KR820000902B1 - Process for preparing cephem and cepham compounds - Google Patents

Abstract

Title compds. (I; R1 = thiadiazolyl, thiazolyl, haloacetyl; A = methylene, aliph. hydrocarbon residue; R3 = H, lower alkyl; R4 = H, halogen, lower alkyl, -O-R7; R7 = H, lower alkyl, acyl; R5 = carboxy) were prepd. by the reaction of II and III. Thus, 2.14 g dried pyridine was added in 100 ml dichloromethane contg. 10.50 g p-nitrobenzyl-7-phenylacetamido-3-cephem-4-carboxylate, and reacted with 5.50 g pentachlorophosphite at -10≰C to give 7.90 g p-nitrobenzyl-7-amino-3-cephem-4-carboxylate (m.p. 182≰C).

Description

Process for preparing novel cefem and sefam compounds

The present invention relates to a process for the preparation of novel cefem and cepam compounds. In particular, the present invention relates to a novel 7-substituted-3-cepem (or sefam) -4-carboxylic acid having antibacterial activity, a pharmaceutically acceptable salt thereof and a method for preparing a pharmaceutically acceptable biological precursor of the compound. will be.

Accordingly, an object of the present invention is a novel 7-substituted-3-cepem (or sefam) -4-carboxylic acid, which exhibits excellent antimicrobial activity against various types of pathogenic microorganisms, including gram-negative and gram-positive bacteria, and pharmaceuticals thereof. To provide an acceptable salt and a method for preparing a pharmaceutically acceptable biological precursor of the compound.

The cefem and cepam compounds provided by the present invention can be represented by the following structural formula (I).

의 티아졸릴 또는 티아디아졸릴 또는 할로아세틸기이고 A는 메틸렌 혹은 R²가 수소 혹은 할로겐, 카르복시 혹은 에스테르화된 카르복시로 치환될 수 있는 지방족 탄화수소기인 구조식

의 기이고Wherein R ¹ is a structural formula wherein R ⁶ is amino or protective amino

Is a thiazolyl or thiadiazolyl or haloacetyl group, and A is an aliphatic hydrocarbon group in which methylene or R ² is substituted with hydrogen or halogen, carboxy or esterified carboxy

Is the flag of

R ³ is hydrogen or lower alkyl

R ⁴ is hydrogen, halogen, lower alkyl or a group of formula -OR ⁷ wherein R ⁷ is hydrogen, lower alkyl or acyl group

R ⁵ is carboxy or functionally regulated carboxy

Dotted lines represent 3-cepm and cepam nuclei. but,

i) when R ³ is hydrogen, R ⁴ is hydrogen, halogen or a group of the formula -OR ⁷ wherein R ⁷ is as defined above;

ii) when R ³ is a lower alkyl group, R ⁴ is a lower alkyl group;

의 티아졸릴일 경우, A는 R²가 상기 정의대로인 구조식

의 그룹iii) a structural formula in which R ¹ is thiadiazolyl, or R ⁶ is as defined above

For a one-thiazolyl, A has the structural formula as R ² have the above-defined

Group of

iv) When R ¹ is a haloacetyl group, the dashed line represents 3-cephem nucleus and R ⁴ represents -OR ⁷ where hydrogen, halogen lower alkyl or R ⁷ is lower alkyl group.

v) when R ⁴ is halogen or a group of —OR ⁷ in which R ⁷ is lower alkyl, R ² is neither hydrogen nor lower alkyl;

The cefem and cefam compound (I) described above include compounds useful as antimicrobial agents and compounds useful as intermediates for producing such antimicrobial agents, as particularly specified below.

Compounds of the present invention useful as antimicrobial agents can be represented by the following structural formula (I ').

의 티아졸릴이며, R²,R³,R⁴및 R⁵는 각각 상기 정의대로이다.Wherein R ¹ _a is _a structural formula wherein thiadiazolyl R ⁶ is as defined above

Is thiazolyl, and R ² , R ³ , R ⁴ and R ⁵ are each as defined above.

