JPS6141516B2 - - Google Patents

Description

[Detailed description of the invention]

This invention provides a general formula useful as an antibacterial substance. (In the formula, R ⁷ means an amino group or a protected amino group, R ² means an alkyl group, R ³ means a carboxyl group or a protected carboxy group, and R ⁴ means a thiadiazolylthiomethyl group.) 3,7-di-substituted-3-cephem-4-
This invention relates to syn isomers of carboxylic acid compounds, salts thereof, and methods for producing them. 3,7-disubstituted compound which is the object compound of this invention
The syn isomer of the 3-cephem-4-carboxylic acid compound is represented by the above general formula (). Here, the syn isomer is represented by the formula (In the formula, R ⁷ and R ² each have the same meaning as before.) Means a geometric isomer having a partial structure represented by the following in its molecule, while the corresponding anti-isomer is a (In the formula, R ⁷ and R ² each have the same meaning as before.) It means the other geometric isomer having the partial structure shown in the molecule in its molecule. Therefore, in this specification, the syn isomer of the target compound and the starting compound has the formula

It is represented by the partial structure shown by [Formula], but if it is convenient for explanation to represent both the syn isomer and the anti isomer by one general formula, the formula

It is represented by a partial structure shown by the formula. The object compound () of this invention is a new compound, and can be produced, for example, by methods 1 and 2 shown below. Method 1

[Table] +

[Table] Method 2 (In the formula, R ⁷ , R ² , R ³ and R ⁴ each have the same meaning as before, and R ⁷ ' means a protected amino group.) It is a new compound including the anti-isomer, and can be produced by Production Methods 1 to 4 shown below. Manufacturing method 1 Manufacturing method 2 Manufacturing method 3 Manufacturing method 4 (In the formula, R ⁷ , R ⁷ ' and R ² each have the same meaning as before, X is a halogen, Z is a protected carboxy group, and Z' is a carboxy group or a protected carboxy group, respectively. ) The object compounds of this invention () and (a),
and raw material compounds (), (f), (), (
), (′), (″), (), (
e), (), (XI) - (), (
) and (h) include tautomers. That is, the formulas of these target compounds and starting compounds

[Formula] (in the formula, R ⁷ has the same meaning as before) is a group represented by the formula

When it takes the form of a group represented by [Formula] (in which R ⁷ has the same meaning as before), this group

