JPH0354953B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to novel cefem compounds and cepham compounds, and more particularly to 7-substituted-3-cefem compounds that have antibacterial activity and are also useful as intermediates for producing compounds with better antibacterial activity. (or Cepham)-4-carboxylic acid and its salts. The object of this invention is to have excellent antibacterial activity against a wide range of pathogenic bacteria including gram-negative and gram-positive bacteria, and to be useful as an intermediate for producing compounds with even more excellent antibacterial activity. An object of the present invention is to provide a novel 7-substituted-3-cephaem (or cefame)-4-carboxylic acid and a salt thereof. The cefem compound and cefam compound provided by this invention are represented by the following general formula (). [In the formula, R ¹ is the formula

[Formula] (where R ⁵ means an amino group or a protected amino group)
A is a methylene group or a thiazolyl group or a haloacetyl group represented by the formula

[Formula] (where R ² means a hydrogen atom or a C ₁ -C ₈ alkyl group), R ³ is a hydrogen atom or a group represented by the formula -O-R ⁶ (where R ⁶ is a hydrogen atom or an acyl group) R ⁴ is a carboxy group or an ester thereof, and the dotted line represents a 3-cephaem nucleus or a cephaem nucleus, respectively, provided that 1) R ¹ is of the formula:

When it is a thiazolyl group represented by [Formula] (where R ⁵ is the same as above), A is the formula:

[Formula] (where R ² is the same as above), 2) When R ¹ is a haloacetyl group, R ³ is a hydrogen atom, the dotted line is a 3-cephem nucleus, 3) R ¹ is the formula

A thiazolyl group represented by [Formula] (where R ⁵ is the same as above), and R ³
When is a hydrogen atom, A has the formula:

[Formula] The dotted line is a 3-cephem nucleus, and 4) When R ³ is a group represented by the formula: -O-R ⁶ (where R ⁶ means an acyl group), , the dotted line indicates a cephalic nucleus] The above compound () is a compound useful as an antibacterial agent, and is also a useful intermediate for producing a better antibacterial agent. That is, a compound useful as an antibacterial agent is represented by the following general formula ('), and this compound is also useful as an intermediate for producing a compound with excellent antibacterial activity. (In the formula, R ² , R ³ , R ⁴ and R ⁵ are the same as above.) On the other hand, an intermediate useful for producing the above compound (') is represented by the following general formula (''). (In the formula, R ¹ _a means a haloacetyl group, and R ⁴ and A are the same as above.) In the formulas representing the raw material compound and target compound of this invention, the formula

The thiazolyl group represented by [Formula] (where R ⁵ is the same as above) is the formula

It is known that it has a tautomeric relationship with the thiazolinyl group represented by [Formula] (where R ⁵ ' means an imino group or a protected imino group) as shown in the following balanced formula. There is. (In the formula, R ⁵ and R ⁵ ' are the same as above.) Both of these tautomeric isomers are generally treated as substantially the same substance. Therefore, for convenience, in this specification, both isomers are referred to as "thiazolyl" and the formula

