JPH072871A - New cephalosporin derivative or its salt - Google Patents

Abstract

PURPOSE:To obtain a new compound, having excellent antimicrobial activity against Gram-positive and Gram-negative bacteria and useful as an antimicrobial agent, etc. CONSTITUTION:This compound is expressed by formula I (R<1> is H, acyl or protecting group of amino; R<2> is H, ester residue or carboxyl-protecting group), e.g. p-methoxybenzyl-7beta-[(Z)-2-(2-tritylamino-4-thiazolyl)--2-(methoxyim ino) acetamido]-3-[(E)-1,3-butadienyl]-3-cephem-4-carboxylate. Furthermore, the compound expressed by formula I is obtained by using, e.g. a compound expressed by formula II (R<1a> is acyl or protecting group of amino; R<2>' is ester residue or carboxyl-protecting group; Y is halogen) as a starting raw material, reacting the resultant compound expressed by formula III with a base and removing a desired protecting group.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a cephalosporin derivative or a salt thereof, which is useful as a medicine, particularly as an antibacterial agent and also as a synthetic intermediate for other cephalosporin compounds.

[0002]

2. Description of the Related Art Many cephalosporin antibacterial agents have been synthesized as antibacterial agents against gram-positive and gram-negative bacteria. Among these, for example, JP-A-61-56185 describes a compound in which a but-1-ene-3-ynyl group is introduced at the 3-position of the cephalosporin skeleton. Further, JP-A-5-70466 describes a compound having a lower alkenyl group at the 3-position of the cephalosporin skeleton.

[0003]

DISCLOSURE OF THE INVENTION The present inventors have conducted diligent research on a cephalosporin derivative having excellent antibacterial activity against Gram-positive bacteria and Gram-negative bacteria. A new cephalosporin derivative having a 1,3-butadienyl group as a group was found. Further, they have found that the compound of the present invention is an excellent intermediate for the production of cephalosporin derivatives having more potent antibacterial activity by introducing or substituting various groups for Butadier group, and completed the present invention.

[0004]

That is, the present invention relates to a cephalosporin derivative represented by the following general formula (I) or a salt thereof.

[Chemical 6]

(The symbols in the formulas have the following meanings: R ¹ : a hydrogen atom, an acyl group or an amino group protecting group; R ² : a hydrogen atom, an ester residue or a carboxyl protecting group)

In the cephalosporin derivative represented by the general formula (I) or a salt thereof, preferably, R ¹ is a hydrogen atom,

[Chemical 7]

(The symbols in the formulas have the following meanings: R ^a : optionally substituted (1) one or more hetero atoms selected from sulfur atom, nitrogen atom or oxygen atom A 5- to 6-membered heterocyclic group having an atom in the ring or (2) a phenyl group or a pentadienyl group R ^b : a hydrogen atom, a protective group for a hydroxyl group, an optionally substituted lower alkyl group, a lower alkenyl group, a lower group Alkynyl group, lower cycloalkyl group or formula

[Chemical 8]

A group represented by: R ³ and R ^{4 are the} same or different and are a hydrogen atom, a methyl group or an ethyl group, or a lower alkylene group and a lower alkenylene group in which R ³ and R ⁴ are integrated. R ⁵ : Protecting group for carboxyl group X: (1) hydrogen atom, (2) optionally protected amino group or hydroxyl group, (3) lower alkyl group substituted with optionally protected hydroxyl group, or ( 4) Carboxyl group or esterified carboxyl group. ) Is a group represented by. Further preferably, R ¹ is a hydrogen atom or a formula

[Chemical 9]

(Where the symbols in the formula have the following meanings: Y: methine group (-CH =) or nitrogen atom ^Re : hydrogen atom or amino-protecting group ^Rb is as described above). .

The compound represented by the above general formula (I) is described in detail below. Unless otherwise specified in the definition of the general formulas herein, the term “lower” means a straight or branched carbon chain having 1 to 6 carbon atoms.

The "lower alkyl group" is specifically a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-group.
Butyl group, pentyl (amyl) group, isopentyl group, neopentyl group, tert-pentyl group, 1-methylbutyl group, 2-methylbutyl group, 1,2-dimethylpropyl group, hexyl group, isohexyl group, 1-methylpentyl group, 2-methylpentyl group, 3-methylpentyl group,
1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,3-dimethylbutyl group, 3,3-dimethylbutyl group, 1- Ethylbutyl group, 2-ethylbutyl group,
Examples include 1,1,2-trimethylpropyl group, 1,2,2-trimethylpropyl group, 1-ethyl-1-methylpropyl group, 1-ethyl-2-methylpropyl group and the like. Of these groups, a methyl group, an ethyl group, a propyl group, and an isopropyl group are preferable.

By "amino-protecting group" is meant in the art a protecting group that can be readily removed under mild conditions. Specifically, for example, tri (lower) alkylsilyl group such as trimethylsilyl group, formyl group, acetyl group, propionyl group, tert-butoxycarbonyl (BOC) group, methoxyacetyl group, methoxypropionyl group, benzyloxycarbonyl group, p- Examples thereof include acyl-based protecting groups such as nitrobenzyloxycarbonyl group and aralkyl-based protecting groups such as benzyl group, benzhydryl group and trityl group. The "acyl group" is a substituent at the 7-position generally used in cephalosporin derivatives,

[Chemical 10]

Is a group represented by: The symbols in the formula are as described above. Here, the amino group which may be protected in X means an amino group which may be protected by the groups mentioned in the above-mentioned "protecting group for amino group". The “optionally protected hydroxyl group” means a hydroxyl group that may be protected by a protecting group that can be eliminated under relatively mild conditions. For example, formyl group, acetyl group, chloroacetyl group, trifluoroacetyl group, methoxyacetyl group, phenoxyacetyl group, benzoyl group, benzoylformyl group, p-nitrobenzoyl group,
A hydroxyl group which may be protected by an ethoxycarbonyl group, a tetrahydropyranyl group or the like.

The "lower alkyl group substituted with an optionally protected hydroxyl group" means one in which any position of the above-mentioned lower alkyl group is substituted with an optionally protected hydroxyl group. Specific examples of the “esterified carboxyl group” include tri (lower) alkylsilyl group such as trimethylsilyl group, benzhydryl group, β
-Means a carboxyl group esterified with a methylsulfonylethyl group, a phenacyl group, a p-methoxybenzyl group, a tert-butyl group, a p-nitrobenzyl group or the like.

The "5- or 6-membered heterocyclic group having in the ring one or more heteroatoms selected from a sulfur atom, a nitrogen atom or an oxygen atom which may have a substituent" is Amino group or hydroxyl group which may be protected, or thiazolyl group which may be substituted with lower alkyl group etc., oxazolyl group, thiadiazolyl group, oxadiazolyl group, thienyl group, furanyl group, pyridyl group, pyridinyl group, pyrazyl group etc. And the bond from the ring is preferably one that originates from a carbon atom in the ring. "A phenyl group which may have a substituent or a cyclopentadienyl group" is an optionally protected amino group or a hydroxyl group, or a phenyl group which may be substituted with a lower alkyl group or a cyclopentadienyl group. Indicates an enyl group. The following are some examples of acyl groups.

[Chemical 11]

(In the formula, other symbols have the following meanings: R ^d : hydrogen atom, optionally protected amino group or hydroxyl group, or lower alkyl group. R ^b and R ^e are as described above. .)

Here, the "lower cycloalkyl group" represented by R ^b is a cyclic saturated hydrocarbon group having 3 to 6 carbon atoms, specifically, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group. Groups and the like.

The "optionally substituted lower alkyl group" means substituted with one or more halogen atoms, lower alkoxycarbonyl groups, cycloalkyl groups and the like. The cycloalkyl group may be unsubstituted or substituted with one or more lower alkyl groups, lower alkoxy groups, halogen atoms, carboxyl groups or lower alkoxycarbonyl groups.

The "lower alkyl group" is as described above, and the "lower alkoxycarbonyl group" includes methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group, butoxycarbonyl group, isobutoxycarbonyl group. Group, sec-butoxycarbonyl group, tert-butoxycarbonyl group, pentyloxy (amyloxy) carbonyl group, isopentyloxycarbonyl group, tert-pentyloxycarbonyl group, neopentyloxycarbonyl group,
Examples thereof include a 2-methylbutoxycarbonyl group, a 1,2-dimethylpropoxycarbonyl group, a 1-ethylpropoxycarbonyl group, and a hexyloxycarbonyl group, and examples of the "lower alkoxy group" include a methoxy group, an ethoxy group, and a propoxy group. , Isopropoxy group, butoxy group, isobutoxy group, sec-butoxy group, tert-
Butoxy group, pentyloxy (amyloxy) group, isopentyloxy group, tert-pentyloxy group, neopentyloxy group, 2-methylbutoxy group, 1,2-dimethylpropoxy group, 1-ethylpropoxy group, hexyloxy group, etc. Is mentioned. Also, "halogen atom"
Means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, and examples of the halogen atom-substituted lower alkyl group include a chloromethyl group, a dichloromethyl group and a chloroethyl group.

The "lower alkenyl group" has 2 to 6 carbon atoms.
Is a linear or branched alkenyl group, specifically, a vinyl group, a propenyl group, a butenyl group, a methylpropenyl group, a dimethylvinyl group, a pentenyl group, a methylbutenyl group, a dimethylpropenyl group, an ethylpropenyl group, a hexenyl group. , A dimethylbutenyl group, a methylpentenyl group and the like.

The "lower alkynyl group" is a linear or branched alkynyl group having 2 to 6 carbon atoms, and is ethynyl group, propynyl group, butynyl group, methylpropynyl group, pentynyl group, methylbutynyl group, hexynyl group. Groups and the like.

Examples of the "hydroxyl protecting group" include lower alkylsilyl groups such as trimethylsilyl group and tert-butyldimethylsilyl group; for example, methoxymethyl group, 2
Lower alkoxy lower alkyl groups such as -methoxyethoxymethyl group and (1-methoxy-1-methyl) ethyl group; for example, tetrahydropyranyl group; for example, benzyl group, p-
Methoxybenzyl group, 2,4-dimethoxybenzyl group,
Aralkyl groups such as o-nitrobenzyl group, p-nitrobenzyl group and trityl group; acyl groups such as formyl group and acetyl group; for example, tert-butoxycarbonyl group, 2-iodoethoxycarbonyl group, 2,2,2- Lower alkoxycarbonyl group such as trichloroethoxycarbonyl group; for example, 2-propenyloxycarbonyl group,
2-chloro-2-propenyloxycarbonyl group, 3-
Methoxycarbonyl-2-propenyloxycarbonyl group, 2-methyl-2-propenyloxycarbonyl group,
Alkenyloxycarbonyl groups such as 2-butenyloxycarbonyl group and cinnamyloxycarbonyl group; for example, benzyloxycarbonyl group, p-methoxybenzyloxycarbonyl group, o-nitrobenzyloxycarbonyl group, p-nitrobenzyloxycarbonyl group, etc. Aralkyloxycarbonyl group and the like, and (1-methoxy-1-methyl) ethyl group, trityl group and the like are particularly preferable. In the description of R ³ and R ^{4 in} R ^b , the “lower alkylene group and lower alkenylene group in which R ³ and R ⁴ are integrated” is specifically a methylene group, an ethylene group, a propylene group or a butylene group. , A pentylene group, a vinylene group, a propenylene group and the like, and preferably a propylene group, a butylene group, a pentylene group and the like.