[Formula] is its tautomerism an expression that is a field

It can also be represented by a group represented by the following formula: (wherein R ^7a means an imino group or a protected imino group). That is, these groups (A) and (B) are in a balanced relationship, which can be expressed by the balanced formula below. (In the formula, R ⁷ and R ^7a have the same meanings as above.) The tautomerism between the above-mentioned amino compounds and the corresponding imino compounds is well known, and both can be easily converted and may belong to the same compound. Well known to those skilled in the art. In the explanation of this specification and the claims, these target compounds and starting compounds will be conveniently expressed by the formula which is one of the tautomers. (In the formula, R ⁷ has the same meaning as above), but the invention is not limited thereto, and both tautomers are included within the scope of the present invention. Salts of the object compound () of this invention include:
For example, alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as calcium salts and magnesium salts, salts with inorganic bases such as ammonium salts, trimethylamine salts, triethylamine salts, pyridine salts, picoline salts, and dicyclohexylamine. salts, salts with organic bases such as N,N'-dibenzylethylenediamine salts, salts with organic salts such as acetates, maleates, tartrates, methanesulfonates, benzenesulfonates, toluenesulfonates, etc. , salts with inorganic acids such as hydrochloride, hydrobromide, sulfate, and phosphate, and salts with amino acids such as arginine salt, aspartate, and glutamate. The following definition of the above general formula will be explained. Protected amino groups include, in addition to acylamino groups, those in which the amino group is substituted with a commonly used protecting group other than an acyl group, such as a benzyl group. Protected imino groups include, in addition to acylimino groups, those in which the imino group is substituted with a commonly used protecting group other than an acyl group, such as a benzyl group. Examples of the acylamino group and the acyl moiety in the acylimino group include a carbamoyl group, an aliphatic acyl group, an acyl group containing an aromatic ring or a heterocycle, and more specifically, formyl, acetyl, propionyl, butyryl, isobutyryl,
Alkanoyl groups such as valeryl, isovaleryl, oxalyl, succinyl, pivaloyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, 1-cyclopropylethoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tertiary butoxycarbonyl, pentyloxycarbonyl, tertiary Alkoxycarbonyl groups such as pentyloxycarbonyl and hexyloxycarbonyl; alkanesulfonyl groups such as mesyl, ethanesulfonyl, propanesulfonyl, isopropanesulfonyl and butanesulfonyl; arenesulfonyl groups such as benzenesulfonyl and tosyl;
These acyl The moiety is, for example, a halogen including chlorine, bromine, iodine, fluorine, a hydroxy group, a cyano, nitro group, an alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, an alkoxy group such as methoxy, ethoxy, propoxy, isopropoxy, etc. Appropriate substitution of alkenyl groups such as vinyl and allyl, protective groups for amino groups, acyl groups such as haloalkanoyl groups such as chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, and aryl groups such as phenyl and tolyl. It may have one or more parts. Preferred examples of acyl having these substituents include mono(or di- or tri)halo-lower alkanoyl groups such as trifluoroacetyl and trichloroacetyl, and mono(or di- or tri)halo-lower alkanoyl carbamoyl groups such as trichloroacetylcarbamoyl. Examples include groups. The alkyl group includes a linear or branched alkyl group, preferably lower alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, and hexyl. . Examples of protected carboxy groups include esterified carboxy groups, where esters include, for example, methyl ester, ethyl ester, propyl ester, isopropyl ester,
Alkyl esters such as butyl ester, isobutyl ester, tertiary butyl ester, pentyl ester, tertiary pentyl ester, hexyl ester, 1-cyclopropylethyl ester, acetoxymethyl ester, propionyloxymethyl ester, butyryloxymethyl ester, Alkanoyloxyalkyl esters such as valeryloxymethyl ester, 2-acetoxyethyl ester, 2-propionyloxyethyl ester, pivaloyloxymethyl ester, alkanesulfonyl alkyl esters such as mesylmethyl ester, ethanesulfonyl ethyl ester, 2-iodo Alkyl esters with one or more suitable substituents such as mono (or di or tri) haloalkyl esters such as ethyl esters, 2,2,2-trichloroethyl esters, alkenyl esters such as vinyl esters, allyl esters, ethynyl esters , alkynyl esters such as propynyl ester, benzyl ester, 4-methoxybenzyl ester, 4-nitrobenzyl ester, phenethyl ester, trityl ester, diphenylmethyl ester, bis(methoxyphenyl)methyl ester, 3,4-dimethoxybenzyl ester, aralkyl ester which may have one or more suitable substituents such as 4-hydroxy-3,5-ditertiary butyl benzyl ester, phenyl ester, tolyl ester, tertiary butyl phenyl Examples include aryl esters which may have one or more suitable substituents, such as esters, xylyl esters, mesityl esters, and cumenyl esters. As the thiadiazolylthiomethyl group, 1,
2,4-thiadiazolylthiomethyl, 1,3,4
-thiadiazolylthiomethyl, 1,2,5-thiadiazolylthiomethyl, and the like. Halogens include chloro, fluoro, bromo and iodo. Preferred examples of the target compound () are listed below.
Preferred examples of R ⁷ include an amino group or acylamino group (more preferably a lower alkanoylamino group, a halo-lower alkanoylamino group, or a lower alkoxycarbonylamino group), and preferred examples of R ² include a lower alkyl group, R ³ A preferred example of R4 is a carboxy group, and a preferred example of ^R4 is a thiadiazolylthiomethyl group (more preferably a 1,3,4-thiadiazolylthiomethyl group). Next, a method for producing the object compound of the present invention will be explained. Method 1 The object compound of the present invention () or its salts is obtained by reacting the compound () or its reactive derivative at the amino group or a salt thereof with the compound () or its reactive derivative at the carboxy group or its salt. Manufactured by. Examples of reactive derivatives at the amino group of compound () include isocyanate, compound ()
Schiff's base (imino type or its enamine type isomer) is produced by the reaction of compound () with carbonyl compounds such as aldehydes and ketones, and Schiff's base (imino type or its enamine type isomer) is produced by the reaction of compound () with silyl compounds such as bis(trimethylsilyl)acetamide and trimethylsilylacetamide. It includes all those commonly used in amidation reactions, such as silyl derivatives or derivatives produced by the reaction of compound () with phosphorus trichloride, phosgene, etc. In addition, salts of compound () include salts with organic acids such as acetate, maleate, tartrate, benzenesulfonate, toluenesulfonate, hydrochloride, hydrobromide, sulfate, phosphoric acid salt, etc. Acid addition salts such as salts with inorganic acids such as salts,
Also included are alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as calcium salts and magnesium salts, salts with inorganic bases such as ammonium salts, and salts with organic bases such as triethylamine salts and pyridine salts. It will be done. Examples of reactive derivatives at the carboxy group of compound () include acid halides, acid anhydrides, active amides, and active esters, and more specifically, acid chlorides, acid azides, dialkyl phosphoric acid mixed acid anhydrides, etc. , substituted phosphoric acid mixed acid anhydrides such as phenyl phosphoric acid mixed acid anhydride, diphenyl phosphoric acid mixed acid anhydride, dibenzyl phosphoric acid mixed acid anhydride, halogenated phosphoric acid mixed acid anhydride, dialkyl phosphorous acid mixed acid anhydride. , sulfite mixed acid anhydride, thiosulfuric acid mixed acid anhydride, sulfuric acid mixed acid anhydride,
Alkyl carbonic acid mixed acid anhydrides, aliphatic carboxylic acid (e.g. pivalic acid, pentanoic acid, isopentanoic acid, 2-ethylbutanoic acid, trichloroacetic acid) mixed acid anhydrides, aromatic carboxylic acid (e.g. benzoic acid) mixed acid anhydrides, symmetrical Acid anhydrides such as acid anhydrides, acid amides with imidazole, 4-substituted imidazole, dimethylpyrazole, triazole, tetrazole, etc., cyanomethyl 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)-pyridone, N-hydroxysuccinimide, N-hydroxyphthalimide, 1-hydroxy-6-chloro-1H-benzotriazole, etc., and these may be used. It is appropriately selected depending on the type of compound (). Examples of the salts of the compound () include salts with inorganic bases such as alkali metal salts and alkaline earth metal salts as described above, and salts with organic bases such as trimethylamine, triethylamine, and pyridine. This reaction typically involves water, acetone, dioxane,
Acetonitrile, chloroform, methylene chloride,
The reaction is carried out in a solvent such as ethylene chloride, tetrahydrofuran, ethyl acetate, dimethylformamide, pyridine, or other general organic solvents that do not adversely affect the reaction. Among these, hydrophilic solvents can also be used in combination with water. can. 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, N,N'-carbonylbis(2-methylimidazole), pentamethyleneketene-N-cyclohexylimine, diphenylketene-N-cyclohexylimine, alkoxyacetylene, 1
-Alkoxy-1-chloroethylene, 1-(4-
chlorobenzenesulfonyloxy)-6-chloro-1H-benzotriazole, phosphorous acid trialkyl ester, polyphosphoric acid ethyl ester, polyphosphoric acid isopropyl ester, phosphorus oxychloride,
Manufactured from phosphorus trichloride, thionyl chloride, oxalyl chloride, triphenylphosphine, N-ethylbenzisoxazolium salt, N-ethyl-5-phenylisoxazolium-3'-sulfonate, dimethylformamide and thionyl chloride This is advantageously carried out in the presence of a condensing agent such as Vilsmeier's reagent, such as a compound prepared from (chloromethylene)dimethylammonium chloride, dimethylformamide and phosphorus oxychloride. In addition, this reaction can be applied to alkali metal hydroxides, alkali metal hydrogen carbonates, alkali metal carbonates, trialkylamines, N,N-dialkylanilines, N,N