It is represented by the formula: (where R ⁵ is the same as above), and both isomers based on the above tautomerism are included within the scope of the present invention. Also, the substructural formula The 3-hydroxy-3-cephem compound represented by has the partial structural formula It has a relationship of so-called keto-enol tautomerism with the 3-oxycepham compound represented by, and the former enol isomer is usually more stable than the latter keto isomer. Therefore, both of these isomers are within the scope of this invention and herein the more stable enol isomer, i.e. 3-hydroxy-3
-Both will be referred to as cefem compounds. Next, regarding various definitions in the general formulas representing the raw material compound and target compound of this invention,
This will be explained in more detail. "Lower" means carbon number 1 unless otherwise specified.
It means a group of 6 to 6. The C ₁ - C ₈ alkyl group of R ² is methyl, ethyl,
propyl, isopropyl, butyl, isobutyl,
It means a residue of a linear or branched C1-C8 alkane such as t-butyl, bentyl, neopentyl, hexyl, heptyl, octyl, and preferable examples thereof include a lower alkyl group, and Preferred examples include alkyl groups having 1 to 4 carbon atoms. Preferred examples of the "carboxy group ester" for ^R4 include methyl ester, ethyl ester,
Alkyl esters, vinyl esters, allyl esters such as propyl ester, isopropyl ester, butyl ester, isobutyl ester, t-butyl ester, pentyl ester, t-bentyl ester, hexyl ester, heptyl ester, octyl ester, 1-cyclopropylethyl ester alkenyl esters such as ethynyl esters, alkynyl esters such as propyl esters, alkoxyalkyl esters such as methoxymethyl ester, ethoxymethyl ester, isopropoxymethyl ester, 1-methoxyethyl ester, 1-ethoxyethyl ester, methylthiomethyl ester, ethyl thiomethyl ester,
Alkylthioalkyl esters such as ethylthioethyl ester and isopropylthiomethyl ester, haloalkyl esters such as 2-iodoethyl ester and 2,2,2-trichloroethyl ester, acetoxymethyl ester, propionyloxymethyl ester, butyryloxymethyl ester, Valeryloxymethyl ester, pivaloyloxymethyl ester, hexanoyloxymethyl ester, 2-acetoxyethyl ester,
Alkanoyloxyalkyl esters such as 2-propionyloxyethyl ester and palmitoyloxymethyl ester, mesylmethyl ester,
Alkanesulfonylalkyl esters such as 2-mesylethyl ester, benzyl ester, 4-methoxybenzyl ester, 4-nitrobenzyl ester, phenethyl ester, trityl ester, benzhydryl ester, bis(methoxyphenyl)methyl ester, 3,4 -dimethoxybenzyl ester, 4-hydroxy-3,5-di-
Substituted or unsubstituted aralkyl esters such as t-butylbenzyl ester, substituted or unsubstituted aryl esters such as phenyl ester, tolyl ester, t-butyl phenyl ester, xylyl ester, mesityl ester, cumenyl ester, salicyl ester, Silyl compounds such as trialkylsilyl compounds, dialkylalkoxysilyl compounds, or trialkoxysilyl compounds such as trimethylsilyl ester, triethylsilyl ester, dimethylmethoxysilyl ester, dimethylethoxysilyl ester, diethylmethoxysilyl ester, trimethoxysilyl ester, triethoxysilyl ester, etc. Examples include esters with compounds. As the protecting group for the "protected amino group" of ^R5 , common N-protecting groups such as benzyl,
Substituted or unsubstituted al(lower) alkyl groups such as benzhydryl, trityl, 4-methoxybenzyl, 3,4-dimethoxybenzyl, halo(lower) alkyl groups such as trichloromethyl, trichloroethyl, trifluoromethyl, and tetrahydropyranyl groups , a substituted phenylthio group, a substituted alkylidene group, a substituted aralkylidene group, a substituted cycloalkylidene group, and an acyl group. Acyl groups suitable as N-protecting groups include, for example, substituted or unsubstituted lower alkanoyl groups such as formyl, acetyl, chloroacetyl, trifluoroacetyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, 1-cyclopropylethoxy. Substituted or unsubstituted lower alkoxycarbonyl groups such as carbonyl, isopropoxycarbonyl, butoxycarbonyl, t-butoxycarbonyl, pentyloxycarbonyl, t-pentyloxycarbonyl, hexyloxycarbonyl, trichloroethoxycarbonyl, 2-pyridylmethoxycarbonyl, benzyloxy carbonyl, benzhydryloxycarbonyl, 4-
Substituted or unsubstituted alkoxycarbonyl groups such as nitrobenzyloxycarbonyl,
Lower cycloalkoxycarbonyl groups such as cyclopentyloxycarbonyl and cyclohexyloxycarbonyl, 8-quinolyloxycarbonyl groups,
Examples include succinyl group and phthaloyl group. Furthermore, reaction products of silicon, boron, aluminum or phosphorus compounds with amino groups are also included in the N-protecting group. Examples of such compounds include trimethylsilyl chloride, trimethoxysilyl chloride, boron trichloride, butoxyboron dichloride, aluminum trichloride, diethoxyaluminum chloride, phosphorus dibromide, and phenylphosphorus dibromide. Examples of the "acyl group" of R ⁶ include formyl, acetyl, butyryl, isobutyryl, isovaleryl,
Examples include lower alkanoyl groups such as pivaloyl, aroyl groups such as benzoyl and toluoryl, lower alkanesulfonyl groups such as mesyl, ethanesulfonyl, 1-methylethanesulfonyl, propanesulfonyl, butanesulfonyl, and arenesulfonyl groups such as benzenesulfonyl and tosyl. be done. In this invention, R ⁵ "protected amino group" and R ⁴ "carboxy group ester" are:
Specifically, these groups refer to the groups described above, and they are used for the purpose of temporarily protecting amino groups and carboxy groups during the production of target compounds by chemical or biological methods, and This includes cases where the target compound itself is used for the purpose of improving its physiological properties or pharmaceutical properties. That is, the meaning of these groups in terms of production is clear from the explanation of the production method described below, for example, when R ⁵ is a free amino group and/or
If R ⁴ is a free carboxy group and there is a risk that such groups may cause undesirable side reactions during the reaction, a protected amino group and/or Each is converted to an ester of carboxyl group,
In order to prevent such side reactions, and to convert the esters of protected amino groups and/or carboxy groups in the reaction product into free amino groups and/or free carboxy groups, respectively, as necessary, after the reaction. be. On the other hand, the use of these groups for the purpose of improving the physiological properties or pharmaceutical properties of the target compound means improving the solubility, stability, and absorption of active substances that have free amino and/or carboxyl groups. For the purpose of improving properties such as toxicity and toxicity, these free radicals are converted into esters of protected amino groups and/or carboxy groups. Salts of the target compound (') include salts with inorganic bases or acids, such as alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as calcium salts and magnesium salts, ammonium salts, hydrochlorides, Inorganic acid salts such as hydrobromides, sulfates, phosphates, carbonates, bicarbonates, and salts with organic bases or organic acids, such as trimethylamine salts, triethylamine salts, pyridine salts, procaine salts, picoline salts , amine salts such as dicyclohexylamine salt, N,N′-dibenzylethylenediamine salt, N-methylglucamine salt, diethanolamine salt, triethanolamine salt, tris(hydroxymethylamino)methane salt, phenethylbenzylamine salt, acetate, maleate, lactate, tartrate, methanesulfonate,
Examples include organic carboxylic acids or sulfonates such as benzenesulfonate and toluenesulfonate, basic or acidic amino acid salts such as arginyl salt, aspartate, glutamate, lysine salt, and serine salt. The object compound () of this invention can be produced by any of the following methods. (In the formula, R ² _a is a C ₁ -C ₈ alkyl group, R ⁴ _a is an ester of a carboxy group, R ⁵ _a is a protected amino group,
R ⁶ _a means an acyl group, R ¹ , R ¹ _a , R ² ,
(R ³ , R ⁴ , R ⁵ , A and dotted lines are all the same as above) Each of the above methods will be explained in detail below. Method A: N-acylation The target compound () and its salt are 7-amino-3-cephaem (or cephaem) compound ()
or a reactive derivative at its amino group or a salt thereof, a carboxylic acid () or a reactive derivative at its carboxy group or a salt thereof, which is well known in the field of so-called β-lactam compounds such as penicillin, cephalosporin, etc. It is produced by acting according to a conventional method applied to amidation reactions. Among the raw material compounds (), novel compounds can be produced according to the method described below. Reactive derivatives at the amino group of the compound () include various derivatives that can be used in so-called amidation reactions, and specifically, for example, isocyanato, isothiocyanato, or reaction with silyl compounds such as trimethylsilylacetamide and bis(trimethylsilyl)acetamide. Derivatives formed by the reaction, aldehyde compounds such as acetaldehyde, isopentaldehyde, benzaldehyde, salicylaldehyde, phenylacetaldehyde, p-nitrobenzaldehyde, m-chlorobenzaldehyde, hydroxynaphthaldehyde, furfural, thiophenecarbaldehyde, or these aldehyde compounds Derivatives formed by reaction with reactive derivatives such as hydrates, acetals, hemiacetals, and enolates, ketone compounds such as acetone, methyl ethyl ketone, methyl isobutyl ketone, acetylacetone, and ethyl acetoacetate, or their ketals, hemiketals, and enolates, etc. Examples include derivatives formed by reaction with reactive derivatives of , reaction products with phosphorus compounds such as phosphorus oxychloride and phosphorus trichloride, and reaction products with sulfur compounds such as thionyl chloride. As the salt of compound (), those exemplified as the salt of compound () are also exemplified here. Examples of reactive derivatives at the carboxy group of the compound () include acid halides, acid anhydrides, active amides, active esters, and more specifically acid halides such as acid chlorides and acid bromides;
Dialkyl phosphoric acid mixed acid anhydride, phenyl phosphoric acid mixed acid anhydride, diphenyl phosphoric acid mixed acid anhydride,
Dibenzyl phosphoric acid mixed acid anhydride, substituted phosphoric acid mixed acid anhydride such as halogenated phosphoric acid mixed acid anhydride, dialkyl phosphorous acid mixed acid anhydride, sulfurous acid mixed acid anhydride, thiosulfuric acid mixed acid anhydride, sulfuric acid mixture Acid anhydrides, alkyl carbonic acid mixed acid anhydrides, aliphatic carboxylic acids (e.g. pivalic acid, pentanoic acid, isopentanoic acid, 2-ethylbutanoic acid, trichloroacetic acid)
Acid anhydrides such as mixed acid anhydrides, aromatic carboxylic acids (e.g. benzoic acid) mixed acid anhydrides, symmetrical acid anhydrides, acid amides with imidazoles, 4-substituted imidazoles, dimethylpyrazoles, triazoles, tetrazoles, etc. methyl ester, methoxymethyl ester, dimethyliminomethyl [(CH ₃ ) ₂ N ⁺ =CH−] ester, vinyl ester, propargyl ester, p-nitrophenyl ester, 2,4-dinitrophenyl ester,
Trichlorophenyl ester, pentachlorophenyl ester, mesyl phenyl ester, phenyl azophenyl ester, phenyl thioester, p-nitrophenyl thioester, p-cresyl thioester, carboxymethyl thioester, pyranyl ester, pyridyl ester, piperidyl ester , 8-quinolylthioester, or N,N-dimethylhydroxylamine, 1-
Examples include esters such as esters with hydroxy-2-(1H)-pyridine, N-hydroxysuccinimide, N-hydroxyphthalimide, 1-hydroxybenzotriazole, 1-hydroxy-6-chloro-1H-benzotriazole, etc. It will be done. Compounds () and reactive derivatives of () are
Depending on the type of raw material compounds () and () and reaction conditions such as other reagents, solvents, and temperature,
Appropriately selected from the above. Salts of the compound () include alkali metal salts such as sodium salts and potassium salts, salts with inorganic bases such as alkaline earth metal salts such as calcium salts and magnesium salts, trimethylamine salts, triethylamine salts, N,N-dimethyl Examples include salts with organic bases such as tertiary amine salts such as aniline salts and pyridine salts, and salts with inorganic acids such as hydrochlorides and hydrobromides. This reaction usually involves water, acetone, dioxane, acetonitrile, chloroform, benzene,
The reaction is carried out in methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine, other solvents that do not adversely affect the reaction, or a mixed solvent thereof. When using the compound () in the form of a free acid or its salt in this reaction, for example, N,
N'-dicyclohexylcarbodiimide, N-cyclohexyl-N'-morpholinoethylcarbodiimide, N-cyclohexyl-N'-(4-diethylaminocyclohexyl)carbodiimide, N,
N'-diethylcarbodiimide, N,N'-diisopropylcarbodiimide, N-ethyl-N'-(3
-dimethylaminopropyl) carbodiimide, bisimidazolide compounds such as N,N'-carbonylbis(2-methylimidazole), and imine compounds such as pentamethyleneketene-N-cyclohexylimine and diphenylketene-N-cyclohexylimine. , ethoxyacetylene, olefinic or acetylenic ether compounds such as β-chlorovinylethyl ether, 1-(4-chlorobenzenesulfonyloxy)
-6-chloro-1H-benzotriazole, N-
Ethylbenzisoxazolium salt, N-ethyl-
5-Phenyl isoxazolium-3'-sulfonate, polyphosphoric acid, phosphorous trialkyl ester, polyphosphoric acid ethyl ester, polyphosphoric acid isopropyl ester, phosphorus oxychloride, phosphorus trichloride, diethylchlorophosphite, orthophenylene chloro Preferably, the reaction is carried out in the presence of a condensing agent such as a phosphorus compound such as a phosphite, a Vilsmeier reagent prepared by the reaction of dimethylformamide with thionyl chloride, phosphorus oxychloride or phosgene. In this reaction, if the reaction between the compound () and the syn isomer of the oxyiminoacylating agent () is carried out in the presence of the Vilsmeier reagent as described above under relatively mild conditions near neutrality, the oxyiminoacylating agent () is The syn isomer of compound () is selectively obtained in high yield. Although the target compound () and its salts are useful as antibacterial agents in themselves, some are also useful as starting materials in the following methods. Method B: C-nitrosation The target compound (a) and its salt are produced by reacting the compound () or its salt with a nitrosating agent. The starting material () is R ¹ is a haloacetyl group, R ³
corresponds to the above 3-cephem compound () when is a hydrogen atom and A is a methylene group, by the above method A, preferably by reacting diketene and a halogen such as chlorine or bromine to the compound (). Manufactured. The compound () produced in this way may be used in the reaction of this method without being particularly isolated or purified. Preferred examples of nitrosating agents include nitrous acid and its derivatives, such as nitrosyl halides such as nitrosyl chloride and nitrosyl bromide, alkali metal nitrites such as sodium nitrite and potassium nitrite, butyl nitrite, and pentyl nitrite. Examples include alkyl nitrite esters such as esters. When using a salt of nitrous acid as a nitrosating agent, the reaction is preferably carried out in the presence of an inorganic or organic acid such as hydrochloric acid, sulfuric acid, formic acid, or acetic acid. Furthermore, when using a nitrous acid ester as a nitrosating agent, it is preferable to carry out the reaction in the presence of a strong base such as an alkali metal alkoxide. This reaction is usually carried out in a solvent, and examples of the solvent include water, acetic acid, benzene, methanol, ethanol, tetrahydrofuran, and other solvents that do not adversely affect this reaction. Although the reaction temperature is not particularly limited, it is usually preferable to carry out the reaction under cooling or at room temperature. Compound (a) and its salts thus obtained are used as starting materials in the following methods C and D. Method C: Etherification The target compound (b) and its salt can also be produced by reacting the compound () or its salt with a C ₁ -C ₈ alkylating agent. The starting material () corresponds to the above compound () when the group A is an N-hydroxyiminomethylene group and can be prepared by methods A and B described above or by the following method D. Preferred examples of C ₁ -C ₈ alkylating agents include:
Di(C ₁ −C ₈ ) such as dimethyl sulfate and diethyl sulfate
Diazo(C ₁ -C ₈ ) alkanes such as alkyl sulfuric acid, diazomethane, diazoethane, halogenated C ₁ - such as iodomethyl, iodoethyl, bromoethyl, etc.
Common C1 _{- C8} alkylating agents such as _{C8 alkyl, sulfonic acid C1-C8 alkyl esters} such as toluenesulfonic acid methyl ester, and the like. Diazo( _C1 - _C8 ) as _C1 - _C8 alkylating agent
When an alkane is used, it is usually preferable to carry out the reaction in diethyl ether, dioxane, or other solvent that does not adversely affect the reaction, under cooling or at room temperature. If other C ₁ -C ₈ alkylating agents are used, the reaction is usually carried out in water, acetone, ethanol, diethyl ether, dimethylformamide, or any other solvent that does not adversely affect the reaction, with cooling or heating. Preferably, it is carried out in the presence of an inorganic or organic base such as that used in the basic hydrolysis in Method E below. Method D: Ring formation of thiazole Compound (c) and its salt can be prepared by forming a compound (
It can also be produced by reacting a) or a salt thereof with a thiourea compound (). In the raw material compound (a), R ¹ is a haloacetyl group, R ³ is a hydrogen atom, and A has the formula

Corresponds to the above 3-cephem compound () when it is a group represented by [Formula], and corresponds to the above method A
and B. This reaction is usually carried out at room temperature or under heating in water, alcohols such as methanol and ethanol, benzene, dimethylformamide, tetrahydrofuran, and other solvents that do not adversely affect the reaction. This method uses a compound (c) having antibacterial activity;
Compound (c) especially when R ⁵ is an amino group
is an advantageous method for producing via method B above. Method E: Removal of amino protecting group The target compound (a) and its salt can also be produced by subjecting compound () or its salt to an elimination reaction of the protecting group at the protected amino group of R ⁵ _a . can do. The starting compound () is R ¹ of the formula

[Formula] (Here, R ₅ means a protected amino group)
is a thiazolyl group represented by the formula

