylate (syn isomer) and 2-mercapto-5- [3,4-di (2-methoxyethoxymethoxy) phenyl] -1,3,4- Using thiadiazole 224 mg (0.56 mmol), the same operation as in Example 37 was carried out, and by ODS column chromatography (LC-Sorb RP-18, Chemco), eluting with 5% methanol aqueous solution, concentrating and freeze-drying. , 46 mg (yield 10.1%) and 40 mg (yield 8.8%) of diastereomer A and diastereomer B, respectively.

High-performance liquid chromatography analysis Column: ODS (YMC-PACK AM-312) 6 x 150 mm Mobile phase: 40% MeOH-0.01 M phosphate buffer (PH3.0) Flow rate: 1 ml / min Detection: UV 254 nm Diastereomer A : 8.2 minutes Diastereomer B: 10.2 minutes Diastereomer A mp: 175 ℃ (decomposition) NMR (DMSO-d ₈ ) δ: 3.55 (2H, m), 4.50 (2H, m), 5,15
(2H, m), 5.70 (1H, m), 6.50 ~ 7.30 (7H, m) Diastereomer B mp: 180 ℃ (decomposition) NMR (DMSO-d ₈ ) δ: 3.50 (2H, m), 4.40 (2H, m), 5.00
(1H, m), 5.22 (1H, m), 5,50 (1H, m), 6..60 ~ 7.30 (7
H, m) Example 39 7β- {2- (2-aminothiazol-4-yl)-
2-Methoxyiminoacetamide] -3- [4- (3,4
-Dihydroxyphenyl) thiazol-2-yl] thiomethyl-3-cephem-4-carboxylate sodium salt (syn isomer) Benzhydryl 3-iodomethyl-7β- [2-methoxyimino-2- (2-tritylamino) Thiazole
4-yl) acetamido] -3-cephem-4-carboxylate (syn isomer) 1.0 g (1.1 mmol) and 4- (3,4
-Dihydroxyphenyl) -2-mercaptothiazole
The trifluoroacetic acid salt obtained by the same operation as in Example 1 was suspended in water using 0.23 g (1.1 mmol), the pH was adjusted to 6.5 with saturated aqueous sodium hydrogen carbonate, and the insoluble matter was filtered off. The filtrate was subjected to ODS reverse-phase column chromatography (LC-Sorb RP-18, Chemco), and the elution fraction containing the desired product (30% methanol aqueous solution) was concentrated under reduced pressure and freeze-dried to give 160m of the title compound.
g (24% yield) are obtained.

MP: 185 ℃ (decomposition) NMR (DMSO-d ₆ ) δ: 3.50 (2H, m), 3.86 (3H, s), 4.36 (1H, d, J = 12Hz), 4.58 (1H, d, J = 12Hz), 5.00 (1H, d) , J = 5Hz), 5.58 (1H, dd, J = 5 and 8Hz), 6.74 (1H, s), 6.80 (1H, d, J = 8Hz), 7.17 (1H, br s), 7.18 (1H, dd , J = 2 and 8 Hz), 7.39 (1H, d, J = 2 Hz), 7.63 (1H, s), 9.50 (1H, br J = 8 Hz) Example 40 3- [4- (3,4-dia) Cetoxyphenyl) thiazol-2-yl] thiomethyl-7β- [2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3-cephem-4-carboxylate sodium salt (syn isomer) Preparation of benzhydryl 3-iodomethyl-7β- [2-methoxyimino-2- (2-tritylaminothiazole-
4-yl) acetamido] -3-cephem-4-carboxylate (syn isomer) 1.0 g (1.1 mmol) and 4- (3,4
-Dihydroxyphenyl) -2-mercaptothiazole
Using 0.23 g (1.1 mmol) and the same procedure as in Example 4, 225 mg of the title compound (yield 28.1%) is obtained.

MP: 170 ℃ (decomposition) NMR (DMSO-d ₆ ) δ: 2.30 (6H, s), 3.50 (2H, m), 3.85 (3H, s), 4.38 (1H, d, J = 12Hz), 4.60 (1H, d, J = 12Hz) ), 5.00 (1H, d, J = 5Hz), 5.60 (1H, dd, J = 5 and 8Hz), 6.72 (1H, s), 7.20 (2H, br s), 7.32 (1H, d, J = 8Hz) ), 7.80 (1H, br s), 7.82 (1H, br d, J = 8Hz), 8.02 (1H, s), 9.50 (1H, br d, J = 8Hz) Example 41 7β- [2- (2 -Aminothiazol-4-yl)-
2-Isoproxyiminoacetamide] -3- [4-
Preparation of (3,4-dihydroxyphenyl) thiazol-2-yl] thiomethyl-3-cephem-4-carboxylate sodium salt (syn isomer) Benzhydryl 3-iodomethyl-7β- [2-isopropoxyimino-2- (2-Tritylaminothiazol-4-yl) acetamido] -3-cephem-4-
Carboxylate (syn isomer) 1.0 g (1.1 mmol) and 4
The same procedure as in Example 1 was carried out using 0.5 g (2.2 mmol) of-(3,4-dihydroxyphenyl) -2-mercaptothiazole to obtain 161 mg of the title compound (yield 22.8%).

MP: 185 ℃ (decomposition) NMR (DMSO-d ₆ ) δ: 1.23 (6H, d, J = 6Hz), 3.55 (2H, m), 4.32 (1H, m), 4,42 (1H, d, J = 15Hz), 4.60 (1H , d, J = 15Hz), 5.05 (1H, d, J = 5Hz), 5.65 (1H, dd, J = 5 and 8Hz), 6.73 (1H, s), 6.82 (1H, d, J = 8Hz), 7.23 (1H, br, d, J = 8Hz), 7.40 (1H, br s), 7.62 (1H, s), 9.43 (1H, br d, J = 8Hz) Example 42 7β- [2-allyloxyimino -2- (2-Aminothiazol-4-yl) acetamide] -3- [4-
Preparation of (3,4-dihydroxyphenyl) thiazol-2-yl] thiomethyl-3-cephem-4-carboxylate sodium salt (syn isomer) Benzhydryl 3-iodomethyl-7β- [2-allyloxyimino-2- (2-Tritylaminothiazol-4-yl) acetamido] -3-cephem-4-carboxylate (syn isomer) 1.0 g (1.1 mmol) and 4-
The same procedure as in Example 1 was carried out using 0.5 g (2.2 mmol) of (3,4-dihydroxyphenyl) -2-mercaptothiazole to obtain 182 mg of the title compound (yield 26.9%).

MP: 175 ℃ (decomposition) NMR (DMSO-d ₆ ) δ: 3.56 (2H, m), 4.50 (2H, m), 4.62
(2H, br d, J = 5Hz), 5.03 (1H, d, J = 5Hz), 5.23 (1H,
m), 5.30 (1H, br d, J = 24Hz), 5.63 (1H, m), 5.80 to 6.3
0 (1H, m), 6.75 (1H, s), 6.80 (1H, d, J = 8Hz), 7.20 (1
H, dd, J = 2 and 8Hz), 7.36 (1H, d, J = 2Hz), 7.62 (1H,
s), 9.54 (1H, m) Example 43 7β- [2- (2-aminothiazol-4-yl)-
2-carboxylate methoxyiminoacetamide]-
Preparation of 3- [4- (3,4-dihydroxyphenyl) thiazol-2-yl] thiomethyl-3-cephem-4-carboxylate disodium salt (syn isomer) Benzhydryl 7β- [2-benzhydryloxy Carbonyl methoxyimino-2- (2-tritylaminothiazol-4-yl) acetamido] -3-iodomethyl-3-cephem-4-carboxylate (syn isomer) 1.0 g (0.88 mmol) and 4- (3,4 -Dihydroxyphenyl) -2-mercaptothiazole (0.23 g, 1.1 mmol) was used to carry out the same procedure as in Example 1 to obtain 149 mg of the title compound.
(Yield 24.9%) is obtained.

MP: 175 ℃ (decomposition) NMR (DMSO-d ₆ ) δ: 3.52 (2H, m), 4.30 (2H, m), 4.48 (2H, m), 5.02 (1H, d, J = 5Hz), 5.62 (1H, m), 6.74 ( 1H, d, J = 8Hz), 6.82 (1H, s), 7.10 (1H, br d, J
= 8 Hz), 7.31 (1H, br s), 7.58 (1H, s) Example 44 7β- [2- (2-aminothiazol-4-yl)-
2- (1-carboxylate-1-methylethoxyimino) acetamido] -3- [4- (3,4-dihydroxyphenyl) thiazol-2-yl] thiomethyl-3-cephem-4-carboxylate disodium salt Preparation of (Syn isomer) Benzhydryl 7β- [2- (1-benzhydryloxycarbonyl-1-methylethoxyimino) -2-
(2-Tritylaminothiazol-4-yl) acetamido] -3-iodomethyl-3-cephem-4-carboxylate (syn isomer) 1.2 g (1.0 mmol) and 4- (3,4
-Dihydroxyphenyl) -2-mercaptothiazole
By the same procedure as in Example 1 using 0.23 g (1.1 mmol), 170 mg of the title compound (yield 24.4%) is obtained.

MP: 180 ℃ (decomposition) NMR (DMSO-d ₆ ) δ: 3.73 (2H, m), 4.25 (1H, d, J = 13Hz), 4.50 (1H, d, J = 13Hz), 5.18 (1H, d, J = 5Hz), 5.82 (1H, dd, J = 5 and 8Hz), 6.78 (1H, d, J = 9Hz), 6.82 (1H, s), 7.22 (1H, br d, J =
9Hz), 7.32 (1H, br s), 7.70 (1H, s), 9.45 (1H, br d, J = 8Hz) Example 45 7β- [2- (2-aminothiazol-4-yl)-
2- (1-carboxylate-1-cyclopropoxyimino) acetamido] -3- [4- (3,4-dihydroxyphenyl) thiazol-2-yl] thiomethyl-3-
Preparation of Cephem-4-carboxylate disodium salt (syn isomer) Benzhydryl 7β- [2- (1-tert-butoxycarbonyl-1-cyclopropoxyimino) -2- (2
-Tritylaminothiazol-4-yl) acetamido] -3-iodomethyl-3-cephem-4-carboxylate (syn isomer) 1.0 g (0.96 mmol) and 4- (3,4
-Dihydroxyphenyl) -2-mercaptothiazole
Using 0.23 g (1.1 mmol) and the same procedure as in Example 1, 60 mg (yield 8.55%) of the title compound is obtained.

MP: 170 ℃ (decomposition) NMR (DMSO-d ₆ ) δ: 1.15 (4H, m), 3.42 (1H, d, J = 18H
z), 3.66 (1H, d, J = 18Hz), 4.40 (1H, d, J = 12Hz), 4.62
(1H, d, J = 12Hz), 5.02 (1H, d, J = 5Hz), 5.60 (1H, m),
6.80 (1H, d, J = 8Hz), 6.85 (1H, s), 7.16 (1H, br d, J =
8Hz), 7.36 (1H, brs), 7.61 (1H, s) Example 46 7β- [2- (2-aminothiazol-4-yl)-
2-Benzyloxyiminoacetamide] -3- [4-
Preparation of (3,4-dihydroxyphenyl) thiazol-2-yl] thiomethyl-3-cephem-4-carboxylate sodium salt (syn isomer) Benzhydryl 7β- [2-benzyloxyimino-2- (2-trityl) Aminothiazol-4-yl) acetamido] -3-iodomethyl-3-cephem-4
-Carboxylate (syn isomer) 1.0 g (1.0 mmol) and 4- (3,4-dihydroxyphenyl) -2-mercaptothiazole 0.37 g (1.5 mmol) were used in the same manner as in Example 1 to give 64 mg of the title compound. (Yield 9.3%) is obtained.

MP: 180 ℃ (decomposition) NMR (DMSO-d ₆ ) δ: 3.45 (1H, d, J = 18Hz), 3.67 (1H,
d, J = 18Hz), 4.52 (2H, m), 5.05 (1H, d, J = 5Hz), 5.18
(2H, dr s), 5.66 (1H, d, J = 5Hz), 6.77 (1H, s), 6.85
(1H, d, J = 8Hz), 7.10 to 7.50 (8H, m), 7.76 (1H, s), Example 47 7β- [2- (2-aminothiazol-4-yl)-
2- (3,4-Dihydroxybenzyloxyimino) acetamido] -3- [4- (3,4-dihydroxyphenyl) thiazol-2-yl] thiomethyl-3-cephem-4-carboxylate sodium salt (syn isomerism body)
Benzhydryl 3-iodomethyl-7β- {2-
1.0 g of [3,4-di (2-methoxyethoxymethoxy) benzyloxyimino] -2- (2-tritylaminothiazol-4-yl) acetamido} -3-cephem-4-carboxylate (syn isomer) 0.82 mmol) and 4-
The same procedure as in Example 1 was carried out using 0.3 g (1.3 mmol) of (3,4-dihydroxyphenyl) -2-mercaptothiazole to obtain 285 mg of the title compound (yield 45.9%).

MP: 160 ℃ (decomposition) NMR (DMSO-d ₆ ) δ: 3.55 (2H, m), 4.52 (2H, m), 5.00
(1H, d, J = 5Hz), 5.04 (2H, br s), 5.60 (1H, m), 6.7
(1H, s), 6.75 (3H, m), 7.18 (1H, br d, J = 8Hz), 7.36
(2H, m), 7.59 (1H, s), 9.32 (1H, brd, J = 8Hz) Example 48 7β- [2- (2-aminothiazol-4-yl)-
2-Ethoxyiminoacetamide] -3- [4- (3,4
-Dihydroxyphenyl) thiazol-2-yl] thiomethyl-3-cephem-4-carboxylate sodium salt (syn isomer) Benzhydryl 7β- [2-ethoxyimino-2-
(2-Tritylaminothiazol-4-yl) acetamido] -3-iodomethyl-3-cephem-4-carboxylate (syn isomer) 516 mg (0.547 mmol) and 4
Using 123 mg (0.507 mmol) of-(3,4-dihydroxyphenyl) -2-mercaptothiazole, the same procedure as in Example 1 was carried out and ODS reverse phase column chromatography (LC
-Sorb RP-18, Chemco), eluting with 30% methanol, and the elution fraction containing the target compound is concentrated under reduced pressure and lyophilized to give 133 mg (yield 34.9%) of the title compound.

MP: 200 ℃ (decomposition) _{NMR (DMSO-d 6) δ} : 1.12 (3H, t, J = 7Hz), 3.60 (2H,
m), 4.08 (2H, q, J = 7Hz), 4.30 (1H, br d, J = 12Hz), 4.
53 (1H, br d, J = 12Hz), 4.98 (1H, d, J = 5Hz), 5.58 (1
H, dd, J = 5 and 8Hz), 6.68 (1H, S), 6.75 (1H, d, J = 9H
z), 7.12 (1H, dd, J = 2 and 9Hz), 7.32 (1H, d, J = 2H
z), 7.57 (1H, s), 9.42 (1H, br d, J = 8 Hz) Example 49 3- [4- (3,4diacetoxyphenyl) thiazol-2-yl] thiomethyl-7β- [2- Preparation of (2-aminothiazol-4-yl) -2-ethoxyiminoacetamide] -3-cephem-4-carboxylate sodium salt (syn isomer) Benzhydryl 7β- [2-ethoxyimino-2-
(2-Tritylaminothiazol-4-yl) acetamido] -3-iodomethyl-3-cephem-4-carboxyle (syn isomer) 10.6 g (11.2 mmol), 4-
Using 3.5 g (15.5 mmol) of (3,4-dihydroxyphenyl) -2-mercaptothiazole, 10.6 mg (0.11 mmol) of acetic anhydride and 9.1 ml (0.11 mmol) of pyridine,
The same operation as in Example 4 was carried out and the results were measured by ODS reverse-phase column chromitography (LC-Sorb RP-18, Chemco).
% Methanol, and the elution fraction containing the desired product was concentrated under reduced pressure and freeze-dried to give 2.83 g of the title compound (yield 33.9%).
%).