The terms and definitions described in the specification and claims are described below.

a) Substructure of the following structural formula means two geometric structures as follows.

The geometric isomer of formula (S) means syn and the other formula (A) represents anti.

Thus, one isomer of a compound having a partial structure represented by the above formula (S) relates to the "neoisomer" and the other isomer represented by the formula (A) relates to the "antiisomer".

The neoisomer of the compound of formula (I ′) tends to have a much higher antimicrobial activity than that of the corresponding antiisomer in terms of the structural activity, so the isomer of compound (I ′) in terms of prophylactic and therapeutic value. Is a much preferred antimicrobial agent than its antiisomer.

의 티아졸릴 그룹은 R⁶′가 아미노 혹은 보호이미노기인 구조식

의 티아졸리닐 그룹과 호변이성(互變異性)관계에 있는 것으로 이미 공지되어 있다.b) a structural formula in which R ⁶ is as defined above

The thiazolyl group of is a structural formula in which R ⁶ ′ is an amino or a protective imino group

It is already known to be in a tautomeric relationship with thiazolinyl groups.

Tautomerism between the thiazolyl and thiazolinyl groups can be represented in the following equilibrium.

Where R ⁶ and R ⁶ ′ are as defined above.

(R⁶는 상기 정의대로임)로 표시된다.Thus, the two groups are substantially the same, and tautomers that make up such groups are considered to be the same compound, especially in the manufacturing chemistry. Therefore, two tautomers of a compound having such a group in its molecule are included in the scope of the present invention and referred to collectively as “thiazolyl”, but for convenience the structural formulas in the present specification and claims

(R ⁶ is as defined above).

c) 3-hydroxy-3-cefem compound having the partial structural formula

3-oxo-sepam compound of the formula

It is known to be tautomatic. Each compound is an enol- or keto- tautomer and is generally a compound in which the enol- tautomer is stable.

Accordingly, two compounds having the tautomeric structure are included in the scope of the present compound, and the structure and nomenclature of the tautomer are collectively referred to as 3-hydroxy-3-cepem compounds in the specification and claims. Shown as the indicated stable enol tautomers.

In the foregoing and following description of the specification, appropriate descriptions and examples of various definitions which the present invention intends to encompass within its scope are described in detail below.

The term "lower" means a group having 1-6 carbon atoms, unless otherwise specified,

“Tiadiazolyl” of R ¹ is 1,2,3-thiadiazolyl (eg, 1,2,3-thiadiazol-4-yl, or 1,2,3-thiadiazol-5-yl) , 1,3,4-thiadiazolyl or 1,2,4-thiadiazolyl, preferably 1,2,3-thiadiazolyl and more preferably 1,2,3-thiadiazol-4- Say work.

The “aliphatic hydrocarbon residues of R ² may include saturated or unsaturated monovalent groups and straight, branched or cyclic aliphatic hydrocarbons, in particular alkyl, alkenyl, alkynyl, cycloalkyl, etc., which are described in more detail below. It is.

“Alkyl” refers to 1-12 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, 1-butyl, pentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, etc. Residues of straight or branched alkanes, preferably lower alkyl, more preferably lower alkyl having 1-4 carbon atoms.

"Alkenyl" is a residue of a straight or branched chain alkene having up to 12 carbon atoms, preferably lower eggs such as vinyl, allyl, 1-propenyl, isopropenyl, butenyl, isobutenyl, pentenyl, hexenyl, etc. Kenyl, more preferably lower alkenyl having up to 4 carbon atoms, and the like.

“Alkynyl” refers to a straight or branched chain alkyl residue having up to 12 carbon atoms, preferably ethynyl, propargyl 1-propynyl, 3-butynyl, 2-butynyl, 4-pentynyl, 3- Lower alkynyl, such as pentynyl, 2-pentynyl, 1-pentynyl, 5-hexynyl, and the like, more preferably lower alkynyl having up to 4 carbon atoms.