It corresponds to the above compound () when it is a group represented by the formula: (where R ² is the same as above), and can be obtained, for example, by the above method A. This elimination reaction is carried out according to conventional methods such as hydrolysis and reduction. These methods are appropriately selected depending on the type of protecting group to be removed. Hydrolysis is a method using acid (acidic hydrolysis),
This includes a method using a base (basic hydrolysis), a method using hydrazine, etc. Among these methods, hydrolysis using acid is
Among the N-protecting groups listed above, for example, acyl groups such as substituted or unsubstituted lower alkanoyl, substituted or unsubstituted lower alkoxycarbonyl, substituted or unsubstituted alkoxycarbonyl, lower cycloalkoxycarbonyl, etc. , a substituted phenylthio group, a substituted alkylidene group, a substituted aralkylidene group, a substituted cycloalkylidene group, and the like. Examples of acids used in this acidic hydrolysis include inorganic or organic acids such as formic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, and hydrochloric acid, and cationic ion exchange resins. Among these, preferred acids are:
Examples include those that can be easily separated from the reaction product by conventional methods such as neutralization or distillation under reduced pressure, such as formic acid, trifluoroacetic acid, and hydrochloric acid. The acid suitable for this reaction is preferably selected as appropriate, taking into consideration the chemical properties of the starting compounds and reaction products and the type of protecting group to be removed. This acidic hydrolysis can be carried out in the presence or absence of water, a usual organic solvent, or a mixed solvent of these and water. Note that when trifluoroacetic acid is used as the acid, the reaction is promoted by adding anisole to the reaction system. Hydrolysis with a base is applied to remove protecting groups such as acyl groups, especially haloalkanoyl groups such as trifluoroacetyl. The bases used here include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide;
Alkaline earth metal hydroxides such as magnesium hydroxide and calcium hydroxide, alkali metal carbonates such as sodium carbonate and potassium carbonate, magnesium carbonate,
Alkaline earth metal carbonates such as calcium carbonate, alkali metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate, alkaline earth metal phosphates such as magnesium phosphate and calcium phosphate, hydrogen phosphates such as disodium hydrogen phosphate and dipotassium hydrogen phosphate. Inorganic bases such as alkali metals, alkali metal acetates such as sodium acetate, potassium acetate, trimethylamine,
Trialkylamines such as triethylamine, picoline, N-methylpyrrolidine, N-methylmorpholine, 1,5-diazabicyclo[4,3,0]-
5-Nonene, 1,4-diazabicyclo[2,2,
2]-octene, 1,5-diazibicyclo[5,
Examples include organic bases such as 4,0]-7-undecene, anionic ion exchange resins, and the like. Hydrolysis using these bases is usually carried out in water, a commonly used organic solvent, or a mixed solvent thereof. Hydrolysis with hydrazine produces succinyl,
It is applied to the removal of protecting groups such as dibasic acyl groups such as phthaloyl. Elimination by reduction can be used to remove halo (lower) alkoxycarbonyls such as trichloroethoxycarbonyl,
Substituted or unsubstituted alkoxycarbonyl such as benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, acyl group such as 2-pyridylmethoxycarbonyl, benzyl,
It can be applied to remove protecting groups such as aralkyl groups such as benzhydryl and trityl. Examples of the reduction method include reduction using an alkali metal borohydride such as sodium borohydride, and catalytic reduction using a common catalyst. Furthermore, protective groups such as halo(lower) alkoxycarbonyl groups and 8-quinolyloxycarbonyl groups can be removed by treatment with heavy metals such as copper and zinc. The reaction temperature is not particularly limited and is selected taking into account the chemical properties of the starting compounds and reaction products, the type of N-protecting group, the application method, etc., but is usually under cooling, at room temperature, or under heating. Preferably, the reaction is carried out under mild conditions. When R ⁴ of the starting compound () is an ester of a carboxy group, it may be converted into a free carboxy group during this reaction or post-treatment, and such cases are also included within the scope of this method. The purpose of this method is to remove the protecting group in the protected amino group of the compound () obtained by other methods, thereby producing a compound (') having an aminothiazolyl group that generally exhibits stronger antibacterial activity.
The purpose is to manufacture. Method F: Formation of 3-Hydroxycepham The target compound (e) and its salts are obtained by reducing compound () or its salts. The raw material compound () has R ¹ as the formula

It is a thiazolyl group represented by [Formula] (where R ⁵ is the same as above), and R ³ is a group represented by the formula -O-R ⁶ (here, R ⁶ means a hydrogen atom). , and A is the expression

It corresponds to the above-mentioned 3-cephem compound () when it is a group represented by the formula: (where R ² is the same as above), and can be produced, for example, by the above-mentioned method A. The reduction method that can be applied to this method is any method that can convert a ketonic carbonyl group to a hydroxymethylene group, including its tautomer enol form, and specifically, hydrogenation such as sodium borohydride. Reduction with an alkali metal boron, or reduction with a combination of acids such as hydrochloric acid, sulfuric acid, formic acid, acetic acid, etc. and metals such as zinc, iron, copper, etc., or reduction with palladium carbon, palladium sponge, Raney nickel, platinum,
Examples include catalytic reduction using a common catalyst such as platinum black. This reaction is often carried out under cooling or heating in water, alcohols such as methanol and ethanol, dimethylformamide, tetrahydrofuran, and other solvents that do not adversely affect the reaction. Compound (e) and its salts obtained in this way exhibit antibacterial activity, but these can be obtained by the following method G.
The more active 3-cephem compound (
It is useful as an intermediate raw material for producing h). Method G: O-acylation The target compound (f) and its salt are produced by reacting compound (e) or its salt with compound (), its salt, or a reactive derivative thereof. As the acyl moiety represented by ^6a in compound (), those exemplified as _the acyl group for ^R6 in compound () are also exemplified here. Examples of reactive derivatives of compound () include acid halides, acid anhydrides, acid azides, active esters, active amides, etc. as exemplified as reactive derivatives of compound () in method A above. . Specific preferred examples include lower alkanoyl halides such as acetyl chloride, aroyl halides such as benzoyl chloride, lower alkanesulfonyl halides such as mesyl chloride, mesyl bromide, and ethanesulfonyl chloride, and arenesulfonyl halides such as tosyl chloride. Examples include lower alkanesulfonyl azides such as mesyl azide, arenesulfonyl azides such as tosyl azide, and more preferred examples include lower alkanesulfonyl halides and arenesulfonyl halides as described above. This reaction is usually carried out in dimethylformamide, chloroform, methylene chloride, or any other solvent that does not adversely affect the reaction, under cooling, at room temperature, or under heating. When using an acyl halide as the acylating agent, this reaction is preferably carried out in the presence of a base as exemplified in Method E above. This method uses a 3-hydroxycephalic compound (
e) to 3-acyloxycephalic compound (
This is the first step to produce the more active 3-cephem compound (h) through step f). Method H: Formation of Carboxy This method uses a target compound (g) with a free carboxy group that generally shows better antibacterial activity.
or its salts, especially where R ¹ is of the formula

[Formula] (where R ⁵ is the same as above) is a thiazolyl group, and A is the formula