MP: 190 ℃ (decomposition) NMR (DMSO-d ₆ ) δ: 1.21 (3H, t, J = 7Hz), 2.30 (6H,
s), 3.30 to 3.80 (2H, m), 4.10 (2H, q, J = 7Hz), 4.40 (1
H, br d, J = 12Hz), 4.64 (1H, br d, J = 12Hz), 5.01 (1H,
d, J = 5Hz), 5.60 (1H, dd, J = 5 and 8Hz), 6.70 (1H,
S), 7.18 (2H, dr s), 7.32 (1H, d, J = 9Hz) 7.80 (1H,
s), 7.82 (1H, d, J = 9Hz), 8.02 (1H, s), 9.45 (1H, br
d, J = 8 Hz) Example 50 Trisodium 7β- [2- (2-aminothiazol-4-yl) -2- (1-carboxylate-1-methylethoxyimino) acetamide] -3- [4-carboxy Preparation of rate-5- (3,4-dihydroxyphenyl) thiazol-2-yl] thiomethyl-3-cephem-4-carboxylate (syn isomer) (A) Benzhydryl 7β- [2- (1-benzhydryl) Oxycarbonyl-1-methylethoxyimino)-
2- (2-Tritylaminothiazol-4-yl) acetamido] -3-chloromethyl-3-cephem-4-carboxylate (syn isomer) (11.9 g, 11 mmol)
Dissolve in 90 ml of N, N-dimethylformamide, add 8.3 g (55 mmol) of sodium iodide, and stir at room temperature for 1 hour. 3.0 g (11.1 g) of 4-carboxy-5- (3,4-dihydroxyphenyl) -2-mercaptothiazole was added to the reaction solution.
Mmol) and 1.55 ml (11.1 mmol) of triethylamine, and the mixture is stirred at the same temperature for 45 minutes. The solvent was distilled off under reduced pressure, 500 ml of ethyl acetate and 150 ml of water were added to the residue, and 2N was added.
Adjust to pH 1.5 with hydrochloric acid. The organic layer is washed with 150 ml of 5% aqueous sodium thiosulfate solution and 150 ml of saturated saline solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (Wako Gel C-30
Benzhydryl 7β- [2- (1-benzhydryloxycarbonyl-1-methylethoxyimino) -2- (2)
-Tritylaminothiazol-4-yl) acetamido] -3- [4-carboxy-5- (3,4-dihydroxyphenyl) thiazol-2-yl] thiomethyl-3-
Cephem-4-carboxylate (syn isomer) 12.2g
(Yield 84%) is obtained.

NMR (DMSO-d ₆ ) δ: 1.52 (6H, s) 3.75 (2H, br s), 4.
25 (2H, ABq), 5.21 (1H, d, J = 4.5Hz), 5.80 (1H, dd, J =
4.5 and 9Hz), 6.67 (1H, s), 6.75 (1H, s), 6.77 (2H, s)
s), 6.90 (1H, s), 6.93 (1H, s), 7.3 (35H, s), 8.77 (1
H, br s), 9.15 (1H, br s), 9.33 (1H, br s), 9.38 (1H,
(d, J = 9 Hz) (B) The compound (1) (1. 2 g (9.22 mmol) obtained in the above reaction (A)) was dissolved in 50 ml of methylene chloride and 10 ml of anisole,
Under ice-cooling, 50 ml of trifluoroacetic acid was added dropwise over 25 minutes, and the mixture was stirred at room temperature for 2 hours. The reaction solution is concentrated under reduced pressure, 200 ml of diisopropyl ether is added to the oily residue, and the insoluble matter is collected by filtration. This insoluble material was dissolved in 36.3 ml of formic acid, and then concentrated hydrochloric acid 8.
After adding 1 ml and stirring at room temperature for 1 hour, the mixture is added to 500 ml of diisopropyl ether and stirred for 15 minutes. The precipitate was collected by filtration, washed with 50 ml of diisopropyl ether and dried under reduced pressure to give powdery hydrochloride of the title compound (6.23 g, yield 87%).
Get.

NMR (DMSO-d ₆ ) δ: 1.53 (6H, s), 3.75 (2H, ABq), 4,
34 (2H, ABq), 5.22 (1H, d, J = 4.5Hz), 5.87 (1H, dd, J =
4.5 and 9Hz), 6.77 (2H, s), 6.90 (1H, s), 7.00 (1H,
s), 8.20 (5H, bs), 9.62 (1H, d, J = 9Hz) (C) The hydrochloride (6.0 g, 7.76 mmol) obtained in the above reaction (B) was suspended in 80 ml of water, and the mixture was cooled with ice. Adjust the pH to 7 with saturated aqueous sodium hydrogen carbonate, and remove the insoluble material by filtration. The filtrate was subjected to reverse phase column chromatography (LC-Sorb RP-18, Chemco 360 ml, eluted with water), and the fractions containing the target compound were concentrated and lyophilized to give 3.94 g of the title compound (yield 61%. ) Get.

MP: 260 ℃ (decomposition) NMR (D ₂ O) δ: 1.50 (6H, s), 3.60 (2H, ABq), 4.19
(2H, ABq), 5.17 (1H, d, J = 4.5Hz), 5.77 (1H, d, J = 4.5)
Hz), 6.91 (2H, s), 6.97 (1H, s), 6.99 (1H, s) Example 51 Trisodium 7β {2- (2-aminothiazole-
4-yl) -2- (α-carboxylate benzyl) oxyimino] acetamido} -3- [4-carboxylate-5- (3,4-dihydroxyphenyl) thiazol-2-yl] thiomethyl-3-cephem-4 -Preparation of carboxylates (diastereomers A and B; syn isomers) Benzhydryl 7β {[2- (α-benzhydryloxycarbonylbenzyl) oxyimino] -2- (2
-Tritylaminothiazol-4-yl) acetamido} -3-chloromethyl-3-cephem-4-carboxylate (syn isomer) 1.58 g (1.4 mmol), sodium iodide 1.05 g (7 mmol), 4-carboxy -5
Diastereomer A of the title compound was treated as in Example 50 with 414 mg (1.57 mmol) of-(3,4-dihydroxyphenyl) -2-mercaptothiazole and 0.215 ml (1.54 mmol) of triethylamine. To
240 mg (21.1% yield) and 210 mg of diastereomer B
(Yield 18.6%) is obtained.

Diastereomer A MP: 270 ℃ (decomposition) NMR (D ₂ O) δ: 3.31 (2H, ABq), 4.12 (2H, ABq), 5.02
(1H, d, J = 4.5Hz), 5.54 (1H, 5), 5.66 (1H, d, J = 4.5H)
z), 6.90 (2H, s), 6.99 (2H, s), 7.38 (5H, m) Diastereomer B MP: 270 ℃ (decomposition) NMR (D ₂ O) δ: 3.27 (2H, ABq), 4.13 (2H, ABq), 4.99
(1H, d, J = 4.5Hz), 5.54 (1H, s), 5.62 (1H, d, J = 4.5H
z), 6.90 (2H, s), 6.97 (2H, s), 7.38 (5H, m) Example 52 Disodium 7β- [2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamide] -3
Preparation of-[4-carboxylate-5- (3,4-dihydroxyphenyl) thiazol-2-yl] thiomethyl-3-cephem-4-carboxylate (syn isomer) Benzhydryl 3chloromethyl-7β- [2- Methoxyimino-2- (2-tritylaminothiazole-4)
-Yl) acetamido] -3-cephem-4-carboxylate (syn isomer) 1.26 g (1.5 mmol), sodium iodide 1.12 g (7.5 mmol), 4-carboxy-5
By using 444 mg (1.65 mmol) of-(3,4-dihydroxyphenyl) -2-mercaptothiazole and 0.23 ml (1.65 mmol) of triethylamine in the same manner as in Example 50, the hydrochloride obtained was treated with saturated aqueous sodium hydrogen carbonate. Neutralize with
Reversed phase column chromatography (LC-Sorb RP-18, Chemco, 180 ml, eluted with 5% aqueous methanol solution) was carried out to obtain 320 mg (yield 20.6%) of the title compound.

MP: 220-230 ℃ (decomposition) NMR (D ₂ O) δ: 3.57 (2H, ABq), 3.97 (3H, s), 4.17
(2H, ABq), 5.13 (1H, d, J = 4.5Hz), 5.73 (1H, d, J = 4.5)
Hz), 6.88 (2H, s), 6.98 (2H, s) Example 53 Disodium 7β- [2- (2-Aminothiazol-4-yl) -2-ethoxyiminoacetamide] -3
Preparation of-[4-carboxylate-5- (3,4-dihydroxyphenyl) thiazol-2-yl] thiomethyl-3-cephem-4-carboxylate (syn isomer) Benzhydryl 7β- [2-ethoxyimino-2 −
(2-Tritylaminothiazol-4-yl) acetamido] -3-iodomethyl-3-cephem-4-carboxylate (syn isomer) 1.42 g (1.5 mmol), 4-
Carboxy-5- (3,4-dihydroxyphenyl) -2
-Using 444 mg (1.65 mmol) of mercaptothiazole and 0.23 ml (1.65 mmol) of triethylamine, the hydrochloride obtained by treating in the same manner as in Example 50 was neutralized with saturated aqueous sodium hydrogen carbonate, and subjected to reverse phase column chromatography ( LC-Sorb
RP-18, 180 ml, eluted with 5% methanol aqueous solution),
320 mg (yield 36.2%) of the title compound are obtained.

MP: 270 ℃ (decomposition) NMR (D ₂ O) δ: 1.28 (3H, t, J = 7Hz), 3.58 (2H, ABq)
4.11 (2H, ABq), 4.25 (2H, q, J = 7Hz), 5.13 (1H, d, J =
4.5Hz), 5.72 (1H, d, J = 4.5Hz), 6.85 (2H, s), 6.95 (2
H, s) Example 54 Disodium 7β- [2- (2-aminothiazol-4-yl) -2-cyclopentyloxyiminoacetamido] -3- [4-carboxylate-5- (3,4-
Preparation of dihydroxyphenyl) thiazol-2-yl] thiomethyl-3-cephem-4-carboxylate (syn isomer) Benzhydryl 3-chloromethyl-7β- [2-cyclopentyloxyimino-2- (2-tritylaminothiazole- 4-yl) acetamido] -3-cephem-4-carboxylate 890 mg (1 mmol), sodium iodide 750 mg (5 mmol), 4-carboxy-5
300 mg (1.1 mmol) of-(3,4-dihydroxyphenyl) -2-mercaptothiazole and triethylamine.
Using 15 ml (1.1 mmol), the hydrochloride obtained by treating in the same manner as in Example 50 was neutralized with saturated aqueous sodium hydrogen carbonate and subjected to reverse phase column chromatography (LC-Sorb RP-18, Chemco, 180 ml). , Eluted with 5% aqueous methanol) to give 150 mg of the title compound (yield 21.5%).

MP: 165-170 ℃ (decomposition) NMR (D ₂ O) δ: 1.4-2.0 (8H, m), 3.55 (2H, ABq), 4.
16 (2H, ABq), 4.80 (1H, br s), 5.14 (1H, d, J = 4.5H
z), 5.72 (1H, d, J = 4,5Hz), 6.86 (2H, s), 6.92 (1H,
s), 6.96 (1H, s) Example 55 Disodium 7β- [2-allyloxyimino-2
-(2-Aminothiazol-4-yl) acetamide]
-3- [4-carboxylate-5- (3,4-dihydroxyphenyl) thiazol-2-yl] thiomethyl-3
-Preparation of cephem-4-carboxylate (syn isomer) Benzhydryl 7β- [2-allyloxyimino-
2- (2-Tritylaminothiazol-4-yl) acetamido] -3-chloromethyl-3-cephem-4-carboxylate (syn isomer) 1.30 g (1.5 mmol),
Using sodium iodide 1.13 g (7.5 mmol), 4-carboxy-5- (3,4-dihydroxyphenyl) -2-mercaptothiazole 444 mg (1.65 mmol) and triethylamine 0.23 ml (1.65 mmol) The hydrochloride obtained by treating in the same manner as the method was neutralized with saturated aqueous sodium hydrogen carbonate and subjected to reverse phase column chromatography (LC-Sorb RP-18, Chemco, 180 ml, eluted with 5% aqueous methanol solution) to give the title compound. 160 mg (14.5% yield) are obtained.

MP: 270 ℃ NMR (D ₂ O) δ: 3.57 (2H, ABq), 4.07 (2H, ABq), 5.17
(1H, d, J = 4.5Hz), 5.1 to 5.5 (5H, m), 5.76 (1H, d, J =
4.5 Hz), 6.90 (1H, s), 7.00 (1H, s) Example 56 Disodium 7β- [2- (2-aminothiazol-4-yl) -2-propargyloxyiminoacetamide] -3- [4 -Carboxylate-5- (3,4-dihydroxyphenyl) thiazol-2-yl] thiomethyl-3-cephem-4-carboxylate (syn isomer) Benzhydryl 3-chloromethyl-7β- [2-propargyloxy] Imino-2- (2-tritylaminothiazol-4-yl) acetamido] -3-cephem-
4-carboxylate (syn isomer) 1.30 g (1.5 mmol), sodium iodide 1.13 g (7.5 mmol), 4-carboxy-5- (3,4-dihydroxyphenyl) -2-
Example using 444 mg (1.65 mmol) mercaptothiazole and 0.23 ml (1.65 mmol) triethylamine.
The hydrochloride obtained by treating in the same manner as in 50 was neutralized with saturated aqueous sodium hydrogen carbonate, and subjected to reverse phase column chromatography (LC-Sorb R
P-18, Chemco, 180 ml, eluted with 5% aqueous methanol solution) to give 410 mg of the title compound (yield 40.0%).

MP: 270 ℃ NMR (D ₂ O) δ: 2.97 (1H, br s), 3.55 (2H, ABq), 4.1
7 (2H, ABq), 4.81 (2H, s), 5.16 (1H, d, J = 4.5Hz), 5.7
4 (1H, d, J = 4.5Hz), 6.88 (2H, s), 6.98 (1H, s), 7.03
(1H, s) Example 57 Disodium 7β- [2- (2-aminothiazol-4-yl) -2-benzyloxyiminoacetamido] -3- [4-carboxylate-5- (3,4-dihydroxy) (Phenyl) thiazol-2-yl] thiomethyl-3-cephem-4-carboxylate (syn isomer)
Preparation of benzhydryl 7β- [2-benzyloxyimino-2- (2-tritylaminothiazol-4-yl) acetamido] -3-chloromethyl-cephem-4-carboxylate (syn isomer) 1.37 g (1.5 mmol) Using sodium iodide 1.13 g (7.5 mmol), 4-carboxy-5- (3,4-dihydroxyphenyl) -2-mercaptothiazole 444 mg (1.65 mmol) and triethylamine 0.23 ml (1.65 mmol). The hydrochloride obtained by the same treatment as in the method was neutralized with saturated aqueous sodium hydrogen carbonate, and subjected to reverse phase column chromatography (LC-Sorb RP-18,
Chemco, 180 ml, eluted with 5% methanol aqueous solution)
140 mg (10.2% yield) of the title compound are obtained.

MP: 270 ℃ NMR (D ₂ O / DMSO-d ₆ ) δ: 3.34 (2H, ABq), 4.13 (2H, AB
q), 5.03 (1H, d, J = 4.5Hz), 5.19 (2H, s), 5.67 (1H, d,
J = 4.5Hz), 5.86 (2H, s), 5.92 (2H, s), 5.99 (1H, s),
7.35 (5H, m) Example 58 Disodium 7β- [2- (2- (aminothiazol-4-yl) -2-methoxyiminoacetamide]-
4- [4- (3,4-dihydroxyphenyl) -5-carboxylate methylthiazol-2-yl] thiomethyl-3-cephem-4-carboxylate (syn isomer)
Preparation of benzhydryl 3-iodomethyl-7β- [2-methoxyimino-2- (2-tritylaminothiazole-
4-yl) acetamido] -3-cephem-4-carboxylate (syn isomer) 524 mg (0.56 mmol) and 4- (3,4-diacetoxyphenyl) -5 obtained in Reference Example 37.
Using 300 mg (0.56 mmol) of benzhydryloxycarbonylmethyl-2-mercaptothiazole, the trifluoroacetic acid salt obtained by the same procedure as in Example 1 is dissolved in saturated aqueous sodium hydrogen carbonate and washed with ethyl acetate. The aqueous layer was subjected to reverse phase column chromatography (LC-Sorb RP-18, Chemco), eluted with 10% aqueous methanol solution, and the elution fraction containing the target compound was concentrated and lyophilized to give 86 mg of the title compound (yield: Rate 21.1%).