Examples of the "ester residue" include a lower alkanoyloxy lower alkyl group, a lower alkenoyl lower alkyl group, a cycloalkylcarbonyloxy lower alkyl group, a lower alkenoyloxy lower alkyl group,
Lower alkoxy lower alkanoyloxy lower alkyl group, lower alkoxy lower alkyl group, lower alkoxy lower alkoxy lower alkyl group, lower alkoxycarbonyloxy lower alkyl group, lower alkoxy lower alkoxycarbonyloxy lower alkyl group, benzoyloxy lower alkyl group, 2-oxo Tetrahydrofuran-5-
Group, 2-oxo-5-alkyl-1,3-dioxolen-4-ylmethyl group

[Chemical 12]

Examples include common ester residues such as a tetrahydrofuranylcarbonyloxymethyl group and a 3-phthalidyl group. Examples of the protective group for the carboxyl group include methyl group, ethyl group, propyl group, isopropyl group, t
lower alkyl groups such as ert-butyl group; for example, 2,2
Halo-substituted lower alkyl group such as 2-trichloroethyl group, 2,2,2-trifluoroethyl group; for example, acetoxymethyl group, propionyloxymethyl group, pivaloyloxymethyl group, 1-acetoxyethyl group, 1-propionyl Lower alkanoyloxyalkyl group such as oxyethyl group; for example, 1- (methoxycarbonyloxy) ethyl group, 1- (ethoxycarbonyloxy) ethyl group, 1-
Lower alkoxycarbonyloxyalkyl group such as (isopropoxycarbonyloxy) ethyl group; for example, 2-propenyl group, 2-chloro-2-propenyl group, 3-methoxycarbonyl-2-propenyl group, 2-methyl-2-
Lower alkenyl groups such as propenyl group, 2-butenyl group, cinnamyl group; for example, benzyl group, p-methoxybenzyl group, 3,4-dimethoxybenzyl group, o-nitrobenzyl group, p-nitrobenzyl group, benzhydryl group, bis Aralkyl groups such as (p-methoxyphenyl) methyl group; (5-substituted-2-oxo-1,3-, such as (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl group) Dioxole-4-yl) methyl group; for example, lower alkylsilyl group such as trimethylsilyl group, tert-butyldimethylsilyl group; indanyl group, phthalidyl group, methoxymethyl group and the like, especially tert.
-Butyl group and the like are preferable. Further, the compound (I) of the present invention
May form a salt with an acid or a base. Such salts include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid,
Mineral acids such as nitric acid and phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, malic acid, tartaric acid, methanesulfonic acid, ethanesulfonic acid and other organic acids, aspartic acid , Acid addition salts with acidic amino acids such as glutamic acid, sodium, potassium,
Examples thereof include inorganic bases such as magnesium, calcium and aluminum, organic bases such as methylamine, ethylamine and ethanolamine, salts with basic amino acids such as lysine and ornithine, and ammonium salts.

Further, the compound (I) of the present invention may have a 2-aminothiazolyl group, a thiadiazolyl group, etc. at the 7-position, and may have an imino ether type oxime in it.
It includes all optical isomers, geometric isomers such as syn and anti, tautomers and mixtures thereof. Further, the compound (I) of the present invention includes various hydrates, solvates and polymorphs.

Although the compound of the present invention has been described in detail above, typical compounds included in the compound of the present invention include the following compounds in addition to those described in Examples below.

[Chemical 13]

[0027]

[Table 1]

[Table 2]

[Table 3]

[Table 4]

[Table 5]

[Table 6]

[Table 7]

[Table 8]

These compounds can be synthesized by a method similar to the synthetic route described in the following process chart and examples.

(Production Method) The compound (I) of the present invention can be produced by applying various production methods. Typical production methods are described below.

(First Production Method) In this production method, 1,3 is added to the 3-position substituent.
-A method for producing a compound having a butadienyl group.

[Chemical 14]

(The symbols in the formula have the following meanings: R ^1a : a protecting group for an acyl group or an amino group, provided that when R ^1a is an acyl group,

[Chemical 15]

R ^a ′: protected amino group or hydroxyl group,
Alternatively, it may be substituted with a lower alkyl group,
(1) 5- to 6-membered heterocyclic group having one or more heteroatoms selected from sulfur atom, nitrogen atom or oxygen atom in the ring, (2) phenyl group or cyclopentadienyl group R ^b ′: Protecting group for hydroxyl group, optionally substituted lower alkyl group, lower alkenyl group, lower alkynyl group, lower cycloalkyl group or formula

[Chemical 16]

As described above, R ³ , R ⁴ and R ⁵ are X ': (1) a protected amino group or hydroxyl group, (2) a lower alkyl group substituted with a protected hydroxyl group, (3) esterified. Means a carboxyl group. R ² ′: Ester residue or carboxyl protecting group R ⁶ , R ⁷ , R ⁸ : same or different, hydrogen atom, lower alkyl group, aminocarbonyl group, lower alkoxy group, cyano group, lower alkoxycarbonyl group and nitro group. (Y: halogen atom)

That is, in this production method, the compound represented by the general formula (II) is reacted with the compound (III), then the compound represented by the general formula (IV) is prepared, and then reacted with a phosphate ester agent. After the compound (V) is prepared, the compound (Va) is preferably reacted with a base regardless of the presence or absence of a halogen donor to a compound (I-a In this method, compound (Ia) is obtained by removing ??? As the halogen atom, specifically, an iodine atom, a bromine atom, a chlorine atom,
A fluorine atom is mentioned.

As the "lower alkoxy group", methoxy, ethoxy, propoxy, butoxy, pentoxy,
Hexyloxy, isobutoxy, tert-butoxy,
Examples include groups such as isopropoxy.

The "lower alkoxycarbonyl group" is methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group,
Butoxycarbonyl group, isobutoxycarbonyl group, s
Examples thereof include an ec-butoxycarbonyl group, a tert-butoxycarbonyl group, a pentyloxy (amyloxy) carbonyl group, an isopentyloxycarbonyl group, a tert-pentyloxycarbonyl group and a neopentyloxycarbonyl group.

In the first step of the present production method, a compound represented by the general formula (II) is added to a reaction-corresponding amount of an organotin compound or a boron compound represented by the general formula (III) (for example, catecholborane, disiamileborane, etc.). ) In the presence of a palladium compound to obtain a compound represented by the general formula (IV). Examples of the palladium compound include tetrakis (triphenylphosphine) palladium (0), bis (dibenzylideneacetone) palladium (0), tris (dibenzylideneacetone) palladium (0), dichlorobis (benzonitrile) palladium (II), carbonyltris. (Triphenylphosphine) palladium (0), trans-dimethylbis (triphenylphosphine) palladium (II), trans- (4-ter
Examples thereof include t-butylcyclohexen-1-yl) chlorobis (triphenylphosphine) palladium (II), and bis (dibenzylideneacetone) palladium (0) is preferable. Further, the addition of a palladium ligand may promote the reaction in some cases, and examples of the ligand include triphenylphosphine, tri (2-furyl) phosphine, tri (2-thienyl) phosphine, and the like. Is tri (2-furyl) phosphine.

In this case, the reaction solvent is a solvent inert to the reaction, and such an inert solvent includes tetrahydrofuran, dioxane, acetonitrile, 1,2.
-Dimethoxyethane, diglyme, N, N-dimethylformamide, dimethylsulfoxide, sulfolane, N-methylpyrrolidinone, hexamethylphosphoramide, 1,3
-Dimethyl-3,4,5,6-tetrahydro-2 (1
H) -pyrimidinone and the like in a conventional inert solvent or a mixed solvent thereof which does not adversely influence the reaction,
Preferable examples include tetrahydrofuran, dioxane, acetonitrile, N, N-dimethylformamide and the like.

The reaction temperature is from room temperature to heating under reflux,
The reaction time varies depending on the reaction conditions, but is several hours to several tens hours.

The second step is a step of reacting the compound represented by the general formula (IV) produced in the first step with a phosphoric acid esterifying agent to obtain the compound represented by the general formula (V). . That is, in this step, a phosphoric acid esterifying agent (reactive derivative of phosphoric acid) is reacted in the presence of an acid scavenger (dimethylaminopyridine, etc.) in an inert solvent to cause 4-phosphoryloxy at the 3-position of the cephalosporin skeleton. -2-butene-1-
This is a step of obtaining a compound having an yl group introduced.

The reaction solvent in this case is benzene,
Aromatic hydrocarbons such as toluene or xylene are preferable, but diethyl ether, dioxane, tetrahydrofuran, cyclohexane, chloroform, dichloromethane, acetonitrile, dimethyl sulfoxide, N, N-.
Examples include dimethylformamide, hexamethylphosphoramide, ethanol and the like.

In the third step, the compound represented by the general formula (V) produced in the second step, which is preferably E-form (trans form) at the 3-position, is halogenated, or directly preferably fat. it is reacted in the presence of a base such as family tertiary amines, to obtain a compound represented by the general formula (I-a ^1). That is, in this step, the compound represented by the general formula (V) is reacted with a halogen donor in an inert solvent under cooling to room temperature to obtain a 4-halogeno-2-buten-1-yl-cephalosporin compound. The obtained compound or the compound represented by the general formula (V) is directly reacted with an amount corresponding to the reaction or an excess amount of a compound such as an aliphatic tertiary amine in an inert solvent to give 1,3-butadiene. -1-
This is a step of producing an il-cephalosporin compound.

Examples of the base include aromatic and aliphatic amines, preferably aliphatic tertiary amines, specifically diisopropylethylamine, dipropylethylamine, diisopropylmethylamine, diethylmethylamine. , Dipropylmethylamine and the like. Examples of the halogen donor include halides such as alkali metals and alkaline earth metals, halogenated silyl compounds such as trialkylsilyl halides, trialkyltin halides, dialkyltin dihalides or monoalkyltin trihalides. And tin halide compounds such as

As the inert solvent used here, the same solvent as in the second step can be used.

Further, in order to remove the protecting group from the compound represented by the general formula (Ia ¹ ), for example, when the protecting group is a tri-lower alkylsilyl group, it is easily carried out by treating with water. be able to. In addition, benzhydryl group, p-methoxybenzyl group, trityl group, tert
-When it is a protecting group such as a butyl group or a formyl group, it can be easily treated by treatment with an acid such as formic acid, trifluoroacetic acid, a trifluoroacetic acid-anisole mixed solution, a hydrobromic acid-acetic acid mixed solution, or a hydrochloric acid-dioxane mixed solution. To be removed. Also,
When it is a protecting group for a hydroxyl group, such as a lower acyl group or other protecting group that can be removed under mild conditions, a base such as
It is removed by solvolysis using an aqueous solvent such as sodium hydrogen carbonate, sodium carbonate, ammonium hydroxide, ammonium carbonate or ammonium carbamate.

(Second Production Method) This production method is the compound (I) of the present invention.
Among them, it is a method for producing a compound in which the 7-position is an amino group.

[Chemical 17]

(The symbols in the formula have the following meanings: R ^2a : phenylacetyl group, amino-protecting group R ² 'is as described above.)

This production method is a method for producing a cephalosporin derivative represented by the general formula (Ib) in the compound (I) of the present invention. That is, this method has the general formula (I-
a compound represented by a ^2), phosphorus pentachloride is reacted, Iminokuroru reduction, followed iminoetherified added lower alcohol, and further hydrolyzed by adding water, the formula (I-b)
Is a method of obtaining a compound represented by.

(Third manufacturing method)

[Chemical 18]

(The symbols in the formulas have the following meanings. R ^3a : acyl group, and the acyl group is the same as R ^{1a in} the first process. R ² is as described above.) Object of the present invention compound (I-a ³⁾ is formula (I-b) the general formula R ^3a to be 3-substituted-7-amino-3-cephem-4-carboxylic acid (or protected acid) that indicated by
It can be produced by reacting an acylcarboxylic acid represented by —OH or a reactive derivative thereof.