[Formula] (where R ² is the same as above)
g) is prepared from the corresponding ester of carboxylic acid (x). Therefore, the ester of the carboxy group in compound () is used for the purpose of temporarily protecting the free carboxy group during the production of the target compound by the chemical or biological method explained above. It is in the point of doing. This method is carried out by converting the ester of the carboxy group of the starting material () into a free carboxy group, and a preferable example of the ester of the carboxy group represented by R ⁴ of the compound () is the group R of the compound (). Examples include esterified carboxy groups as exemplified in the explanation of ⁴ . In this method, conventional methods such as hydrolysis and reduction are applied. Examples of the hydrolysis method include conventional methods using salts, bases, enzymes, enzyme preparations, and the like. Preferred examples of acids and bases include those exemplified in the above method E, and acidic or basic hydrolysis reactions are carried out in the above method E.
This is done in the same way as in the case of . Enzymes and enzyme preparations include all those exhibiting esterase activity, and specific examples include microbial cultures or processed products thereof, and processed products of animal or plant tissue. The esterase used in enzymatic hydrolysis may be purified as well as crude. Such esterase activity can be obtained, for example, from microorganisms that can be easily isolated from soil samples by conventional methods, or from deposited bacteria that can be obtained from microorganism depositories such as the ATCC and the Microbial Industry Research Institute. It has been confirmed that they are widely present in a variety of selected microorganisms, such as Bacillus, Corynebacterium, Micrococcus, Flavobacterium,
Salmonella, Staphylococcus, Vibrio, Microbacterium, Escherichia, Arthrobacter, Azotobacter, Alcaligenes, Rhizobium, Brevibacterium, Kluybella, Proteus, Sarcina,
Examples include microorganisms belonging to the genus Pseudomonas, Xanthomonas, Protaminobacter, Comamonas, and the like. Specific examples of these microorganisms include:
For example, Bacillus subtilis IAM-1069,
IAM-1107, IAM-1214, Bacillus sphaericus IAM-1286, Corynebacterium equi IAM-1308, Micrococcus variens
IAM−1314, Flavobacterium lygeus
IAM−1238, Salmonella teifuimurium
IAM-1406, Staphylococcus epidermides IAM-1296, Microbacterium flavum IAM-1642, Alcaligenes faecalis ATCC-8750, Arthrobacter simplex ATCC-6946, Azotobacter vinelandii IAM-1078, Escherichia coli IAM−
1101, Rhizobium japonicum IAM-0001, Vibrio mechnikovii IAM-1039, Brevibacterium herbonium IAM-1637, Procuminobacter alboflavum IAM-1040, Comamonas terrigena IFO-12685, Sarcina lutea IAM-1099, Pseudomonas Examples include Xanthomonas trifolii ATCC-12287 and Xanthomonas trifolii ATCC-12287. In enzymatic hydrolysis, it is convenient to use esterase in the form of a culture obtained by appropriately culturing esterase-producing microorganisms, or in the form of a processed product thereof. Cultivation of microorganisms can be carried out by conventional methods.
The medium used includes assimilable carbon and nitrogen sources and inorganic salts as nutritional sources. Examples of carbon sources include glucose, sucrose, lactose, sugar, glycerol, and starch. Nitrogen sources include meat extract, peptone, gluten meal, corn meal, cottonseed meal, soybean flour, corn steep liquor, yeast extract, casein hydrolyzate, amino acids or ammonium sulfate, ammonium nitrite, Examples include ammonium salts such as ammonium phosphate, and inorganic or organic nitrogen compounds such as sodium nitrite. If desired, further calcium carbonate,
Metal salts such as sodium phosphate, potassium phosphate, magnesium salts, copper salts, or various vitamins may be added to the medium. The pH of the culture medium, temperature during culture, culture time, etc. are determined as appropriate depending on the type of microorganism, but usually pH5~
8 and incubated at a temperature of 20-35°C for 20-120 hours. The processed culture product obtained in this way is
It refers to various processed products obtained by conventional methods in order to increase esterase activity. The esterase activity of the culture exists within the bacterial cells and/or outside the bacterial cells. When the esterase activity is mainly present within the bacterial cells, a processed product of the culture can be obtained, for example, in the following manner. (1) Bacterial cells; separated from the culture by conventional methods such as filtration or centrifugation. (2) Dried bacterial cells: Obtained by drying the above bacterial cells by a conventional method such as freeze drying or vacuum drying. (3) Sterile cell extract; obtained by conventional methods such as crushing the above-mentioned bacterial cells or dried bacterial cells with alumina, sea sand, etc., or treating with ultrasonic waves. (4) Enzyme solution; obtained by partially or fully purifying the above-mentioned sterile body extract by conventional methods. Furthermore, when the esterase activity is mainly present outside the bacterial cells, a processed product of the culture can be obtained in the following manner. (1) Supernatant or liquid; obtained from culture by conventional methods. (2) Enzyme solution: Obtained by partially or fully purifying the above supernatant or liquid by a conventional method. Enzymatic hydrolysis involves contacting the compound () with a culture of microorganisms or a treated product thereof in an aqueous solution such as water or a buffer such as a phosphate buffer, preferably in the presence of a conventional surfactant. This is done by That is, this reaction is usually carried out by adding the compound () to a microbial culture or a liquid treated product such as a supernatant, liquid, or oxygen solution, or an aqueous solution or suspension of the culture or its treated product. It will be done. In some cases, it may be preferable to stir the reaction mixture. The pH of the reaction mixture, the concentration of the substrate, the reaction time, the reaction temperature, etc. are determined as appropriate depending on the nature of the culture or its treated product, or the compound () used, but usually preferably a pH of 4 to 10, more preferably a pH of 4 to 10. , pH in the range of 6 to 8, 20 to 50°C, more preferably 25 to 35°C, and a period of 1 to 100 hours. Also, the concentration of compound (x) used as a substrate in the reaction mixture is 0.1
It is preferably about 100 mg/ml, preferably about 1 to 20 mg/ml. The reduction method is carried out in the same manner as the reduction method in method E above. Incidentally, the case where the protecting group in the protected amino group of R ⁵ which is a substituent of the thiazolyl group of R ¹ of compound () is removed during this reaction or post-treatment is also included in the scope of this method. The target compounds obtained by the various methods of this invention are isolated and purified by conventional methods. When R ⁴ of the target compound () is a free carboxy group and/or when R ⁵ is a free amino group, this can be converted into a salt by a conventional method. Among the target compounds (), compound (') and its salts have excellent antibacterial activity that inhibits the growth of a wide range of pathogenic bacteria, including gram-negative and gram-positive bacteria, and are useful as antibacterial agents. It is useful as a synthetic intermediate for a novel 3-cephem compound (h) having stronger antibacterial activity and its salts produced by the method. (In the formula, R ¹ _a , R ² _a , R ⁴ , R ⁵ and R ⁶ _a have the same meanings as above) Since the above methods 1 and 2 are substantially the same methods as the above methods D and C, respectively, Explanations of those methods can be used. Further, preferred examples of the base used in Method 3 include metal hydroxides such as sodium hydroxide and potassium hydroxide, metal carbonates such as sodium carbonate, potassium carbonate, and magnesium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, etc. Examples include inorganic bases such as metal hydrogen carbonate, tertiary amines such as trimethylamine, triethylamine, and pyridine, and organic bases such as alkali metal alkoxides such as sodium methoxide and sodium ethoxide. This method 3
The reaction is usually carried out in alcohol, dimethylformamide, chloroform, methylene chloride, or other solvents that do not adversely affect the reaction, under cooling, at room temperature, or under heating. In addition, the compound (″) and its salts are all new, and the above compound (′) and the new 3-cephem compound (
h) and their salts. In order to demonstrate the usefulness of compound (') having antibacterial activity, we present the test results for a representative compound (') and the test results for a new 3-cephem compound (h) produced from compound (). It is shown below. In vitro antibacterial activity test (1) Test method: Antibacterial activity was measured by the usual agar plate dilution method. 1 of a 100-fold dilution of each test strain cultured overnight in trypticase-soy broth.
Heart Infusion Agar (HI-agar) containing platinum looper and test compound at graded concentrations.
and cultured at 37°C for 20 hours. The minimum inhibitory concentration (MIC) is determined and expressed in μg/ml. (2) Test compound: Compound (') 7-[2-(2-amino-4-thiazolyl)-
2-Hydroxyiminoacetamide]-3-cephem-4-carboxylic acid (syn isomer) (hereinafter referred to as
(referred to as compound 1) Compound (h) 7-[2-(2-amino-4-thiazolyl)-
2-Methoxyiminoacetamide]-3-cephem-4-carboxylic acid (syn isomer) (hereinafter referred to as
7-[2-(2-amino-4-thiazolyl)-
2-ethoxyiminoacetamide]-3-cephem-4-carboxylic acid (syn isomer) (hereinafter referred to as
7-[2-(2-amino-4-thiazolyl)-
2-n-propoxyiminoacetamide]-3
-Cefem-4-carboxylic acid (syn isomer)
(Hereinafter referred to as compound C) (3) Test results:

[Table] The object compound of the present invention () can be used in the form of solid preparations such as capsules, tablets, granules, troches, and suppositories, as well as liquid preparations such as ointments, solutions, suspensions, and emulsions, together with ordinary carriers. It is administered to patients by oral administration, rectal administration, or parenteral administration such as injection. Various formulations such as those exemplified above include excipients, binders, stabilizers,
Conventional additives such as suspending agents, emulsifying agents, solubilizing agents, flavoring agents, and buffering agents may be added. The dosage depends on the patient's age, weight, etc., the type of disease,
It is determined as appropriate depending on the severity and type of drug, but usually 10mg, 50mg, 100mg, 250mg, 500mg
It is administered as a preparation containing etc. Generally, the dose is administered in the range of 1 mg/Kg to 100 mg/Kg, preferably in the range of 5 mg/Kg to 50 mg/Kg. The raw material compound () used in the above method A is:
It can be manufactured by the following method. (In the formula, R ² _a and R ⁵ _a have the same meanings as above,
(X means halogen, Z means lower alkyl group) Next, this invention will be explained with reference to Examples. Manufacturing method example of raw material compound A (1) Sulfuryl chloride (35.2 th) was stirred at room temperature in a solution consisting of ethyl ester of 2-ethoxyimino-3-oxobutyric acid (syn isomer, 48.9 g) and acetic acid (49 ml). Add to the bottom all at once, and then stir at the same temperature for 1 hour. The reaction solution was added to water (200 ml) and extracted with methylene chloride. After washing the extract with a saturated aqueous sodium chloride solution, it was neutralized with an aqueous sodium bicarbonate solution,
Then wash with water. This was dried over magnesium sulfate and concentrated under reduced pressure to obtain ethyl ester of 2-ethoxyimino-3-oxo-4-chlorobutyric acid (syn isomer, 53.8 g) as a pale yellow oil. (2) Ethyl ester of 2-ethoxyimino-3-oxo-4-chlorobutyric acid (syn isomer, 38.7
g), thiourea (13.2 g), sodium acetate (14.3 g), methanol (95 ml) and water (95 g)
ml) at 48 °C for 40 min.
The reaction solution was adjusted to pH 6.5 with an aqueous sodium bicarbonate solution, and the precipitate was removed and washed with diisopropyl ether to give ethyl ester of 2-(2-aminothiazol-4-yl)-2-ethoxyiminoacetic acid (synthetic acid). isomer, 14.7 g). mp130~131℃ IRνnujiol max: 3450, 3275, 3125, 1715,
1620cm ^-1 (3) 2-(2-aminothiazol-4-yl)-2
- Ethyl ester of ethoxyiminoacetic acid (syn isomer, 5 g) is added to a mixture consisting of 1N aqueous sodium hydroxide solution (45.9 ml) and ethanol (30 ml) and then stirred at room temperature for 5 hours. Ethanol was distilled off from the reaction solution under reduced pressure, the residue was dissolved in water (60 ml), and the pH was adjusted to 2.0 with 10% hydrochloric acid. This solution was salted out, and the precipitate was removed and dried to produce 2-(2-aminothiazol-4-yl).
-2-ethoxyiminoacetic acid (syn isomer, 2.9
g) is obtained. IRνnujiol max: 3625, 3225 (shoulder), 3100,
1650, 1615 cm ^-1 NMRδ (DMSO-d ₆ , ppm): 1.20 (3H, t,
J=7Hz), 4.09 (2H, q, J=7Hz), 6.82
(1H, s), 7.24 (2H, broad s) (4) 2-(2-aminothiazol-4-yl)-2
- ethoxyiminoacetic acid (syn isomer, 100 g),
When formic acid (85.5 g) and acetic anhydride (190.1 g) were treated in the same manner as in Example B-(5), 2-(2-
Formamidothiazol-4-yl)-2-ethoxyiminoacetic acid (syn isomer, 99.1 g) is obtained. IRν Nujior max: 3200, 3140, 3050, 1700cm
^-1 NMRδ (DMSO-d ₆ , ppm): 1.18 (3H, t,
J=6Hz), 4.22 (2H, q, J=6Hz), 7.56
(1H, s), 8.56 (1H, s), 12.62 (1H,
Example B (1) A suspension of ethyl ester of 2-hydroxyimino-3-oxobutyric acid (syn isomer, 15 g), potassium carbonate (19.8 g) and acetone (75 ml) was mixed with propyl iodide (propyl iodide). 16.2g) was added under stirring and stirred at room temperature for 1.5 hours. Remove the insoluble matter and wash it with acetone. Combine the liquid and washing liquid and dry under reduced pressure. Add water to the residue,
Extract twice with chloroform. The extract was washed with an aqueous sodium chloride solution, dried over magnesium sulfate, and then dried under reduced pressure to form an oily 3
The ethyl ester of -oxo-2-propoxyiminobutyric acid (syn isomer, 15.4 g) is obtained. (2) Ethyl ester of 3-oxo-2-propoxyiminobutyric acid (syn isomer, 15.4 g) and sulfuryl chloride (10.6 g) in acetic acid (15.4 ml),
Add the mixture over 10 minutes while stirring at 35-40°C, and after dissolving, stir at room temperature for 6 hours. The reaction solution was poured into ice water (200 ml) and extracted twice with chloroform. The extract is added to an aqueous sodium chloride solution,
Then, twice with a saturated aqueous solution of sodium bicarbonate,
The mixture was then washed once with water, dried over magnesium sulfate, and dried under reduced pressure to obtain oily ethyl ester of 4-chloro-3-oxo-2-propoxyiminobutyric acid (syn isomer, 15.4 g). IRν film max: 1740, 1710, 1695, 1455 cm ^-1 (3) Ethyl ester of 4-chloro-3-oxo-2-propoxyiminobutyric acid (syn isomer, 15.4
g), thiourea (4.97 g) and sodium acetate hydrate (8.89 g) were dissolved in a mixture of water (40 ml) and ethanol (50 ml) and heated at 40°C for 1 hour.
Stir for an hour. The reaction solution was adjusted to pH 6.5 with a saturated aqueous solution of potassium carbonate under cooling, and then heated at the same temperature for 30 minutes.
Stir for a minute. After collecting the precipitated crystals and washing them sequentially with water and diisopropyl ether,
Upon drying, crystalline ethyl ester of 2-(2-aminothiazol-4-yl)-2-propoxyiminoacetic acid (syn isomer, 10.55 g) is obtained. mp142～144℃ IRνnujiol max: 3460, 3260, 3120, 1720,
1620, 1540 cm ^-1 NMRδ (d ₆ -DMSO, ppm): 0.88 (3H, t,
J=7Hz), 1.27 (3H, t, J=6Hz), 1.60
(2H, sextet, J=7Hz), 4.04 (2H, t, J
= 7Hz), 4.28 (2H, q, J = 6Hz), 6.86
(1H,s), 7.32(2H,s) (4) 2-(2-aminothiazol-4-yl)-2
- Ethyl ester of propoxyiminoacetic acid (syn isomer, 10 g) in tetrahydrofuran (39 g)
ml), methanol (39 ml) and 1N aqueous sodium hydroxide solution (75.8 ml), and stirred at 35-40°C for 5 hours. The reaction solution was concentrated under reduced pressure, and the residue was adjusted to pH 2.5 with 10% hydrochloric acid.
The precipitate was collected and dried to obtain 2-(2-aminothiazol-4-yl)-2-propoxyiminoacetic acid (syn isomer, 6.2 g). mp161℃ (decomposition) IRνnujiol max: 3380, 3120 (broad), 1630,
1610, 1460 cm ^-1 NMRδ (DMSO-d ₆ , ppm): 0.89 (3H, t,
J=7Hz), 1.63 (2H, sextet, J=7Hz),
4.05 (2H, t, J=7Hz), 6.83 (1H, s),
6.9-8.8 (3H, broad) (5) Add formic acid (17.5 g) to acetic anhydride (38.8 g) under ice-cooling and stirring.
g) was added dropwise over 3 to 4 minutes and stirred at 50°C for 1 hour. 2-(2-aminothiazol-4-yl)-2-n-propoxyiminoacetic acid (syn isomer, 21.8 g) was added to this mixed solution while stirring under ice cooling, and the mixture was allowed to react at room temperature for 2.5 hours. The reaction solution is dried under reduced pressure, and diisopropyl ether is added to the residue to powder it to obtain 2-(2-formamidothiazol-4-yl)-2-n-propoxyiminoacetic acid (syn isomer, 19.2 g). . mp164℃ (decomposition) IRνnujiol max: 3200, 3120, 3050, 1700,
1550cm ^-1 NMRδ (DMSO-d ₆ , ppm): 0.92 (3H, t,
J=7Hz), 1.67 (2H, sextet, J=7Hz),
4.12 (2H, t, J=7Hz), 7.53 (1H, s),
8.54 (1H, s) Example C (1) Ethyl ester of 2-hydroxyimino-3-oxobutyric acid (syn isomer, 40 g), potassium carbonate (52.7 g), N,N-dimethylformamide (200 ml) and odor Isobutyl chloride (34.94g)
When treated in the same manner as in Example B-(1), the ethyl ester of 2-isobutoxyimino-3-oxobutyric acid (syn isomer, 42 g) is obtained. IRν Nudiol max: 1740, 1670 (broad) cm ^-1 (2) Ethyl ester of 2-isobutoxyimino-3-oxobutyric acid (syn isomer, 42 g), sulfuryl chloride (27.1 g) and acetic acid (42 ml) were carried out. Working up analogously to Example B-(2) gives the ethyl ester of 2-isobutoxyimino-4-chloro-3-oxobutyric acid (syn isomer, 31.9 g). IRν film max: 1750, 1720, ^{1680mg -1} (3) Ethyl ester of 4-chloro-3-oxo-2-isobutoxyiminobutyric acid (syn isomer,
When 31.9 g), thiourea (9.72 g), sodium butyrate trihydrate (17.4 g), water (80 ml) and ethanol (120 ml) were treated in the same manner as in Example B-(3), 2-(2 -aminothiazol-4-yl)-2-isobutoxyiminoacetic acid ethyl ester (syn isomer, 17.6 g) is obtained. mp122~124℃ IRνnujiol max: 3470, 3260, 3120, 1730,
1620, 1545 cm ^-1 NMRδ (DMSO-d ₆ , ppm): 0.86. (6H, d,
J=7Hz), 1.28 (3H, t, J=7Hz), 1.6~
2.2 (1H, m), 3.86 (2H, d, J=7Hz),
4.28 (2H, q, J = 7Hz), 6.86 (1H, s),
1.22(2H,s) (4) 2-(2-aminothiazol-4-yl)-2
Example B - Ethyl ester of isobutoxyiminoacetic acid (syn isomer, 19.6 g), 2N aqueous sodium hydroxide solution (72.2 ml), methanol (72.2 ml) and tetrahydrofuran (72.2 ml)
The same procedure as in (4) gives 2-(2-aminothiazol-4-yl)-2-isobutoxyiminoacetic acid (syn isomer, 16.1 g). mp180℃ (decomposition) IRνnujiol max: 3375, 3300, 3130, 3050,
1640cm ^-1 NMRδ (DMSO-d ₆ , ppm): 0.91 (6H, d,
J=7Hz), 1.5-2.3 (1H, m), 3.90 (2H,
d, J=7Hz), 6.87 (1H, s), 7.26 (2H,
(5) 2-(2-aminothiazol-4-yl)-2
-isobutoxyiminoacetic acid (syn isomer, 11.5
g), 2-(2-
Formamidothiazol-4-yl)-2-isobutoxyiminoacetic acid (syn isomer, 11.15g)
get. mp163℃ (decomposition) IRνnujiol max: 3175, 3110, 3050, 1695,
1550cm ^-1 NMRδ (DMSO-d ₆ , ppm): 0.91 (6H, d,
J=7Hz), 1.7-2.3 (1H, m), 3.92 (2H,
d, J=7Hz), 7.52 (1H, s), 8.52 (1H,
s), 12.58 (1H, broad s) Example 1 (1) 4- of 7-(2-phenylacetamido)-3-hydroxy-3-cephem-4-carboxylic acid
Triethylamine (2.37 g) and dimethylaniline (7.12 g) were added to a suspension of nitrobenzyl ester (10 g) and methylene chloride (200 ml).
and trimethylsilyl chloride (3.93g)
was added under stirring and stirred at room temperature for 1 hour. To this solution, phosphorus pentachloride (4.88 g) was added at -30 to -25°C, stirred at -25 to -20°C for 3 hours, and methanol (42 ml) was added at -25 to -20°C. Stir for 1 hour. Add water (35ml) to this at -25 to -20℃.
and stir at room temperature. The precipitate was collected, washed successively with methylene chloride and ethyl ether, and then dried to obtain 4-nitrobenzyl ester of 7-amino-3-hydroxy-3-cephem-4-carboxylic acid (5.2 g). mp148℃ (decomposition) IRνnujiol max: 3440, 3300, 1760, 1740cm
^-1 NMRδ (DMSO−d ₆ , ppm): 2.8 to 3.7 (2H,
m), 4.90 (1H, t, J=4Hz), 5.29 (1H,
d, J=4Hz), 5.38 (2H, s), 7.71 (2H,
d, J = 8 Hz), 8.26 (2H, d, J = 8 Hz) (2) Phosphorous oxychloride (2.87 g) was dissolved in N, N-dimethylformamide (1.37 g) and ethyl acetate (10
ml) at 5-10°C, then ethyl acetate (40 ml) was added, and the mixture was stirred for 40 minutes under ice-cooling. To this solution was added 2-(2-formamido-4-thiazolyl)-2-methoxyiminoacetic acid (syn isomer, 3.58 g), and
Stir for 40 minutes. Add this solution to 7-amino-3
-4-nitrobenzyl ester of hydroxy-3-cephem-4-carboxylic acid (5 g), ethyl acetate (50 ml), trimethylsilylacetamide (14.3 g) and bis(trimethylsilyl)
A mixture of acetamide (5.8 g) was heated to −15°C.
Add all at once and stir at -20 to -15°C for 1.2 hours. Water (50 ml) was added to the reaction solution at -25 to -20°C, and the mixture was stirred until the temperature rose to 5°C. Separate the aqueous layer and extract with ethyl acetate. The ethyl acetate layer and extract are combined, washed with saturated aqueous sodium chloride solution, and dried over magnesium sulfate. This was concentrated under reduced pressure to 50 ml, the precipitate was collected, and washed with ethyl acetate.
-formamide-4-thiazolyl)-2-methoxyiminoacetamide]-3-hydroxy-
4-nitrobenzyl ester of 3-cephem-4-carboxylic acid (syn isomer, 3.5 g) is obtained. mp163℃ (decomposition) IRνnujiol max: 3210, 3160, 3050, 1780,
1665cm ^-1 NMRδ (DMSO−d ₆ , ppm): 3.0 to 4.2 (2H,
m), 3.95 (3H, s), 5.28 (1H, d, J=4
Hz), 5.41 (2H, s), 5.64 (1H, dd, J=4
Hz, 9Hz), 7.49 (1H, s), 7.67 (2H, d,
J=8Hz), 8.21 (2H, d, J=8Hz), 8.50
(1H, t, J=9Hz) (3) A solution consisting of the compound obtained above (1g), methanol (15ml), tetrahydrofuran (5ml) and concentrated hydrochloric acid (0.72g) was stirred at room temperature for 1 hour. Add diethyl ether (100ml) to the reaction solution.
and crystallize. When the precipitated crystals are taken, 7-[2-(2-aminothiazole-4-
yl)-2-methoxyiminoacetamide]-3
The hydrochloride of 4-nitrobenzyl ester of -hydroxy-3-cephem-4-carboxylic acid (syn isomer, 0.65 g) is obtained. IRνnujiol max: 3180, 1780, 1680, 1670,
1640cm ^-1 NMRδ (DMSO−d ₆ , ppm): 3.2 to 4.0 (2H,
m), 3.97 (3H, s), 5.27 (1H, d, J=4
Hz), 5.41 (2H, s), 5.60 (1H, dd, J=4