MP: 185-190 ℃ (decomposition) NMR (DMSO-d ₆ ) δ: 3.52 (4H, m), 3.82 (3H, s), 4.26
(1H, d, J = 12Hz), 4.55 (1H, d, J = 12Hz), 5.00 (1H,
d, J = 5.0Hz), 5.62 (1H, d, J = 5.0Hz), 6.76 (1H, s), 6.
78 (1H, d, J = 20Hz), 6.98 (1H, dd, J = 3.0 and 20Hz), 7.
24 (1H, d, J = 3.0 Hz) Example 59 Trisodium 7β- [2- (2- (aminothiazol-4-yl) -2- (1-carboxylate-1-)
Methylethoxyimino) acetamide] -3- [4-
(3,4-Dihydroxyphenyl) -5-carboxylate methylthiazol-2-yl] thiomethyl-3-cephem-4-carboxylate (I) and trisodium 7β- [2- (2- (aminothiazol-4- Ill)
-2- (1-carboxylate-1-methylethoxyimino) acetamide] -3- [4- (3,4-diacetoxyphenyl) -5-carboxylate methylthiazol-2-yl] thiomethyl-3-cephem- Production of 4-carboxylate (II) (Syn isomer) (A) Benzhydryl 7β- [2- (1-benzhydryloxycarbonyl-1-methylethoxyimino)-
2- (2-tritylaminothiazol-4-yl) acetamido] -3-iodomethyl-3-cephem-4-carboxylate (syn isomer) 1.0 g (0.85 mmol)
Dissolved in 10 ml of N, N-dimethylformamide, 4- (3,4-
Diacetoxyphenyl) -5-benzhydryloxycarbonylmethyl-2-mercaptothiazole 0.45 g (0.8
(4 mmol) and then stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (Wakogel C-300, ethyl acetate: hexane =
1: 3), and the elution fraction containing the desired product was concentrated to give benzhydryl 3- [4- (3,4-diacetoxyphenyl) -5-benzhydryloxycarbonylmethylthiazol-2-yl]. Thiomethyl-7β- [2- (1-benzhydryloxycarbonyl-1-methylethoxyimino) -2- (2-tritylaminothiazol-4-yl) acetamido] -3-cephem-4-carboxylate (syn isomerism Body (692 mg, 51% yield) is obtained as a foam.

_{NMR (DMSO-d 6) δ} : 1.52 (6H, br s), 2.30 (6H s) 3.
78 (2H, m), 4.10 ~ 4.40 (4H, m), 5.25 (1H, d, J = 5.0H
z), 5.90 (1H, m), 6.70 ~ 7.80 (49H, m), 8.90 (1H, br
s), 9.48 (1H, br d, J = 8.0Hz) (B) The compound (692 mg, 0.44 mmol) obtained in the above reaction (A) was dissolved in methylene chloride (3.0 ml) and anisole (0.7 ml),
Add 3.0 ml of trifluoroacetic acid under ice cooling and stir for 1 hour. The solvent is distilled off under reduced pressure, ether is added to the residue, and the precipitate is collected by filtration. The precipitate was suspended in water, adjusted to pH 6.5 with saturated aqueous sodium hydrogen carbonate, and subjected to reverse-phase column chromatography (LC-Sorb RP-18, Chemco) to elute the target product with water. The eluted fractions containing it are collected and lyophilized to obtain 136 mg (yield 38%) of the title compound (I). 5% more
The title compound (I
I) 89 mg (22% yield) are obtained.

Title compound (I) MP: 175-180 ° C (decomposition) NMR (DMSO-d ₆ ) δ: 1.40 (3H, br s), 1.46 (3H s),
4.20 (1H, d, J = 12Hz), 4.54 (1H, d, J = 12Hz) 5.02 (1H,
d, J = 5.0Hz), 5.68 (1H, m), 6.76 (1H, s), 6.80 (1H, d,
J = 7.0Hz), 6.96 (1H, br d, J = 7.0Hz), 7.13 (1H, br
s) Title compound (II) MP: 195-200 ℃ (decomposition) NMR (DMSO-d ₆ ) δ: 1.40 (3H, br s), 1.45 (3H, br
s), 2.28 (H, s), 4.18 (1H, m), 4.70 (1H, m), 5.00 (1
H, m), 6.70 (1H, s), 7.10 to 7.70 (3H, m) Example 60 Trisodium 7β- [2- (2-aminothiazol-4-yl) -2- (1-carboxylate- 1-
Cyclopropoxyimino) acetamide] -3- [4-
(3,4-Dihydroxyphenyl) -5-carboxylate methylthiazol-2-yl] thiomethyl-3-cephem-4-carboxylate (I) and 3- [4- (3,
4-diacetoxyphenyl) -5-carboxylate methylthiazol-2-yl] thiomethyl-7β- [2-
(2-Aminothiazol-4-yl) -2- (1-carboxylate-1-cyclopropoxyimino) acetamido] -3-cephem-4-carboxylate (II)
(Syn isomer) Benzhydryl 7β- [2- (1-tert-butoxycarbonyl-1-cyclopropoxyimino) -2- (2
-Tritylaminothiazol-4-yl) acetamido] -3-iodomethyl-cephem-4-carboxylate (syn isomer) 1.0 g (0.96 mmol) and 4- (3,4
-Diacetoxyphenyl) -5-benzhydryloxycarbonylmethyl-2-mercaptothiazole 0.51 g
(0.96 mmol) was used to suspend the trifluoroacetate salt obtained in the same manner as in Example 59 in water, and the pH was adjusted to 6.5 with saturated aqueous sodium hydrogen carbonate, followed by reverse phase column chromatography (LC-Sorb RP -18, Chemco Co., Ltd.), and eluate fractions containing the target compound by elution with water are collected and freeze-dried to obtain 61 mg (7.8% yield) of the title compound (I). By eluting with the title compound (II)
173 mg (20% yield) are obtained.

Title compound (I) MP: 165-170 ° C (decomposition) NMR (DMSO-d ₆ ) δ: 1.05 (2H, m), 1.16 (2H, m), 5.00
(1H, m), 6.80 (1H, s) Title compound (II) MP: 165-170 ℃ (decomposition) NMR (DMSO-d ₆ ) δ: 1.06 (2H, m), 1.22 (2H, m), 2.28
(6H, s), 4.20 (1H, m), 4.60 (1H, m), 4.98 (1H, d, J =
5.0Hz), 5.55 (1H, d, J = 5.0Hz), 6.80 (1H, s), 7.25 (1
H, d, J = 9.0 Hz), 7.55 (1H, br s), 7.58 (1H, m) Example 61 Trisodium 3- [4- (3,4-diacetoxyphenyl) -5-carboxylate methylthiazole -2
-Yl] thiomethyl-7β- {2- (2-aminothiazol-4-yl) -2-[(α-carboxylatebenzyl) oxyimino] acetamido} -3-cephem-
4-carboxylate (preparation of diastereomers A and B (syn isomers) benzhydryl 7β-{[2- (α-benzhydryloxycarbonylbenzyl) oxyimino] -2-
(2-tritylaminothiazol-4-yl) acetamido} -3-iodomethyl-3-cephem-4-carboxylate (syn isomer) 1.0 g (0.82 mmol) and 4-
(3,4-diacetoxyphenyl) -5-benzhydryloxycarbonylmethyl-2-mercaptothiazole 0.
Using 44 g (0.82 mmol), the trifluoroacetate salt obtained by the same operation as in Example 59 was suspended in water, and the pH was adjusted to 6.5 with saturated aqueous sodium hydrogen carbonate, followed by reverse phase column chromatography (LC-Sorb). RP-18, Chemco) and eluted with 5% aqueous methanol solution to separate diastereomers A and B. Eluted fractions were collected, concentrated and lyophilized to give the title compound diastereomer A. 103 mg (13% yield) and 164 mg of diastereomer B (21% yield) are obtained.

High Performance Liquid Chromatography Analysis Column: ODS (YMC-Pack AM-312) 6 × 150mm Mobile phase: 60% MeOH-0.01M Phosphate buffer (pH3.0) Flow rate: 1.0ml / min Detection: UV254nm Diastereomer A : 12min Diastereomer B: 13min Diastereomer A MP: 185-190 ℃ (decomposition) NMR (DMSO-d ₆ ) δ: 2.28 (6H, s), 4.15 (1H, m), 4.65
(1H, m), 5.00 (1H, d, J = 5.0Hz), 5.30 (1H, s), 5.70
(1H, m), 6.76 (1H, s), 7.00 to 7.70 (8H, m) Diastereomer B MP: 185 to 190 ° C (decomposition) NMR (DMSO-d ₆ ) δ: 2.28 (6H, s), 4.10-4.80 (2H,
m), 5.00 (1H, H), 5.38 (2H, m), 6.88 (1H, s), 7.00〜
7.70 (8H, m) Example 62 Sodium 7β- [2- (2-aminothiazole-
4-yl) -2-methoxyiminoacetamide] -3-
[5- (3,4-dihydroxyphenyl) oxazole-
Preparation of 2-yl] thiomethyl-3-cephem-4-carboxylate (syn isomer) Benzhydryl 3-iodomethyl-7β- [2-methoxyimino-2- (2-tritylaminothiazole-
4-yl) acetamido] -3-cephem-4-carboxylate (syn isomer) 1.0 g (1.10 mmol) and 5- (3,4-dihydroxyphenyl) -2-obtained in Reference Example 33.
Using 0.260 g (1.2 mmol) of mercaptooxazole, the trifluoroacetic acid salt obtained by the same operation as in Example 1 was suspended in water, the pH was adjusted to 6.5 with saturated aqueous sodium hydrogen carbonate, and the insoluble material was filtered off. . This filtrate was subjected to reverse phase column chromatography (LC-Sorb RP-18, Chemco), and the elution fraction containing the desired product (eluted with 20% aqueous methanol solution) was collected, concentrated and lyophilized to give 180 mg of the title compound. (Yield 26.6
%).

MP: 185 ℃ (decomposition) NMR (DMSO-d ₆ ) δ: 3.20 to 3.60 (2H, m), 3.83 (3H,
s), 4.33 (2H, br s), 5.00 (1H, d, J = 4.5Hz), 5.60 (1
H, d, J = 4.5Hz), 6.77 (1H, s), 6.80 ~ 7.15 (3H, m), 7.3
5 (1H, s) Example 63 Sodium 7β- [2- (2-aminothiazole-
4-yl) -2-ethoxyiminoacetamide] -3-
[5- (3,4-dihydroxyphenyl) oxazole-
Preparation of 2-yl] thiomethyl-3-cephem-4-carboxylate (syn isomer) Benzhydryl 7B- [2-ethoxyimino-2-
(2-Tritylaminothiazol-4-yl) acetamido] -3-iodomethyl-3-cephem-4-carboxylate (syn isomer) 1.0 g (1.06 mmol) and 5-
Using 0.260 g (1.2 mmol) of (3,4-dihydroxyphenyl) -2-mercaptooxazole, the trifluoroacetic acid salt obtained by the same procedure as in Example 1 was suspended in water, and the pH was adjusted to 6.5 with saturated aqueous sodium hydrogen carbonate. After adjusting to, the insoluble matter is filtered off. This filtrate was subjected to reverse phase column chromatography (LC-
Sorb RP-18, Chemco), and the elution fraction containing the desired product (eluted with a 20% aqueous methanol solution) is collected, concentrated and freeze-dried to obtain 70 mg of the title compound (yield 10.2%).

MP: 185 ℃ (decomposition) NMR (DMSO-d ₆ / D ₂ O) δ: 1.23 (3H, t, J = 6.0Hz), 3.
52 to 3.70 (2H, m), 4.13 (2H, q, J = 6.0Hz), 4.33 (2H, Br
s), 5.00 (1H, d, J = 4.5Hz), 5.62 (1H, d, J = 4.5Hz),
6.75 (1H, s), 6.80-7.10 (3H, m), 7.35 (1H, s) Example 64 Disodium 7β- [2- (2-aminothiazol-4-yl) -2- (1-carboxylate) -1-Methylethoxyimino) acetamide] -3- [5- (3,4
Preparation of -dihydroxyphenyl) oxazol-2-yl] thiomethyl-3-cephem-4-carboxylate (syn isomer) Benzhydryl 7β- [2- (1-benzhydryloxycarbonyl-1-methylethoxyimino) -2 −
(2-Tritylaminothiazol-4-yl) acetamido] -3-iodomethyl-3-cephem-4-carboxylate (syn isomer) 1.0 g (0.86 mmol) and 5-
0.23 g (1.0 mmol) of (3,4-dihydroxyphenyl) -2-mercaptoxazole was used to suspend the trifluoroacetate salt obtained in the same manner as in Example 1 in water, and the pH was adjusted to 6.5 with saturated aqueous sodium hydrogen carbonate. After adjusting to, the insoluble matter is filtered off. This filtrate was subjected to reverse phase column chromatography (LC-
Sorb RP-18, Chemco), and the elution fraction containing the desired product (eluted with 7.5% aqueous methanol solution) is collected, concentrated and freeze-dried to obtain 100 mg of the title compound (yield 16.3%).

MP: 180 ℃ (decomposition) NMR (DMSO-d ₆ / D ₂ O) δ: 1.42 (3H, s), 1.47 (3H,
s) 3.00 to 3.70 (2H, m), 4,30 (2H, m), 5.20 (1H, d, J =
4.5Hz), 5.65 (1H, d, J = 4.5Hz), 6.75 (1H, s), 6.80〜
7.15 (3H, m), 7.33 (1H, s) Example 65 Disodium 7β- {2- (2-aminothiazol-4-yl) -2-[(α-carboxylate-3,4-
Dihydroxybenzyl) oxyimino] acetamide}
Preparation of -3- [5- (3,4-dihydroxyphenyl) oxazol-2-yl] thiomethyl-3-cephem-4-carboxylate (syn isomer) (A) Benzhydryl 7β- {2-[[α- Benzhydryloxycarbonyl-3,4-di (2-methoxyethoxymethoxy) benzyl] oxyimino] -2- (2-
Tritylaminothiazol-4-yl) acetamide]
1.0 g (0.75 mmol) of -3-chloromethyl-3-cephem-4-carboxylate (syn isomer) was dissolved in 10 ml of N, N-dimethylformamide to give 124 m of sodium iodide.
Add g (0.83 mmol) and stir at room temperature for 30 minutes. To the reaction solution was added 5- (3,4-dihydroxyphenyl) -2-mercaptooxazole 0.185 g (0.88 mmol),
Stir at room temperature for 3 hours. Ethyl acetate is added to the reaction solution, washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and the filtrate is concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Wakogel C-300, chloroform: methanol = 98: 2), and the elution fraction containing the desired product was concentrated under reduced pressure to give benzhydryl 7β-.
{2-[[α-Benzhydryloxycarbonyl-3,4
-Di (2-methoxyethoxymethoxy) benzyl] oxyimino] -2- (2-tritylaminothiazole-4
-Yl) acetamido} -3- [5- (3,4-dihydroxyphenyl) oxazol-2-yl] thiomethyl-
3-Cephem-4-carboxylate (syn isomer) 0.
80 g (71% yield) are obtained.

NMR (DMSO-d ₆ ) δ: 3.17 (3H, s), 3.20 (3H, s), 3.25 to 3.50 (6H, m), 3.60 to 3.85 (4H, m), 3.95 to 4.50 (2H, m), 5.05 to 5.35 (3H, m), 5.65 to 5.90 (2H, m), 6.70 to 7.70 (45H, m), 8.85 (1H, m), 9.15 (1H, br s) (B) In the above reaction (A) The obtained compound (0.80 g, 0.53 mmol) was dissolved in methylene chloride (8 mg) and anisole (0.8 ml) to give 0
Add 11 ml of trifluoroacetic acid at ℃ and stir at the same temperature for 2.5 hours. The reaction solution is concentrated under reduced pressure, ether is added to the residue, and the precipitate is collected by filtration. The precipitate is suspended in water, adjusted to pH 6.5 with saturated aqueous sodium hydrogen carbonate, and the insoluble material is removed by filtration. This filtrate was subjected to reverse phase column chromatography (LC-Sorb RP-1
(8, Chemco), and the elution fraction containing the desired product (eluted with a 3% aqueous methanol solution) is collected, concentrated and freeze-dried to obtain 70 mg of the title compound (yield 16.5%).

MP: 180 ℃ (decomposition) _{NMR (DMSO-d 6 / D} 2 O) δ: 3.25~3.50 (2H, m), 4.10
~ 4.40 (2H, m), 5.03 (1H, m), 5.15 (1H, m), 5.63 (1H,
m), 6.65-7.15 (7H, m), 7.32 (1H, s) Example 66 Disodium 7β- [2- (2-aminothiazol-4-yl) -2- (1-carboxylate-1-cyclo) Propoxyimino) acetamide] -3- [5- (3,
4-dihydroxyphenyl) oxazol-2-yl]
Preparation of thiomethyl-3-cephem-4-carboxylate (syn isomer) Benzhydryl 7β- [2- (1-tert-butoxycarbonyl-1-cyclopropoxyimino) -2- (2
-Tritylaminothiazol-4-yl) acetamido] -3-chloromethyl-3-cephem-4-carboxylate (syn isomer) 0.65 g (0.68 mmol), sodium iodide 122 mg (0.81 mmol) and 5- (3 , 4-Dihydroxyphenyl) -2-mercaptooxazole 0.
142 g (0.68 mmol) of the trifluoroacetic acid salt obtained by the same operation as in Example 67 was suspended in water, the pH was adjusted to 6.5 with saturated aqueous sodium hydrogen carbonate, and the insoluble material was filtered off. This filtrate was subjected to reverse phase column chromatography (LC-Sorb RP-1
8, Chemco), and the elution fraction containing the desired product (eluted with a 3% aqueous solution of methanol) is collected, concentrated and freeze-dried to obtain 22 mg of the title compound (yield 2.3%).