The reaction may be carried out in the presence of an organic or inorganic base such as dialkylbenzylamine, pyridine or N-alkylmorpholine, and a liquid base or the above-mentioned condensing agent can also be used as a solvent. Although the reaction temperature is not particularly limited, it is usually carried out under cooling or at room temperature. In this reaction, when reacting the starting compound () with the compound () or its reactive derivative at the amino group or their salts, for example, when phosphorus pentachloride, thionyl chloride, etc. are used,
Even if a starting compound (), i.e. a syn isomer, is used, for example in the so-called activation step of this compound (), the syn isomer is partially or completely isomerized to the more stable anti-isomer; The isomerized target compound is obtained. Therefore, when trying to obtain the target compound ( ), i.e., the syn isomer, selectively and in high yield, first, the starting compound ( ), i.e., the syn isomer, is used,
It is necessary to select reaction conditions suitable for obtaining the target compound () selectively and in high yield. For example, if this reaction is carried out in the presence of the above-mentioned Vilsmeier reagent or the like under near-neutral reaction conditions, the target compound (2), that is, the syn isomer, can be obtained selectively and in high yield. Furthermore, when a compound in which R ⁷ is an amino group is used as the starting compound (), for example, this reaction is carried out in the presence of a Vilsmeier reagent prepared from dimethylformamide and phosphorus oxychloride under near-neutral reaction conditions. When carried out, the target compound ( ), ie, the syn isomer, can be obtained selectively and in high yield. In this reaction or subsequent treatment, a compound in which a protected carboxy group is converted to a free carboxy group may be obtained, and of course, this case is also included within the scope of the present invention. Method 2 The target compound (a) or its hydrochloric acid is produced by subjecting the compound () or its salts to an amino-protecting group elimination reaction. Examples of the salts of the compound () include the metal salts, ammonium salts, and organic amine salts described above. The elimination reaction of this amino protecting group includes hydrolysis,
All methods commonly used for removal of amino protecting groups, such as reducing and reacting a compound whose protecting group is an acyl group with an imino halogenating agent and then an imino etherifying agent, followed by hydrolysis as necessary. Methods can be applied, including, for example, hydrolysis using acids, bases, hydrazine, and the like. These methods are appropriately selected depending on the type of protecting group to be removed. Among these methods, hydrolysis using acids is one of the common methods, for example, substituted or unsubstituted alkoxycarbonyl groups such as tertiary pentyloxycarbonyl, alkanoyl groups such as formyl, cycloalkoxy carbonyl group, substituted or unsubstituted aralkoxycarbonyl group such as benzyloxycarbonyl, substituted benzyloxycarbonyl, aralkyl group such as benzyl or trityl, substituted phenylthio group, substituted alkylidene, substituted cycloalkylidene, substituted aralkylidene, etc. Applies to detachment. Examples of the acids used include organic and inorganic acids such as formic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, and hydrochloric acid. Among these, formic acid, trifluoroacetic acid, etc. Those that can be easily removed by conventional methods such as vacuum distillation are preferred. These acids are appropriately selected depending on the type of amino protecting group to be removed. When an acid is used in this elimination reaction, the reaction can be carried out either in the absence of a solvent or in the presence of a solvent such as water, a hydrophilic organic solvent, or a mixed solvent thereof. Furthermore, when trifluoroacetic acid is used, the reaction may be carried out in the presence of anisole. Hydrolysis using hydrazine is applied, for example, to eliminate succinyl, phthaloyl, etc. Hydrolysis with bases is frequently used to remove acyl groups such as trifluoroacetyl.
Examples of the base used 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, and carbonic acid. Alkaline earth metal carbonates such as magnesium and calcium carbonate, alkali metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate, alkali metal acetates such as sodium acetate and potassium acetate, alkaline earth phosphates such as calcium phosphate and magnesium phosphate. metals, inorganic bases such as alkali metal hydrogen phosphates such as disodium hydrogen phosphate and dipotassium hydrogen phosphate, trialkylamines such as trimethylamine and triethylamine, picoline, N-methylpyrrolidine, N-methylmorpholine, 1,5 -Diazabicyclo [4,
Examples include organic bases such as 3,0]non-5-ene, 1,4-diazabicyclo[2,2,2]octane, and 1,8-diazabicyclo[5,4,0]undecene-7. Hydrolysis using a base is usually carried out in water, a hydrophilic organic solvent, or a mixed solvent thereof.
Furthermore, when the amino protecting group is an acyl group,
These are generally removed by the hydrolysis described above or other conventional hydrolysis. The acyl group is
For example, in the case of a haloalkoxycarbonyl group, 8-quinolyloxycarbonyl group, etc., it can be eliminated by treatment with a heavy metal such as copper or zinc. Reductive elimination methods are applied, for example, to the elimination of groups such as haloalkoxycarbonyl groups such as chloroethoxycarbonyl, substituted or unsubstituted aralkoxycarbonyl groups such as benzyloxycarbonyl, 2-pyridylmethoxycarbonyl, etc. . Examples of the reductive elimination method include a reduction method using an alkali metal borohydride such as sodium borohydride. Compounds whose protecting group is acyl can be used as an iminohalogenating agent used in a method in which the protecting group is removed by reacting an iminohalogenating agent and an iminoetherifying agent, followed by hydrolysis as necessary. For example, phosphorus trichloride, phosphorus pentachloride,
Examples include phosphorus tribromide, phosphorus pentabromide, phosphorus oxychloride, thionyl chloride, and phosgene. The reaction temperature is not particularly limited, but it is usually carried out at room temperature or under cooling. The iminoetherification agent that acts on the reaction product obtained in this way includes alcohols or metal alkoxides, and alcohols include alkanols such as methanol, ethanol, propanol, isopropanol, butanol, and tertiary butanol. Or compounds in which these alkyl moieties are substituted with alkoxy groups such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, etc.
Examples of metal alkoxides include alkali metal alkoxides such as sodium alkoxide and potassium alkoxide derived from the above-mentioned alcohols, and calcium alkoxides;
Examples include alkaline earth metal alkoxides such as barium alkoxide. Although the reaction temperature is not particularly limited, the reaction is usually carried out under cooling to room temperature. The reaction product thus obtained is subjected to a hydrolysis reaction, if necessary. The hydrolysis reaction will proceed satisfactorily if the reaction solution obtained in the first step is directly poured into water, but if a hydrophilic solvent such as methanol or ethanol, an alkali metal hydrogen carbonate, a base such as a trialkylamine, or an acid such as dilute hydrochloric acid or acetic acid is used, It may be added to water in advance. The reaction temperature in the amino-protecting group elimination reaction is not particularly limited, and is appropriately selected depending on the type of amino-protecting group, the type of elimination method, etc. It is desirable that the test be carried out under the following conditions. In this reaction, a protected carboxy group may be converted to a free carboxy group, which is also within the scope of the present invention. Next, the starting compound (), i.e. the syn isomer,
and the method for producing the corresponding anti-isomer used in Reference Examples will be explained. 1 Method for producing ()→(XI) [Production Example 1] Compound (XI) is produced by nitrosating compound (). The nitrosating agent used in this reaction is
Conventional reagents which react with active methylene groups to produce C-nitroso compounds include, for example, nitrous acid, alkali metal salts of nitrite such as sodium nitrite, nitrite tertiary butyl ester, nitrite iso Examples include alkyl esters of nitrous acid such as pentyl esters. When a salt of nitrous acid is used as the nitrosating agent, this reaction is usually carried out in the presence of an inorganic or organic acid such as hydrochloric acid or acetic acid. On the other hand, when using an ester of nitrous acid, the reaction is preferably carried out in the presence of a strong base such as an alkali metal alkoxide. This reaction is usually carried out in a solvent, and in addition to water, acetic acid, alcohols such as benzene, methanol, and ethanol, any solvent that does not adversely affect this reaction can be used. Although the reaction temperature is not particularly limited, it is usually carried out under cooling to room temperature. 2 (XI) + (XII) → () and (
) + (XII) → (XI) manufacturing method [Manufacturing method 1
and 2] Compound () or (XI) is the compound (XI) or (), respectively.
XII). This reaction is usually carried out in a solvent, and examples of the solvent include water, alcohols such as methanol and ethanol, benzene, dimethylacetamide, dimethylformamide, tetrahydrofuran, and all other solvents that do not adversely affect this reaction. These solvents may be used in combination. The reaction temperature is not particularly limited, but is usually room temperature to
This is often carried out under heating to about the boiling point of the solvent. In this reaction, the target substance () or (
) to obtain the syn isomer of the starting material (
XI) or using the syn isomer as (),
Preferably, the reaction is carried out in the presence of a base such as sodium acetate or pyridine at around neutrality. 3 ()→()′, ()→(
e), () → () and (
)→(f) [Production methods 1, 2 and 3(2)] Compound ('), (e), () or (f) is the compound (), (