Hz, 8Hz), 7.10 (1H, s), 7.66 (2H, d,
J=9Hz), 8.25 (2H, d, J=9Hz), 9.73
(1H, d, J=8Hz) Example 2 2-(2-formamidothiazol-4-yl)
-2-propoxyiminoacetic acid (syn isomer,
0.515 g), N,N-dimethylformamide (0.161 g), phosphorus oxychloride (0.337 g) and ethyl acetate (7.9 ml) were treated in the same manner as in Example 1-(2) to obtain an activated acid. Obtain a solution. Meanwhile, trimethylsilylacetamide (1.85 g) and bis(trimethylsilyl)acetamide (1.60 g) were added to 7-amino-3-hydroxy-3-cephem-4.
-Add to a suspension of 4-nitrobenzyl ester of carboxylic acid (0.703 g) and ethyl acetate (10 ml) and stir at room temperature for 1 hour. To this solution, the previously obtained activated acid solution was added all at once at -10°C, and the mixture was stirred at the same temperature for 1 hour. Add water (20
ml) and ethyl acetate (20 ml) are added, and the organic material is separated, washed successively with a saturated aqueous sodium bicarbonate solution (8 ml) and water (14 ml), and then dried over magnesium sulfate. This was concentrated under reduced pressure, the residue was powdered with diethyl ether, and the precipitate was collected to give 7-[2-(2-formamidothiazole-4
-yl)-2-propoxyiminoacetamide]-
4-nitrobenzyl ester of 3-hydroxy-3-cephem-4-carboxylic acid (syn isomer,
0.75g). IRν Nujior max: 3250, 1765, 1740, 1670cm
^-1 NMRδ (DMSO-d ₆ , ppm): 0.90 (3H, t,
J=8Hz), 1.67 (2H, m), 3.40 (2H, AB−
q, J = 20Hz), 4.08 (2H, q, J = 8Hz),
5.03-5.83 (4H, m), 7.40 (1H, s), 7.70
(2H, d, J=9Hz), 8.27 (2H, d, J=
9Hz), 8.53 (1H, s), 9.50 (1H, d, J=
8Hz), 12.60 (1H, broad s) Example 3 2-(2-formamidothiazol-4-yl)
-2-isobutoxyiminoacetic acid (syn isomer,
0.54 g), N,N-dimethylformamide (0.16
g), phosphorus oxychloride (0.34 g) and ethyl acetate (10 ml) are treated in the same manner as in Example 1-(2) to obtain a solution of the activated acid. Meanwhile, trimethylsilylacetamide (1.85g) and bis(trimethylsilyl)acetamide (1.62g) were added to 7-amino-
Add to a suspension of 4-nitrobenzyl ester of 3-hydroxy-3-cephem-4-carboxylic acid (0.7 g) and ethyl acetate (10 ml) and stir at 40°C for 30 minutes. The previously obtained activated acid solution was added at once to this solution at -20°C, and the mixture was stirred at the same temperature for 1 hour. Water (10 ml) is added to the reaction solution, and the organic layer is separated, washed successively with water, a saturated aqueous solution of sodium bicarbonate, and a saturated aqueous solution of sodium chloride, and then dried. This was concentrated under reduced pressure, the residue was powdered with diisopropyl ether, and the precipitate was collected. 3-CEFEM-4-
4-nitrobenzyl ester of carboxylic acid (syn isomer, 1.09 g) is obtained. IRνnujiol max: 3250, 3050, 1750, 1650,
1610cm ^-1 NMRδ (DMSO-d ₆ , ppm): 0.97 (6H, d,
J=6Hz), 2.0 (1H, m), 3.60 (2H, AB−
q, J = 18Hz), 3.95 (2H, d, J = 6Hz),
5.1-5.8 (4H, m), 7.53 (1H, s), 7.63
(2H, d, J=8Hz), 8.18 (2H, d, J=
8Hz), 8.58 (1H, s), 9.47 (1H, d, J=
9Hz), 12.77 (1H, broad s) Example 4 N,N-dimethylformamide (0.114g), phosphorus oxychloride (0.240g) and ethyl acetate (0.5
ml) according to a conventional method to prepare Vilsmeier reagent. Add ethyl acetate (5 ml) and 2-(2-formamidothiazol-4-yl) to this solution.
2-Ethoxyiminoacetic acid (syn isomer, 0.35g)
was added over a period of 30 minutes at the same temperature to obtain a solution of activated acid. Meanwhile, trimethylsilylacetamide (1.31g) and bis(trimethylsilyl)
Acetamide (1.14 g) was added to a suspension of 4-nitrobenzyl ester of 7-amino-3-hydroxy-3-cephem-4-carboxylic acid (0.50 g) and ethyl acetate (7.5 ml), and the mixture was stirred at room temperature for 1 hour. Stir. To this solution, the previously obtained activated acid solution was added all at once at -10°C, and the mixture was stirred at the same temperature for 30 minutes. Water (15 ml) and ethyl acetate (15 ml) were added to the reaction solution.
ml), and the organic layer is separated, washed with saturated aqueous sodium bicarbonate solution (15 ml) and water (10 ml), and then dried over magnesium sulfate. This was concentrated under reduced pressure, the residue was powdered with diethyl ether, and the precipitate was collected. -4-nitrobenzyl ester of cefem-4-carboxylic acid (syn isomer, 0.634 g) is obtained. IRνnudjol max: 3200, 1760, 1740, 1670cm ^-1 NMRδ (DMSO-d ₆ , ppm): 1.24 (3H, t,
J=8Hz), 3.36 (2H, AB-q, J=20Hz),
4.15 (2H, q, J=8Hz), 5.10~5.60 (4H,
m), 7.37 (1H, s), 7.65 (2H, d, J=9
Hz), 8.22 (2H, d, J=9Hz), 8.48 (1H,
s), 9.52 (1H, d, J=8Hz), 12.58 (1H,
Example 5 (1) 4-nitrobenzyl ester of 7-amino-3-cephem-4-carboxylic acid (5 g) was mixed with trimethylsilylacetamide (13.8 g) and bis(trimethylsilyl)acetamide (10 ml).
and dry ethyl acetate (50 ml) and stirred at 45°C for 1.5 hours. Separately, a solution consisting of bromine (2.88 g) and methylene chloride (7 ml) was added dropwise to a solution consisting of diketene (1.5 g) and methylene chloride (7 ml) at -40°C over 20 minutes, and then at -30°C. Stir for 1 hour. This solution was added dropwise to the previously obtained solution containing 4-nitrobenzyl ester of 7-amino-3-cephem-4-carboxylic acid at -15°C, and the mixture was stirred at the same temperature for 30 minutes. Add water (50 ml) to the reaction solution and extract with ethyl acetate. The ethyl acetate extract was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure to yield an oily 7-[2-(2-bromoacetyl)acetamide]-3-cepheme-4-.
4-nitrobenzyl ester of carboxylic acid (6.15 g) is obtained. IRν Nujiol max: 1780, 1740, 1630cm ^-1 NMRδ (DMSO−d ₆ , ppm): 3.62 (2H,
broad s), 4.37 (2H, s), 5.08 (1H, d,
J=5Hz), 5.40 (2H, s), 5.77-6.05 (m),
6.67 (1H, t, J=5Hz), 7.68, 8.08 (4H,
m, J = 9 Hz), 9.07 (1H, d, J = 8 Hz) (2) 4-nitrobenzyl ester of 7-[2-(2-bromoacetyl)acetamide]-3-cephem-4-carboxylic acid (8.40 g) is suspended in a mixture of tetrahydrofuran (150 ml) and water (30 ml). Acetic acid (50 ml) and an aqueous solution (15 ml) of sodium nitrite (1.20 g) are added to this suspension under ice cooling, and the mixture is stirred at 20-22°C for 1.5 hours.
Pour the reaction solution into ice water (300 ml) and stir for 20 minutes. After removing the precipitate, washing with water and drying,
Recrystallization from ethyl acetate yields 7-[2-(2-
4-nitrobenzyl ester (syn isomer,
3.1g). mp153~162℃ IRνnujiol max: 3250, 1780, 1720, 1705,
1650, 1610, 1600 (shoulder), 1550, 1520 cm ^-1 NMRδ (DMSO-d ₆ , ppm): 3.67 (2H, d,
J=4Hz), 4.63 (1.5H, s), 4.88 (0.5H,
s), 5.18 (1H, d, J=5Hz), 5.45 (2H,
s), 5.93 (1H, dd, J=5Hz, 8Hz), 6.72
(1H, t, J = 4Hz), 7.73 (2H, d, J =
9Hz), 8.28 (2H, d, J = 9Hz), 9.38 (1H,
d, J = 8 Hz), 11.27 (1H, s) (3) 7-[2-(2-bromoacetyl)-2-hydroxyiminoacetamide]-3-cephem-
A diethyl ether solution of diazomethane was added dropwise to a solution consisting of 4-nitrobenzyl ester of 4-carboxylic acid (0.9 g) and tetrahydrofuran (30 ml) under ice cooling little by little until the reaction was completed. Acetic acid is added to the reaction solution to decompose excess diazomethane. When the reaction solution was concentrated under reduced pressure, a foamy 7-[2-(2-bromoacetyl)-2-methoxyiminoacetamide]-3-cephem-
4-nitrobenzyl ester of 4-carboxylic acid (syn isomer, 0.9 g) is obtained. (4) 7-[2-(2-bromoacetyl)-2-methoxyiminoacetamide]-3-cephem-4
- Thiourea (0.14 g) is added to a solution of 4-nitrobenzyl ester of carboxylic acid (syn isomer, 0.8 g), ethanol (20 ml) and water (15 ml).
g) and stir at room temperature for 3.5 hours. After concentrating the reaction solution under reduced pressure, water and ethyl acetate are added to the residue. The ethyl acetate layer is separated, washed with water, dried over magnesium sulfate, and concentrated under reduced pressure to obtain a crude compound (0.6 g). This product was subjected to silica gel column chromatography, and a mixture of benzene and ethyl acetate (8:
2), 7-[2-(2-amino-4
-thiazolyl)-2-methoxyiminoacetamide]-3-cephem-4-carboxylic acid 4-
Nitrobenzyl ester (syn isomer, 0.21
g) is obtained. mp165~170℃ (decomposition) IRνnujiol max: 3350~3200, 1770, 1720,
1665, 1615, 1515 cm ^-1 NMRδ (DMSO−d ₆ , ppm): 3.60 (2H,
broad s), 3.81 (3H, s), 5.12 (1H, d,
J=5Hz), 5.36 (2H, s), 5.83 (1H, dd,
J = 5Hz, 8Hz), 6.64 (1H, t, J = 4
Hz), 6.70 (1H, s), 7.20 (2H, s), 7.65
(2H, d, J=9Hz), 8.19 (2H, d, J=
9Hz), 9.60 (1H, d, J = 8Hz) (5) The thus obtained 7-[2-(2-amino-
4-thiazolyl)-2-methoxyiminoacetamide]-3-cephem-4-carboxylic acid 4
-Nitrobenzyl ester (syn isomer, 7.8
g) in a mixture of ethanol (60 ml) and water (60 ml), and added 1N potassium hydroxide aqueous solution (45 ml).
ml) was added dropwise over 10 minutes while stirring on ice, and then stirred at 5°C for 15 minutes. The reaction solution was diluted with concentrated hydrochloric acid.
After adjusting to PH7.0 and washing with ethyl acetate, 1/2
Concentrate under reduced pressure to volume. Adjust the concentrate to PH5.0,
Porous non-ionic adsorption resin Diaion HP
-20 (trademark: manufactured by Mitsubishi Chemical Industries, Ltd.) (80ml)
The sample was applied to a column packed with 5% isopropyl alcohol and eluted with 5% isopropyl alcohol. Combine the fractions containing the target compound and adjust the pH to 3.2 with 10% hydrochloric acid. When the precipitated crystals are taken and dried, 7
-[2-(2-amino-4-thiazolyl)-2-
Methoxyiminoacetamide]-3-cephem-4-carboxylic acid (syn isomer, 2.3 g) is obtained. mp＞290℃ IRνnujiol max: 3470, 3280, 3200, 1780,
1695, 1655, 1622 cm ^-1 NMRδ (DMSO−d ₆ , ppm): 3.60 (2H,
broad s), 3.84 (3H, s), 5.12 (1H, dd,
J=5Hz), 5.84 (1H, dd, J=5.8Hz), 6.52
(1H, broad t), 6.76 (1H, s), 7.26 (2H,
Example 6 The following compounds are prepared in a similar manner to Example 5. (1) 7-[2-(2-aminothiazol-4-yl)-2-ethoxyiminoacetamide]-3-
4-Nitrobenzyl ester (syn isomer) of cefem-4-carboxylic acid. IRνnujiol max: 3330, 1780, 1730, 1680,
1640, 1610cm ^-1 (2) 7-[2-(2-aminothiazol-4-yl)-2-propoxyiminoacetamide]-3
-4-nitrobenzyl ester (syn isomer) of cefem-4-carboxylic acid. IRνnujiol max: 3300, 1780, 1730, 1670,
1640cm ^-1 (3) 7-[2-(2-aminothiazol-4-yl)-2-isopropoxyiminoacetamide]
4-nitrobenzyl ester (syn isomer) of -3-cephem-4-carboxylic acid. IRνnujiol max: 3320, 3270, 1775, 1730,
1670, 1630 cm ^-1 Furthermore, the compound obtained above was converted into a compound having a free carboxyl group by the following method. (4) 7-[2-(2-amino-4-thiazolyl)-
In a solution consisting of 4-nitrobenzyl ester of 2-ethoxyiminoacetamide]-3-cephem-4-carboxylic acid (syn isomer, 2.3 g), tetrahydrofuran (30 ml), methanol (15 ml) and acetic acid (0.3 ml), Palladium on carbon (1.0 g) moistened with water (3 ml) was added, and the mixture was subjected to catalytic reduction at room temperature and pressure for 2 hours. The catalyst is removed from the reaction solution, and the solution is concentrated under reduced pressure. Ethyl acetate is added to the residue, and the pH is adjusted to 7.5 with an aqueous sodium hydrogen carbonate solution, and then insoluble materials are removed.
The aqueous layer is separated, washed with ethyl acetate, adjusted to pH 5.5, and then treated with activated carbon. This is PH3.2
7-
[2-(2-amino-4-thiazolyl)-2-ethoxyiminoacetamide]-3-cephem-
4-carboxylic acid (syn isomer, 0.6 g) is obtained. IRνnujiol max: 3500, 3300, 3200, 1785,
1625, 1600cm ^-1 (5) 7-[2-(2-amino-4-thiazolyl)-
2-isopropoxyiminoacetamide]-3
- Acetic acid (1 ml) and 10% palladium on carbon (2.0 g) in a solution consisting of 4-nitrobenzyl ester of cefem-4-carboxylic acid (syn isomer, 5.0 g) and tetrahydrofuran (150 ml).
A suspension of water (8 ml) containing the mixture was added, and the mixture was subjected to catalytic reduction at room temperature and pressure. After removing the catalyst, the liquid is concentrated under reduced pressure. Add ethyl acetate (80 ml) to the residue, and adjust the pH to 7.5 with an aqueous sodium hydrogen carbonate solution. The organic layer is separated and extracted with an aqueous sodium hydrogen carbonate solution. The aqueous layer and extract are combined, adjusted to pH 3.0 with concentrated hydrochloric acid, and then extracted with tetrahydrofuran. The extract is washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated under reduced pressure. When the precipitated crystals are collected and dried, 7-[2-(2-amino-4-
Thiazolyl)-2-isopropoxyiminoacetamide]-3-cephem-4-carboxylic acid (syn isomer, 0.8 g) is obtained. IRν Nujior max: 3320, 1780, 1670, 1635cm
^-1 (6) 7-[2-(2-amino-4-thiazolyl)-
Example 6-4-nitrobenzyl ester of 2-propoxyiminoacetamide]-3-cephem-4-carboxylic acid (syn isomer, 5.0 g)
7-[2-(2-amino-4
-thiazolyl)-2-propoxyiminoacetamide]-3-cephem-4-carboxylic acid (syn isomer, 0.9 g). IRνnujiol max: 3250, 1770, 1650, 1660,