MP: 170 ℃ (decomposition) NMR (DMSO-d ₆ / D ₂ O) δ: 0.80 to 1.40 (4H, m), 3.30
~ 3.70 (2H, m), 4.30 (2H, br s), 5.02 (1H, d, J = 4.5H
z), 5.60 (1H, d, J = 4.5Hz), 6.70 ~ 7.15 (4H, m), 7.33
(1H, s) Example 67 Disodium 3- [5- (3,4-diacetoxyphenyl) oxazol-2-yl] thiomethyl-7β-
Preparation of [2- (2-aminothiazol-4-yl) -2-ethoxyiminoacetamide] -3-cephem-4-carboxylate (syn isomer) Benzhydryl 7β- [2-ethoxyimino-2-
(2-Tritylaminothiazol-4-yl) acetamido] -3-iodomethyl-3-cephem-4-carboxylate (syn isomer) 0.45 g (0.48 mmol), 5
-(3,4-Dihydroxyphenyl) -2-mercaptooxazole 0.1 g (0.48 mmol), acetic anhydride 1.0 ml (1.0
(6 mmol) and 0.86 ml (1.06 mmol) of pyridine, the trifluoroacetic acid salt obtained by the same operation as in Example 26 was suspended in water, and the pH was adjusted to 6.5 with saturated aqueous sodium hydrogen carbonate. Remove by filtration. The filtrate was subjected to reverse phase column chromatography (LC-Sorb RP-18, Chemco), and the elution fraction containing the desired product (eluted with 40% aqueous methanol solution) was collected, concentrated and lyophilized to give the title compound. 23 mg (yield 6.6
%).

MP: 190 ℃ (decomposition) _{NMR (DMSO-d 6 / D} 2 O) δ: 1.20 (3H, t, J = 6.0Hz), 2.
30 (6H, s), 3.35 to 3.65 (2H, m), 4.13 (2H, q, J = 6.0H
z), 4.35 (2H, br s), 5.02 (1H, d, J = 4.5Hz), 5.62 (1
H, d, J = 4.5 Hz), 6.74 (1H, s), 7.30 to 7.70 (4H, m) Example 68 7β- [2- (2-aminothiazol-4-yl)-
2-Methoxyiminoacetamido] -3- (5,6-dihydroxybenzimidazol-2-yl) thiomethyl-
Preparation of 3-Cephem-4-carboxylate sodium salt (syn isomer) Benzhydryl 3-iodomethyl-7β- [2-methoxyimino-2- (2-tritylaminothiazole-
4-yl) acetamido] -3-cephem-4-carboxylate (syn isomer) 0.93 g (1.0 mmol) and 2-
Using 357 mg (1.0 mmol) of mercapto-5,6-di (2-methoxyethoxymethoxy) benzimidazole, the same procedure as in Example 1 was carried out to suspend the resulting trifluoroacetic acid in water, and the pH was adjusted to 6 with saturated aqueous sodium hydrogen carbonate. After adjusting to .5,
The insoluble matter is filtered off. The filtrate is subjected to ODS column chromatography (LC-Sorb RP-18, Chemco), eluted with 30% aqueous methanol solution, concentrated and lyophilized to give 196 mg of the title compound (yield 33.8%).

MP: 170 ℃ (decomposition) NMR (DMSO-d ₆ ) δ: 3.60 to 3.90 (2H, m), 3.85 (3H,
s), 4.30 (2H, br s), 5.15 (1H, d, J = 6Hz), 5.75 (1H,
m), 6.74 (1H, s), 6.96 (2H, s), 9.56 (1H, br d, J = 8H
z) Example 69 7β- [2- (2-aminothiazol-4-yl)-
2-Methoxyiminoacetamide] -3- (5,6-dihydroxy-2-methylbenzimidazol-2-yl)
Production of thiomethyl-3-cephem-4-carboxylic acid / trifluoroacetic acid salt (syn isomer) Benzhydryl 3-iodomethyl-7β- [2-methoxyimino-2- (2-tritylaminothiazole-
4-yl) acetamido] -3-cephem-4-carboxylate (syn isomer) 168 mg (0.18 mmol) and 2
By the same procedure as in Example 32 using 67 mg (0.18 mmol) of -mercapto-5,6-di (2-methoxyethoxymethoxy) -2-methylbenzimidazole, 74 mg of the title compound was obtained.

MP: 180 ℃ (decomposition) NMR (DMSO-d ₆ ) δ: 3.60 (2H, m), 3.80 (3H, s), 3.88
(3H, s), 4.22 (2H, m), 5.15 (1H, d, J = 5Hz), 5.78 (1
H, m), 6.78 (1H, s), 7.02 (2H, s) Example 70 7β- [2- (2-aminothiazol-4-yl)-
2-Isopropoxyiminoacetamide] -3- (5,6
-Dihydroxybenzimidazol-2-yl) thiomethyl-3-cephem-4-carboxylate sodium salt (syn isomer) Benzhydryl 3-iodomethyl-7β- [2-isopropoxyimino-2- (2-tritylamino) Thiazol-4-yl) acetamido] -3-cephem-4-
Carboxylate (syn isomer) 0.87 g (0.91 mmol) and 2-mercapto-5,6-di (2-methoxyethoxymethoxy) benzimidazole 357 mg (1.0 mmol)
The trifluoroacetic acid obtained by the same procedure as in Example 1 is suspended in water, the pH is adjusted to 6.5 with saturated aqueous sodium hydrogen carbonate, and the insoluble matter is removed by filtration. The filtrate was subjected to ODS column chromatography (LC-Sorb RP-18, Chemco), and the elution fraction (eluted with 30% aqueous methanol solution) was concentrated under reduced pressure and lyophilized to give 99 mg of the title compound (yield 25 %).

MP: 150 ℃ (decomposition) NMR (DMSO-d ₆ ) δ: 1.17 (6H, d, J = 6Hz), 3.70 (2H,
m), 4.28 (1H, m), 4.40-5.30 (2H, m), 5.05 (1H, d, J =
6Hz), 5.60 (1H, m), 6.61 (1H, s), 6.70 (2H, br s), 9.
38 (1H, m), Example 71 7β- [2- (2-aminothiazol-4-yl)-
2-allyloxyiminoacetamide] -3- (5,6-
Preparation of dihydroxybenzimidazol-2-yl) thiomethyl-3-cephem-4-carboxylate sodium salt (syn isomer) Benzhydryl 3-iodomethyl-7β- [2-allyloxyimino-2- (2-tritylaminothiazole) -4-yl) acetamido] -3-cephem-4-carboxylate (syn isomer) 0.89 g (0.93 mmol)
And 2-mercapto-5,6-di (2-methoxyethoxymethoxy) benzimidazole 333 mg (0.93 mmol) in the same manner as in Example 1 except that the title compound 140 m
g (yield 25.8%) is obtained.

MP: 165 ℃ (decomposition) NMR (DMSO-d ₆ ) δ: 3.70 (2H, m), 4.53 (2H, br d, J =
4Hz), 4.70-5.10 (2H, m), 5.00-5.50 (3H, m), 5.60
(1H, m), 5.70 to 6.10 (1H, m), 6.68 (1H, s), 6.72 (2H,
br s), 7.15 (2H, br s), 9.38 (1H, br d) Example 72 7β- {2- (2-aminothiazol-4-yl)-
2- [2-Pyrrolidone-3-yl) oxyimino] acetamido} -3- (5,6-dihydroxybenzimidazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid / trifluoroacetic acid salt (syn isomer ) Benzhydryl 3-iodomethyl-7β- [2-
(2-Pyrrolidone-3-yl) oxyimino-2- (2
-Tritylaminothiazol-4-yl) acetamido] -3-cephem-4-carboxylate (syn isomer) 0.90 g (0.90 mmol) and 2-mercapto-5,6-di (2-methoxyethoxymethoxy) benzimidazole
By the same procedure as in Example 32 using 350 mg (0.98 mmol), 155 mg of the title compound (yield 26.7%) is obtained.

MP: 200 ℃ (decomposition) NMR (DMSO-d ₆ ) δ: 2.10 to 2.50 (2H, m), 3.72 (4H,
m), 4.30 (2H, br s), 4.70 (1H, m), 5.18 (1H, m), 5.80
(1H, m), 6.80 (1H, s), 6.98 (2H, br s), 9.58 (1H, m) Example 73 7β- [2- (2-aminothiazol-4-yl)-
2- (1-Carboxy-1-methylethoxyimino) acetamido} -3- (5,6-dihydroxybenzimidazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid / trifluoroacetic acid salt (syn isomer ) Benzhydryl 7β- [2- (1-benzhydryloxycarbonyl-1-methylethoxyimino) -2-
1.5 g (1.37 mmol) of (2-tritylaminothiazol-4-yl) acetamido] -3-iodomethyl-3-cephem-4-carboxylate (syn isomer) and 2-
Using the same procedure as in Example 32, using 0.59 g (1.65 mmol) of mercapto-5,6-di (2-methoxyethoxymethoxy) benzimidazole, 519 mg of the title compound was obtained.
(Yield 61.5%) is obtained.

MP: 130 ℃ (decomposition) NMR (DMSO-d ₆ ) δ: 1.46 (6H, br s), 3.75 (2H, m),
4.31 (2H, m), 5.23 (1H, d, J = 5Hz), 5.82 (1H, m), 6.78
(1H, s), 6.99 (2H, m), 9.45 (1H, m) Example 74 7β- [2- (2-aminothiazol-4-yl)-
2- (1-Carboxy-1-cyclopentyloxyimino) acetamido] -3- (5,6-dihydroxybenzimidazol-2-yl) thiomethyl-3-cephem-
4-carboxylate disodium salt (syn isomer)
Production of benzhydryl 7β- [2- (1-benzhydryloxycarbonyl-1-cyclopentyloxyimino)
-2- (2-Tritylaminothiazol-4-yl) acetamido] -3-iodomethyl-3-cephem-4-
Carboxylate (syn isomer) 1.1 g (0.91 mmol)
And 2-mercapto-5,6-di (2-methoxyethoxymethoxy) benzimidazole (0.33 g, 0.91 mmol) were used in the same manner as in Example 1 to give 77 mg of the title compound.
(Yield 11.7%) is obtained.

MP: 175 ℃ (decomposition) NMR (DMSO-d ₆ ) δ: 1.62 (4H, m), 2.08 (4H, m), 3.70
(2H, m), 4.40 to 4.90 (2H, m), 5.04 (1H, d, J = 5Hz), 5.
69 (1H, m), 6.70 (1H, s), 6.76 (2H, br s) Example 75 7β- [2- (2-aminothiazol-4-yl)-
2-Methoxyiminoacetamido] -3- (5,6-dihydroxybenzoxazol-2-yl) thiomethyl-
Preparation of 3-Cephem-4-carboxylate sodium salt (syn isomer) Benzhydryl 7β- [2-methoxyimino-2-
(2-Tritylaminothiazol-4-yl) acetamido] -3-iodomethyl-3-cephem-4-carboxylate (syn isomer) 1.0 g (1.07 mmol) and 2-
By the same procedure as in Example 1, using 380 mg (1.06 mmol) of mercapto-5,6-di (2-methoxyethoxymethoxy) benzoxazole, 106 mg of the title compound was obtained.
(Yield 16.6%) is obtained.

MP: 180 ℃ (decomposition) NMR (DMSO-d ₆ ) δ: 3.72 (2H, m), 3,80 (3H, s), 4.35
(2H, m), 4.96 (1H, d, J = 5Hz), 5.55 (1H, m), 6.70 (1
H, m), 6.92 (1H, s), 7.00 (1H, s), 7.22 (2H, m), 9.43
(1H, br d, J = 8 Hz) Example 76 7β- [2- (2-aminothiazol-4-yl)-
2- (1-carboxylate-1-methylethoxyimino) acetamido] -3- (5,6-dihydroxybenzoxazol-2-yl) thiomethyl-3-cephem-
Preparation of 4-Carboxylxylate disodium salt (syn isomer) Benzhydryl 7β- [2- (1-benzhydryloxycarbonyl-1-methoxyethoxy) imino-2
1.2 g (1.03 mmol) of 2- (2-tritylaminothiazol-4-yl) acetamido] -3-iodomethyl-3-cephem-4-carboxylate (syn isomer) and 2
Using 0.37 g (1.03 mmol) of -mercapto-5,6-di (2-methoxyethoxymethoxy) benzoxazole, the same procedure as in Example 1 was carried out, and 30% aqueous methanol solution was eluted by ODS column chromatography.
40 mg (5.06% yield) of the title compound are obtained.

MP: 185 ℃ (decomposition) NMR (DMSO-d ₆ ) δ: 1.42 (6H, m), 3.70 (2H, m), 4.00
~ 4.60 (2H, m), 5.06 (1H, d, J = 5Hz), 5.75 (1H, m), 6.
66 (1H, m), 6.89 (1H, s), 6.96 (1H, s), 7.18 (1H, br
s), 9.40 (1H, m) Reference Example Reference Example 1 7β- [2- (2-aminothiazol-4-yl)-
2-Methoxyiminoacetamido] -3- (5-phenyl-1,3,4-oxadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid / trifluoroacetic acid salt (syn isomer) Benzhydryl 3-iodomethyl-7β- [2-methoxyimino-2- (2-tritylaminothiazole-
4-yl) acetamido] -3-cephem-4-carboxylate (syn isomer) 1.0 g (1.1 mmol) and 5-mercapto-2-phenyl-1,3,4-oxadiazole 0.19 g
Using (1.1 mmol) and the same procedure as in Example 1, 225 mg of the title compound (yield 36.6%) is obtained.

MP: 150 ℃ (decomposition) NMR (DMSO-d ₆ ) δ: 3.75 (2H, m), 4,30 (1H, dr d, J =
13Hz), 4.42 (1H, br d, J = 13Hz), 5.18 (1H, d, J = 5H
z), 5.78 (1H, dd, J = 5 and 8Hz), 6.86 (1H, s), 7.27
(1H, m), 7.60 (2H, m), 7.96 (2H, m), 9.70 (1H, br d, J = 8Hz).

Reference Example 2 7β- [2- (2-aminothiazol-4-yl)-
2-Methoxyiminoacetamide] -3- [5- (4-
Hydroxyphenyl) -1,3,4-oxadiazole-2
-Yl] thiomethyl-3-cephem-4-carboxylic acid
Preparation of trifluoroacetic acid salt (syn isomer) Benzhydryl 3-iodomethyl-7β- [2-methoxyimino-2- (2-tritylaminothiazole-
4-yl) acetamido] -3-cephem-4-carboxylate (syn isomer) 1.0 g (1.1 mmol) and 5- (4
Using 0.21 g (1.1 mmol) of -hydroxyphenyl) -2-mercapto-1,3,4-oxadiazole, the same operation as in Example 1 was performed to obtain 444 mg of the title compound (yield 64.7%).

MP: 155 ℃ (decomposition) NMR (DMSO-d ₆ ) δ: 3.72 (2H, m), 4.36 (2H, m), 5.20 (1H, d, J = 5Hz), 5.80 (1H, m), 6.87 (1H, s), 6.96 ( 2H, d, J = 9Hz), 7.80 (2H, d, J = 9Hz), 9.72 (1H, brd, J = 8Hz).

Reference Example 3 7β- [2- (2-aminothiazol-4-yl)-
2- (1-carboxylate-1-methylethoxyimino) acetamido] -3- [5-phenyl-1,3,4-oxadiazol-2-yl) thiomethyl-3-cephem-4-carboxylate di Production of sodium salt (syn isomer) Benzhydryl 7β- [2- (1-benzhydryloxycarbonyl-1-methylethoxyimino) -2-
(2-Tritylaminothiazol-4-yl) acetamido] -3-iodomethyl-3-cephem-4-carboxylate (syn isomer) 1.0 g (0.85 mmol) and 2-mercapto-5-phenyl-1,3, 4-oxadiazole 0.15 g
Using (0.85 mmol) and the same procedure as in Example 1, the title compound (195 mg, yield 17.8%) is obtained.

MP: 175 ℃ (decomposition) NMR (DMSO-d ₆ ) δ: 1.40 (3H, br s), 1.46 (3H, br
s), 3.60 (2H, m), 4.42 (2H, dr s), 5.02 (5H, d, J = 5H
z), 5.68 (1H, m), 6.71 (1H, s), 7.18 (1H, m), 7.60 (2
H, m), 7.95 (2H, m).

Reference Example 4 7β- [2- (2-aminothiazol-4-yl)-
2- (1-carboxylate-1-methylethoxyimino) acetamido] -3- [5- (4-hydroxyphenyl) -1,3,4-oxadiazol-2-yl) thiomethyl-3-cephem-4 -Production of carboxylate disodium salt (syn isomer) Benzhydryl 7β- [2- (1-benzhydryloxycarbonyl-1-methylethoxyimino) -2-
(2-Tritylaminothiazol-4-yl) acetamido] -3-iodomethyl-3-cephem-4-carboxylate (syn isomer) 1.0 g (0.85 mmol) and 5- (4
By using 0.16 g (0.85 mmol) of -hydroxyphenyl) -2-mercapto-1,3,4-oxadiazole, the same operation as in Example 1 was performed to obtain 84 mg of the title compound (yield 14%).