The acylation reaction of compound (Ib) with R ^3a —OH or its reactive derivative is usually carried out in a solvent under cooling to room temperature. The solvent is not particularly limited as long as it does not participate in the reaction. Examples of commonly used solvents include dioxane, ethyl ether, tetrahydrofuran, chloroform, dichloroethane, methylene chloride, ethyl acetate, ethyl formate, dimethylformamide, dimethyl sulfoxide, water and the like. These solvents may be appropriately mixed and used. R ^3a —OH is used in the form of a free carboxylic acid, and is also used in the reaction as a reactive derivative of carboxylic acid. As the reactive derivative of carboxylic acid, active ester (eg, henzotriazole ester), mixed acid anhydride, acid halide, active amide, acid anhydride, acid azide and the like are used. When R ^3a —OH is used in the form of a free carboxylic acid, it is preferable to use a condensing agent such as N, N-dicyclohexylcarbodiimide or N, N-diethylcarbodiimide.

Depending on the kind of the reactive derivative of the carboxylic acid used, the reaction may be carried out in the presence of a base.
It may be preferable for the reaction to proceed smoothly. Such bases include inorganic bases such as sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, trimethylamine, triethylamine, dimethylaniline,
Organic bases such as pyridine are mentioned. Fourth manufacturing method

[Chemical 19]

(Symbols in the formula are as described above.) The object compound (Ia) of the present invention is a trifluoromethanesulfonyloxy derivative represented by the general formula (Ia ⁴ ) which is an organotin having a butadienyl group. Alternatively, it can be produced by reacting a boron compound (for example, catecholborane, disiamileborane, etc.) with zinc chloride or lithium halide, trifurylphosphine, and bis (dibenzylideneacetone palladium) in the presence of compound (Ia). The reaction between ⁴ ) and a butadienyl compound is usually carried out at room temperature using a solvent such as methylpyrrolidinine, THF,
Acetonitrile, DMF, DMSO and the like can be mentioned.
Further, the isolation and purification of the target substance from the reaction solution are carried out by a conventional method by appropriately combining extraction with an organic solvent, chromatography, crystallization and the like. When the compound (I) has an ester residue, the compound (I) can be converted into a salt by reacting with an esterifying agent such as alcohol or its halide, sulfonate, sulfate, diazo compound, etc. by a conventional method. When it has, it can be obtained by subjecting it to a conventional salt-forming reaction.

[0054]

The compound of the present invention represented by the general formula (I) or a salt thereof is also useful as an intermediate for producing a compound having excellent antibacterial activity as shown in the following reaction formula. Furthermore, among the compounds of the present invention or salts thereof, particularly those having an acyl group show excellent antibacterial activity against a wide range of bacteria belonging to Gram-positive and Gram-negative per se.

[Chemical 20]

(In the formula, the other symbols have the following meanings. R ^{8 is a} lower alkyl group. The other symbols are as described above.)

That is, the compound (Ia ') of the present invention is reacted with a nitrone compound represented by the general formula (VI) to carry out a cyclization reaction at the 3-position to give an isoxazolidinyl compound represented by the general formula (VII). To obtain a compound of formula (VIII)
A compound having an excellent antibacterial activity represented by

Furthermore, the isoxazolidinyl group at the 3-position of compound (VIII) can be betaine. It can be produced by stirring a nitrogen-containing heterocyclic compound and a lower alkyl halide or a lower alkyl triflate in an inert solvent such as dimethylformamide, chloroform or benzene at room temperature or under heating. One of the compounds obtained by these reactions from the compound of the present invention is, for example,

[Chemical 21]

7β-[(Z) -2- (5-amino-1,
2,4-thiadiazol-3-yl) -2-methoxyiminoacetamide] -3-[(E) -2- (2-methyl-5-isoxazolidinyl) vinyl] -3-cephem-4-carboxylic An acid is mentioned. This compound has isomers (A, B) derived from the 5-position of isoxazole. The antibacterial activity of this compound is shown in the table below.

[Table 9]

Also

[Chemical formula 22]

7β-[(Z) -2- (5-amino-1,
2,4-thiadiazol-3-yl) -2-methoxyiminoacetamide] -3-[(E) -2- (2,2-dimethyl-5-isooxazolidinio) vinyl] -3-cephem-4 -Carboxylates. This compound also has isomers (C, D) derived from the 5-position of isoxazole. The antibacterial activity of this compound is shown in the table below.

[Table 10]

[Chemical formula 23]

Further, 7β-[(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2-fluoromethoxyimino) acetamido] -3-[(E)-
2- (2,2-dimethyl-5-isooxazolidinio)
Vinyl] -3-cephem-4-carboxylate. This product also has an isomer (EF) derived from the 5-position of isoxazole. The antibacterial activity of this compound is shown in the table below.

[Table 11]

The antibacterial agent containing the compound (I) of the present invention or a salt thereof as a main component can be prepared by an optional conventional method using an optional conventional pharmaceutical carrier or excipient. Administration may be in any form of oral administration such as tablets, pills, capsules and granules, injection such as intravenous injection and intramuscular injection, and parenteral administration such as suppositories. The dose is appropriately determined depending on the individual case in consideration of symptoms, age of the recipient, sex, etc., but is generally about 200 to 4000 mg per day.

[0063]

The present invention will be described in more detail with reference to the following examples, which should not be construed as limiting the invention. In addition, since the raw material compound of the present invention is a novel compound,
The production method of the compound is shown as a reference example.

Reference Example 1 (1) Dry argon (6
4 ml) with p-methoxybenzyl 7β-[(Z) -2.
-(2-Tritylamino-4-thiazolyl-2- (methoxyimino) acetamido] -3-chloromethyl-3-
Cephem-4-carboxylate 6.36 g (8 mmo
l), (E) -3-Hydroxy-1-tributylstannyl-1-propene 2.78 g (8.03 mmol), bis (dibenzylideneacetone) palladium (0) 92 m
g (0.16 mmol) and tri (2-furyl) phosphine 74.4 mg (0.32 mmol) were added, and the mixture was heated under reflux for 2 hours. After completion, 50 ml of acetonitrile was added to the residue obtained by distilling off the solvent under reduced pressure, and adding 50 ml of hexane to the residue.
It was washed twice with 1 and the acetonitrile layer was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and eluted with hexane-ethyl acetate (2: 3, v / v) to collect fractions containing the desired product. The solvent was evaporated under reduced pressure to obtain a foamy product, which was ethyl acetate. Solidify with ether-hexane to give p-methoxybenzyl 7β-[(Z) -2- (2-tritylamino-4-thiazolyl) -2- (methoxyimino) acetamide] -3-[(E) -4-hydroxy. -2-butenyl] -3-cephem-4-carboxylate 6 g (92
%) Was obtained.

Physicochemical properties Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard); δ (ppm): 2.88 (1H, dd, J = 14.2)
7.3 Hz), 3.17 (1H, dd, J = 14.2,
4.9 Hz), 3.56 (1H, d, J = 18.1H
z), 3.74 (3H, s), 3.80 (3H, s),
3.86 (2H, d, J = 4.9Hz), 4.66 (1
H, t, J = 5.4 Hz), 5.1-5.63 (3H,
m), 6.71 (1H, s), 6.92 (2H, d, J
= 8.3 Hz), 7.2-7.3 (17H, m), 8.
82 (1H, s), 9.51 (1H, d, J = 7.8H
z) Positive ion-FAB-mass spectrum: m / z; 816
(M + 1) ⁺ infrared absorption spectrum ν _max (KBr); 1784,
1522, 1250, 702 cm ^-1

(2) The obtained p-methoxybenzyl 7
β-[(Z) -2- (2-tritylamino-4-thiazolyl) -2- (methoxyimino) acetamide] -3
-[(E) -4-Hydroxy-2-butenyl] -3-cephem-4-carboxylate (3.26 g) was dissolved in methylene chloride (25 ml) under an argon atmosphere, and-
After cooling to 50 ° C., N, N-dimethylaminopyridine (7
33 mg), diphenylphosphoric acid chloride (1.2 ml)
Was added and the mixture was stirred at -50 ° C for 80 minutes. After the completion, poured into methylene chloride (200 ml), 10% sodium dihydrogen phosphate aqueous solution (100 ml, 2 times), saturated sodium hydrogen carbonate aqueous solution (100 ml), water (100 ml, 2 times),
After washing with saturated saline (100 ml), the organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and eluted with hexane-ethyl acetate (3: 4, v / v) to collect fractions containing the desired product. The solvent was evaporated under reduced pressure to give a foamy product with ethyl ether- Hexane is added to solidify,
p-Methoxybenzyl 7β-[(Z) -2- (2-Tritylamino-4-thiazolyl) -2- (methoxyimino) acetamido] -3-[(E) -4-diphenylphosphoryloxy-2-butenyl] -3-Cephem-4-
The carboxylate (3.30 g, 79%) was obtained.

Physicochemical properties Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ (ppm): 2.94 (1H, dd, J = 13.4,
6.7 Hz), 3.19 (1H, dd, J = 13.4,
4.8 Hz), 3.26 (1H, d, J = 18.3H)
z), 3.45 (1H, d, J = 18.3 Hz), 3.
73 (3H, s), 3.80 (3H, s), 4.71
(2H, t, J = 6.7 Hz), 5.10 (1H, d,
J = 4.3 Hz), 5.16 (2H, dd, J = 19.
5, 12.2Hz), 5.64 (1H, dt, J = 1
0.4, 5.5 Hz), 5.69 (1H, t, J = 6.
1 Hz), 5.75-5.79 (1 H, m), 6.7
1 (1H, s), 6.91 (2H, d, J = 7.9H
z), 7.22-7.43 (27H, m), 8.83
(1H, s), 9.53 (1H, d, J = 7.9Hz) Positive ion-FAB-mass spectrum: m / z; 1048
(M) ⁺ infrared absorption spectrum ν _max (KBr); 1784,
1520, 1492, 1190, 1168, 956cm
^-1

Reference Example 2 (1) Under an argon stream, 400 ml of dried N, N-dimethylformamide was added to p-methoxybenzyl 7β- (2
-Phenylacetamide) -3-chloromethyl-3-cephem-4-carboxylate 38.96 g (80 mm
ol), (E) -3-hydroxy-1-tributylstannyl-1-propene 27.69 g (80 mmol), bis (dibenzylideneacetone) palladium (0) 920
mg (1.6 mmol) and tri (2-furyl) phosphine 743 mg (3.2 mmol) were added, and the mixture was heated under reflux for 3 hours. After the completion, 400 ml of acetonitrile was added to the residue obtained by distilling off the solvent under reduced pressure, and 400 ml of hexane was added.
It was washed 3 times with and the acetonitrile layer was distilled off under reduced pressure. Ethyl acetate-benzene (1: 1, v / v) was added to the obtained residue.
400 ml was added, this was washed with 400 ml of water three times,
The organic layer was dried over anhydrous magnesium sulfate and then evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, chloroform-methanol (100: 1, v / v).
The fractions containing the desired product were collected, and the solvent was evaporated under reduced pressure to remove p-methoxybenzyl 7β- (2-phenylacetamido) -3-[(E) -4-hydroxy-2.
-Butenyl] -3-cephem-4-carboxylate 3
8.5 g, (94.6%) was obtained.