1620cm ^-1 Example 7 (1) Diketin (22.6g) and methylene chloride (30
A solution consisting of bromine (43.0 g) and methylene chloride (30 ml) was added dropwise to a solution consisting of bromine (43.0 g) and methylene chloride (30 ml) at -30°C over 35 minutes, and the mixture was stirred at the same temperature for 30 minutes.
This solution was mixed with 4-nitrobenzyl ester of 7-amino-3-cephem-4-carboxylic acid (75.1
g), bis(trimethylsilyl)acetamide (68.4g) and tetrahydrofuran (1.5)
The solution was added dropwise over 10 minutes while stirring at -15°C, and the mixture was stirred at the same temperature for 50 minutes. Water (35 ml) and sodium nitrite (18.6
Add an aqueous solution (35 ml) of g). During this time, maintain the pH of the reaction solution at 2.0. Add this solution to 10-15℃
After stirring for 15 minutes, adjust the pH to 4.5 with a saturated aqueous solution of sodium hydrogen carbonate. After adding an aqueous solution (150 ml) of thiourea (17.1 g) to this and adjusting the pH to 6.0 with a saturated aqueous solution of sodium bicarbonate,
Stir for 20 minutes. The organic layer was separated, concentrated under reduced pressure, and the residue was dissolved in tyl acetate (1.5).
Wash three times with water. This is dried over magnesium sulfate, treated with activated carbon, and then concentrated under reduced pressure.
After crystallizing the residue with diethyl ether (200 ml), the precipitate was collected by decanting. This was washed with ethyl acetate (300 ml), then with a mixture of tetrahydrofuran (500 ml) and ethyl acetate (1) at 60°C, then with ethyl acetate (100 ml).
After washing three times with
4-nitrobenzyl ester (syn isomer, 55.5 g) of -amino-4-thiazolyl)-2-hydroxyiminoacetamide]-3-cephem-4-carboxylic acid is obtained. IRνnujiol max: 1760, 1710, 1660, 1630
cm ^-1 NMRδ (DMSO-d ₆ , ppm): 3.60 (2H, d,
J=5Hz), 5.12 (1H, d, J=5Hz), 5.39
(2H, s), 5.88 (1H, dd, J=8Hz, 5
Hz), 6.63 (1H, s), 6.53-6.77 (1H, m),
7.08 (2H, broads), 7.68 (2H, d, J=9
Hz), 8.22 (2H, d, J=9Hz), 9.47 (1H,
d, J = 8 Hz), 11.33 (1H, s) (2) 7-[2-(2-amino-4-thiazolyl)-
Adding 10% palladium on carbon (0.35 g) to a solution consisting of 4-nitrobenzyl ester of 2-hydroxyiminoacetamide]-3-cephem-4-carboxylic acid (syn isomer, 0.7 g) and methanol (70 ml), Subject to catalytic reduction for 1.5 hours at room temperature and pressure. After filtering the reaction solution, the solution is concentrated under reduced pressure. After adding an aqueous sodium hydrogen carbonate solution to the residue, insoluble materials are removed. The liquid is washed successively with ethyl acetate and methylene chloride, nitrogen gas is sucked in to remove the organic solvent, and then freeze-dried. The resulting residue was dissolved in water (30ml),
After adjusting the pH to 3.8 with 10% hydrochloric acid, it was subjected to column chromatography filled with a porous nonionic adsorption resin "Diaion HP-20" (trademark: manufactured by Mitsubishi Chemical Industries, Ltd.) (20 ml). After washing this with water, it is eluted with 40% aqueous acetone.
Acetone was distilled off from the eluate under reduced pressure and the residue was lyophilized to yield 7-[2-(2-amino-4-thiazolyl)-2-hydroxyiminoacetamide].
-3-Cefem-4-carboxylic acid (syn isomer, 0.25 g) is obtained. IRνnujiol max: 3350~3200, 1770, 1670,
1630cm ^-1 NMRδ (DMSO−d ₆ , ppm): 3.60 (2H,
broad s), 5.10 (1H, d, J=5Hz), 5.83
(1H, dd, J = 5Hz, 8Hz), 6.47 (1H, t,
J=4Hz), 6.67 (1H, s), 9.47 (1H, d,
J=8Hz) Example 8 (1) 7-[2-(2-bromoacetyl)-2-hydroxyiminoacetamide]-3-cephem-
4-nitrobenzyl ester of 4-carboxylic acid (syn isomer, 1.05 g), ethanol (25 ml),
Tetrahydrofuran (25ml) and water (5ml)
Add thiourea (0.18 g) to the suspension and stir at room temperature for 4 hours. After concentrating the reaction solution under reduced pressure,
Cooling. Add a mixture of tetrahydrofuran and ethyl acetate to the residue and crystallize it.
7-[2-(2-amino-4-thiazolyl)-2
Colorless crystals of 4-nitrobenzyl ester of -hydroxyiminoacetamide]-3-cephem-4-carboxylic acid (syn isomer, 0.95 g) are obtained. mp172~175℃ (decomposition) IRνnujiol max: 3350~3200, 1770, 1725,
1670, 1625, 1520 cm ^-1 NMRδ (DMSO-d ₆ , ppm): 3.68 (2H, d,
J=4Hz), 5.20 (1H, d, J=5Hz), 5.43
(2H, s), 5.90 (1H, dd, J=8Hz, 5
Hz), 6.70 (1H, t, J=4Hz), 6.88 (1H,
s), 7.70 (2H, d, J=9Hz), 8.32 (2H,
d, J = 9Hz), 9.68 (1H, d, J = 8Hz) (2) 7-[2-(2-amino-4-thiazolyl)-
Add a small amount of diethyl ether solution of diazomethane to a solution consisting of 4-nitrobenzyl ester of 2-hydroxyiminoacetamide]-3-cephem-4-carboxylic acid (syn isomer, 0.3 g) and methanol (30 ml) until the reaction is complete. Add one by one. The reaction solution was concentrated under reduced pressure, and the residue was powdered with diethyl ether, taken, and dried to give 7-[2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamide]-3-
4-nitrobenzyl ester of cefem-4-carboxylic acid (syn isomer, 0.26 g) is obtained. This product is identified from the standard. Example 9 The following compounds are produced in the same manner as in Example 8-(2). (1) 7-[2-(2-aminothiazol-4-yl)-2-ethoxyiminoacetamide]-3-
4-Nitrobenzyl ester (syn isomer) of cefem-4-carboxylic acid. (2) 7-[2-(2-aminothiazol-4-yl)-2-propoxyiminoacetamide]-3
-4-nitrobenzyl ester (syn isomer) of cefem-4-carboxylic acid. (3) 4-nitrobenzyl ester (syn isomer) of 7-[2-(2-aminothiazol-4-yl)-2-(isopropoxyiminoacetamide]-3-cephem-4-carboxylic acid (syn isomer). 10 7-Amino-3-cephem-4-carboxylic acid (2.54 g) is dissolved in a solution consisting of trimethylsilylacetamide (11.7 g), bis(trimethylsilyl)acetamide (15 ml) and dry ethyl acetate (50 ml). (2.43 g) and dry methylene chloride (10 ml) was added dropwise to a solution of diketene (1.28 g) and dry methylene chloride (25 ml) at -30°C over 10 minutes, and then at the same temperature for 1.5 hours. This solution was added dropwise to the previously obtained solution containing 7-amino-3-cephem-4-carboxylic acid at -15°C over 10 minutes, and then stirred at -15 to -10°C for 1.5 minutes. Stir for an hour. Add water (50 ml) to the reaction solution, separate the ethyl acetate layer,
Extract with aqueous sodium bicarbonate solution. extract liquid
Adjust the pH to 2.0 with 10% hydrochloric acid and extract with ethyl acetate. The extract was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure to obtain 7-[2-(2-bromoacetyl)acetamide]-3-cephem-4-carboxylic acid (2.82 g). IRν Nujiol max: 1760, 1660cm ^-1 NMRδ (DMSO-d ₆ , ppm): 3.58 (2H, d,
J=4Hz), 3.65 (2H, s), 4.40 (2H, s),
5.06 (1H, d, J = 5Hz), 5.73 (1H, dd, J
=8Hz, 5Hz), 6.50 (1H, t, J = 4Hz),
9.08 (1H, d, J = 8Hz) Example 11 (1) 7-[2-(2-formamido-4-thiazolyl)-2-methoxyiminoacetamide]-3-
4-nitrobenzyl ester of hydroxy-3-cephem-4-carboxylic acid (syn isomer, 1
g), tetrahydrofuran (10 ml), acetic acid (3
ml) and water (1 ml) was added sodium borohydride (160 mg) over 10 minutes at 0°C and stirred at 0-3°C for 55 minutes. Add water to the reaction solution and extract with ethyl acetate. The extract is washed successively with a saturated aqueous sodium chloride solution, a saturated aqueous sodium bicarbonate solution, and a saturated aqueous sodium chloride solution, and then dried over magnesium sulfate. After concentrating this under reduced pressure, the residue was powdered with diethyl ether to obtain 4 -Nitrobenzyl ester (syn isomer, 0.77 g) is obtained. mp172~175℃ (decomposition) IRνnujiol max: 3250, 1775, 1745, 1660cm
^-1 NMRδ (DMSO−d ₆ , ppm): 2.76 (1H, dd,
J = 14Hz, 3Hz), 3.17 (1H, dd, J = 14Hz,
13Hz), 3.92 (3H, s), 4.03 (1H, m), 4.72
(1H, d, J=6Hz), 5.24 (1H, d, J=
4Hz), 5.37 (2H, s), 5.56 (1H, dd, J=
9Hz, 4Hz), 6.07 (1H, d, J=4Hz),
7.44 (1H, s), 7.72 (2H, d, J=8Hz),
8.27 (2H, d, J = 8Hz), 8.54 (1H, s),
9.67 (1H, d, J = 9Hz) (2) 4-Nitrogen of 7-[2-(2-formamido-4-thiazolyl)-2-methoxyiminoacetami]-3-hydroxycepham-4-carboxylic acid Benzyl ester (syn isomer, 1 g), N,
Mesyl chloride (0.406 g) was added to a mixture of N-dimethylformamide (10 ml) and potassium carbonate (0.732 g) at 0 to 5°C with stirring.
After the dropwise addition, the mixture was stirred at room temperature for 2.5 hours. After adding ethyl acetate and water to the reaction solution, the mixture is extracted with ethyl acetate. The remaining aqueous layer is extracted again with ethyl acetate. The ethyl acetate extracts are combined, washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated under reduced pressure.
The residue was subjected to column chromatography packed with silica gel (30 g) and eluted with a mixture of chloroform and ethyl acetate. The eluate was concentrated under reduced pressure to give 7-[2-(2-formamide-4
-thiazolyl)-2-methoxyiminoacetamide]-3-cephem-4-carboxylic acid 4-
Nitrobenzyl ester (syn isomer, 0.12
g) is obtained. mp224℃ (decomposition) (3) 4-nitrobenzyl ester of 7-[2-(2-formamido-4-thiazolyl)-2-methoxyiminoacetami]-3-cephem-4-carboxylic acid (syn isomer, 1.25 g) was dissolved in a mixture of methanol (40 ml) and tetrahydrofuran (50 ml), 10% palladium on carbon (0.65 g) was added thereto, and the mixture was subjected to catalytic reduction at room temperature and pressure for 3.5 hours. After removing the catalyst from the reaction solution,
Concentrate the liquid under reduced pressure. Add water (80 ml) to the residue and adjust the pH to 7.5 with an aqueous sodium hydrogen carbonate solution. After removing insoluble matter from this mixture and washing the liquid with ethyl acetate (50 ml), ethyl acetate (100 ml) is added. PH this solution with 10% hydrochloric acid.
After adjusting to 1.5, shake thoroughly. After separating the ethyl acetate layer, the aqueous layer was diluted with ethyl acetate (80%
ml) twice. This extract was combined with the ethyl acetate layer obtained earlier, washed with an aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated under reduced pressure. 2-Methoxyiminoacetamide]-3-cephem-4-carboxylic acid (syn isomer, 0.60 g) is obtained. mp176-183℃ (decomposition) IRνnujiol max: 3250, 1780, 1690, 1660,
1550cm ^-1 NMRδ (DMSO-d ₆ , ppm): 3.63 (2H, d,
J=4Hz), 3.93 (3H, s), 5.10 (1H, d,
J=5Hz), 5.90 (1H, q, J=5,8Hz),
6.53 (1H, t, J=4Hz), 7.47 (1H, s),
8.57 (1H, s), 9.70 (1H, d, J=8Hz),
12.63(1H,s) (4) 7-[2-(2-formamido-4-thiazolyl)-2-methoxyiminoacetamide]-3-
Cefem-4-carboxylic acid (syn isomer, 95
mg) was suspended in methanol (4 ml), concentrated hydrochloric acid (110 mg) was added thereto, and the mixture was stirred at room temperature for 4 hours. Methanol is distilled off by fermentation from the reaction solution.
The residue was dissolved in water (30 ml), washed successively with ethyl acetate (10 ml) and methylene chloride (15 ml), nitrogen gas was blown in to completely remove the remaining organic solvent, and then freeze-dried to give 7-
[2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamide]-3-cephem-
4-Carboxylic acid hydrochloride (syn isomer, 83mg)
get. mp180~190℃ (decomposition) IRνnujiol max: 3300, 1770, 1710, 1660,
1630cm ^-1 NMRδ (DMSO−d ₆ , ppm): 3.64 (2H,
broad s), 3.95 (3H, s), 5.14 (1H, d,
J=5Hz), 5.82 (1H, t, J=4Hz), 6.95
(1H, s), 9.80 (1H, d, J = 8Hz) Example 12 Phosphorus oxychloride (704 mg) was added dropwise to a solution consisting of N,N dimethylformamide (336 mg) and ethyl acetate (8 ml) at 5°C or below. , stir for 30 minutes at the same temperature. 2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetic acid (syn isomer, 1 g) is added to this solution and stirred at 5-10°C for 1 hour. This solution was added dropwise to a solution consisting of 7-amino-3-hydroxycepham-4-carboxylic acid (872 mg), trimethylsilylacetamide (1.05 g) and ethyl acetate (20 ml) at -20°C over 5 minutes. Stir at -20 to -25°C for 1 hour. Add water (50ml) to the reaction solution and dilute with sodium hydrogen carbonate.
Adjust to PH7.0. Separate the aqueous layer and extract the ethyl acetate layer with water (10 ml). After combining both aqueous layers and adjusting the pH to 6, they were adsorbed in a column chromatography system filled with porous nonionic adsorption resin "Diaion HP-20" (trademark: manufactured by Mitsubishi Chemical Industries, Ltd.) (50 ml). let This is washed with water (50 ml) and then eluted with 30% isopropyl alcohol.
The eluate containing the target compound is adjusted to pH 6.5 and then concentrated under reduced pressure. The resulting residue was freeze-dried to give 7-[2-(2-formamidothiazole-4
-yl)-2-methoxyiminoacetamide]-3
-Hydroxycephem-4-carboxylic acid sodium salt (syn isomer, 1.1 g) is obtained. NMRδ ( _D2O , ppm): 2.72-3.18 (2H, m),
4.02 (3H, s), 4.02~4.28 (1H, m), 4.54
(1H, d, J=4Hz), 5.28 (1H, d, J=
4Hz), 5.53 (1H, d, J = 4Hz), 7.50 (1H,
s), 8.53 (1H, s)