), () or () to an elimination reaction of the carboxy protecting group. In this elimination reaction, conventional methods used for elimination reactions of carboxy protecting groups such as hydrolysis can be applied. When the protecting group is an ester, it is removed by hydrolysis, and this hydrolysis is preferably carried out in the presence of a base or an acid. Examples of the base used include the above-mentioned inorganic bases and organic bases. Examples of acids include organic acids such as diric acid, acetic acid, propionic acid, and trifluoroacetic acid, or hydrochloric acid;
Examples include inorganic acids such as hydrobromic acid and sulfuric acid. This reaction is usually carried out in a solvent, and examples of the solvent include water, alcohols such as methanol and ethanol, mixed solvents thereof, and all solvents that do not adversely affect this reaction. A liquid base or acid can also be used as a solvent. Although the reaction temperature is not particularly limited, it is usually carried out under cooling to heating. 4 Manufacturing method of ()→() [Manufacturing method 2] Compound () is manufactured by alkylating compound (). The alkylating agent used in this reaction is
Examples include dialkyl sulfates such as dimethyl sulfate and diethyl sulfate, diazo alkanes such as diazomethane and diazoethane, alkyl halides such as methyl iodide and ethyl iodide, and alkyl esters of sulfonic acids such as methyl ester of p-toluenesulfonic acid. . Reactions using dialkyl sulfates, alkyl halides or alkyl esters of sulfonic acids are usually carried out in water, acetone, ethanol, ether, dimethylformamide or other solvents that do not adversely affect the reaction. This reaction is preferably carried out in the presence of a base such as an inorganic base or an organic base as described above. Although the reaction temperature is not particularly limited, it is usually carried out under cooling to heating to about the boiling point of the solvent. Reactions using diazoalkanes are usually carried out in a solvent such as ether or tetrahydrofuran. Although the reaction temperature is not particularly limited, it is often carried out under cooling to room temperature. 5 Manufacturing method of ()→() [Manufacturing method 2] Compound () is manufactured by halogenating compound (). The halogenating agent used in this reaction is
Halogens such as bromine and chlorine, sulfuryl halides such as sulfuryl chloride, hypochlorous acid, hypobromous acid, hypohalous acid or its salts such as sodium hypochlorite, N-bromosuccinimide, N-chlorosuccinimide Examples include halogenating agents commonly used for halogenating so-called active methylene groups, such as N-halogenated imide compounds such as imide and N-bromophthalimide. This reaction is usually carried out in a solvent, and examples of the solvent include organic acids such as dinic acid, acetic acid, and propionic acid;
In addition to carbon tetrachloride, all solvents which do not adversely affect this reaction may be mentioned. Although the reaction temperature is not particularly limited, it is usually carried out at any temperature from cooling to heating. 6 () → (XI) and ()
→Production method of (h) [Production methods 3(1) and 4] Compound (XI) or (h) is compound () or a reactive derivative thereof at the amino group or a salt thereof or compound (XI)
Alternatively, it is produced by reacting a reactive derivative at the amino group or a salt thereof with an amino-protecting agent. Examples of the reactive derivatives at the amino group of the compound () or () and the salts of these compounds include the reactive derivatives at the amino group of the compound () and salts thereof, respectively. Examples of amino-protecting agents include acylating agents, such as aliphatic, aromatic and heterocyclic carboxylic acids, their corresponding sulfonic acids or thio acids, halogen acid esters, and isocyanate esters. , carbamic acid and reactive derivatives of the aforementioned acids. Reactive derivatives of this acid include the compound ()
Examples of reactive derivatives at the carboxy group include those exemplified. These amino-protecting agents allow compounds () or ()
Examples of the protecting group (eg, acyl group) introduced into the amino group include the acyl group exemplified as the acyl moiety of the acylamino group. This acylation reaction is carried out in the same manner as the reaction of compound () and compound () (method 1) described above. 7. Manufacturing method of (″)→() [Manufacturing method 3(2)] Compound () is manufactured by hydrolyzing compound (″). This hydrolysis is carried out in the presence of alkali metal hydrogen sulfites such as sodium hydrogen sulfite, titanium trichloride, hydrohalic acids such as hydrochloric acid and hydrobromic acid, inorganic acids or organic acids such as sulfuric acid, and nitrous acid. The hydrohalic acid is preferably used in combination with an aldehyde such as formaldehyde. This reaction is usually carried out in a solvent, and examples of the solvent include water, aqueous alcohols such as aqueous methanol and aqueous ethanol, water and acetic acid, and all other solvents that do not adversely affect this reaction. Although the reaction temperature is not particularly limited, it is usually carried out at room temperature to heating. In this reaction, a protected carboxy group may be converted into a free carboxy group, which is also within the scope of this invention. 8. Method for producing (XII)→() [Production method 3(2)] Compound () is produced by oxidizing compound (XII). This oxidation reaction is carried out by conventional methods of converting so-called active methylene groups into carbonyl groups. That is, the reaction is carried out by conventional methods such as oxidation using conventional oxidizing agents such as selenium dioxide, potassium permanganate, and the like. This reaction is
Usually, this reaction is carried out in a solvent that does not adversely affect the reaction, such as water, dioxane,
Examples include tetrahydrofuran and pyridine. Although the reaction temperature is not particularly limited, the reaction is usually carried out with or without heating. 9 Manufacturing method of () + () → () and () + () → (f) [Manufacturing method 3 (2)] Compound () or (f) is replaced with compound () or (), respectively. or by reacting its salts. Examples of the salts of the compound () include inorganic acid salts such as hydrochloride, hydrobromide, and sulfate, and organic acid salts such as acetate and p-toluenesulfonate. This reaction is usually carried out in a solvent, and examples of the solvent include water, alcohols such as methanol and ethanol, mixed solvents thereof, and all other solvents that do not adversely affect this reaction. When the compound () is used in the form of its salt, for example, the above-mentioned alkali metal hydroxide, alkaline earth metal hydroxide, alkali metal carbonate, alkaline earth metal carbonate, alkali hydrogen carbonate, etc. Preferably, the reaction is carried out in the presence of a base such as an inorganic base such as a metal or an organic base such as an alkali metal alkoxide, trialkylamine, N,N-dialkylamine, N,N-dialkylbenzylamine, or pyridine. Although the reaction temperature is not particularly limited, it is usually carried out under cooling to heating. In this reaction, a mixture of syn and anti isomers of compound () or (f) may be obtained depending on the reaction conditions. In this case, both isomers are separated and isolated from the mixture by conventional separation and isolation means. For example, the mixture is esterified, the ester is separated into both isomers, for example, by chromatography, and the separated syn or anti isomer esters are hydrolyzed in a conventional manner to obtain the respective corresponding esters. It can be separated and isolated by converting it into a syn or anti isomer carboxylic acid. In this reaction, the target product () or (f)
When attempting to obtain the syn isomer of , it is preferable to carry out this reaction near neutrality. 10 Manufacturing method of ()→() [Manufacturing method 3 (2)] Compound () is manufactured by reacting compound () with hydroxyamine or a salt thereof. Examples of the salts of hydroxylamine include those exemplified as the salts of compound (). This reaction is ()+()→
() and () + () → (
It is carried out under the same reaction conditions as in method f). The above-mentioned tautomers in this invention may mutually change into tautomers during the reaction of each step and/or during the post-treatment of those reactions, but of course, these cases also fall within the scope of this invention. included in. In this invention, the target compound () has a free carboxy group at the 4-position, or (and) a free amino group in the substituent at the 7-position. When obtained in a state in which the molecule contains a group, etc., it may be converted into the above-mentioned salts by conventional methods, if necessary. The object compound () and its salts of this invention are all new compounds, have high antibacterial activity, and are useful as medicines. In addition, the target compound (), i.e., the syn isomer, has much higher antibacterial activity than the corresponding anti-isomer; It is essentially much better than its anti-isomer. In addition, all the methods of the present invention take special care to obtain the target compound () and its salts, that is, syn isomers, and the point is that such syn isomers can be produced selectively and in high yields. Excellent. Next, data on the in vitro antibacterial activity and infection protection test in mice of the following test compounds and their corresponding anti-isomers among the target compounds () of this invention are shown. Test compound (1) 7-[2-methoxyimino-2-(2-formamido-1,3-thiazol-4-yl)acetamide]-3-(1,3,4-thiadiazol-2-yl)thiomethyl- 3-Sefuem-
4-Carboxylic acid (syn isomer) (2) 7-[2-methoxyimino-2-(2-formamido-1,3-thiazol-4-yl)acetamide]-3-(1,3,4-thiadiazole -2-yl)thiomethyl-3-cephem-
4-Carboxylic acid (antiisomer) (3) 7-[2-methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamide]-3-(1,3,4-thiadiazole) ―
2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) 1 In vitro antibacterial activity Testing was performed using agar plate dilution method (inoculum amount: 10 ⁸ cells/
ml), and the minimum inhibitory concentration (MIC) at which growth of each test bacterium no longer occurs was observed and recorded.