MP: 175 ℃ (decomposition) NMR (DMSO-d ₆ ) δ: 1.40 (3H, br s), 1.46 (3H, br
s), 3.50 (2H, m), 4.38 (2H, dr s), 5.00 (1H, d, J = 5H
z), 5.68 (1H, m), 6.71 (1H, s), 6.88 (2H, d, J = 9Hz),
7.68 (2H, d, J = 9Hz) Reference Example 5 7β- [2- (2-aminothiazol-4-yl)-
2-Methoxyiminoacetamido] -3- (5-phenyl-1,3,4-thiadiazol-2-yl) thiomethyl-
Preparation of 3-cephem-4-carboxylic acid / trifluoroacetic acid salt (syn isomer) Benzhydryl 3-iodomethyl-7β- [2-methoxyimino-2- (2-tritylaminothiazole-
4-yl) acetamido] -3-cephem-4-carboxylate (syn isomer) 800 mg (0.86 mmol) and 2-
Mecalcapto-5-phenyl-1,3,4-thiadiazole 1
The procedure of Example 32 is repeated using 67 mg (0.86 mmol) to obtain 364 mg of the title compound (yield 71.2%).

MP: 165 ℃ (decomposition) NMR (DMSO-d ₆ ) δ: 3.80 (2H, m), 3.90 (3H, s), 4.32
(1H, d, J = 12Hz), 4.63 (1H, d, J = 12Hz), 5.20 (1H, d, J
= 5Hz), 5.82 (1H, m), 6.86 (1H, s), 7.60 (3H, m), 7.9
5 (2H, m), 9.72 (1H, brd, J = 8Hz) Reference Example 6 7β- [2- (2-aminothiazol-4-yl)-
2- (1-carboxylate-1-methylethoxyimino) acetamido] -3- (5-phenyl-1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-
4-carboxylate disodium salt (syn isomer)
Benzhydryl 3-iodomethyl-7β- [2-
(1-Benzhydryloxycarbonyl-1-methylethoxyimino) -2- (2-tritylaminothiazol-4-yl) acetamido] -3-cephem-4-carboxylate (syn isomer) 800 mg (0.68 mmol) And 2
-Mercapto-5-phenyl-1,3,4-thiadiazole 1
Using 33 mg (0.68 mmol) and following the same procedure as in Example 1, 171 mg (yield 35%) of the title compound is obtained.

MP: 190 ℃ (decomposition) NMR (DMSO-d ₆ ) δ: 1.45 (6H, br s), 3.80 (2H, m),
4.20 ~ 4.80 (2H, m), 5.06 (1H, d, J = 5Hz), 5.70 (1H,
m), 6.75 (1H, s), 7.58 (3H, m), 7.90 (2H, m) Reference Example 7 7β- [2- (2-aminothiazol-4-yl)-
2-Methoxyiminoacetamide] -3- [5- (4-
Hydroxyphenyl) -1,3,4-thiadiazole-2-
Il) thiomethyl-3-cephem-4-carboxylic acid / trifluoroacetic acid salt (syn isomer) Benzhydryl 3-iodomethyl-7β- [2-methoxyimino-2- (2-tritylaminothiazole-
4-yl) acetamido] -3-cephem-4-carboxylate (syn isomer) 800 mg (0.68 mmol) and 5-
(4-Hydroxyphenyl) -2-mercapto-1,3,4
Using 180 mg (0.85 mmol) of thiadiazole, Example 3
By the same procedure as in 2, 276 mg of the title compound (yield 53%) is obtained.

MP: 180 ℃ (decomposition) NMR (DMSO-d ₆ ) δ: 3.78 (2H, m), 3.92 (3H, s), 4.30
(1H, d, J = 14Hz), 4.60 (1H, d, J = 14Hz), 5.20 (1H, d, J
= 5Hz), 5.80 (1H, m), 6.88 (1H, s), 6.92 (2H, d, J = 9H
z), 7.75 (2H, d, J = 9Hz) Reference Example 8 7β- [2- (2-aminothiazol-4-yl)-
2- (1-carboxylate-1-methylethoxyimino) acetamido] -3- [5- (4-hydroxyphenyl) -1,3,4-thiadiadiazol-2-yl) thiomethyl-3-cephem-4 -Production of carboxylate disodium salt (syn isomer) Benzhydryl 3-iodomethyl-7β- [2-
(1-Benzhydryloxycarbonyl-1-methylethoxyimino) -2- (2-tritylaminothiazol-4-yl) acetamido] -3-cephem-4-carboxylate (syn isomer) 800 mg (0.68 mmol) And 5
-(4-hydroxyphenyl) -2-mercapto-1,3,
Example 1 using 4-thiadiazole 200 mg (0.95 mmol)
By a similar operation to, 218 mg of the title compound (yield 44%) is obtained.

MP: 195 ℃ (decomposition) NMR (DMSO-d ₆ ) δ: 3.80 (2H, m), 4.20-4.90 (2H,
m), 5.08 (1H, d, J = 5Hz), 5.78 (1H, m), 6.76 (1H, s),
6.96 (1H, d, J = 9Hz), 7.7 (2H, d, J = 9Hz) Reference Example 9 7β- [2- (2-aminothiazol-4-yl)-
2-Methoxyiminoacetamido] -3- (4-phenylthiazol-2-yl) thiomethyl-3-cephem-
Preparation of 4-carboxylate sodium salt (syn isomer) Benzhydryl 3-iodomethyl-7β- [2-methoxyimino-2- (2-tritylaminothiazole-
4-yl) acetamido] -3-cephem-4-carboxylate (syn isomer) 1.0 g (1.1 mmol) and 2-mercapto-4-phenylthiazole 0.31 g (1.0 mmol) were used as in Example 1. The operation gives 117 mg of the title compound (yield 6.45).

MP: 175 ℃ (decomposition) NMR (DMSO-d ₆ ) δ: 3.57 (2H, m), 3.86 (3H, s), 4.48
(1H, d, J = 12Hz), 4.60 (1H, d, J = 12Hz), 5.04 (1H, d, J
= 5Hz), 5.60 (1H, dd, J = 5 and 8Hz), 6.73 (1H, s), 7.
21 (2H, br s), 7.38 (3H, m), 7.95 (1H, m), 7.99 (1H, m)
s), 9.50 (1H, brd, J = 8Hz) Reference Example 10 7β- [2- (2-aminothiazol-4-yl)-
2-Methoxyiminoacetamide] -3- [4- (4-
Hydroxyphenyl) thiazol-2-yl] thiomethyl-3-cephem-4-carboxylate sodium salt (syn isomer) Benzhydryl 3-iodomethyl-7β- [2-methoxyimino-2- (2-tritylaminothiazole) −
4-yl) acetamido] -3-cephem-4-carboxylate (syn isomer) 1.0 g (1.1 mmol) and 2-mercapto-4- (4-hydroxyphenyl) thiazole.
The same operation as in Example 1 was carried out using 30 g (14 mmol) to obtain 205 mg of the title compound (yield 30.3%).

MP: 185 ℃ (decomposition) NMR (DMSO-d ₆ ) δ: 3.56 (2H, m), 4.47 (1H, d, J = 12H
z), 4.63 (1H, d, J = 12Hz), 5.08 (1H, d, J = 5Hz), 5.65
(1H, dd, J = 5 and 8Hz), 6.79 (1H, s), 6.90 (1H, b, J =
8Hz), 7,26 (2H, br s), 7.72 (1H, s), 7,74 (1H, b, J = 8
Hz), 9.57 (1H, brd, J = 8Hz) Reference Example 11 7β- [2- (2-aminothiazol-4-yl)-
2- (1-carboxylate-1-methylethoxyimino) acetamido] -3- (4-phenylthiazole-
Preparation of 2-yl) thiomethyl-3-cephem-4-carboxylate disodium salt (syn isomer) Benzhydryl 7β- [2 (1-benzhydryloxycarbonyl-1-methylethoxyimino) -2-
(2-Tritylaminothiazol-4-yl) acetamido] -3-iodomethyl-3-cephem-4-carboxylate (syn isomer) 1.2 g (1.0 mmol) and 2-mercapto-4-phenylthiazole 0.30 g (1.5 mmol) and perform the same operation as in Example 1 to obtain 170 mg of the title compound (yield 17.3).

MP: 180 ℃ (decomposition) NMR (DMSO-d ₆ ) δ: 1.42 (3H, br s), 1.50 (3H, br
s), 3.55 (2H, m), 4.37 (1H, br d, J = 13Hz), 4.62 (1H,
br d, J = 13Hz), 5.03 (1H, d, J = 5Hz), 5.70 (1H, m), 6.
71 (1H, s), 7.20 (2H, br s), 7.39 (3H, m), 7.95 (1H,
d, J = 8 Hz), 8.00 (1H, s) Reference Example 12 7β- [2- (2-aminothiazol-4-yl)-
2- (1-carboxylate-1-methylethoxyimino) acetamido] -3- [4- (4-hydroxyphenyl) thiazol-2-yl] thiomethyl-3-cephem-4-carboxylate disodium salt (syn Preparation of benzhydryl 7β- [2- (1-benzhydryloxycarbonyl-1-methylethoxyimino) -2-
(2-Tritylaminothiazol-4-yl) acetamido] -3-iodomethyl-3-cephem-4-carboxylate (syn isomer) 1.0 g (0.85 mmol) and 4- (4
-Hydroxyphenyl) -2-mercaptothiazole 0.
The same operation as in Example 1 was carried out using 27 g (1.3 mmol) to obtain 30 mg of the title compound (yield 5.35%).

MP: 170 ℃ (decomposition) NMR (DMSO-d ₆ ) δ: 1.43 (3H, br s), 1.50 (3H, br
s), 3.60 (2H, m), 4.36 (1H, br d, J = 12Hz), 4.60 (1H,
d, J = 12Hz), 5.03 (1H, d, J = 5Hz), 5.70 (1H, m), 6.73
(1H, s), 6.86 (1H, d, J = 8Hz), 7.20 (2H, br s), 7.69
(1H, s), 7.72 (1H, d, J = 8Hz) Reference Example 13 7β- [2- (2-aminothiazol-4-yl)-
2-Methoxyiminoacetamide] -3- [4- (3,4
-Dimethoxyphenyl) thiazol-2-yl] thiomethyl-3-cephem-4-carboxylate trifluoroacetic acid salt (syn isomer) Benzhydryl 3-iodomethyl-7β- [2-methoxyimino-2- (2- Tritylaminothiazole-
4-yl) acetamido] -3-cephem-4-carboxylate (syn isomer) 1.0 g (1.1 mmol) and 4- (3,4
-Dimethoxyphenyl) -2-mercaptothiazole 0.
By the same procedure as in Example 32 using 27 g (1.1 mmol), 262 mg (yield 26.3%) of the title compound is obtained.

MP: 135 ℃ (decomposition) NMR (DMSO-d ₆ ) δ: 3.80 (2H, m), 3.82 (3H, s), 3.88
(3H, s), 3.93 (3H, s), 4.28 (1H, d, J = 12Hz), 4.58 (1
H, d, J = 12Hz), 5.20 (1H, d, J = 5Hz), 5.80 (1H, dd, J =
5 and 8Hz), 6.88 (1H, s), 7.30 (1H, d, J = 6Hz), 7.50
(1H, br s), 7.52 (1H, br, d, J = 6Hz), 8.95 (1H, s), 9.
70 (1H, br, d, J = 8Hz) Reference Example 14 Trisodium 7β- [2- (2-aminothiazol-4-yl) -2- (1-carboxylate-1-methylethoxyimino) acetamide]- Preparation of 3- (4-carboxylate-5-phenylthiazol-2-yl) thiomethyl-3-cephem-4-carboxylate (syn isomer) Benzhydryl 7β [2- (1-benzhydryloxycarbonyl-1- Methyl ethoxyimino) -2-
(2-Tritylaminothiazol-4-yl) acetamido] -3-chloromethyl-3-cephem-4-carboxylate (syn isomer) 1.08 g (1.0 mmol), sodium iodide 0.75 g (5.0 mmol), 4 -Carboxy-
5-phenyl-2-mercaptothiazole 237 mg (1.0 mmol) and triethylamine 0.14 mg (1.0 mmol)
Is treated in the same manner as in Example 50 to give the title compound (212 mg, yield 27.4%).

MP: 230 ℃ (decomposition) NMR (D ₂ O) δ: 1.52 (6H, s), 3.61 (2H, ABq), 4.23
(2H, ABq), 5.18 (1H, d, J = 4.5Hz), 5.86 (1H, d, J =
4.5Hz), 6.96 (1H, s), 7.47 (5H, s) Reference Example 15 Disodium 7β- [2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamide] -3
Preparation of-(5-carboxylate methyl-4-phenylthiazol-2-yl) thiomethyl-3-cephem-4-carboxylate (syn isomer) Benzhydryl 3-iodomethyl-7β- [2-methoxyimino-2- ( 2-Tritylaminothiazole-
4-yl) acetamido] -3-cephem-4-carboxylate (syn isomer) 1.0 g (1.07 mmol) and 5
-Benzhydryloxycarbonylmethyl-2-mercapto-4-phenylthiazole 0.45 g (1.08 mmol)
Was carried out in the same manner as in Example 1 to obtain 276m of the title compound.
g (37% yield) are obtained.

MP: 195-200 ℃ (decomposition) NMR (DMSO-d ₆ ) δ: 3.92 (3H, s), 4.32 (1H ,, d, J12H
z), 4.78 (1H, d, J = 12Hz), 5.10 (1H, d, J) = 5.0Hz),
5.68 (1H, m), 6.80 (1H, s), 7.30 ~ 7.80 (5H, m), 9.60
(1H, br d, J = 6.0 Hz) Reference Example 16 Trisodium 7β- [2- (2-aminothiazol-4-yl) -2- (1-carboxylate-1-methylethoxyimino) acetamide] -3 Preparation of-(5-carboxylate methyl-4-phenylthiazol-2-yl) thiomethyl-3-cephem-4-carboxylate (syn isomer) Benzhydryl 7β- [2- (1-benzhydryloxycarbonyl-1) -Methylethoxyimino) -2-
(2-Tritylaminothiazol-4-yl) acetamido] -3-iodomethyl-3-cephem-4-carboxylate (syn isomer) 1.2 g (1.03 mmol) and 5
-Benzhydryloxycarbonylmethyl-2-mercapto-4-phenylthiazole 0.43 g (1.04 mmol)
Was carried out in the same manner as in Example 1 to obtain the title compound 178m
g (24% yield) are obtained.

MP: 180-185 ℃ (decomposition) NMR (DMSO-d ₆ ) δ: 1.48 (3H, br s), 1.48 (3H, br
s), 4.10 ~ 4.70 (2H, m), 5.10 (1H, m), 5.68 (1H, m),
6.72 (1H, s), 7.30 to 7.80 (5H, m) Reference Example 17 Disodium 7β- [2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamide] -3
-[5-carboxylate methyl-4- (4-hydroxyphenyl) thiazol-2-yl) thiomethyl-3-
Preparation of cephem-4-carboxylate (syn isomer) Benzhydryl 3-iodomethyl-7β- [2-methoxyimino-2- (2-tritylaminothiazole-
4-yl) acetamido] -3-cephem-4-carboxylate (syn isomer) 450 mg (0.48 mmol) and 5-benzhydryloxycarbonylmethyl-4- [4]
-(2-Methoxyethoxymethoxy) phenyl] -2-
The same procedure as in Example 1 was carried out using 250 mg (0.48 mmol) of mercaptothiazole to give 105 mg of the title compound (yield 3
1%).

MP: 200-205 ℃ (decomposition) NMR (DMSO-d ₆ ) δ: 3.85 (3H, s), 4.25 (1H, d, J = 12H
z), 4.62 (1H, d, J = 12Hz), 5.00 (1H, d, J = 5.0Hz), 5.6
8 (1H, m), 6.72 (1H, s), 6.80 (2H, d, J = 8.0Hz), 7.46
(2H, d, J = 8.0Hz), 9.55 (1H, m) Reference Example 18 Disodium 3- [4- (4-acetoxyphenyl) -5-carboxylate methylthiazol-2-yl] thiomethyl-7β- [ 2- (2-Aminothiazol-4-yl) -2-methoxyiminoacetamide] -3
-Preparation of cephem-4-carboxylate (syn isomer) Benzhydryl 3-iodomethyl-7β- [2-methoxyimino-2- (2-tritylaminothiazole-
4-yl) acetamido] -3-cephem-4-carboxylate (syn isomer) 1.0 g (1.07 mmol) and (4-acetoxyphenyl) -5-4-benzhydryloxycarbonylmethyl-2-mercaptothiazole 0 .
The same operation as in Example 1 was performed using 51 g (1.07 mmol) to obtain 202 mg (yield 25%) of the title compound.