Claims (1)

[Claims] 1. General formula [Wherein R ¹ is a thiazolyl group or haloacetyl group represented by the formula: [Formula] (where R ⁵ means an amino group or a protected amino group),
A is a methylene group or a group represented by the formula: [Formula] (where R ² means a hydrogen atom or a C ₁ -C ₈ alkyl group), R ³ is a hydrogen atom or a group represented by the formula: -O-R ⁶ (where where R ⁶ is a hydrogen atom or an acyl group), R ⁴ is a carboxy group or its ester, and the dotted line represents a 3-cephaem nucleus or a cephaem nucleus, respectively, provided that 1) R ¹ is of the formula: When a thiazolyl group is represented by the formula: [Formula] (where R ⁵ is the same as above), A is a group represented by the formula: [Formula] (where R ² is the same as above), and 2) R ¹ is haloacetyl When it is a group, R ³ is a hydrogen atom, the dotted line is a 3-cephem nucleus, 3) R ¹ is a thiazolyl group represented by the formula [formula] (where R ⁵ is the same as above), and R ³
When is a hydrogen atom, A is a group represented by the formula: [Formula], the dotted line is a 3-cephem nucleus, and 4) R ³ is a group represented by the formula: -O-R ⁶ (where R ⁶ is an acyl group). ), the dotted line means a cephalic nucleus] or a salt thereof.