【table】

[Table] As is clear from the above test results, the target compound (2) of the present invention, that is, the syn isomer, has much higher antibacterial activity than the corresponding anti-isomer. 2 Infection protection test in mice Test method Mice are ICR strain, 4 weeks old, weighing 20-23 g, male,
was used in a group of 8 animals. The test bacteria were cultured overnight at 37°C on HI agar, and bacterial solutions corresponding to the amount of each successful bacteria were prepared using a 2.5-5% mucin solution. 0.5 ml of the bacterial solution was injected intraperitoneally into mice, and one hour later, solutions containing the test compound were subcutaneously administered at various doses. The survival of the mice was observed for one week, and the ED ₅₀ was determined from the mouse survival rate for each dose after one week.

[Table] When the object compound () of this invention is used as a medicine, it may be used in the form of a pharmaceutically acceptable salt. The object compound of this invention () and its pharmaceutically acceptable salts are administered in the form of a composition containing an effective and non-toxic amount thereof. The dosage varies depending on the patient's age, type of disease, type of target compound (), etc., but in general, one dose is approximately 1 to 1,000.
mg or more can be administered. The composition is used in a dosage form suitable for oral or parenteral administration, together with inorganic or organic, solid or liquid pharmaceutical carriers commonly used in pharmaceutical formulations. In this case, the oral preparation is
Examples include solid preparations such as tablets, capsules, troches, and powders, and liquid preparations such as syrups. Examples of parenteral preparations include injections and suppositories. These various formulations can be manufactured by methods well known in the art. Next, the present invention will be explained with reference to manufacturing examples and examples. Production of raw material compounds used in Examples and Reference Examples described later. Production example 1 1 Add 160 g of powdered potassium carbonate to 152 g of ethyl ester of 2-hydroxyiminoacetoacetic acid (mixture of syn and anti isomers) to 500 ml of acetone.
Add to the solution dissolved in Dimethyl sulfate
130 g was added dropwise at 45 to 50° C. over 1 hour while stirring, and the mixture was stirred for 2 hours. After leaving the insoluble,
Concentrate the liquid under reduced pressure. Remove the insoluble matter with water.
Dissolve in 500 ml and add this solution to the residue. This is extracted twice with 300 ml of ethyl acetate. The extract is washed twice with 200 ml of water and then with 200 ml of saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent is distilled off under reduced pressure, and the residue is distilled under reduced pressure to obtain 145.3 g of ethyl ester of 2-methoxyiminoacetoacetic acid (mixture of syn and anti isomers) as a colorless oil. bp55~64℃/
0.5mmHg. IR spectrum (liquid film) 1745, 1695, 1600cm ^-1 N, MR spectrum (CDCl ₃ , δ) ppm4.33 (4H, q, J = 8Hz), 40.8
(3H, s), 3.95 (3H, s), 2.40 (3H,
s), 1.63 (3H, s), 1.33 (6H, t, J
=8Hz) 2 Ethyl ester of 2-methoxyiminoacetoacetic acid (mixture of syn and anti isomers) 100
100 g of bromine is added dropwise to a solution of 100 g of bromine dissolved in a mixture of 300 ml of carbon tetrachloride and 300 ml of acetic acid over 40 minutes under heating under reflux. This mixture is stirred at 70-80°C until the evolution of hydrogen bromide stops. The reaction solution is washed twice with 300 ml of water, then sequentially with an aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, and dried over magnesium sulfate. 2g activated carbon
After treatment with and concentration under reduced pressure, the ethyl ester of 2-methoxyimino-4-bromoacetoacetic acid (mixture of syn and anti isomers) 120.8
get g. IR spectrum (liquid film) 1740, 1705, 1600 cm ^-1 N, MR spectrum (CDCl ₃ , δ) ppm4.17-4.54 (8H, m), 4.15 (3H,
s), 4.13 (3H, s), 1.33 (6H, t, J
= 8 Hz) 3 235 ml of sulfuryl chloride was converted into 2-methoxyiminoacetoacetic acid ethyl ester (syn isomer).
It was added dropwise to a solution of 500 g dissolved in 500 ml of acetic acid over 20 minutes under ice-cooling and stirring, and the mixture was stirred overnight under water-cooling. Nitrogen gas was passed through the reaction solution for 2 hours, and then poured into 2.5 liters of water. 1 with 500ml of methylene chloride
Extract twice with 200 ml. Combine the extracts,
After washing with saturated sodium chloride aqueous solution, 800ml of water.
Next, add sodium hydrogen carbonate to adjust the pH to 6.5. The methylene chloride layer is separated, washed with an aqueous sodium chloride solution, and then dried over magnesium sulfate. When the solvent is distilled off, 2-methoxyimino-
559 g of ethyl ester of 4-chloroacetoacetic acid (syn isomer) is obtained. IR spectrum (liquid film) 1735, 1705 cm ^-1 Production example 2 1 A solution of 17.4 g of ethyl ester of 2-methoxyimino-4-bromoacetoacetic acid (mixture of syn and anti isomers) and 5.4 g of thiourea dissolved in 100 ml of ethanol. Heat to reflux for 4 hours. When the reaction solution is allowed to stand and then cooled, crystals precipitate. When the crystals are collected, washed with ethanol, and dried, 2-methoxyimino-2-
9.5 g of the hydrobromide salt (anti-isomer) of the ethyl ester of (2-amino-1,3-thiazol-4-yl)acetic acid are obtained. Combine the liquid and washing liquid and concentrate under reduced pressure. Add 100 ml of water to the residue and wash with ether. The aqueous layer is made basic with 28% aqueous ammonia and extracted with ethyl acetate. The extract is washed with water and then with saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent is distilled off under reduced pressure to obtain 5.2 g of ethyl ester of 2-methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetic acid (syn isomer) as a crystalline substance. IR spectrum (nujiol) 3400, 3300, 3150, 1725, 1630, 1559 cm ^-1 N, MR spectrum (CDCl ₃ , δ) ppm6.72 (1H, s), 5.91 (2H, broad
s), 4.38 (2H, q, J = 7Hz), 4.03
(3H, s) 1.38 (3H, t, J=7Hz) 2-Methoxyimino-2-(2-
9.5 g of the hydrobromide (anti-isomer) of the ethyl ester of amino-1,3-thiazol-4-yl) acetic acid is suspended in 200 ml of ethyl acetate, and 4.0 g of triethylamine is added thereto. After stirring at room temperature for 1 hour, insoluble matter was removed and the liquid was concentrated under reduced pressure to obtain a crystalline substance of 2-methoxyimino-
2-(2-amino-1,3-thiazole-4-
yl) ethyl ester of acetic acid (anti-isomer)
Obtain 6.15g. IR spectrum (nujiol) 3450, 3250, 3150, 1730, 1620 cm ^-1 N, MR spectrum (CDCl ₃ , δ) ppm7.50 (1H, s), 5.60 (2H, broad
s), 4.35 (2H, q, J = 7Hz), 4.08