MP: 180-185 ℃ (decomposition) _{NMR (DMSO-d 6) δ} : 2.30 (6H, s), 3.83 (3H, s) 4.10
~ 4.48 (2H, m), 5.02 (1H, d, J = 5.0Hz), 5.60 (1H,
m), 6.78 (1H, s), 7.18 (1H, d, J = 8.0Hz), 7.78 (1
H, d, J = 8.0 Hz) Reference Example 19 Trisodium 7β- [2- (2-aminothiazol-4-yl) -2- (1-carboxylate-1-methylethoxyimino) acetamide] -3- [ 5-carboxylate methyl-4- (4-hydroxyphenyl)
Thiazol-2-yl] thiomethyl-3-cephem-4
-Production of carboxylate (syn isomer) Benzhydryl 7β- [2- (1-benzhydryloxycarbonyl-1-methylethoxyimino) -2-
(2-Tritylaminothiazol-4-yl) acetamido] -3-iodomethyl-3-cephem-4-carboxylate (syn isomer) 584 mg (0.50 mmol) and 5-benzhydryloxycarbonylmethyl-2-mercapto- 4- [4- (2-methoxyethoxymethoxy)
The same procedure as in Example 1 was carried out using 250 mg (0.48 mmol) of phenyl] thiazole to give 104 mg of the title compound (yield 2
6%).

MP: 170-175 ℃ (decomposition) NMR (DMSO-d ₆ ) δ: 1.42 (3H, br s), 1.46 (3H, br
s), 4.10 to 4.70 (2H, m), 5.00 (1H, d, J = 5.0Hz), 5.66
(1H, d, J = 5.0Hz), 6.75 (1H, s), 6.86 (2H, d, J = 8.0H
z), 7.48 (2H, d, J = 8.0Hz) Reference Example 20 Trisodium 3- [4- (4-acetoxyphenyl) -5-carboxylate methylthiazol-2-yl] thiomethyl-7β- [2- ( 2-Aminothiazol-4-yl) -2- (1-carboxylate-1-methylethoxyimino) acetamido] -3-cephem-4
-Production of carboxylate (syn isomer) Benzhydryl 7β- [2- (1-benzhydryloxycarbonyl-1-methylethoxyimino) -2-
(2-Tritylaminothiazol-4-yl) acetamido] -3-iodomethyl-3-cephem-4-carboxylate (syn isomer) 1.2 g (1.03 mmol) and 4
-(4-acetoxyphenyl) -5-benzhydryloxycarbonylmethyl-2-mercaptothiazole 0.49
The same operation as in Example 1 was carried out using g (0.49 mmol) to obtain 247 mg of the title compound (yield 29%).

MP: 180-185 ℃ (decomposition) NMR (DMSO-d ₆ ) δ: 1.44 (3H, br s), 1.48 (3H, br
s), 2.32 (6H, s), 4.10 ~ 4.48 (2H, m), 5.02 (1H, m),
5.68 (1H, m), 6.80 to 7.80 (5H, m) Reference Example 21 Sodium 7β- [2- (2-aminothiazole-
4-yl) -2-methoxyiminoacetamide] -3-
(5-Phenyloxazol-2-yl) thiomethyl-
Preparation of 3-cephem-4-carboxylate (syn isomer) Benzhydryl 3-chloromethyl-7β- [2-methixiimino-2-(-2tritylaminothiazole-
4-yl) acetamido] -3-cephem-4-carboxylate (syn isomer) 600 mg (0.71 mmol), sodium iodide 160 mg (1.07 mmol) and 2-mercapto-5-phenyloxazole 130 mg (0.72 mmol) were used. Then, perform the same operation as in Example 65 to obtain the title compound
70 mg (yield 7.1%) are obtained.

MP: 180 ℃ (decomposition) NMR (DMSO-d ₆ ) δ: 3.40 to 3.65 (2H, m), 3.83 (3H,
s), 4.32 (2H, m), 5.03 (1H, d, J = 4.5Hz), 5.63 (1H, d,
J = 4.5 Hz), 6.80 (1H, s), 7.30 to 7.75 (6H, m) Reference Example 22 Disodium 7β- [2- (2-aminothiazol-4-yl) -2- (1-carboxylate- 1-Methylethoxyimino) acetamido] -3- (5-phenyloxazol-2-yl) thiomethyl-3-cephem-4-carboxylate (syn isomer) Benzhydryl 7β- [2- (1-benzhydryl) Oxycarbonyl-1-methylethoxyimino) -2-
(2-Tritylaminothiazol-4-yl) acetamido] -3-iodomethyl-3-cephem-4-carboxylate (syn isomer) 850 mg (0.72 mmol), and 2-mercapto-5-phenyloxazole 130 mg
(0.72 mmol) was used to carry out the same operation as in Example 1 to obtain 70 mg (yield 15.7%) of the title compound.

MP: 180 ℃ (decomposition) _{NMR (DMSO-d 6 / D} 2 O) δ: 1.43 (6H, m), 3.30~3.70
(2H, m), 4.37 (2H, m), 5.03 (1H, d, J = 4.5Hz), 5.65
(1H, d, J = 4.5Hz), 6.75 (1H, s), 7.25 to 7.80 (6H, m) Reference Example 23 Sodium 7β- [2- (2-aminothiazole-
4-yl) -2-methoxyiminoacetamide] -3-
[5- (4-hydroxyphenyl) oxazole-2-
Illy] thiomethyl-3-cephem-4-carboxylate (syn isomer) Benzhydryl 3-chloromethyl-7β- [2-methoxyimino-2- (2-tritylaminothiazole-
4-yl) acetamido] -3-cephem-4-carboxylate (syn isomer) 840 mg (1.0 mmol), sodium iodide 225 mg (1.5 mmol) and 5- (4-hydroxyphenyl) -2-mercaptooxazole 193 mg
The same operation as in Example 65 is performed using (1.0 mmol) to obtain 55 mg (yield 9.0%) of the title compound.

MP: 195 ℃ (decomposition) _{NMR (DMSO-d 6 / D} 2 O) δ: 3.30~3.70 (2H, m), 3.83
(3H, s), 4.32 (2H, br s), 5.01 (1H, d, J = 4.5Hz), 5.6
3 (1H, d, J = 4.5Hz), 6.78 (1H, s), 6.88 (2H, d, J = 9.0H
z), 7.40 (1H, s), 7.50 (2H, d, J = 9.0Hz) Reference Example 24 Disodium 7β- [2- (2-aminothiazol-4-yl) -2- (1-carboxylate- 1-Methylethoxyimino) acetamide] -3- [5- (4-
Preparation of hydroxyphenyl) oxazol-2-yl] thiomethyl-3-cephem-4-carboxylate (syn isomer) Benzhydryl 7β- [2- (1-benzhydryloxycarbonyl-1-methylethoxyimino) -2-
(2-Tritylaminothiazol-4-yl) acetamido] -3-iodomethyl-3-cephem-4-carboxylate (syn isomer) 1.0 g (0.85 mmol) and (5- (4-hydroxyphenyl) -2- The same procedure as in Example 1 was performed using 173 mg (0,89 mmol) of mercaptooxazole to obtain 39 mg of the title compound (yield 7.3%).

MP: 190 ℃ (decomposition) _{NMR (DMSO-d 6 / D} 2 O) δ: 1.40 (6H, br s), 3.35~3.
60 (2H, m), 4,25 to 4.55 (2H, m), 5.00 (1H, d, J = 4.5H
z) 5.63 (1H, m), 6.65 ~ 7.00 (3H, m), 7.20 ~ 7.55 (3H,
m) Reference Example 25 Preparation of 2-mercapto-5- [3,4-di (2-methoxyethoxymethoxy) phenyl] -1,3,4-oxadiazole (A) 2.5 g (14.9 mmol) of methyl protocatechuate Is suspended in 50 ml of methylene chloride, and 7.84 ml (45 mmol) of ethyldiisopropylamine is added at 0 ° C. to make a homogeneous solution. 2-
5.8 ml (45 mmol) of methoxyethoxymethyl chloride was added dropwise, and after stirring for 30 minutes, the reaction solution was washed successively with water, 0.5N sodium hydroxide aqueous solution and saturated saline. The aqueous layer was extracted twice each with methylene chloride, the organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give methyl 3,4-di (2-methoxyethoxymethoxy) benzoate. 5.1 g (99% yield) are obtained.

NMR (CDCl ₃ ) δ: 3.32 (3H, s), 3.34 (3H, s), 3.55 (4
H, m), 3.83 (4H, m), 3.86 (3H, s), 5.32 (4H, m), 7.18
(1H, d, J = 9Hz), 7.67 (1H, dd, J = 2 and 9Hz), 7.79 (1
H, d, J = 2Hz).

(B) 5.1 g (15 mmol) of the compound obtained in the above reaction (A) was dissolved in 100 ml of methanol to obtain 40 ml of hydrazine hydrate (80 ml).
mmol), and after heating under reflux for 1 hour, 40 ml of 80% hydrazine hydrate is further added, and the mixture is heated under reflux for 2 hours again. After cooling the reaction mixture, it is poured into water and extracted three times with ethyl acetate. The extract is washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 4.2 g of crude 3,4-di (2-methoxyethoxymethoxy) benzoic acid hydrazide.

(C) To 42 ml of an ethanol solution containing 1.27 g (18 mmol; 1.0 g of potassium hydroxide and 0.27 ml of water) of 80% potassium hydroxide, 4.2 g (12 mmol) of the compound obtained in the above reaction (B) and carbon disulfide
Add 3.64 ml (61 mmol) and heat to reflux for 1 hour. After evaporating the solvent under reduced pressure, the residue was dissolved in water and the pH was adjusted to 1.5 with 1N hydrochloric acid.
And extracted 3 times with ethyl acetate. The organic layer is washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (Wakogel C-300, ethyl acetate: hexane = 3: 1).
The title compound (3.03 g, yield 52.3%) is obtained.

MP: 84 ℃ NMR (DMSO-d ₆ ) δ: 3.27 (6H, s), 3.51 (4H, m), 3.80
(4H, m), 5.38 (2H, s), 5.39 (2H, s), 7.32 (1H, d, J = 6
Hz), 7.54 (1H, dd, J = 1.8 and 6Hz) 7.62 (1H, d, J = 1.8H)
z) Elemental analysis value: Calculated as C ₁₆ H ₂₂ N ₂ O ₇ S (%): C, 49.73; H, 5.74; N, 7.25; S, 8.30 Actual value (%): C, 49.66; H, 5.85 ; N, 7.10; S, 8.24 Reference Example 26 7β-amino-3- [5- (3,4-dihydroxyphenyl) -1,3,4-oxadiazol-2-yl] thiomethyl-3-cephem-4 -Production of carboxylic acid (A) 19.8 g (0.353 mol) of potassium hydroxide was dissolved in 5.1 ml of water and 830 ml of ethanol, and 39.6 g (0.236 mol) of 3,4-dihydroxybenzoic acid hydrazide and 99 ml (1.6 ml of carbon disulfide).
(5 mol) and heat to reflux for 24 hours. After stirring under ice cooling for 1.5 hours, the precipitated crystals are collected by filtration and washed with 200 ml of ethanol. This crystal was dissolved in 3 liters of water, and with ice cooling with 6N hydrochloric acid.
Adjust to pH 1.5 and extract with 1 and 400 ml of ethyl acetate. The organic layers were combined, washed with 300 ml of saturated saline solution (twice), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 2-mercapto-5- (3,4-dihydroxyphenyl) -1,3,4-oxa. 42.8 g of diazole (yield 86.5%) is obtained.

MP: 225-230 ℃ (decomposition) NMR (DMSO-d ₆ ) δ: 6.92 (1H, d, J = 9Hz), 7.24 (1H, d, J = 9Hz), 7.28 (1H, s), 9.53 (1H, br)
s), 9.80 (1H, br s), 14.40 (1H, br s) (B) 7β-aminocephalosporanic acid 16.3 g (60 mmol), 2-mercapto-5- (3,4) in 520 ml of acetonitrile.
-Dihydroxyphenyl) -1,3,4-oxadiazole 1
3.9 g (66 mmol) and 45.4 ml (360 mmol) of boron trifluoride diethyl ether complex are added and stirred at 50 ° C. for 3 hours. After cooling the reaction solution, it is poured into 450 ml of cold water and stirred at room temperature for 1 hour. Adjust the pH to 2.0 with 25% ammonia water,
After stirring at 5 ° C or lower for 1 hour, the precipitate was collected by filtration, washed with water and ethyl acetate, and dried to give 21.3 g of the title compound (yield 84.1
%).

MP: 188 ~ 193 ℃ (decomposition) NMR (DMSO-d ₆ ) δ: 3.68 (2H, ABq), 4.31 (2H, ABq),
4.78 (1H, d, J = 4.5Hz), 4.98 (1H, d, J = 5Hz), 6.89 (1
H, d, J = 9Hz), 7,27 (1H, d, J = 9Hz), 7.33 (1H, s) Reference Example 27 2-{[α-benzhydryloxycarbonyl-3,4
-Di (2-methoxyethoxymethoxy) benzyl] oxyimino] -2- (2-tritylaminothiazole-4
-) Production of acetic acid (syn isomer) (A) A suspension of 88 g (0.8 mol) of catechol and 109.5 g (about 0.5 mol) of 40% aqueous glyoxylic acid solution in a nitrogen stream under ice-cooling 48 g of sodium hydroxide ( 500 ml of an aqueous solution containing 1.2 mol)
After dripping, the mixture is heated at 40 ° C. for 5 hours. The reaction mixture was cooled to 6N under ice cooling.
The pH is adjusted to 2.0 with hydrochloric acid, unreacted catechol is extracted with ethyl acetate, and then the aqueous layer is dried under reduced pressure. The residue was dissolved in N, N-dimethylformamide (700 ml) and potassium carbonate (276 g) was added.
(2 mol), potassium iodide 10 g (60 mmol) and benzyl chloride 230 ml (2 mol) are added, and the mixture is stirred at room temperature for 15 hours and further at 40 ° C. for 8 hours. The reaction solution is poured into ice water (1.5 L), extracted with ethyl acetate, and then washed with water and saturated saline. The extract was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain a crude oily residue containing crude benzyl 3,4-dibenzyloxymandelate. To this residue was added 200 ml of an aqueous solution containing methanol 1 and 60 g of sodium hydroxide, and the mixture was stirred at room temperature for 5 hours. The reaction mixture is concentrated under reduced pressure, ice water 1 is added to the residue, the pH is adjusted to 2.0 with concentrated hydrochloric acid, and the mixture is extracted with ethyl acetate. The extract is dried over anhydrous sodium sulfate and then concentrated under reduced pressure. After cooling, the precipitated crystals were collected and washed with isopropyl ether to give 3,4-dibenzyloxymandelic acid 83%
(Yield 45.5%) is obtained.

NMR (DMSO-d ₆ ) δ: 4.95 (1H, s), 5.10 (4H, s), 6.99
(2H, s), 7.17 (1H, s), 7.40 (10H, br s) (B) Compound obtained in the above reaction (A) 2.00 g (5.49 mmol)
Is dissolved in 20 ml of tetrahydrofuran, 0.50 g of 10% palladium-carbon catalyst is added, and catalytic hydrogenation is performed at room temperature for 1.5 hours. The catalyst was filtered off and the filtrate was filtered with diphenyldiazomethane 1.20.
Add g (6.1 mmol) and stir at room temperature for 12 hours. The solvent is distilled off under reduced pressure, the residue is dissolved in ethyl acetate and washed with 5% aqueous sodium hydrogen carbonate. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain 1.38 g of crude 3,4-dihydroxymandelic acid (yield 76%), which was used in the next reaction without purification.

_{NMR (DMSO-d 6) δ} : 5.09 (1H, d, J = 4Hz), 5.86 (1H,
d, J = 4Hz), 6.60 ~ 6.90 (3H, m), 6.76 (1H, s), 7.00 ~
7.60 (10H, m) (C) 6.9 g (corresponding to 19.7 mmol) of the compound obtained in the above reaction (B) is dissolved in 140 ml of methylene chloride, 13.8 ml (79 mmol) of diisopropylethylamine is added, and the mixture is cooled to 0 ° C.
8.9 ml of 2-methoxyethoxymethyl chloride in this solution
(79 mmol) is added dropwise and the mixture is stirred for 1 hour. The reaction solution is washed with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution and saturated saline, dried over anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (Wakogel C-300), and the elution fraction containing the desired product (ethyl acetate: hexane = 2: 1) was concentrated to give 3,4-di (2-methoxyethoxymethoxy). 6.0 g (58% yield) of benzhydryl mandelate are obtained.