Physicochemical properties Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ (ppm): 2.88 (1H, dd, J = 14.2)
7.3 Hz), 3.18 (1H, dd, J = 14.2,
4.9 Hz), 3.36 (1H, d, J = 18.1H)
z), 3.52 (2H, dd, J = 28.8, 14.2)
Hz), 3.57 (1H, d, J = 18.1Hz),
3.75 (3H, s), 3.88 (2H, brs),
4.67 (1H, t, J = 5.4Hz), 5.08 (1
H, d, J = 4.4 Hz), 5.12 (1H, d, J =
12.2 Hz), 5.22 (1H, d, J = 12.2H
z), 5.51-5.57 (1H, m), 5.59-
5.65 (2H, m), 6.93 (2H, d, J = 8.
8 Hz), 7.2-7.3 (5 H, m), 7.34 (2
H, d, J = 8.8 Hz), 9.09 (1H, d, J =
8.3 Hz) Positive ion-FAB-mass spectrum: m / z; 509
(M + 1) ⁺ infrared absorption spectrum ν _max (KBr); 3292,
3048, 2972, 1784, 1718, 1654,
1618, 1540, 1520, 1366, 1252
1174,700 cm ^-1

(2) p-Methoxybenzyl 7β- (2-phenylacetamido) -3-obtained in (1)
[(E) -4-hydroxy-2-butenyl] -3-cephem-4-carboxylate 33.3 g (66 mmo
l) was dissolved in 350 ml of methylene chloride under an argon atmosphere, cooled to -70 ° C, and added with 32.0 g (262 mmol) of N, N-dimethylaminopyridine, then -7
54.6 ml of diphenylphosphoric chloride at 0 ° C to 65 ° C
(262 mmol) was added dropwise over 50 minutes, and-
Stir for 10 minutes at 65 ° C. After completion, methylene chloride 65
Pour into 0 ml, saturated ammonium chloride aqueous solution 500 m
After washing once and twice with 500 ml of saturated aqueous sodium hydrogen carbonate solution, 500 ml of water and 500 ml of saturated saline, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and methylene chloride-ethyl acetate (10: 1, v /
The fractions containing the desired product were collected by elution with v) and the solvent was evaporated under reduced pressure to remove p-methoxybenzyl 7β- (2-phenylacetamido) -3-[(E) -4-diphenylphosphoryloxy-2-butenyl]. -3-Cephem-4
32.9 g of carboxylate were obtained.

Physicochemical properties Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ (ppm): 2.93 (1H, dd, J = 14.7,
7.3 Hz), 3.21 (1H, dd, J = 14.0,
5.5 Hz), 3.29 (1H, d, J = 18.3H)
z), 3.53 (2H, dd, J = 36.0, 14.0)
Hz), 3.54 (1H, d, J = 18.3Hz),
3.73 (3H, s), 4.73 (2H, dd, J =
8.5, 6.1 Hz), 5.07 (1H, d, J = 4.
9 Hz), 5.18 (2H, dd, J = 35.4, 1
2.2 Hz), 5.65-5.68 (1 H, m), 5.
70-5.73 (1H, m), 5.77-5.83 (1
H, m), 6.92 (2H, d, J = 8.5 Hz),
7.1-7.4 (17H, m), 9.10 (1H, d,
J = 8.5 Hz) Positive ion-FAB-mass spectrum: m / z; 741
(M + 1) ⁺ infrared absorption spectrum ν _max (CHCl ₃ ); 344
0,3012,2976,1788,1728,168
8, 1616, 1594, 1494, 1286, 116
8,1014,964 cm ^-1

Reference Example 3 (1) 80 m of dry tetrahydrofuran under argon flow
p-methoxybenzyl 7β-[(Z) -2- (5
-Tritylamino-1,2,4-thiadiazole-3-
Ii) -2-Methoxyiminoacetamido] -3-chloromethyl-3-cephem-4-carboxylate 7.
95 g (10 mmol), (E) -3-hydroxy-1
-Tributylstannyl-1-propene 3.47 g (10
mmol), bis (dibenzylideneacetone) palladium (0) 115 mg (0.2 mmol), and tri (2-furyl) phosphine 93 mg (0.4 mmol), and added 3
Reflux for hours. After the completion, the solvent was distilled off under reduced pressure, and 200 ml of acetonitrile was added to the obtained residue. This was washed with 200 ml of hexane and then 100 ml, and the acetonitrile layer was separated and distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and hexane-ethyl acetate (1: 1)
To 3: 7 in different ratios (v / v) and the fractions containing the desired product were collected, the solvent was distilled off under reduced pressure, and the resulting foam was solidified with ethyl ether-hexane to give p-methoxy. Benzyl 7β-[(Z) -2- (5-tritylamino-1,2,4-thiadiazol-3-yl) -2-
(Methoxyimino) acetamide] -3-[(E) -4
5.94 g (72.7%) of -hydroxy-2-butenyl] -3-cephem-4-carboxylate were obtained.

Physicochemical properties Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ (ppm): 2.87 (1H, dd, J = 13.7,
6.8 Hz), 3.16 (1H, dd, J = 13.7,
4.6Hz), 3.54 (1H, d, J = 18.6H
z), 3.75 (3H, s), 3.88 (5H, m),
3.86 (2H, d, J = 4.9Hz), 4.66 (1
H, t, J = 5.5 Hz), 5.1-5.21 (3H,
m), 5.49-5.70 (2H, m), 5.72 (1
H, m), 6.92 (2H, d, J = 8.8Hz),
7.2-7.4 (17H, m), 9.50 (1H, d,
J = 8.8 Hz), 9.99 (1H, s) positive ion-FAB-mass spectrum: m / z; 817
(M + H) ⁺ infrared absorption spectrum ν _max (KBr); 3416,
3316, 2952, 1778, 1726, 1690,
1520, 1248, 1042, 702cm ^-1

(2) p-Methoxybenzyl 7β-[(Z) -2- (5-tritylamino-) obtained in (1)
1,2,4-thiadiazol-3-yl) -2- (methoxyimino) acetamido] -3-[(E) -4-hydroxy-2-butenyl] -3-cephem-4-carboxylate 5 g (6. 1 mmol) was dissolved in methylene chloride (40 ml) under an argon atmosphere, cooled to -50 ° C, and then N, N-dimethylaminopyridine (826 m) was added.
g) and diphenylphosphoric acid chloride (1.55 ml) were added and the mixture was stirred at -45 ° C for 60 minutes. After the completion, pour into methylene chloride (200 ml), and use 10% sodium dihydrogen phosphate aqueous solution (100 ml, 2 times), saturated sodium hydrogen carbonate aqueous solution (100 ml), water (100 ml, 2 times), saturated saline solution (100 ml). After washing each, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
The residue was subjected to silica gel column chromatography, and eluted with hexane-ethyl acetate (2: 3 to 3: 7, v / v) to collect the fractions containing the target compound. The solvent was evaporated under reduced pressure to give a foam. Ethyl ether-hexane was added to solidify,
p-Methoxybenzyl 7β-[(Z) -2- (5-tritylamino-1,2,4-thiadiazol-3-yl) -2- (methoxyimino) acetamide] -3-
[(E) -4-diphenylphosphoryloxy-2-butenyl] -3-cephem-4-carboxylate (5.1
7g, 80.5%) was obtained.

Physicochemical properties Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ (ppm): 2.91 (1H, dd, J = 14.2)
6.8 Hz), 3.18 (1 H, dd, J = 14.2,
5.1 Hz), 3.24 (1H, d, J = 18.6H)
z), 3.51 (1H, d, J = 18.6 Hz), 3.
73 (3H, s), 3.89 (3H, s), 4.71
(2H, t, J = 5.9 Hz), 5.07-5.2 (3
H, m), 5.65-5.8 (3H, m), 6.91.
(2H, d, J = 8.3 Hz), 7.21-7.44
(27H, m), 9.51 (1H, d, J = 8.3H
z), 9.99 (1H, s) positive ion-FAB-mass spectrum: m / z; 1049.
(M) ⁺ infrared absorption spectrum ν _max (KBr); 3300,
2952, 1778, 1726, 1686, 1520,
1492, 1394, 1248, 1188, 1168,
1094, 1040, 952, 754, 702, 690
cm ^-1

Reference Example 4 (1) Dry tetrahydrofuran 80 under argon atmosphere
p-methoxybenzyl 7β-[(Z) -2-
(2-Tritylamino-4-thiazolyl) -2- (1-
tert-Butoxycarbonyl-1-methylethoxyimino) acetamido] -3-chloromethyl-3-cephem-4-carboxylate 9.23 g (10 mmo
l), (E) -3-Hydroxy-1-tributylstannyl-1-propene 3.47 g (10 mmol), bis (dibenzylideneacetone) palladium (0) 115 m
g (0.2 mmol) and tri (2-furyl) phosphine 93 mg (0.4 mmol) were added, and the mixture was heated under reflux for 3 hours. After the completion, 200 ml of acetonitrile was added to the residue obtained by distilling off the solvent under reduced pressure, and adding 100 ml of this to hexane.
It was washed twice with and the acetonitrile layer was evaporated under reduced pressure.
The residue was subjected to silica gel column chromatography and eluted with hexane-ethyl acetate (1: 1 to 2: 3, v / v) to collect fractions containing the target compound, and the solvent was distilled off under reduced pressure to give a foam. The solid was solidified with ethyl ether-hexane to give p-methoxybenzyl 7β-[(Z) -2- (2-
Tritylamino-4-thiazolyl) -2- (1-ter
t-butoxycarbonyl-1-methylethoxyimino)
Acetamide] -3-[(E) -4-hydroxy-2-
Butenyl] -3-cephem-4-carboxylate 9.
15 g (96.9%) were obtained.

Physicochemical properties Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ (ppm): 1.35 (15 H, s), 2.90
(1H, dd, J = 14.2, 7.3Hz), 3.1
8 (1H, dd, J = 14.2, 4.9 Hz), 3.
35 (1H, d, J = 8.6Hz), 3.55 (1H,
d, J = 18.6 Hz), 3.74 (3H, s), 3.
86 (2H, m), 4.66 (1H, t, J = 5.5H
z), 5.1-5.21 (3H, m), 5.49-5.
67 (3H, m), 6.69 (1H, s), 6.92
(2H, d, J = 8.8Hz), 7.1-7.4 (17
H, m), 8.79 (1H, s), 9.29 (1H,
d, J = 8.3) Positive ion FAB mass spectrum: m / z; 944
(M) ⁺ infrared absorption spectrum ν _max (KBr); 3416,
3072, 2992, 1790, 1728, 1690,
1520, 1372, 1302, 1248, 1174,
1144,702cm ^-1

(2) p-Methoxybenzyl 7β-[(Z) -2- (2-tritylamino-4) obtained in (1)
-Thiazolyl) -2- (1-tert-butoxycarbonyl-1-methylethoxyimino) acetamide] -3
-[(E) -4-hydroxy-2-butenyl] -3-cephem-4-carboxylate 9.1 g (9.6 mmo)
l) was dissolved in 62 ml of methylene chloride under an argon atmosphere, cooled to -50 ° C, and then 1.28 g of N, N-dimethylaminopyridine and 2.39 ml of diphenylphosphoric acid chloride.
Was added and the mixture was stirred at -45 ° C for 2 hours. After the completion, pour into 200 ml of methylene chloride, and twice with 100 ml of 10% sodium dihydrogen phosphate aqueous solution, saturated sodium hydrogen carbonate aqueous solution 1
00 ml, water 100 ml twice, saturated saline 100 ml
After washing with water, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and eluted with hexane-ethyl acetate (3: 2 to 2: 3, v / v) to collect fractions containing the target product, and the solvent was distilled off under reduced pressure to obtain a foamy product. Ethyl ether-hexane was added to and solidified, and p-methoxybenzyl 7β-[(Z) -2- (2-tritylamino-4 was added.
-Thiazolyl) -2- (1-tert-butoxycarbonyl-1-methylethoxyimino) acetamide] -3
-[(E) -4-Diphenylphosphoryloxy-2-butenyl] -3-cephem-4-carboxylate 10.
21 g (90%) were obtained.