(3H, s), 1.33 (3H, t, J = 7 Hz) 2 A mixture of 6.1 g of acetic anhydride and 2.8 g of acidic acid was
Stir at ℃ for 2 hours. After cooling, add 2-
Methoxyimino-2-(2-amino-1,3-
Add 4.6 g of ethyl ester (syn isomer) of thiazol-4-yl)acetic acid. After stirring for 3.5 hours at room temperature, add 100 ml of cold water. ethyl acetate 200ml
After extraction, the extract is washed with water and then with a saturated aqueous sodium bicarbonate solution until the washing becomes weakly basic. After further washing with a saturated aqueous sodium chloride solution, it is dried over magnesium sulfate. After distilling off the solvent and washing the residue with diisopropyl ether, it was taken and dried to give the ethyl ester (syn isomer) of 2-methoxyimino-2-(2-formamido-1,3-thiazol-4-yl)acetic acid. ) Obtain 4.22g. mp122-124℃ (decomposition). IR spectrum (nujiol) 3150, 1728, 1700 cm ^-1 N, MR spectrum (CDCl ₃ , δ) ppm12.58 (1H, broad s), 8.95 (1H,
s), 7.17 (1H, s), 4.42 (2H, q, J
=8Hz), 4.00 (3H, s), 1.37 (3H,
t, J=8Hz) 3 2-methoxyimino-2-(2-amino-
6.5 g of 1,3-thiazol-4-yl) acetic acid ethyl ester (syn isomer) was mixed with 60 g of ethyl acetate.
ml and 20 ml of dimethylformamide, and 3 g of pyridine is added thereto. Add 8 ethyl esters of chloroformic acids to this solution at 4°C with stirring.
Drop g. Add 50 ml of water to the reaction solution, separate the organic layer, wash with water and then with a saturated aqueous sodium chloride solution, and dry over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to column chromatography using 120 g of silica gel and eluted with a mixed solvent of ether and petroleum ether (5:2) to obtain 2-methoxyimino-2-(2
5.4 g of ethyl ester (syn isomer) of -ethoxycarbonylamino-1,3-thiazol-4-yl)acetic acid is obtained. N, MR spectrum (CDCl ₃ , δ) ppm9.36 (1H, broad s), 7.10 (1H,
s), 4.00-4.66 (4H, m), 4.00 (3H,
s), 1.20-1.60 (6H, m) 4 Theourea 18.4g and sodium acetate 19.8g
2-Methoxyimino-
Add 50 g of ethyl ester of 4-chloroacetoacetic acid (syn isomer) over a period of 3 minutes. 40-45
After stirring at ℃ for 35 minutes, cool on ice and adjust the pH to 6.3 by adding saturated aqueous sodium hydrogen carbonate solution. 30 at the same temperature
After stirring for a minute, the precipitated crystals were collected, washed with 200 ml of water and then with 100 ml of diisopropyl ether, and dried to form colorless crystals of 2-methoxyimino-2.
-(2-amino-1,3-thiazol-4-yl)acetic acid ethyl ester (syn isomer) 37.8
get g. mp161~162℃. IR spectrum (nujiol) 3400, 3300, 3150, 1725, 1630, 1559 cm ^-1 N, MR spectrum (CDCl ₃ , δ) ppm6.72 (1H, s), 5.91 (2H, broad
s), 4.38 (2H, q, J = 7Hz), 4.03
(3H, s), 1.38 (3H, t, J=7Hz) 5 The following compound is obtained in the same manner as in Production Example 2-2. Ethyl ester of 2-methoxyimino-2-(2-formamido-1,3-thiazol-4-yl)acetic acid (antiisomer), mp96-99℃
(Disassembly). IR spectrum (nujiol) 3150, 1740, 1650, 1600 cm ^-1 N, MR spectrum (CDCl ₃ , δ) ppm11.20 (1H, broad s), 8.60 (1H,
s), 7.90 (1H, s), 4.32 (2H, q, J
= 8Hz), 4.13 (3H, s) 1.32 (3H, t,
J=8Hz) Production example 3 1 2-methoxyimino-2-(2-amino-
Add 10 ml of ethanol to a suspension of 2.2 g of 1,3-thiazol-4-yl) acetic acid ethyl ester (syn isomer) in 12 ml of 1N aqueous sodium hydroxide solution.
ml and stir at room temperature for 15 hours. 10% of reaction solution
Adjust the pH to 7.0 with % hydrochloric acid and distill off the ethanol under reduced pressure. After washing the aqueous layer with ethyl acetate, adjust the pH to 2.8 with 10% hydrochloric acid and stir under ice cooling to precipitate crystals. After taking this crystal and washing it with acetone,
When recrystallized from ethanol, colorless needle crystals of 2
-methoxyimino-2-(2-amino-1,3
-thiazol-4-yl)acetic acid (syn isomer)
Obtain 1.1g. IR spectrum (nujiol) 3150, 1670, 1610, 1585 cm ^-1 N, MR spectrum (d ₆ -DMSO, δ) ppm7.20 (2H, broad s), 6.85 (1H,
s), 3.83 (3H, s), 2 The following compound is obtained in the same manner as in Production Example 3-1. (1) 2-methoxyimino-2-(2-formamido-1,3-thiazol-4-yl)acetic acid (syn isomer), mp152°C (decomposition). IR spectrum (nujiol) 3200, 2800-2100, 1950, 1600cm ^-1 N, MR spectrum (d ₆ -DMSO, δ) ppm8.60 (1H, s), 7.62 (1H, s),
3.98(3H,s) (2) 2-methoxyimino-2-(2-ethoxycarbonylamino-1,3-thiazole-4
-yl) acetic acid (syn isomer) IR spectrum (nudiol) 3200, 1730, 1710, 1690, 1570 cm ^-1 NMR spectrum (d ₆ -DMSO, δ) ppm12.16 (1H, broad s), 7.50
(1H, s), 7.20 (1H, broad s), 4.25
(2H, q, J=7Hz), 3.93 (3H, s),
1.25 (3H, t, J = 7Hz) 3 2-methoxyimino-2-(2-amino-
Add 5 ml of pyridine to a suspension of 2.0 g of 1,3-thiazol-4-yl)acetic acid (syn isomer) in 20 ml of ethyl acetate. Add screws (2, 2,
A solution of 2.5 g of 2-trifluoroacetic acid (2-trifluoroacetic acid) anhydride dissolved in 3 ml of ethyl acetate is added dropwise with stirring at 5-7°C, and then stirred at 3-5°C for 30 minutes. Add 30 ml of water to the reaction solution and separate the ethyl acetate layer. The aqueous layer is further extracted with ethyl acetate, and the ethyl acetate layers are combined. The ethyl acetate solution is washed with water and then with a saturated aqueous sodium chloride solution, and then dried over magnesium sulfate. When the solvent was distilled off under reduced pressure, 2-methoxyimino-2-[2-(2,
2,2-trifluoroacetamide)1,3-
Thiazol-4-yl]acetic acid (syn isomer)
Obtain 0.72g. IR spectrum (Nujiol) 1725, 1590 cm ^-1 N, MR spectrum (d ₆ -DMSO, δ) ppm 7.68 (1H, s), 3.91 (3H, s) 4 The following compound was prepared in the same manner as in Production Example 3-1. get. 2-Methoxyimino-2-(2-formamido-1,3-thiazol-4-yl)acetic acid (antiisomer), mp 156-158°C (decomposition). IR spectrum (Nujiol) 3200, 2700-2100, 1690, 1590, 1560 cm ^-1 N, MR spectrum (d ₆ -DMSO, δ) ppm8.05 (1H, s), 4.20 (3H, s) Example 1 Dimethylformamide 0.63 g and 1.33 g of phosphorus oxychloride are mixed under ice cooling, and then heated at 40°C for 30 minutes. This solution was suspended in 20 ml of dry ethyl acetate, and then 1.8 g of 2-methoxyimino-2-(2-formamido-1,3-thiazol-4-yl)acetic acid (syn isomer) was added to it while stirring under ice cooling. Add and stir at the same temperature for 40 minutes. On the other hand, 2.6 g of 7-amino-3-(1,3,4-thiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid
Add and dissolve 8.2 g of trimethylsilylacetamide and 30 ml of dry ethyl acetate. Add the ethyl acetate solution obtained above to this solution at -30℃,
Stir at ~-10°C for 2 hours. When 100 ml of aqueous sodium chloride solution is added at -20°C, an oily substance precipitates out.