NMR (DMSO-d ₆ ) δ: 3.22 (6H, s) 3.45 (4H, m), 3.75
(4H, m), 5.18 (2H, s), 5.22 (2H, s), 5.25 (1H, d, J = 5
Hz), 6.22 (1H, d, J = 5Hz), 6.78 (1H, s), 6.90 to 7.60
(13H, m) (D) 5.0 g (9.5 mmol) of the compound obtained in the above reaction (C) was dissolved in 100 ml of methylene chloride, and 4.35 ml (55.0 mmo of pyridine).
l) is added, and a solution of 1.2 ml (16.5 mmol) of thionyl chloride and 12 ml of methylene chloride is added dropwise at 0 ° C. After stirring for 30 minutes,
The reaction mixture is poured into 10% aqueous sodium hydrogen carbonate and extracted with methylene chloride. After drying the organic layer, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (Wakogel C-
300), and the elution fraction containing the target compound (ethyl acetate: hexane = 1: 1) was concentrated to give 2-chloro-2- [3,4-di (2-methoxyethoxymethoxy) phenyl] acetate benzhydryl. 3.35 g (yield 65%) is obtained and immediately used for the next reaction.

(E) 9.0 g (16.5 mmol) of the compound obtained in the above reaction (D)
Dissolve in 90 ml of N, N-dimethylformamide, add 31 ml of N, N-dimethylformamide solution containing 3.1 g (19 mmol) of N-hydroxyphthalimide and 2.68 ml (19 mmol) of triethylamine to this solution at 0 ° C., and then at room temperature. Stir for 12 hours. The reaction mixture is poured into 10% aqueous sodium hydrogen carbonate, extracted three times with ethyl acetate, washed with saturated brine, dried, and the solvent is evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (Wako Gel C-300), and the elution fraction containing the desired product (ethyl acetate: hexane = 3: 1) was concentrated to give N-
{[Α-Benzhydryloxycarbonyl-3,4-di (2-methoxyethoxymethoxy) benzyl] oxy}
9.75 g (yield 88%) of phthalimide is obtained.

NMR (DMSO-d ₆ ) δ: 3.20 (6H, s), 3.38 (4H, m), 3.70
(4H, m), 5.15 (2H, s), 5.20 (2H, m), 5.95 (1H, s), 6.
83 (1H, s), 7.00 to 7.50 (13H, m), 7.78 (4H, s) (F) 9.75 g (14.5 mmol) of the compound obtained in the above reaction (E)
Is dissolved in 100 ml of methylene chloride and 80% hydrazine hydrate 3.1 is added.
45 ml of a methanol solution containing 2 ml (49 mmol) is added dropwise at 0 ° C. The reaction solution is stirred for 15 minutes, the precipitate is filtered off, and the filtrate is dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, the residue was subjected to silica gel column chromatography (Wakogel C-300), and the elution fraction containing the desired product (ethyl acetate: hexane = 1: 3) was concentrated to give O- [ α
5.1 g (65% yield) of benzhydryloxycarbonyl-3,4-di (2-methoxyethoxymethoxy) benzyl] hydroxylamine are obtained.

NMR (DMSO-d ₆ ) δ: 3.20 (6H, s), 3.38 (4H, m), 3.72
(4H, m), 5.14 (3H, s), 5.22 (2H, s), 6.38 (2H, br
s), 6.80 (1H, s), 7.00 to 7.50 (13H, m) (G) 5.1 g (9.4 mmol) of the compound obtained in the above reaction (F) was dissolved in 50 ml of methanol, and 2- (2- Tritylaminothiazol-4-yl) glyoxylic acid 3.5 g (8.5 m
mol) and 41 ml of methanol are added. After stirring for 15 minutes, the white precipitate formed was collected by filtration, washed with methanol,
Dry to obtain 4.87 g (55% yield) of the title compound.

NMR (DMSO-d ₆ ) δ: 3.20 (6H, s), 3.38 (4H, m),
3.72 (4H, m), 5.15 (2H, s), 5.26 (2H, br s), 5.26
(2H, br s), 5.77 (1H, s), 6.85 (2Hms), 6.90−7.70
(28H, m), 8,80 (1H, br s) Reference Example 28 Preparation of 2-mercapto-5- [3,4-di (2-methoxyethoxymethoxy) phenyl] -1,3,4-thiazoazole ( A) 15.0 g (50.7 mmol) 3,4-di (2-methoxyethoxymethoxy) benzonitrile are dissolved in 15.0 ml pyridine and 7.5 ml (50 mmol) triethylamine are added. Hydrogen sulfide gas was introduced into this solution at room temperature for 6 hours with stirring. Ethyl acetate and water are added to the reaction solution, the organic layer is separated, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 18.8 g (yield 100%) of crude 3,4-di (2-methoxyethoxymethoxy) thiobenzamide, which was used for the next reaction without purification.

(B) 2.0 g (5.8 mmol) of the compound obtained in the above reaction (A) is dissolved in 20.0 ml of ethanol, 0.40 ml of hydrazine hydrate is added, and the mixture is stirred at 70 ° C. for 1 hour. Potassium hydroxide in the reaction solution
Add 0.40 g (5.70 mmol) and 1.38 ml (18 mmol) carbon disulfide and reflux for 20 minutes. The solvent is distilled off under reduced pressure, the residue is dissolved in water and washed with ethyl acetate. Aqueous layer was adjusted to pH3 with 2N hydrochloric acid.
After adjusting to 0, it is extracted with ethyl acetate and dried over anhydrous sodium sulfate. The solvent is distilled off under reduced pressure, and the crystal residue is washed with ether to obtain 0.94 g (yield 40%) of the title compound.

NMR (DMSO-d ₆ ) δ: 3.25 (6H, s), 3.50 (4H, m) 3.78
(4H, m), 5.34 (4H, br s), 7.26 (1H, d, J = 8Hz) 7.33
(1H, dd, J = 1 and 8Hz), 7.52 (1H, d, J = 1Hz) Elemental analysis value as C ₁₆ H ₂₂ N ₂ O ₈ S ₂ (%) Calculated value: C, 47.75 H, 5.51 N , 6.96 S, 15.93 Example: C, 47.75 H, 5.44 N, 6.94 S, 15.72 Reference Example 29 Preparation of 5- (3,4-dihydroxyphenyl) -2-mercapto-1,3,4-thiadiazole (A) 400 g of ethanol with 10 g (178 mmol) of potassium hydroxide
20 g (119 mmol) of protocatechuic acid hydrazide are added at a temperature of 5 ° C. or lower with stirring. To this solution, 10 ℃
Below, carbon disulfide (28.0 ml) is added dropwise over 10 minutes at 0-10 ° C.
After stirring for 30 minutes, the precipitate was collected by filtration, washed with ethanol and dried to obtain 25.3 g (yield 75.3%) of potassium 3-protocatechueyldithiocarbazate.

(B) 25.3 g (89.6 mmol) of the compound obtained in the above reaction (A)
Is added little by little to 125 ml of concentrated sulfuric acid at 10 ° C or lower over 20 minutes, and then stirred at 10 ° C for 20 minutes. 600 g of ice and water
After adding little by little to 300 ml, the mixture was stirred for another 10 minutes, and the precipitate was collected by filtration. Dissolve this precipitate in 125 ml of acetone,
Add 600 ml of ethyl acetate, 20 ml of water and 1 g of activated carbon and stir for 15 minutes. After removing the activated carbon by filtration, the filtrate is washed successively with 200 ml of a 5% sodium thiosulfate aqueous solution, 150 ml of water and saturated saline. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off, and the crystal residue was washed with ether to give the title compound 3.
6 g (yield 17.8%) are obtained.

NMR (DMSO-d ₆ ) δ: 6.82 (1H, d, J = 9Hz), 7.01 (1H, d
d, J = 2 and 9Hz), 7.13 (1H, d, J = 2Hz), 9.50 (2H, br
s), 14.38 (1H, br s) Reference Example 30 Preparation of 4- (3,4-dihydroxyphenyl) -2-mercaptothiazole 2-chloro-3′4′-dihydroxyacetophenone
After dissolving 10.0 g (53.6 mmol) in 100 ml of methanol, add 5.90 g (53.6 mmol) of ammonium dithiocarbamate and stir at room temperature for 30 minutes. The solvent is distilled off under reduced pressure, water is added to the residue to adjust the pH to 2.0, and the mixture is extracted twice with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated, and the crystal residue was washed with ether to give the title compound (8.80 g).
(Yield 72.9%) is obtained.

MP: 236 ℃ (Recrystallization solvent; ethyl acetate) _{NMR (DMSO-d 6) δ} : 6.77 (1H, d, J = 9Hz), 6.92 (1H,
s), 7.03 (1H, dd, J = 2 and 9Hz), 7.08 (1H, d, J = 2H
z), 9.15 (1H, m) Elemental analysis value: Calculated value as C ₃ H ₇ NO ₂ S ₂ (%): C, 47.98; H, 3.13; N, 6.21; S, 28.47 Actual value (%): C , 48.07; H, 3.02; N, 6.22; S, 28.16 Reference Example 31 Preparation of 4-carboxy-5- (3,4-dihydroxyphenyl) -2-mercaptothiazole (A) Organic synthes starting from 60.1 g of piperonal (Org.Syn.), Coll. Vol.II, pp. 1-3, 11
-12, 519 ~ 520, the same procedure as described,
(3,4-Methylenedioxyphenyl) pyruvic acid 48.3g
(Yield 58%) is obtained.

NMR (DMSO-d ₆ ) δ: 6.03 (2H, s), 6.38 (1H, s), 6,87
(1H, d, J = 7.5Hz), 7.23 (1H, d, J = 7.5Hz), 7.46 (1H,
s), 9.00 (2H, s) (B) 10.4 g (0.05 mol) of the compound obtained in the above reaction (A)
Was suspended in 100 ml of ethyl acetate, and 2.56 ml (0.0
(5 mol) and stirred at the same room temperature for 30 minutes. 200 ml of ethanol was added to the reaction solution, 9.92 g (0.09 mol) of ammonium dithiocarbamate was added at -10 ° C, and the mixture was stirred at room temperature for 20 minutes and at room temperature for 2 hours. The reaction solution was cooled in an ice bath for 40 minutes, the insoluble material was filtered off, and the insoluble material was washed with ethyl acetate (40 ml).
Wash with. The filtrate and washings are combined and concentrated under reduced pressure.
After adding 350 ml of water to the residue and heating at 80 ° C for 18 hours, the gum-like insoluble matter is filtered off while hot. The filtrate was cooled to pH 1 with 6N hydrochloric acid at pH 1.
5, the precipitate is filtered off, washed with 30 ml of water and dried to give 7.23 g of the title compound as a yellow powder.

Further, the above gum-like insoluble matter is suspended in 20 ml of acetone, the insoluble matter is filtered and dried to obtain 1.02 g of secondary crystals. Total yield 8.25g
(Yield 66%).

NMR (DMSO-d ₆ ) δ: 6.10 (2H, s), 6.97 (2H, s), 7.12
(1H, s), 12.0-15.0 (2H, br s) (C) The compound (6.99 g, 0.024 mol) obtained in the above reaction (B) was suspended in 180 ml of methylene chloride and 13 ml of ethanethiol and dried at 5 ° C. 16.0 g (0.12 mol) of aluminum chloride is added, and the mixture is stirred at the same temperature for 4 hours and at 10 ° C for 24 hours. After adding 100 ml of 6N hydrochloric acid under ice cooling, the mixture is stirred at the same temperature for 1.5 hours. The insoluble matter was collected by filtration, washed with 50 ml of water × 2 and dried to obtain 5.35 g of a crude product, which was recrystallized from a mixed solvent of methanol and water to give 3.93 g of the title compound as yellow needles (yield 61 %).

MP: 245-247 ℃ (decomposition) NMR (DMSO-d ₆ ) δ: 5.00 to 7.50 (2H, br s), 6.79 (2
H, s), 6.90 (1H, s), 8.00 to 10.0 (2H, br s) UV mm (E): 309.5 (480), 340.5 (481) Reference Example 32 4- (3,4-diacetoxyphenyl) Preparation of 5-benzhydryloxycarbonylmethyl-2-mercaptothiazole (A) Succinic anhydride 70 g (0.7 mol) and veratrol 96.6 g
Dissolve (0.7 mol) in 2000 ml of methylene chloride, add 237 g (1.75 mol) of anhydrous aluminum chloride at room temperature, and add 6 at the same temperature.
Stir for hours. The reaction solution is allowed to stand for 15 hours, 1600 ml of 6N hydrochloric acid is added dropwise with stirring, and the mixture is further stirred for 1 hour. Separate the organic layer, add 300 ml of water, adjust to pH 7.5 with saturated aqueous sodium hydrogen carbonate,
Separate the aqueous layer. The aqueous layer was adjusted to pH 2.5 with 6N hydrochloric acid and left in the refrigerator for 2 days, then the precipitated crystals were collected by filtration, washed with water and dried to give 3- (3,4-dimethoxybenzoyl) propionic acid 106.8.
g (64% yield) are obtained.

NMR (DMSO-d ₆ ) δ: 2.56 (2H, t, J = 6.0Hz), 3.21 (2
H, t, J = 6.0Hz), 3.93 (3H, s), 3.95 (3H, s), 7.04 (1H,
d, J = 8.7Hz), 7.45 (1H, d, J = 1.5Hz), 7.67 (1H, dd, J =
1.5 and 4.5 Hz), 11.0-12.5 (1H, br) (B) 1070 ml of 48% hydrobromic acid is added to 106 g (0.445 mol) of the compound obtained in the above reaction, and the mixture is boiled under reflux for 5 hours. The solvent was distilled off under reduced pressure, and 1000 ml of water was added to the residue. After dissolving by heating, the mixture is treated with activated carbon, and the filtrate is kept cold overnight to obtain blackish brown crystals. The colored crystals were dissolved in 1000 ml of water while hot, treated twice with activated carbon, and then kept cold overnight to give 37.2 g of 3- (3,4-dihydroxybenzoyl) propionic acid as colorless plate crystals (yield: 39.8
%).

NMR (DMSO-d ₆ ) δ: 2.53 (2H, t, J = 6.2Hz), 3.12 (2
H, t, J = 6.2Hz), 6.82 (1H, d, J = 8.2Hz), 7.30 ~ 7.50
(2H, m), 9.00 to 10.50 (2H, br), 11.30 to 12.80 (1H, b
r) (C) To 2.0 g (9.52 mmol) of the compound obtained in the above reaction (B), 9.0 ml of acetic anhydride and 0.78 g (9.5 mmol) of sodium acetate are added, and the mixture is heated under reflux for 30 minutes. The solvent is distilled off under reduced pressure, ethyl acetate is added to the residue, washed with 5% aqueous sodium hydrogen carbonate, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure,
The residue is subjected to silica gel column chromatography (Wakogel
C-300, 2% methanol / methylene chloride)
(3,4-diacetoxyphenyl) -2 (3H) -furanone
1.33 g (yield 50%) is obtained.

NMR (DMSO-d ₆ ) δ: 2.30 (6H, s), 3.58 (2H, m), 6.24
(1H, m), 7.30 to 7.60 (3H, m) (D) 300 mg (1.08 mol) of the compound obtained in the above reaction (C) was dissolved in 8 mg of a mixed solvent of dioxane / water (3: 1), and the mixture was stirred at room temperature. Add 193 mg of N-bromosuccinimide and stir for 15 minutes. The reaction solution is poured into ethyl acetate, the organic layer is dried over anhydrous magnesium sulfate, 300 mg (1.54 mmol) of diphenyldiazomethane is added to the filtrate, and the mixture is stirred for 1 hour.
The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (Wakogel C-300, ethyl acetate: hexane = 1: 3) to give 3- (3,4-diacetoxybenzoyl) -3-bromo. Benzhydryl propionate 350mg
(Yield 60%) is obtained.

NMR (DMSO-d ₆ ) δ: 2.33 (6H, s), 3.20 to 3.80 (2H,
m), 6.00 (1H, t, J = 8.0Hz), 6.80 (1H, s), 7.10 to 7.60
(13H, m) (E) 700 mg (1.30 mmol) of the compound obtained in the above reaction was added to N, N-
Dissolve in 7.0 ml of dimethylformamide and add 143 mg (1.30 mmol) of ammonium dithiocarbamate under ice cooling.
Stir for minutes. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (Wakoegl C-300, ethyl acetate: hexane = 1: 2) to give 470 mg of the title compound.
(Yield 68%) is obtained.