Physicochemical properties Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ (ppm): 1.34 (15 H, s), 2.95 (1
H, dd, J = 14.6, 7.4 Hz), 3.19 (1
H, m), 3.52 (1H, d, J = 18.3 Hz),
3.72 (3H, s), 4.71 (2H, t, J = 6.
1 Hz), 5.1-5.2 (3H, m), 5.6-5.
8 (3H, m), 6.69 (1H, s), 6.91 (2
H, d, J = 8.6 Hz), 7.18-7.43 (27
H, m), 8.79 (1H, s), 9.28 (1H,
d, J = 8.5 Hz) Positive ion FAB mass spectrum; m / z: 1176
(M) ⁺ infrared absorption spectrum ν _max (KBr); 3412,3
072, 2988, 1788, 1728, 1692, 1
520, 1494, 1368, 1300, 1192, 1
172, 1144, 1012, 954, 759, 702
cm ^-1

Reference Example 5 (1) 5.15 g (12 mmo) of (Z) -2-hydroxyimino-2- (tritylamino-4-thiazolyl) acetic acid
1) is suspended in 60 ml of methylene chloride, and 5.2 ml of 2-methoxypropene is added at 4 ° C. After stirring at room temperature for 30 minutes, the solvent is distilled off under reduced pressure. 50 ml of methylene chloride in the residue
, 2.63 g of phosphorus pentachloride was added at -25 ° C, and -4
Stir for 60 minutes at 5-20 ° C to obtain a solution of (Z) -2- (1-methoxy-1-methyl) ethoxyimino-2- (2-tritylamino-4-thiazolyl) acetic acid chloride. On the other hand, p-methoxybenzyl 7β-amino-3-
Chloromethyl-3-cephem-4-carboxylate
The hydrochloride salt (ACLE · HCl) is suspended in 50 ml of methylene chloride, and 2.8 ml of bis (trimethylsilyl) acetamide is added at 10 ° C. After stirring at room temperature for 30 minutes, -60
At 4 ° C., 4 ml of pyridine and the above acetic acid chloride solution are sequentially added. After stirring at −35 to −20 ° C. for 30 minutes, pour into 150 ml of a saturated aqueous solution of monopotassium phosphate and add 100 ml of methylene chloride.
Extract twice with ml. The extract was washed with saturated monopotassium phosphate solution and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was subjected to silica gel column chromatography to give hexane-ethyl acetate (3: 2
˜1: 1, v / v) and the fractions containing the desired product are collected and the solvent is distilled off under reduced pressure to give the foam compound p-methoxybenzyl 3-chloromethyl-7β-[(Z) -2.
-(2-Tritylamino-4-thiazolyl) -2- (1
-Methoxy-1-methyl) ethoxyiminoacetamide] -3-cephem-4-carboxylate 7.65 g
(81.5%) was obtained.

Physicochemical properties Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ (ppm): 3.11 (3H, s), 3.53 (1
H, d, J = 18.1 Hz), 3.70 (11, d, J
= 18.6 Hz), 3.74 (3 H, s), 4.50
(2H, q, J = 23.4, J = 11.2 Hz), 5.
1-5.3 (3H, m), 5.73 (1H, q, J =
4.9 Hz), 6.71 (1 H, s), 6.92 (2
H, d, J = 6.8 Hz), 7.2-7.4 (17H,
m), 8.86 (1H, s), 9.53 (1H, d, J
= 8.3) Positive ion-FAB-mass spectrum: m / z; 852
(M) ⁺ infrared absorption spectrum ν _max (KBr); 3416,
3072, 2948, 1794, 1730, 1692,
1630, 1618, 1522, 1386, 1374,
1250, 1178, 1164, 1068, 956, 9
24,702 cm ^-1

(2) Under an argon atmosphere, p-methoxybenzyl 3-chloromethyl-7β-[(Z) -2- (2-tritylamino-4-thiazolyl) -2- (1-methoxy) was added to 80 ml of dry tetrahydrofuran. -1-Methyl) ethoxyiminoacetamide] -3-cephem-4
-Carboxylate 8.53 g (0.01 mol), 3
-Hydroxy-1-tributylstannyl-1-propene 3.47 g (0.01 mol), bis (dibenzylideneacetone) palladium (0) 115 mg (0.2 mmo
l), tri (2-furyl) phosphine 93 mg (0.4
mmol) was added and the mixture was heated under reflux for 23 hours. After the completion, the solvent was distilled off under reduced pressure and the residue obtained was added with 100 m of acetonitrile.
1 was added, this was washed twice with 100 ml of hexane, and the acetonitrile layer was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and eluted with hexane-ethyl acetate (3: 2 to 2: 3, v / v) to collect the fractions containing the target compound, and the solvent was distilled off under reduced pressure to give a foam. The solid was solidified with ethyl ether-hexane to give p-methoxybenzyl 7β-[(Z) -2- (2-tritylamino-
4-thiazolyl) -2- (1-methoxy-1-methyl)
2.54 g (29.2%) of ethoxyiminoacetamide] -3-[(E) -4-hydroxy-2-butenyl] -3-cephem-4-carboxylate was obtained.

Physicochemical properties Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ (ppm): 1.38 (6H, s), 2.89 (1
H, dd, J = 14.2, 6.8 Hz, 3.17 (1
H, dd, J = 14.2, 5.4 Hz), 3.31 (3
H, s), 3.35 (d, J = 18.6 Hz), 3.5
5 (1H, d, J = 18.6Hz), 3.74 (3H,
s), 3.86 (2H, m), 4.65 (1H, t, J
= 5.4 Hz), 5.1-5.2 (3H, m), 5.5
-5.7 (4H, m), 6.71 (1H, s), 6.9
2 (2H, d, J = 6.8 Hz), 7.1-7.4 (1
7H, m), 8.85 (1H, s), 9.45 (1H,
d, J = 7.8) Positive ion-FAB-mass spectrum: m / z; 874
^{(M) +, 802 (M} -C (CH 3) 2 OCH 3 +1)
⁺ Infrared absorption spectrum ν _max (KBr); 3416,
3072, 3008, 2952, 2848, 1788,
1728, 1686, 1618, 1520, 1376,
1300, 1248, 1176, 1072, 1034
978,902,848,824,754,702cm
^-1

(3) p-Methoxybenzyl 7β-[(Z) -2- (2-tritylamino-4) obtained in (2)
1.6 g (1.-thiazolyl) -2- (1-methoxy-1-methyl) ethoxyiminoacetamide] -3-[(E) -4-hydroxy-2-butenyl] -3-cephem-4-carboxylate. (83 mmol) was dissolved in 12 ml of methylene chloride under an argon atmosphere, cooled to -50 ° C, and then N, N-dimethylaminopyridine 0.27 g (2
mmol), diphenylphosphoric acid chloride 0.455 ml
Was added and the mixture was stirred at −45 to −20 ° C. for 2 hours. After the end, 1
Pour into 100 ml of 0% aqueous solution of sodium dihydrogen phosphate,
It was extracted twice with 50 ml of methylene chloride. The extract was mixed with 20 ml of saturated aqueous sodium hydrogen carbonate solution and 20 ml of water twice,
The organic layer was washed with 20 ml of saturated saline and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, eluted with hexane-ethyl acetate (3: 2-1: 1-2: 3, v / v) to collect the fractions containing the desired product, and the solvent was evaporated under reduced pressure. The foam obtained was solidified with ethyl ether-hexane to give p-methoxybenzyl 7β-[(Z) -2- (2-tritylamino-4-thiazolyl) -2- (1-methoxy-1-methyl). Ethoxyiminoacetamide] -3-
[(E) -4-Diphenylphosphoryloxy-2-butenyl] -3-cephem-4-carboxylate 1.46
g (71.9%) were obtained.

Physicochemical properties Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ (ppm): 1.37 (6 H, s), 2.95 (1
H, dd, J = 14.7, 6.8 Hz), 3.10 (3
H, s), 3.18 (1H, dd, J = 14.7, 9.
3Hz), 3.29 (1H, d, J = 18.6Hz),
3.54 (1H, d, J = 18.6 Hz), 3.72
(3 H, s), 4.70 (2 H, dd, J = 9.3,
8.8 Hz), 5.1-5.2 (3H, m), 5.6-
5.8 (3H, m), 6.71 (1H, s), 6.90
(2H, d, J = 8.8Hz), 7.19-7.44
(27H, m), 8.86 (1H, s), 9.47 (1
H, d, J = 7.8 Hz) Positive ion-FAB-mass spectrum: m / z; 1106
^{(M) +, 1034 (M} -C (CH 3) 2 OCH 3 +1)
⁺ Infrared absorption spectrum ν _max (KBr); 3420,
3072, 2954, 2884, 1788, 1728,
1686, 1592, 1520, 1492, 1376,
1286, 1248, 1220, 1190, 1166
1072, 1012, 954, 772, 754, 70
2,692 cm ^-1

Reference Example 6 (1) 1.38 g of (Z) -2- (2-tritylamino-4-thiazolyl) -2-fluoromethoxyiminoacetic acid
(3.0 mmol) suspended in 30 ml of methylene chloride,
Under cooling to -10 ° C, phosphorus pentachloride 621 mg (3.0 mm
ol) was added and the mixture was stirred at the same temperature for 30 minutes to obtain an acid chloride solution. On the other hand, ACLE hydrochloride 1.22 g (3.0 mm
Ol) was suspended in 30 ml of methylene chloride, 1.5 ml of N, O-bis (trimethylsilyl) acetamide and 1.5 ml of pyridine were added, and the mixture was stirred for 10 minutes. This solution was cooled to −50 ° C., the acid chloride solution prepared above was added, and the mixture was stirred at the same temperature for 30 minutes. This reaction solution was poured into 160 ml of a saturated sodium dihydrogen phosphate aqueous solution, the organic layer was separated, washed with water and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography, eluted with chloroform-methanol (20: 1), the fractions containing the target compound were collected, the solvent was evaporated under reduced pressure, and the obtained foam was extracted with ethyl ether. Solidify to p-methoxybenzyl 3-chloromethyl-7β-[(Z) -2- (2-tritylamino-4-thiazolyl) -2-fluoromethoxyimino)
Acetamide] -3-cephem-4-carboxylate (1.87 g, 76.8%) was obtained.

Physicochemical properties Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ (ppm): 3.53 (1H, d, J = 17.6H)
z), 3.70 (1H, d, J = 17.6 Hz), 3.
76 (3H, s), 4.46 (1H, d, J = 11.2)
Hz), 4.53 (1H, d, J = 11.2Hz),
5.10-5.25 (3H, m), 5.70 (2H,
d, J = 55.2 Hz), 5.72 (1H, m), 6.
88 (1H, s), 6.93 (1H, d), 7.20-
7.40 (17H, m), 8.92 (1H, s), 9.
77 (1H, m) positive ion-FAB-mass spectrum: m / z; 812
(M + 1) ⁺ infrared absorption spectrum ν _max (KBr); 1792,
1730, 1692, 1522, 1496, 1366,
1250, 1176, 1098, 1068, 702cm
^-1

(2) p-methoxybenzyl 7β-[(Z) -2- (2-tritylamino-4-thiazolyl) -2-fluoromethoxyimino) acetamide] -in dry tetrahydrofuran (80 ml) under an argon atmosphere.
3-Chloromethyl-3-cephem-4-carboxylate 1.7 g (2.1 mmol), 3-hydroxy-1-
Tributylstannyl-1-propene 724 mg (2.1
mmol), bis (dibenzylideneacetone) palladium (0) 24 mg (0.042 mmol), tri (2-
20 mg (0.086 mmol) of furyl) phosphine was added and the mixture was heated under reflux for 4 hours. After the completion, the solvent was distilled off under reduced pressure, 25 ml of acetonitrile was added to the obtained residue, this was washed twice with 20 ml of hexane, and the acetonitrile layer was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and hexane-ethyl acetate (3: 2-2:
(3, v / v), the fractions containing the desired product were collected, the solvent was distilled off under reduced pressure, and the resulting foam was solidified with ethyl ether-hexane to give p-methoxybenzyl 7β-.
[(Z) -2- (2-Tritylamino-4-thiazolyl) -2-fluoromethoxyimino) acetamide]-
3-[(E) -4-hydroxy-2-butenyl] -3-
Cefem-4-carboxylate 1.48 g (84.8
%) Was obtained.