“Cycloalkyl” may include residues of cycloalkanes having up to eight carbon atoms, preferably lower cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, more preferably cyclohexyl.

The aliphatic hydrocarbon moiety may be substituted with a halogen atom, carboxy or esterified carboxy group. Thus, “aliphatic hydrocarbon residues substituted with halogen atoms, carboxyl or esterified carboxy groups” also include “halogen-substituted aliphatic hydrocarbon residues”, “carboxy-substituted aliphatic hydrocarbon residues” and “esterified carboxy-substituted aliphatic hydrocarbon residues”. Each of which may be more particularly halo-alkyl, alkenyl, alkynyl and cycloalkyl carboxy-alkyl, alkenyl, alkynyl and cycloalkyl and esterified carboxy-alkyl, alkenyl, alkynyl and cycloalkyl Each may include.

Suitable examples of “halogens” include chlorine, bromine, iodine and fluorine, and suitable examples of “esterified carboxy” include alkoxycarbonyl and the like, “alkyl”, “alkenyl”, “alkynyl” Preferred examples of the alkyl moiety of “”, “cycloalkyl” and “alkoxy-carbonyl” are the corresponding lower alkyls mentioned above.

Preferred examples of “halo-alkyl, alkenyl, alkynyl and cycloalkyl” include chloromethyl, bromomethyl, iodomethyl, fluoromethyl, trichloromethyl, trifluoromethyl, 2-chloroethyl, 1,2 -Dichloroethyl, 2,2,2-trifluoroethyl, 3-chloropropyl, 4-iodobutyl, 5-fluoropentyl, 6-bromohexyl, 3-fluoroallyl, 3-chloropropa Gil, 4-fluorocyclohexyl, and the like.

Preferred examples of “carboxy-alkyl, alkenyl, alkynyl and cycloalkyl” include carboxymethyl, 1-carboxyethyl, 2-carboxyethyl, 1-carboxypropyl, 3-carboxypropyl, 4-carboxybutyl, 5-carboxypentyl , 6-carboxyhexyl, 1-carboxyisopropyl, 1-ethyl-1-carboxyethyl, 2-methyl-2-carboxypropyl, 3-carboxyallyl, 3-carboxy-propargyl, 4-carboxycyclohexyl and the like have.

Preferred examples of “esterified carboxyalkyl, alkenyl, alkynyl and cycloalkyl” include lower alkoxycarbonyl (lower) alkyls such as methoxycarbonylmethyl, methoxycarbonylmethyl, propoxycarbonylmethyl, t -Butoxycarbonylmethyl, 2-ethoxycarbonylethyl, 2-ethoxycarbonylpropyl, 4-ethoxycarbonylbutyl, 1-t-butoxycarbonylisopropyl, 1-t-butoxycarbonyl -1-methyl-propyl, 4-t-butoxycarbonylbutyl, 5-t-butoxycarbonylpentyl 6-butoxycarbonylhexyl, etc., lower alkoxycarbonyl (lower) -alkenyl (e.g. 3 Lower alkoxycarbonyl (lower) alkynyl (eg, 3-methoxycarbonylpropargyl, etc.) lower alkoxycarbonyl (lower) -cycloalkyl (eg, 4-methoxycarbonyl) Cyclohexyl, etc.), and more preferred examples thereof include lower alkoxycarbonylmethyl.

The “lower alkyl” of R ³ , R ⁴ and R ⁷ is the same as R ² exemplified by the aliphatic hydrocarbon residue term, more preferred is lower alkyl having up to 4 carbon atoms, more preferably methyl .

The “halogen” of R ⁴ is chlorine, bromine, iodine or fluorine, with chlorine or bromine being preferred.