The ethyl acetate layer and the aqueous layer are separated by decantation, and the aqueous layer is extracted with 200 ml of ethyl acetate. Dissolve the oil in 20 ml of acetone and add to the ethyl acetate solution. After washing the ethyl acetate solution with 100 ml of water, it is treated with activated carbon. After filtering, add 100 ml of water to the solution, and adjust the pH to 7 with saturated aqueous sodium hydrogen carbonate solution. After separating the aqueous layer, layer it with 200 ml of ethyl acetate, adjust the pH to 1.5 with 10% hydrochloric acid, and extract with ethyl acetate. After further extracting the aqueous layer with 100 ml of ethyl acetate, the ethyl acetate layers are combined, washed with 1 ml of saturated aqueous sodium chloride solution, and dried over magnesium sulfate.
After evaporation, the solvent was distilled off to give a pale yellow solid of 7-[2
-Methoxyimino-2-(2-formamide-
1,3-thiazol-4-yl)acetamide]
2.37 g of -3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cefem-4-carboxylic acid (syn isomer) is obtained. mp145-147℃ (decomposition). IR spectrum (nujiol) 3150-3400, 1780, 1725, 1680, 1640 cm ^-1 N, MR spectrum (d ₆ -DMSO, δ) ppm12.58 (1H, broad s), 9.70 (1H,
d, J=8Hz), 9.58 (1H, s), 8.50
(1H, s), 7.40 (1H, s), 5.82 (1H,
dd, J = 5.8Hz), 5.17 (1H, d, J = 5
Hz), 4.43 (2H, ABq, J=13Hz), 3.88
(3H, s), 3.70 (2H, broad s) Example 2 8.6 g of phosphorus oxychloride is added dropwise to 4.0 g of dimethylformamide while stirring under ice cooling. After heating at 40°C for 40 minutes, add 80 ml of ethyl acetate and suspend.
2-Methoxyimino-2-(2,
Add 16 g of 2,2-trifluoroacetamido-1,3-thiazol-4-yl)acetic acid (syn isomer) and stir to form a solution. Meanwhile, 83.8 g of trimethylsilylacetamide was dissolved in 500 ml of ethyl acetate, and 26.4 g of 7-amino-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid was added thereto. Stir at room temperature to form a solution. This solution is cooled to -20°C, and the ethyl acetate solution obtained above is added dropwise thereto at -20°C, followed by stirring at -20 to -10°C for 2 hours. Add 300 ml of water to the reaction solution to separate the ethyl acetate layer, add 200 ml of water to this, adjust the pH to 7.0 with a saturated aqueous sodium bicarbonate solution, and separate the aqueous layer. Add 200 ml of ethyl acetate to the aqueous layer, adjust the pH to 4.5 with 10% hydrochloric acid, and then separate the ethyl acetate layer. Add 400ml of ethyl acetate to the aqueous layer, adjust the pH to 2.5 with 10% hydrochloric acid,
Separate the ethyl acetate layer. The ethyl acetate layer was washed with water and a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure to give 7-[2-methoxyimino-2-
{2-(2,2,2-trifluoroacetamide)-1,3-thiazol-4-yl}acetamide]-3-(1,3,4-thiadiazole-2
25.4 g of thiomethyl-3-cephem-4-carboxylic acid (syn isomer) are obtained. IR spectrum (nujiol) 3200, 1780, 1720, 1650 cm ^-1 N, MR spectrum (d ₆ -DMSO, δ) ppm9.81 (1H, d, J = 8Hz), 9.6 (1H,
m), 9.57 (1H, s), 7.56 (1H, s), 5.83
(1H, dd, J=5.8Hz), 5.20 (1H, d, J=
5Hz), 4.47 (2H, ABq, J=14Hz), 3.96
(3H, s), 3.72 (2H, ABq, J=18Hz) Example 3 The following compound is obtained in the same manner as in Examples 1 and 2. (1) 7-[2-methoxyimino-2-(2-ethoxycarbonylamino-1,3-thiazole-
4-yl)acetamide]-3-(1,3,4
-thiadiazol-2-yl)thiomethyl-3
-Cefem-4-carboxylic acid (syn isomer) IR spectrum (nudiol) 3200, 1775, 1720, 1680, 1660 cm ^-1 N, MR spectrum (d ₆ -DMSO, δ) ppm11.9 (1H, m), 9.70 (1H, d, J=
10Hz), 9.55 (1H, s), 7.31 (1H, s),
5.80 (1H, dd, J=5, 10Hz), 5.18
(1H, d, J=5Hz), 4.44 (2H, ABq,
J = 16Hz), 4.22 (2H, q, J = 7Hz),
3.89 (3H, s), 3.72 (2H, ABq, J=16
Hz), 1.23 (3H, t, J = 7Hz) (2) 7-[2-methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamide]-3-(1,3 ,4-thiadiazole-
2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer), mp172-175°C (decomposition). IR spectrum (nujiol) 3300, 1770, 1665 cm ^-1 N, MR spectrum (d ₆ -DMSO, δ) ppm9.80 (1H, d, J = 8Hz), 9.63
(1H, s), 6.95 (1H, s), 6.8 (2H,
m), 5.82 (1H, dd, J=5,8Hz),
5.22 (1H, d, J = 5Hz), 4.48 (2H,
ABq, J=15Hz), 3.97 (3H, s), 3.76
(2H, ABq, J=18Hz) Example 4 7-[2-methoxyimino-2-{2-(2,
2,2-trifluoroacetamide)-1,3-
Thiazol-4-yl}acetamide]-3-
23 g of (1,3,4-thiadiazol-2-yl)thiomethyl-3-cefem-4-carboxylic acid (syn isomer) was mixed with 74.8 g of sodium acetate trihydrate.
in 230 ml of water and then stirred at room temperature for 15 hours. The reaction solution was adjusted to pH 5.0 with concentrated hydrochloric acid, and insoluble materials were removed. The pH of the solution was adjusted to 2.5, and the precipitated crystals were collected and dried to form 7-[2-methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamide]-3-(1,
3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer)
Get 14g. mp172-175℃ (decomposition). IR spectrum (nujiol) 3300, 1770, 1665 cm ^-1 N, MR spectrum (d ₆ -DMSO, δ) ppm9.80 (1H, d, J=8Hz), 9.63 (1H,
s), 6.95 (1H, s), 6.8 (2H, m), 5.82
(1H, dd, J=5,8Hz), 5.22 (1H, d,
J = 5Hz), 4.48 (2H, ABq, J = 15Hz),
3.97 (3H, s), 3.76 (2H, ABq, J=18
Hz) Example 5 7-[2-methoxyimino-2-(2-formamido-1,3-thiazol-4-yl)acetamide]-3-(1,3,4-thiadiazole-
2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) 10.8g in methanol 200ml
In addition to this, 7.2 g of phosphorus oxychloride is added dropwise at 2 to 9° C. while stirring under ice cooling. Then, after stirring at the same temperature for 1.5 hours, the total volume was about 100ml on a 25-28℃ water bath.
Concentrate under reduced pressure until . 300 ml of ether was added to the concentrated solution under ice-cooling and stirring, and the precipitate was collected and dried to give 7-[2-methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamide]-3- (1,3,4-thiadiazole-2-
12.3 g of hydrochloride (syn isomer) of thiomethyl-3-cephem-4-carboxylic acid are obtained. 12.3 g of this powder is suspended in 100 ml of water, and a saturated aqueous sodium bicarbonate solution is added to the suspension to adjust the pH to 7.5. Add 100ml of ethyl acetate to this solution, adjust the pH to 2.5 with 10% hydrochloric acid, remove the precipitate, wash with cold water,
When dried, 7-[2-methoxyimino-2-
(2-amino-1,3-thiazol-4-yl)
Acetamide]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cepheme-4
- Obtain 6.1 g of carboxylic acid (syn isomer). Separate the aqueous layer of this mother liquor, add sodium chloride to it, stir it while cooling, and remove the precipitate to obtain 3.8 g of the same target compound. Total yield 9.9g. This product was identified by IR and N,MR spectra as that obtained in other Examples. Reference Example The following compound was obtained in the same manner as in Examples 1 and 2. 7-[2-methoxyimino-2-(2-formamido-1,3-thiazol-4-yl)acetamide]-3-(1,3,4-thiadiazole-
2-yl)thiomethyl-3-cephem-4-carboxylic acid (antiisomer), mp152°C (decomposition). IR spectrum (nujiol) 3300-3100, 1775, 1720, 1670, 1630 cm ^-1 N, MR spectrum (d ₆ -DMSO, δ) ppm12.63 (1H, broad s), 9.66 (1H,
s), 9.57 (1H, d, J=8Hz), 8.50
(1H, s), 80.7 (1H, s), 5.75 (1H,
dd, J=5,8Hz), 5.15(1H, d, J=5
Hz), 4.27 (2H, ABq, J=13Hz), 4.00
(3H, s), 3.70 (2H, broad s)