Physicochemical properties Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ (ppm): 2.89 (1H, dd, J = 14.2)
6.8 Hz), 3.17 (1H, dd, J = 14.2,
5.4Hz), 3.34 (1H, d, J = 18.6H)
z), 3.55 (1H, d, J = 18, 6Hz), 3.
74 (3H, s), 3.86 (2H, m), 4.65
(1H, t, J = 5.5Hz), 5.1-5.2 (3
H, m), 5.51-5.65 (4H, m), 5.76.
(1H, s), 6.88 (1H, s), 6.92 (2
H, d, J = 8.8 Hz), 7.1-7.4 (17H,
m), 8.91 (1H, s), 9.71 (1H, d, J
= 7.8) Positive ion-FAB-mass spectrum: m / z; 834
(M + 1) ⁺ infrared absorption spectrum ν _max (KBr); 3416,
3320, 3068, 3040, 2972, 1784,
1728, 1686, 1520, 1368, 1302
1248, 1174, 1096, 1034, 966, 7
54,702 cm ^-1

(3) p-Methoxybenzyl 7β-[(Z) -2- (2-tritylamino-4) obtained in (2)
-Thiazolyl) -2-fluoromethoxyimino) acetamido] -3-[(E) -4-hydroxy-2-butenyl] -3-cephem-4-carboxylate 1.4 g
(1.68 mmol) was dissolved in methylene chloride (11 ml) under an argon atmosphere, cooled to 50 ° C, and then N, N-.
Add 0.25 g (2 mmol) of dimethylaminopyridine and 0.42 ml of diphenylphosphoric acid chloride, and then add −45 to −.
The mixture was stirred at 35 ° C for 5 hours. After the completion, pour into 100 ml of 10% sodium dihydrogen phosphate aqueous solution, and add 50 methylene chloride.
Extracted twice with ml. The extract was washed with 20 ml of a saturated aqueous solution of sodium hydrogen carbonate and 20 ml of water twice, and saturated saline solution of 20 m.
After washing with 1 each, it was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and hexane-ethyl acetate (3: 2
(1: 1 to 2: 3, v / v), and the fractions containing the target substance were collected, the solvent was distilled off under reduced pressure, and ethyl ether-hexane was added to the foamed substance to solidify it. Benzyl 7β-[(Z) -2- (2-tritylamino-
4-thiazolyl) -2-fluoromethoxyimino) acetamido] -3-[(E) -4-diphenylphosphoryloxy-2-butenyl] -3-cephem-4-carboxylate (1.34 g, 74.8%) Obtained.

Physicochemical properties Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ (ppm): 2.95 (1H, dd, J = 14.7,
7.3 Hz), 3.20 (1H, dd, J = 14.7,
5.4 Hz), 3.25 (1H, d, J = 18.1H
z), 3.51 (1H, d, J = 18.6 Hz), 3.
73 (3H, s), 4.70 (2H, dd, J = 8.
8, 5.9 Hz), 5.1-5.2 (3 H, m), 5.
6-5.8 (6H, m), 6.80-6.94 (3
H, m), 7.2-7.44 (27 H, m), 8.9.
1 (1H, s), 9.72 (1H, d, J = 8.3H
z) Positive ion-FAB-mass spectrum; m / z: 1066
(M) ⁺ infrared absorption spectrum ν _max (KBr); 3420, 3
300,3072,2976,1786,1728,1
686, 1592, 1520, 1492, 1370, 1
286, 1248, 1224, 1190, 1168, 1
096, 1070, 1012, 952, 754, 70
2,690 cm ^-1

Reference Example 7 (1) p-Methoxybenzyl 7β-[(Z) -2-
(5-Tritylamino-1,2,4-thiadiazole-
3-yl) -2-fluoromethoxyimino) acetamido] -3-chloromethyl-3-cephem-4-carboxylate As a starting material, the same procedure as in Reference Example 3 (1) was used. Using p-methoxybenzyl 7β-[(Z) -2- (5-tritylamino-1,2,4-thiadiazol-3-yl) -2-
Fluoromethoxyimino) acetamide] -3-
[(E) -4-Hydroxy-2-butenyl] -3-cephem-4-carboxylate 1.25 g (91.0%)
Got

Physicochemical properties Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ (ppm): 2.87 (1H, dd, J = 7.3, 1)
4.2 Hz), 3.16 (1H, dd, J = 4.9, 1
3.7z), 3.32 (1H, d, J = 18.6H)
z), 3.55 (1H, d, J = 18.6 Hz), 3.
75 (3H, s), 3.86 (2H, m), 4.65
(1H, t, J = 5.5Hz), 5.1-5.21 (3
H, m), 5.49-5.75 (4H, m), 5.83.
(1H, s), 6.92 (2H, d, J = 8.9H
z), 7.2-7.5 (17H, m), 9.68 (1
H, d, J = 8.3 Hz), 10.08 (1 H, s) positive ion-FAB-mass spectrum; m / z: 835
(M + 1) ⁺ infrared absorption spectrum; ν _max (KBr): 3416,
3044, 2972, 1780, 1724, 1692,
1618, 1532, 1520, 1450, 1394,
1368, 1304, 1248, 1174, 1124,
1076, 1004, 754, 702 cm ^-1

(2) p-Methoxybenzyl 7β-[(Z) -2- (5-tritylamino-) obtained in (1)
1,2,4-thiadiazol-3-yl) -2-fluoromethoxyimino) acetamido] -3-[(E) -4
-Hydroxy-2-butenyl] -3-cephem-4-carboxylate Using 1.25 g (1.5 mmol) as a starting material, and using the same method as in Reference Example 3 (2), p-
Methoxybenzyl 7β-[(Z) -2- (5-tritylamino-1,2,4-thiadiazol-3-yl)-
2-Fluoromethoxyimino) acetamide] -3-
1.4 g of [(E) -4-diphenylphosphoryloxy-2-butanyl] -3-cephem-4-carboxylate
(87.5%) was obtained.

Physicochemical properties Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ (ppm): 2.92 (1H, dd, J = 7.3, 1)
4.7 Hz), 3.19 (1 H, m), 3.24 (1
H, d, J = 18.6 Hz), 3.52 (1H, d, J
= 18.6 Hz), 3.73 (3H, s), 4.70
(2H, dd, J = 5.9, 8.8Hz), 5.1-
5.2 (3H, m), 5.6-5.9 (5H, m),
6.91 (2H, d, J = 8.5 Hz), 7.1-7.
5 (27H, m), 9.68 (1H, d, J = 8.3H
z), 10.08 (1H, s) positive ion-FAB-mass spectrum; m / z: 1067
(M + 1) ⁺ infrared absorption spectrum ν _max (KBr); 3416,3
280, 3072, 2976, 1784, 1726, 1
692, 1616, 1592, 1522, 1492, 1
452, 1392, 1368, 1286, 1250, 1
2221, 1188, 1164, 1124, 1076, 1
012,954,756,702,690,522cm
^-1

Example 1 (1) p-Methoxybenzyl 7β-[(Z) -2- (2-tritylamino-4-thiazolyl) -2- (methoxyimino) acetamide obtained in Reference Example 1 (2) ]-
3-[(E) -4-diphenylphosphoryloxy-2-
Butenyl] -3-cephem-4-carboxylate 3.
03 g (2.89 mmol) of acetonitrile 60 ml
Dissolved in diisopropylethylamine (1.5 ml)
Was added dropwise under ice cooling. After stirring at the same temperature for 24 hours, the solvent was distilled off under reduced pressure and the obtained residue was subjected to silica gel column chromatography to give methylene chloride-ethyl acetate (15:
1, v / v) and the fractions containing the desired product were collected, the solvent was distilled off under reduced pressure, and the resulting foam was solidified with ethyl ether-hexane to give p-methoxybenzyl 7β-.
[(Z) -2- (2-Tritylamino-4-thiazolyl) -2- (methoxyimino) acetamide] -3-
[(E) -1,3-Butadienyl] -3-cephem-4
-2.19 g (94%) of the carboxylate was obtained. or,
P-Methoxybenzyl 7β obtained in Reference Example 1 (2)
-[(Z) -2- (2-Tritylamino-4-thiazolyl) -2- (methoxyimino) acetamide] -3-
[(E) -4-Diphenylphosphoryloxy-2-butenyl] -3-cephem-4-carboxylate (83
8.5 mg, 0.8 mmol), potassium iodide (17
3 mg) was dissolved in acetonitrile (8 ml) and cooled to 10 ° C. Carbamoylmethylethylmethylamine (120 mg, 1.03 mmol) was added thereto, and the mixture was stirred at room temperature overnight. The solvent was distilled off from the filtrate obtained by filtering the precipitated solid matter under reduced pressure. The obtained residue was subjected to silica gel column chromatography, and hexane-ethyl acetate (2: 3,
v / v) was eluted and the fractions containing the desired product were collected, the solvent was distilled off under reduced pressure and the resulting foam was solidified with ethyl ether-hexane to give p-methoxybenzyl 7β-.
[(Z) -2- (2-Tritylamino-4-thiazolyl) -2- (methoxyimino) acetamide] -3-
[(E) -1,3-Butadienyl] -3-cephem-4
-Carboxylate (524 mg, 63%) was obtained.

Physicochemical properties Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ (ppm): 3.61 (1H, d, J = 17.6H)
z), 3.75 (3H, s), 3.81 (3H, s),
3.89 (1H, d, J = 17.6Hz), 5.18
(1H, d, J = 4.9HZ), 5.20 (2H,
s), 5.26 (1H, d, J = 11.5Hz), 5.
39 (1H, d, J = 17.1 Hz), 5.69 (1
H, dd, J = 8.0, 4.9 Hz), 6.3 to 6.4.
(1H, m), 6.7 to 6.8 (3H, m), 6.94
(2H, d, J = 9.2 Hz), 7.2-7.4 (17
H, m), 8.85 (1H, s), 9.59 (1H,
d, J = 7.9 Hz) Positive ion-FAB-mass spectrum: m / z; 799
(M + 1) ⁺ infrared absorption spectrum ν _max (KBr); 3304,
1780, 1724, 1686, 1520, 1306,
1248, 1168, 1038, 702cm ^-1

(2) p-Methoxybenzyl 7β-[(Z) -2- (2-tritylamino-4) obtained in (1)
-Thiazolyl) -2- (methoxyimino) acetamido] -3-[(E) -1,3-butadienyl] -3-cephem-4-carboxylate 516 mg was dissolved in methylene chloride (4 ml) and anisole (2 ml). 10 ° C
After cooling to, trifluoroacetic acid (5 ml) was added,
The mixture was stirred at room temperature for 60 minutes. After the completion, the solvent was distilled off under reduced pressure and the resulting residue was added with ethyl ether: hexane (1: 1) 20 m.
1 was added to make powder, which was collected by filtration. This was added to trifluoroacetic acid (7 ml) cooled to 10 ° C. or lower, water (3 ml) was further added, and the mixture was stirred for 60 minutes. After the completion, the solvent was distilled off under reduced pressure, and ethanol was further added to azeotropically remove water. Ethyl ether (20 ml) on the residue
Was added, solidified and collected by filtration, then dissolved in a saturated aqueous solution of sodium hydrogen carbonate, purified by HP-20, and lyophilized to give sodium 7β-[(Z) -2- (2-amino-4-thiazolyl) -2-. (Methoxyimino) acetamide] -3-
[(E) -1,3-Butadienyl] -3-cephem-4
-Carboxylate (80 mg) was obtained.