The “acyl” of R ⁷ is lower alkanyl (eg formyl, acetyl, porionyl, butyryl, isobutyryl, isovaleryl, pivaloyl, etc.), aroyl (eg benzoyl, etc.) Phonyl (eg, mesyl, ethanesulfonyl, 1-methylethanesulfonyl, propanesulfonyl, butanesulfonyl, etc.), arylsulfonyl (eg, benzenesulfonyl, tosyl, etc.).

The "protecting group" in the "protecting amino" group of R ⁶ is substituted or unsubstituted (lower) alkyl (eg benzyl, benzyl, trityl, 4-methoxybenzyl, 3,4-dimethoxybenzyl, etc.), halo Known such as (lower) alkyls (e.g., trichloromethyl, trichloroethyl, trifluoromethyl, etc.), tetrahydropyranyl, substituted phenylthio, substituted acylidene, substituted aralkylidene, substituted cycloalkylidene, acyl and the like N-protection group.

Suitable acyl of the protecting group are substituted or unsubstituted lower alkanoyls (e.g. formyl, acetyl, chloroacetyl, trifluoroacetyl, etc.), substituted or unsubstituted lower alkoxycarbonyls (e.g. methoxycarbonyl, ethoxy Carbonyl, propoxycarbonyl, 1-cyclopropylethoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, t-butoxycarbonyl, pentyloxycarbonyl, t-pentyloxycarbonyl, hexyloxyca Carbonyl, trichloroethoxycarbonyl, 2-pyridylmethoxycarbonyl, etc.), substituted or unsubstituted car (lower) -alkoxy carbonyl (eg, benzyloxycarbonyl, benzyloxycarbonyl, 4-nitrobenzyl) Oxycarbonyl and the like), lower cycloalkoxycarbonyl (eg, cyclopentyloxycarbonyl, cyclohexyloxycarbonyl and the like), 8-quinolyloxycarbonyl, succinyl, phthaloyl and the like.

In addition, phosphorus compounds having a reaction product of silane, boron, aluminum or amino groups may also be included in the protecting group. Suitable examples of such compounds include trimethylsilyl chloride, trimethoxysilyl chloride, boron trichloride, dibutoxyboron chloride, aluminum trichloride, diethoxy chloride, phosphorus dibromide, phenylphosphorus dibromide and the like.

“Functionally controlled carboxy” of R ⁵ means esters, amides and the like.

Suitable examples of esters include alkyl esters (eg, methyl esters, ethyl esters, propyl esters, isopropyl esters, butyl esters, isobutyl esters, t-butyl esters, pentyl esters, t-pentyl esters, hexyl esters, heptyl esters, octyl Esters, 1-cyclopropylethyl esters, etc.), alkenyl esters (eg, vinyl esters, allyl esters, etc.), alkynyl esters (eg, ethynyl esters, propynyl esters, etc.), alkoxyalkyl esters (eg, methoxymethyl Esters, ethoxymethyl esters, isopropoxymethyl esters, 1-methoxyethyl esters, 1-methoxyethyl esters and the like), alkylthioalkyl esters (e.g. methylthiomethyl esters, ethylthiomethyl esters, ethylthioethyl esters) , Isopropylthiomethyl ester, etc.), haloalkyl esters (eg 2-iodoethyl ester, 2,2,2-tri Chloroesters, etc.), alkanoyloxyalkyl esters (e.g. acetoxymethyl ester, propionyloxymethyl ester, butyryloxy ester, valeryloxymethyl ester, pivaloyloxymethyl ester, hexanoyloxymethyl ester, 2- Acetoxyethyl ester, 2-propionyloxyethyl ester palmitoyloxymethyl ester, and the like), alkanesulfonylalkyl esters (e.g., mesylmethylester, 2-mesylethyl ester, etc.), substituted or unsubstituted aralkyl esters (e.g., , Benzyl ester, 4-methoxybenzyl ester, 4-nitrobenzyl ester, phenethyl ester, trityl ester, benzyl ester, bis (methoxyphenyl) methyl ester, 3,4-dimethoxybenzyl ester, 4- Hydroxy-3,5-di-t-butylbenzyl esters, etc.), substituted or unsubstituted aryl esters (e.g., phenyl esters, tolyl esters, t-butylphenyl esters, xylyl es) Le, mesityl esters, cumenyl esters, salicylic esters, etc.), esters having silyl compounds such as trialkylsilyl compounds, dialkylalkoxysilyl compounds, or trialkoxy silyl compounds, for example trialkylsilyl esters (e.g., Trimethylsilyl ester, triethylsilyl ester, etc.), dialkylalkoxysilyl esters (e.g., dimethylmethoxysilyl ester, dimethyl ethoxysilyl ester, diethyl methoxysilyl ester, etc.) or trialkoxysilyl esters (e.g., trimethoxy Sealing esters, triethoxysilyl esters, and the like).