Claims (1)

[Claims] 1. General formula (In the formula, R ⁷ means an amino group or a protected amino group, R ² means an alkyl group, R ³ means a carboxyl group or a protected carboxy group, and R ⁴ means a thiadiazolylthiomethyl group.) 3,7-di-substituted-3-cephem-4-
Syn-isomers of carboxylic acid compounds and their salts. 2 The group represented by the formula [Formula] is [Formula], and R ₇ is an amino group or an acylamino group,
The compound and salts thereof according to claim 1, wherein R ³ is a carboxy group. 3. The compound and salts thereof according to claim 2, wherein R ⁷ is an amino group, a lower alkanoylamino group, a halo-lower alkanoylamino group, or a lower alkoxycarbonylamino group. 4 R ⁷ is an amino group, formamide group, trifluoroacetamide group, or ethoxycarbonylamino group, R ² is a methyl group, and R ₄ is 1,3,4
-thiadiazol-2-ylthiomethyl group and its salts according to claim 3. 5 7-[2-methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamide]-3-(1,3,4-thiadiazole-2-
5. The compound according to claim 4, which is yl)thiomethyl-3-cefem-4-carboxylic acid (syn isomer), and salts thereof. 6 7-[2-methoxyimino-2-(2-formamido-1,3-thiazol-4yl)acetamide]-3-(1,3,4-thiadiazole-
Claim 4 which is 2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer)
Compounds and their salts described in Section 1. 7 7-[2-methoxyimino-2-{2-
(2,2,2-trifluoroacetamide)-
1,3-thiazol-4-yl}acetamide]
The compound according to claim 4, which is -3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer), and salts thereof. 8 7-[2-methoxyimino-2-(2-ethoxycarbonylamino-1,3-thiazole-4
-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) and the compound according to claim 4, which is salts. 9 General formula (In the formula, R ² is an alkyl group, R ³ is a carboxy group or a protected carboxy group, R ⁴ is a thiadiazolylthiomethyl group, and R ⁷ ' is a protected amino group.) or its salts are subjected to an amino-protecting group elimination reaction, and the general formula (In the formula, R ² , R ³ and R ⁴ each have the same meaning as above) 3,7-disubstituted-3-cepheme-4- A method for producing a syn isomer of a carboxylic acid compound or its salts.