Physicochemical properties Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ (ppm): 3.45 (1 H, d, J = 17 Hz),
3.53 (1H, d, J = 17Hz), 3.84 (3
H, s), 5.0 to 5.04 (2H, m), 5.18.
(1H, d, J = 16Hz), 5.57 (1H, m),
6.23 (1H, m), 6.34 (1H, m), 6.7
4 (1H, s), 6.98 (1H, d, J = 16H
z), 7.2 (1H, d, J = 8 Hz) Positive ion-FAB-mass spectrum: m / z; 436
(M + 1) ⁺ , 458 (M + Na) ⁺ , 480 (M + N)
a) ⁺ infrared absorption spectrum ν _max (KBr); 3432,
2952, 1766, 1612, 1540, 1396,
1182, 1044, 1006cm ^-1

Example 2 (1) p-Methoxybenzyl 7β- (2-phenylacetamido) -3-[(E) obtained in Reference Example 2 (2)
-4-Diphenylphosphoryloxy-2-butenyl]-
3-Cephem-4-carboxylate 32.1 g (43
mmol) in 480 ml of acetonitrile and 14.6 ml (86 mmol) of diisopropylethylamine.
Was added dropwise at room temperature, and the mixture was stirred overnight at the same temperature. After the completion, the precipitate was collected by filtration, washed with diisopropyl ether, and dried under reduced pressure and p-methoxybenzyl 7β- (2-phenylacetamido) -3-[(E) -1,3-butadienyl] -3-cephem. 5.1 g of -4-carboxylate was obtained. Further, the above filtrate was distilled off under reduced pressure, the obtained residue was subjected to silica gel column chromatography, and eluted with methylene chloride-ethyl acetate (10: 1, v / v) to collect fractions containing a target substance, The solvent was distilled off under reduced pressure to obtain 4.9 g of p-methoxybenzyl 7β- (2-phenylacetamido) -3-[(E) -1,3-butadienyl] -3-cephem-4-carboxylate. .

Physicochemical properties Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ (ppm): 3.53 (2H, dd, J = 25.9,
14.2Hz), 3.62 (1H, d, J = 17.6H
z), 3.75 (3H, s), 3.94 (1H, d, J
= 17.6 Hz), 5.15 (1H, d, J = 4.9H)
z), 5.17 to 5.27 (3H, m), 5.39 (1
H, d, J = 17.1 Hz), 5.70 (1H, dd,
J = 8.3, 4.9 Hz), 6.66 to 6.77 (2
H, m), 6.94 (2H, d, J = 8.8Hz),
7.21 to 7.32 (5H, m), 7.36 (2H,
d, J = 8.8 Hz), 9.16 (1H, d, J = 8.
3 Hz) Positive ion-FAB-mass spectrum: m / z; 491
(M + 1) ⁺ infrared absorption spectrum ν _max (KBr); 3284,
3048, 2976, 1780, 1718, 1660,
1538, 1520, 1388, 1360, 1234,
1,170,698 cm ^-1

Alternative method p-methoxybenzyl 7β- (2-
Phenylacetamido) -3-trifluoromethanesulfonyloxy-3-cephem-4-carboxylate 586 mg (1 mmol) was dissolved in 1-methyl-2-pyrrolidinone 2 ml, and zinc chloride 273 mg (2 m
mol), tri (2-furyl) phosphine 12 mg
(0.05 mmol) and bis (dibenzylideneacetone) palladium (0) 15 mg (0.025 mmo
l) was added. After stirring for 10 minutes, 377 mg of (E) -1-tributylstannyl-1,3-butadiene (1.
1 mmol) was added together with 2 ml of 1-methyl-2-pyrrolidine and reacted at room temperature for 4 hours. The reaction solution was diluted with 30 ml of ethyl acetate, washed 3 times with water and once with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain a residue. Dissolve this residue in 80 ml of acetonitrile,
Wash with hexane three times. Concentrate the acetonitrile layer,
The obtained crude product (608 mg) was purified by subjecting it to silica gel column chromatography to obtain 385 mg (79%) of the desired product.
%) Was obtained. The physicochemical properties of this compound are shown in Example 2.
P-Methoxybenzyl 7β- (2- obtained in (3)
Phenylacetamide) -3-[(E) -1,3-butadienyl] -3-cephem-4-carboxylate. (2) p-Methoxybenzyl 7β- (2-phenylacetamido) -3-[(E) obtained in Example 2 (1)
-1,3-Butadienyl] -3-cephem-4-carboxylate was treated as in Example 1 (2) to give sodium 7β-[(Z) -2- (2-phenylacetamido)]-3-. [(E) -1,3-Butadienyl] -3-
Cephem-4-carboxylate is obtained.

Example 3 312 mg (1.5 mm) of phosphorus pentachloride under an argon atmosphere
was dissolved in 5 ml of methylene chloride, 122 μl (1.5 mmol) of pyridine was added to the solution at 5 ° C., and the mixture was stirred for 1 hour. The obtained reaction liquid was added with (1) of Example 2
245 mg of p-methoxybenzyl 7β- (2-phenylacetamido) -3-[(E) -1,3-butadienyl] -3-cephem-4-carboxylate obtained in 1.
(0.5 mmol) was added, and the mixture was stirred at 8 ° C. for 1.5 hours. The reaction solution was further cooled to -30 ° C, and then methanol 2m
1 was added and the mixture was stirred at -15 ° C for 1.5 hours. After the completion, 5 ml of methylene chloride and 10 ml of water were added. The aqueous layer was separated from the reaction solution, the organic layer was extracted with water, the aqueous layers were combined, neutralized with a saturated aqueous sodium hydrogen carbonate solution under ice cooling, and the resulting aqueous solution was extracted with chloroform. The chloroform extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to remove p-methoxybenzyl.
7β-amino-3-[(E) -1,3-butadienyl]
175 mg of -3-cephem-4-carboxylate was obtained as a crude product.

Physicochemical properties Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ (ppm): 3.32 (2H, brs), 4.82
(1H, d, J = 4.9 Hz), 5.04 (1H, d,
J = 5.4 Hz), 5.19 (2H, d, J = 2.4H)
z), 5.23 (1H, d, J = 11.7 Hz), 5.
97 (1H, d, J = 16.6Hz), 6.38 (1
H, dt, J = 17.1, 9.8 Hz), 6.63-
6.75 (2H, m) positive ion-FAB-mass spectrum: m / z; 372
(M + 1) ⁺

Example 4 p-Methoxybenzyl 7β obtained in Reference Example 3 (2)
-[(Z) -2- (5-tritylamino-1,2,4-
Thiadiazol-3-yl) -2- (methoxyimino)
Acetamide] -3-[(E) -4-diphenylphosphoryloxy-2-butenyl] -3-cephem-4-carboxylate (5 g, 4.76 mmol) was dissolved in 100 ml of acetonitrile, and diisopropylethylamine (2.6 ml) was added. It was added dropwise at room temperature. After stirring at room temperature for 24 hours, the solvent was distilled off under reduced pressure and the obtained residue was subjected to silica gel column chromatography and eluted with methylene chloride-ethyl acetate (15: 1, v / v) to give a fraction containing the desired product. The solvent was distilled off under reduced pressure, and the resulting foam was solidified with ethyl ether-hexane to give p-methoxybenzyl 7β-[(Z) -2- (5-tritylamino-1,2,2,
4-Thiadiazol-3-yl) -2- (methoxyimino) acetamido] -3-[(E) -1,3-butadienyl] -3-cephem-4-carboxylate 3.4 g
(89.5%) was obtained.

Physicochemical properties Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ (ppm): 3.58 (1H, dd, J = 17.6H)
z), 3.74 (3H, s), 3.85-3.93 (5
H, s, d), 5.17 (2H, m), 5.21 (1
H, d, J = 11.72 Hz), 5.38 (1H, d,
J = 17.1 Hz), 5.77 (1H, m), 6.3-
6.5 (1H, m), 6.6-6.8 (2H, m),
6.94 (2H, d, J = 8.7 Hz), 7.2-7.
4 (17H, m), 9.57 (1H, d, J = 8.3H
z), 9.99 (1 H, s) positive ion-FAB-mass spectrum: m / z; 799
(M + 1) ⁺ infrared absorption spectrum ν _max (KBr); 3296,
2952, 1778, 1724, 1688, 1520,
1388, 1364, 1248, 1220, 1160,
1042,702 cm ^-1

Example 5 p-Methoxybenzyl 7β obtained in Reference Example 4 (2)
-[(Z) -2- (2-tritylamino-4-thiazolyl) -2- (1-tert-butoxycarbonyl-1)
-Methylethoxyimino) acetamide] -3-
[(E) -4-Diphenylphosphoryloxy-2-butenyl] -3-cephem-4-carboxylate 9.95
g (8.46 mmol) was dissolved in 177 ml of acetonitrile, and diisopyropyrethylamine (4.6 ml) was added dropwise under ice cooling. After stirring the mixture at the same temperature for 24 hours, the solvent was distilled off under reduced pressure and the obtained residue was subjected to silica gel column chromatography to obtain methylene chloride-ethyl acetate (15: 1,
v / v) was eluted and the fractions containing the desired product were collected, the solvent was distilled off under reduced pressure and the resulting foam was solidified with ethyl ether-hexane to give p-methoxybenzyl 7β-.
[(Z) -2- (2-Tritylamino-4-thiazolyl) -2- (1-tert-butoxycarbonyl-1-
Methylethoxyimino) acetamide] -3-[(E)
7.53 g (96.3%) of -1,3-butadienyl] -3-cephem-4-carboxylate was obtained.

Physicochemical properties Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ (ppm): 1.35 (15 H, s), 3.60 (1
H, d, J = 17.6 Hz), 3.91 (1H, d, J
= 15.8 Hz), 5.09-5.20 (1H, m),
5.20 (2H, s), 5.25 (1H, d, J = 1
1.2Hz), 5.38 (1H, d, J = 16.6H
z), 5.70 (1 H, m), 6.3-6.45 (1
H, m), 6.69-6.78 (3H, m), 6.93.
(2H, d, J = 8.8 Hz), 7.2-7.4 (17
H, m), 8.80 (1H, s), 9.36 (1H,
d, J = 8.3 Hz) Positive ion FAB mass spectrum; m / z: 926 (M +
1) ⁺ infrared absorption spectrum ν _max (KBr); 3408,2
922, 2952, 1788, 1726, 1696, 1
520, 1386, 1368, 1304, 1252, 1
220, 1168, 1146, 1006, 702cm ^-1

Example 6 p-Methoxybenzyl 7β obtained in Reference Example 5 (3)
-[(Z) -2- (2-Tritylamino-4-thiazolyl) -2- (1-methoxy-1-methyl) ethoxyiminoacetamide] -3-[(E) -4-diphenylphosphoryloxy-2- 1.4 g (1.27 mmol) of butenyl] -3-cephem-4-carboxylate was dissolved in 20 ml of acetonitrile, and 0.69 ml of diisopropylethylamine was added under ice cooling. After stirring under ice cooling for 3 days, the solvent was distilled off under reduced pressure and the obtained residue was subjected to silica gel column chromatography and eluted with methylene chloride-ethyl acetate (15: 1, v / v) to obtain the desired product. The fractions containing were collected. The solvent was distilled off under reduced pressure, and the obtained foam was solidified with ethyl ether-hexane to give p-methoxybenzyl 7β-[(Z) -2- (2-tritylamino-4).
-Thiazolyl) -2- (1-methoxy-1-methyl) ethoxyiminoacetamide] -3-[(E) -1,3-
Butadienyl] -3-cephem-4-carboxylate 896 mg (82.7%) was obtained.