NMR (DMSO-d ₆ ) δ: 2.30 (6H, s), 3.00 (2H, m), 4.40
(1H, brt, J = 7.0Hz), 6.78 (1H, s), 7.10 to 7.60 (13H,
m) Reference Example 33 Preparation of 5- (3,4-dihydroxyphenyl) -2-mercaptooxazole (A) 2-Chloro-3 ', 4'-dihydroxyacetophenone 10 g (53.6 mmol) was dissolved in acetone 50 ml to give iodine. 600 mg (4.0 mmol) sodium azide and 5.23 g (80.5 mmol) sodium azide are added and refluxed for 24 hours.
The insoluble matter in the reaction solution is filtered off, and concentrated under reduced pressure. Ethyl acetate is added to the reaction solution, washed with water and saturated brine in that order, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, the oily residue was dissolved in 100 ml of methanol and 13.6 ml of concentrated hydrochloric acid, 1.5 g of 10% palladium carbon catalyst was added, and the mixture was heated and stirred at 40 ° C. for 5 hours in a hydrogen gas stream. The reaction solution is filtered and the filtrate is concentrated under reduced pressure. Acetone is added to the concentrated residue, and the precipitated crystals are collected by filtration to obtain 5.5 g of 2-amino-3 ', 4'-dihydroxyacetophenor hydrochloride (yield 50.4%).

_{NMR (DMSO-d 6 / D} 2 O) δ: 4.40 (2H, s), 6.90 (1H, d,
J = 9.0 Hz), 7.30 to 7.50 (2H, m) (B) 1.0 g (4.9 mmol) of the compound obtained in the above reaction (A) was added to a 0.0434 N sodium ethoxide ethanol solution 17 m
Suspend in 1 l, add 2.1 ml (35 mmol) of carbon disulfide,
Stir at ℃ for 20 hours. The reaction solution is poured into 50 ml of water, adjusted to pH 1.5 with 6N hydrochloric acid, stirred for 1 hour and then extracted with ethyl acetate. The organic layer is washed with water and saturated brine in this order and dried over anhydrous sodium sulfate. The solvent is distilled off under reduced pressure to obtain 750 mg of the title compound (yield 73%).

MP: 215-8 ℃ _{NMR (DMSO-d 6 / D} 2 O) δ: 6.70~6.95 (2H, m), 7.00
(1H, s), 7.42 (1H, s), Elemental analysis: Calculated as C ₉ H ₇ NO ₃ S: C, 51.12; H, 3.12; N, 6.43 Found: C, 51.67; H, 3.37; N, 6.69 Reference Example 34 Preparation of 2-mercapto-5,6-di (2-methoxyethoxymethoxy) benzimidazole (A) 4,5-Dimethoxy-1,2-dinitrobenzene 10 g (4
4 mmol) was suspended in 150 ml of 45% hydrobromic acid, and the mixture was boiled under reflux for 6 hours. The reaction solution is allowed to cool to room temperature, 500 ml of water is added, and the mixture is extracted 3 times with ethyl acetate. The organic layer is washed with 10% aqueous sodium hydrogen carbonate, dried over anhydrous sodium sulfate, and the solvent is evaporated under reduced pressure. The crystal residue was washed with methylene chloride to give 4,5-
7 g of dihydroxy 1,2-dinitrobenzene (79% yield) is obtained.

NMR (DMSO-d ₆ ) δ: 7.48 (2H.s), 8.50 (2H, br s) (B) 28 g (0.14 mol) of the compound obtained in the above reaction (A) was suspended in 280 ml of methylene chloride and allowed to stand at room temperature. Add 30 ml (0.42 mol) of ethyldiisopropylamine and dissolve. 30 ml of 2-methoxyethoxymethyl chloride (0.
(42 mol) is added dropwise and stirred for 30 minutes. The reaction solution is poured into water, the organic layer is washed with a 1N sodium hydroxide aqueous solution and saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 39 g of 4,5-di (2-methoxyethoxymethoxy) -1,2-dinitrobenzene (yield 74%).

NMR (DMSO-d ₆ ) δ: 3.23 (6H, s), 3.50 (4H, m), 3.78
(4H, m), 5.58 (4H, s), 8.01 (2H, s) (C) Compound obtained in the above reaction (B) 9.5 g (25 mmol)
Dissolved in 180 ml of ethanol, 10% palladium on carbon catalyst 1
g, and catalytic hydrogenation is carried out at 80 ° C. for 2 hours. 1 g of 10% palladium carbon catalyst is added to the reaction solution, and catalytic hydrogenation is performed under the same conditions (this operation is repeated twice). The catalyst is filtered off and the filtrate is concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (Wakogel C-300, ethyl acetate / hexane = 1: 1), and the elution fraction containing the desired product was concentrated to give 4,5-di (2-methoxyethoxymethoxy)-. 5.07 g (yield 57%) of 2-nitroaniline is obtained (because it is unstable, it is immediately used for the next reaction).

(D) 3.5 g (10 mmol) of the compound obtained in the above reaction (C)
Is dissolved in 70 ml of ethanol and a 10% palladium carbon catalyst is added.
Add 6 g and catalytic hydrogenate at 80 ° C. for 1 hour. 0.6 g of 10% palladium catalyst is added to the reaction solution, and the reduction reaction is performed under the same conditions (this operation is repeated twice). After the catalyst was filtered off, potassium 0-ethyldithicarbonate was added to the filtrate.
10 g (6.1 mmol) and 3 ml of water are added, and the mixture is boiled under reflux for 3 hours. The solvent is distilled off under reduced pressure, the residue is dissolved in water, adjusted to pH 3.0 with acetic acid, and extracted 3 times with ethyl acetate. The organic layer is dried and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (Wakogel C-300, ethyl acetate.
The mixture is subjected to hexane = 3: 1) and the eluate fraction containing the desired product is concentrated to give 2-mercapto-5,6-di (2-methoxyethoxymethoxy) benzimidazole (yield 61%).

NMR (DMSO-d ₆ ) δ: 3.25 (6H, s), 3.32 (2H, s), 3.48
(4H, m), 3.75 (4H, m), 5.20 (4H, s), 6.94 (2H, s) Reference Example 35 2-Mercapto-5,6-di (2-methoxyethoxymethoxy) -1-methylbenzo Production of imidazole (A) 1.57 g (4.54 mmol) of 4,5-di (2-methoxyethoxymethoxy) -2-nitroaniline obtained in Reference Example 34 (C) was dissolved in 16 ml of N, N-dimethylformamide,
Silver oxide 2 g (8.63 mmol) and methyl iodide 10 ml (160
Mmol) and stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (Wakogel C-300, ethyl acetate / hexane = 1: 1.
To 1), concentrate the elution fraction containing the desired product,
-Di (2-methoxyethoxymethoxy) -N-methyl-
0.85 g of 2-nitroaniline is obtained.

(B) 0.85 g of the crude product obtained in the above reaction (A) was dissolved in 16 ml of ethanol, and 0.4 g of 10% palladium carbon catalyst was added,
Perform catalytic hydrogenation at 80 ° C. for 2 hours. After filtering off the catalyst,
1 g of potassium 0-ethyldithiocarbonate (6.
25 mmol) is added and the mixture is boiled under reflux for 2 hours. The reaction solution is concentrated under reduced pressure, the residue is dissolved in water, adjusted to pH 5.0 with acetic acid and then extracted with ethyl acetate. The organic layer is dried over anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (Wako Gel C
-300, ethyl acetate-hexane = 3: 1) to give 67 mg of the title compound.

NMR (CDCl ₃ ) δ: 3.40 (6H, s), 3.60 (4H, m), 3.68 (3
H, s), 3.88 (4H, m), 5.27 (2H, s), 5.30 (2H, s), 7.02
(1H, s), 7.08 (1H, s) Reference Example 36 Preparation of 2-mercapto-5,6-di (2-methoxyethoxymethoxy) benzoxazole (A) 3,4-di (2-methoxyethoxy) Methoxy) benzaldehyde 5.4 g (17 mmol) methylene chloride 216 ml
80% m-chloroperbenzoic acid, and the mixture is boiled under reflux for 20 hours. The reaction solution was washed with aqueous sodium hydrogen carbonate and saturated brine, dried, and the solvent was evaporated under reduced pressure to give 0-formyl-3,4.
-Di (2-methoxyethoxymethoxy) phenol 4.85
g (86% yield) is obtained and used in the next reaction without purification.

NMR (CDCl ₃ / DMSO-d ₆ ) δ: 3.36 (6H, s) 3.58 (4H,
m), 3.82 (4H, m), 5.28 (4H, br s), 6.73 (1H, dd, J = 2
And 9Hz), 7.02 (1H, d, J = 2Hz), 7.29 (1H, d, J = 9Hz) (B) 4.85 g (14.7 mmol) of the compound obtained in the above reaction (A) was dissolved in 4 ml of methanol to obtain 10 %Sodium hydroxide
Add 7.0 ml (17.6 mmol) and stir at room temperature for 30 minutes. The reaction solution is poured into 1000 ml of water and washed with ethyl acetate. The aqueous layer is adjusted to pH 5.0 with 6N hydrochloric acid, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure. Dissolve the residue in 8 ml of acetic acid and add 0.70 ml of concentrated nitric acid (1
1 mmol) and stirred for 1 hour. The reaction solution is poured into ethyl acetate, washed successively with water and saturated aqueous sodium hydrogen carbonate, the organic layer is dried and concentrated. The residue was subjected to silica gel column chromatography (Wakogel C-300, ethyl acetate / hexane = 1: 3), and the elution fraction containing the desired product was concentrated to give 4,5-di (2-methoxyethoxymethoxy)-. 2-
1.51 g (29.6% yield) of nitrophenol is obtained.

NMR (DMSO-d ₆ ) δ: 3.25 (6H, s), 3.50 (4H, m), 3.76
(4H, m), 5.23 (4H, s), 6.87 (1H, s), 7.75 (1H, s) (C) 1.5 g (4.3 mmol) of the compound obtained in the above reaction (B) was dissolved in 30 ml of ethanol, 0.5g of 10% palladium carbon catalyst is added, and catalytic hydrogenation is performed at 70 ° C for 1.5 hours. After filtering off the contact, 0.36 g (4.76 mmol) of carbon disulfide and 0.35 g (5.0 mmol) of 80% aqueous potassium hydroxide solution were added to the filtrate.
And 0.78 ml (43 mmol) of water are added and the mixture is boiled under reflux for 1.5 hours. The solvent is distilled off under reduced pressure, the residue is dissolved in water, adjusted to pH 5.0 with 6N hydrochloric acid, and then extracted with ethyl acetate. The organic layer is dried and concentrated, and the residue is subjected to silica gel column chromatography (Wakogel C-300, ethyl acetate / hexane = 1: 1) to obtain 857 mg of the title compound (yield 55.5%).

NMR (DMSO-d ₆ ) δ: 3.22 (6H, s), 3.46 (4H, m), 3.75
(4H, m), 5.23 (4H, s), 7.00 (1H, s), 7.34 (1H, s) Effect of the invention The compound of the present invention is a novel compound not described in the literature, and is a sensitive and resistant Gram-positive bacterium. And Gram-negative bacteria, especially against glucose non-fermenting Gram-negative bacilli including Pseudomonas aeruginosa, has strong antibacterial activity, excellent stability against β-lactamase, and low β-lactamase inducing ability, and useful as an antibacterial agent Is.

Particularly, the compound of the present invention having a di-substituted phenyl aromatic heterocycle or a di-substituted benzene ring-fused aromatic heterocyclic thiomethyl group having two hydroxyl groups or acetoxy groups adjacent to the 3-position of the cephem nucleus is a phenyl nucleus or a condensed ring. It shows unexpectedly strong antibacterial activity against Gram-negative bacteria, which are sensitive and resistant, as compared with a compound whose benzene nucleus is unsubstituted, mono-substituted or dimethoxy-substituted (Compound of Reference Example).

 ─────────────────────────────────────────────────── ─── Continuation of front page (72) Inventor Moriaki Ishikawa 88-1 Hongo, Koshikoshi-cho, Okazaki-shi, Aichi (72) Inventor Takashi Sanyu 46-1 Ikeda, Tsutsunee-cho, Okazaki-shi, Aichi (72) Inventor Ryosuke Ushijima Aichi 14-3 Tozaki Motomachi, Okazaki City Examiner Masato Ikeda (56) References JP 54-9296 (JP, A) JP 53-130689 (JP, A)

Claims (4)

(57) [Claims] 1. A general formula [I] [In the formula, R is a linear or branched lower alkyl group which may have a substituent, a cyclic lower alkyl group, a lower alkenyl group (however, 1-carboxy-1-vinyl group is excluded) , A lower alkynyl group, an aralkyl group, a phenyl group or a 2-pyrrolidon-3-yl group, and Q is a general formula. (In the formula, R ¹ is a hydrogen atom or an acetyl group, R ² is a hydrogen atom,
A carboxyl group or a carboxymethyl group, Y represents a sulfur atom or an oxygen atom, Z represents a sulfur atom, an oxygen atom or an imino group which may be substituted by a lower alkyl group)]. , Its non-toxic salts or physiologically hydrolyzable non-toxic esters. 2. A general formula [IV] [In the formula, R ³ is a hydrogen atom or an amino protecting group, R ⁴ may have a substituent, and is a linear or branched lower alkyl group, a cyclic lower alkyl group, a lower alkenyl group, a lower alkynyl. Group, an aralkyl group, a phenyl group or a 2-pyrrolidone-3-yl group, R ⁵ represents a hydrogen atom or a carboxyl protecting group, and X represents a leaving group (provided that the substituent of R ⁴ is optionally protected. The compound represented by the formula [III] HS-Q ¹ [III] [wherein Q ¹ ′ is a compound represented by the general formula] (In the formula, R ⁶ is a hydrogen atom or a hydroxyl group protecting group, R ⁷ is a hydrogen atom, an optionally protected carboxyl group or a carboxymethyl group, Y is a sulfur atom or an oxygen atom, Z is a sulfur atom, an oxygen atom. Or an imino group which may be substituted by a lower alkyl group), or a salt thereof to act on the compound of the general formula [II] (Wherein R ³ , R ⁴ , R ⁵ and Q ¹ have the above-mentioned meanings), and a protecting group is removed, if necessary, in the general formula (I) [In the formula, R is a linear or branched lower alkyl group which may have a substituent, a cyclic lower alkyl group, a lower alkenyl group (however, 1-carboxy-1-vinyl group is excluded) , A lower alkynyl group, an aralkyl group, a phenyl group or a 2-pyrrolidon-3-yl group, and Q is a general formula. (In the formula, R ¹ is a hydrogen atom or an acetyl group, R ² is a hydrogen atom, a carboxyl group or a carboxymethyl group, Y is a sulfur atom or an oxygen atom, and Z is a sulfur atom, an oxygen atom or a lower alkyl group. Which represents a good imino group)], a process for producing a non-toxic salt or a physiologically hydrolyzable non-toxic ester thereof. 3. General formula (VI) [In the formula, R ⁵ is a hydrogen atom or a carboxyl protecting group, and Q ¹ is a general formula. (In the formula, R ⁶ is a hydrogen atom or a hydroxyl group protecting group, R ⁷ is a hydrogen atom, an optionally protected carboxyl group or a carboxymethyl group, Y is a sulfur atom or an oxygen atom, Z is a sulfur atom, an oxygen atom. Or an imino group which may be substituted with a lower alkyl group)] or a salt thereof is represented by the general formula [V] [In the formula, R ³ is a hydrogen atom or an amino protecting group, R ⁴ is an optionally substituted linear or branched lower alkyl group, a cyclic lower alkyl group, a lower alkenyl group, a lower alkynyl Group, aralkyl group, phenyl group or 2-pyrrolidon-3-yl group, (provided that the substituent of R ⁴ may be protected if necessary)] or a reaction thereof. Acylation with a sex derivative to give a compound of general formula [II] (Wherein R ³ , R ⁴ , R ⁵ and Q ¹ have the above-mentioned meanings), and a protecting group is removed, if necessary, in the general formula [I] [In the formula, R is a linear or branched lower alkyl group which may have a substituent, a cyclic lower alkyl group, a lower alkenyl group (however, 1-carboxy-1-vinyl group is excluded) , A lower alkynyl group, an aralkyl group, a phenyl group or a 2-pyrrolidon-3-yl group, and Q is a general formula. (In the formula, R ¹ is a hydrogen atom or an acetyl group, R ² is a hydrogen atom,
A carboxymethyl group, Y is a sulfur atom or an oxygen atom, Z is a sulfur atom, an oxygen atom or an imino group which may be substituted by a lower alkyl group. A method for producing a salt or a physiologically hydrolyzable non-toxic ester. 4. A compound of the formula [I] [In the formula, R is a linear or branched lower alkyl group which may have a substituent, a cyclic lower alkyl group, a lower alkenyl group (however, 1-carboxy-1-vinyl group is excluded) , A lower alkynyl group, an aralkyl group, a phenyl group or a 2-pyrrolidon-3-yl group, and Q is a general formula. (In the formula, R ¹ is a hydrogen atom or an acetyl group, R ² is a hydrogen atom,
A carboxyl group or a carboxymethyl group, Y represents a sulfur atom or an oxygen atom, Z represents a sulfur atom, an oxygen atom or an imino group which may be substituted with a lower alkyl group). An antibacterial agent containing a nontoxic salt or a physiologically hydrolyzable nontoxic ester as an active ingredient.