Physicochemical properties Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ (ppm): 1.39 (6H, s), 3.11 (3
H, s), 3.60 (1H, d, J = 17.6 Hz),
3.74 (3H, s), 3.91 (1H, d, J = 1
7.6 Hz), 5.06-5.49 (5H, m), 5.
69 (1H, d, J = 7.8Hz), 6.39 (1H,
m), 6.66-6.78 (3H, m), 6.93 (2
H, d, J = 8.79 Hz), 7.20-7.4 (17)
H, m), 8.87 (1H, s), 9.77 (1H,
d, J = 8.3 Hz) Positive ion-FAB-mass spectrum: m / z; 856
(M) ⁺ , 784 (MC (CH ₃ ) ₂ OCH ₃ +1) ⁺ infrared absorption spectrum ν _max (KBr); 3336,
3072, 3004, 2952, 2844, 1790,
1722, 1692, 1618, 1516, 1450,
1384, 1306, 1248, 1220, 1170,
1106, 1070, 1034, 1004, 978, 8
92,848,824,808,754,702cm ^-1

Alternative method (Z) -2-Hydroxyimino-2- (tritylamino-4-thiazolyl) acetic acid 2.1 g (4.9 mmol) was suspended in 25 ml of methylene chloride, and 2-methoxypropene was added at 4.degree. Add 1 ml. After stirring at room temperature for 30 minutes, the solvent is distilled off under reduced pressure. Add 20 ml of methylene chloride to the residue,
Add phosphorus pentachloride 1.05g at -21 ℃,
Stir at 0 ° C. for 50 minutes and then (Z) -2- (1-methoxy-
A solution of 1-methyl) ethoxyimino-2- (2-tritylamino-4-thiazolyl) acetic acid chloride is obtained. On the other hand, p-methoxybenzyl 7β-amino-3-
[(E) -1,3-Butadienyl] -3-cephem-4
-Carboxylate / hydrochloride 1.82 g (4.45 mm)
Ol) is suspended in 20 ml of methylene chloride, and 1.12 ml of bis (trimethylsilyl) acetamide is added at 4 ° C. After stirring at room temperature for 30 minutes, pyridine 1.6 at -60 ° C.
ml and the above acetic acid chloride solution are added sequentially. -35-
After stirring for 30 minutes at 20 ° C., the mixture is poured into 100 ml of a saturated aqueous solution of monopotassium phosphate and extracted twice with 100 ml of methylene chloride. The extract was washed with saturated potassium phosphate monobasic solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography and subjected to hexane-ethyl acetate (3: 2). ~ 1: 1, v /
v) was eluted and the fractions containing the desired product were collected and the solvent was distilled off under reduced pressure to give the foam compound p-methoxybenzyl.
7β-[(Z) -2- (2-Tritylamino-4-thiazolyl) -2- (1-methoxy-1-methyl) ethoxyiminoacetamide] -3-[(E) -1,3-butadienyl]- 3-Cephem-4-carboxylate 625
mg (16.4%) was obtained. The physicochemical properties are the same as those described above.

Example 7 p-Methoxybenzyl 7β obtained in Reference Example 6 (3)
-[(Z) -2- (2-Tritylamino-4-thiazolyl) -2-fluoromethoxyimino) acetamide]-
3-[(E) -4-diphenylphosphoryloxy-2-
Butenyl] -3-cephem-4-carboxylate 1.
32 g (1.24 mmol) of acetonitrile 20 ml
Dissolve in, and under ice cooling, diisopyropyrethylamine 0.6
7 ml was added. After stirring for 2 days under ice cooling, the solvent was distilled off under reduced pressure and the obtained residue was subjected to silica gel column chromatography to give methylene chloride-ethyl acetate (15: 1, v
/ V) and the fractions containing the desired product were collected, the solvent was evaporated under reduced pressure, and the resulting foam was solidified with ethyl ether-hexane to give p-methoxybenzyl 7β-[(Z).
-2- (2-Tritylamino-4-thiazolyl) -2-
Fluoromethoxyimino) acetamide] -3-
[(E) -1,3-Butadienyl] -3-cephem-4
-Provided 966 mg (95.6%) of carboxylate.

Physicochemical properties Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ (ppm): 3.62 (1H, d, J = 17.6H)
z), 3.88 (1H, d, J = 17.6Hz), 5.
09-5.30 (4H, m), 5.39 (1H, d, J
= 17.1 Hz), 5.63 (1 H, s), 5.70
(1H, dd, J = 7.8, 4.9 Hz), 5.77
(1H, s), 6.3-6.5 (1H, m), 6.65
-6.8 (2H, m), 6.89 (1H, s), 6.9
3 (2H, d, J = 8.8 Hz), 7.2-7.4 (1
7H, m), 8.92 (1H, s), 9.77 (1H,
d, J = 7.8 Hz) Positive ion-FAB-mass spectrum; m / z: 816
(M + 1) ⁺ infrared absorption spectrum ν _max (KBr); 3312,3
068,3040,2980,2844,1788,1
726, 1692, 1616, 1520, 1466, 1
386, 1364, 1306, 1248, 1220, 1
168, 1098, 1068, 1034, 1004, 7
70,702 cm ^-1

Example 8 5.69 g of (Z) -2- (5-tert-butoxycarbonylamino-1,2,4-thiadiazol-3-yl) -2-hydroxyiminoacetic acid was added to 60 ml of methylene chloride.
And 8.5 ml of 2-methoxypropene were added to the mixture at room temperature for 30
After stirring for a minute, the solvent was distilled off and 7.22 g of (Z) -2-
(5-tert-butoxycarbonylamino-1,2,
4-Thiadiazol-3-yl) -2- (1-methoxy-1-methyl) ethoxyiminoacetic acid was obtained as a foamy compound. From this, 1.72 g (4.77 mmol) was taken, dissolved in 20 ml of methylene chloride, 1.03 g (4.95 mmol) of phosphorus pentachloride was added to this at -20 ° C, and the mixture was stirred for 1 hour to prepare an acid chloride. On the other hand, 4-methoxybenzyl 7-amino-3- (1,3-butadienyl)
-3-Cephem-4-carboxylate hydrochloride 1.60
20 g of methylene chloride and 1 g (4.30 mmol) of bistrimethylsilylacetamide (BSA) 1.12
ml was added and stirred at room temperature for 85 minutes to form a uniform solution.
This solution was cooled to -40 ° C, 1.6 ml of pyridine and then the above-mentioned acid chloride were added, and the reaction was carried out for 1.5 hours. The reaction solution was poured into 100 ml of saturated monobasic sodium phosphate, extracted twice with 100 ml of chloroform, and the organic layer was collected, washed with saturated sodium monobasic sodium phosphate three times and saturated saline once, and then anhydrous magnesium sulfate. Dried in. The crude product obtained by distilling off the solvent under reduced pressure was applied to a silica gel column, and hexane-ethyl acetate (1:
1, v / v) and p-methoxybenzyl 7β-
[(Z) -2- (5-tert-Butoxycarbonylamino-1,2,4-thiadiazol-3-yl) -2-
(1-Methoxy-1-methyl) ethoxyiminoacetamide] -3-[(E) -1,3-butadienyl] -3-
368 mg of cephem-4-carboxylate were obtained.

Physicochemical properties Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ (ppm): 1.46 (6H, s), 1.50 (9
H, s), 3.17 (3H, s), 3.63 and 3.9.
5 (2H, ABq), 3.76 (3H, s), 5.21
(1H, d, J = 6Hz), 5.23-5.27 (2
H, m), 5.38 (1H, d, J = 17 Hz), 5.
88 (1H, q, J = 6, 8Hz), 6.38-6.4
2 (1H, m), 6.7 (1H, m), 6.94 and 7.36 (4H, ABq), 9.69 (1H, d) Positive ion-FAB-mass spectrum: m / z; 643 _{(M-CH (CH 3)} 2 OCH 3 + H) + infrared absorption _{spectrum: ν max (KBr): 2996} ,
1788, 1722, 1548, 1386, 1374,
1250,1154cm ^-1

Example 9 p-Methoxybenzyl 7 obtained in Reference Example 10 (2)
β-[(Z) -2- (5-tritylamino-1,2,4
-Thiadiazol-3-yl) -2-fluoromethoxyimino) acetamido] -3-[(E) -4-diphenylphosphoryloxy-2-butenyl] -3-cephem-
By using 1.4 g (1.3 mmol) of 4-carboxylate as a starting material and using the same method as in Example 4, p-methoxybenzyl 7β-[(Z) -2- (5-tritylamino-1,2) was prepared. , 4-thiadiazol-3-yl) -2
-Fluoromethoxyimino) acetamide] -3-
[(E) -1,3-Butadienyl] -3-cephem-4
-840 mg (79.1%) of the carboxylate was obtained.

Physicochemical properties Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ (ppm): 3.60 (1H, d, J = 17.6H)
z), 3.75 (3H, s), 3.90 (1H, d, J
= 17.6 Hz), 5.09-5.20 (1H, m),
5.19 (2H, s), 5.25 (1H, d, J = 1
0.7Hz), 5.38 (1H, d, J = 17.1H
z), 5.70 (1H, s), 5.80 (1H, m),
5.84 (1H, s), 6.3-6.45 (1H,
m), 6.34-6.76 (2H, m), 6.94 (2
H, d, J = 8.3 Hz), 7.2-7.4 (17H,
m), 9.75 (1H, d, J = 8.3 Hz), 10.
08 (1H, s) positive ion-FAB-mass spectrum; m / z: 817
(M + 1) ⁺ infrared absorption spectrum; ν _max (KBr): 3308,
3040, 2980, 1780, 1698, 1616,
1520, 1450, 1390, 1366, 1306,
1250, 1222, 1168, 1124, 1076
1004,756,702cm ^-1

[0118]

[Table 12]

[Table 13]

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display area C07D 501/22 108 7602-4C 109 7602-4C 111 7602-4C 113 7602-4C // A61K 31 / 545 ADZ 9454-4C (72) Inventor Kenichiro Sakamoto 2-5-9 Ninomiya, Tsukuba City, Ibaraki Prefecture Rumi Tsukuba 232 (72) Inventor Hiroyuki Kudou 2-37-2-402 Kasuga, Tsukuba City, Ibaraki Prefecture

Claims (3)

[Claims] 1. The following general formula (I): (The symbols in the formula have the following meanings: R ¹ : a hydrogen atom, an acyl group or an amino group protecting group; R ² : a hydrogen atom, an ester residue or a carboxyl protecting group.) Or a cephalosporin derivative or Its salt. 2. R ¹ is a hydrogen atom or a compound of the formula (The symbols in the formulas have the following meanings. ^Ra : optionally substituted (1) one or more heteroatoms selected from a sulfur atom, a nitrogen atom or an oxygen atom is a ring. A 5- to 6-membered heterocyclic group or (2) a phenyl group or a cyclopentadienyl group, R ^b : a hydrogen atom, a protective group for a hydroxyl group, an optionally substituted lower alkyl group, a lower alkenyl group, a lower group Alkynyl group, lower cycloalkyl group or formula Group represented by. R ³ and R ^{4 are the} same or different and are a hydrogen atom, a methyl group or an ethyl group, or a lower alkylene group and a lower alkenylene group in which R ³ and R ⁴ are integrated. R ⁵ : Protecting group for carboxyl group X: (1) hydrogen atom, (2) optionally protected amino group or hydroxyl group, (3) lower alkyl group substituted with optionally protected hydroxyl group, or ( 4) Carboxyl group or esterified carboxyl group. ] The cephalosporin derivative or its salt of Claim 1 which is a group shown by these. 3. R ¹ is a hydrogen atom or a compound of the formula: (The symbols in the formulas have the following meanings: Y: Methine group (-CH =) or nitrogen atom ^Re : Hydrogen atom or amino group protecting group ^Rb : Hydrogen atom, hydroxyl group protecting group, substituted A lower alkyl group, a lower alkenyl group, a lower alkynyl group, a lower cycloalkyl group or a compound of the formula: Group represented by. R ³ and R ^{4 are the} same or different and are a hydrogen atom, a methyl group or an ethyl group, or a lower alkylene group and a lower alkenylene group in which R ³ and R ⁴ are integrated. R ⁵ : Protecting group for carboxyl group X: (1) hydrogen atom, (2) optionally protected amino group or hydroxyl group, (3) lower alkyl group substituted with optionally protected hydroxyl group, or ( 4) Carboxyl group or esterified carboxyl group. ] The cephalosporin derivative or its salt of Claim 1 which is a group shown by these.