In the term “protecting amino” of R ⁶ and functionally regulated carboxy of R ⁵ the groups should be understood to mean the physiological and pharmaceutical properties of the target compound as well as the synthetic preparation of the target compound by chemical methods.

That is, in the synthesis process, the free amino group of R ⁶ or the carboxy group of R ⁵ may be used to prevent the occurrence of undesirable side reactions, as described above before entering the synthesis process, as described above. Functionally regulated carboxy "and the" protective amino "and / or" functionally regulated carboxy "groups of the resulting compound may be translocated to free amino and / or carboxy groups after the reaction has proceeded.

On the other hand, in the sense of the physiological and pharmaceutical properties of the target compound, the compounds having “protective amino” and / or “functionally regulated carboxy” groups are the solubility of particularly active target compounds having free amino and / or carboxy groups. It is optionally allowed to improve properties such as stability, flood, and properties.

Suitable “pharmaceutically acceptable salts” of the desired compound (I ′) include known non-toxic salts, for example alkali metal surfaces (eg sodium salts, potassium salts, etc.) and alkaline earth metal salts (eg calcium salts). Metal salts such as magnesium salts, ammonia salts, inorganic salts including inorganic salts (e.g. hydrochloride, hydrochloride, sulfate, phosphate, carbonate, bicarbonate, etc.), for example, amine salts (e.g., Trimethylamine salt, triethylamine salt, pyridine salt, procaine salt, picoline salt, dicyclohexylamine salt, N, N-dibenzylethylenediamine salt, N-methylglucamine salt, diethanolamine salt, triethanolamine Salts, tris (hydroxymethylamino methane salt, pinethylbenzylamine salt, etc.), organic carboxyl or sulfonates (e.g. acetate, malate, lactate, tartrate, mesylate, benzenesulfonate, tosylate), Basic and acidic amino acid salts (e.g., Ninyeom, and organic bases, and acid salts such as aspartate tic acid salt, glutamic acid salt, lysine salt, serine salt, etc.).

If the active agent has undesirable physiological or pharmaceutical properties in terms of solubility, stability, and absorbency, the drug is translocated into a controlled derivative to improve such undesirable properties, and thus the derivative is delivered to the patient. When administered, it is known that it can be transposed into the body of a patient as a parent drug and have an active effect.

In the above meaning, the term "pharmaceutically acceptable bioprecursor" in the present specification and claims, when administered while having a structure different from the active compound of the present invention, refers to the active compound of the present invention in the body. It refers to a controlled derivative that is translocated, and also refers to a derivative that has a physiologically induced anti-group effect in the body from the compound of the present invention.

The method of this invention can be represented by the following process.

N-acylated

Wherein R ¹ , R ³ , R ⁴ , R ⁵ and A are as defined above, respectively.

The manufacturing process is described in more detail below.

N-acylated

Compound (I) and salts thereof are known methods of the so-called amidation reactions, which are well known in β-lactam compound, for the reaction derivatives or salts of 7-amino-3-cepem (or sefam) compound (II) and amino positions with carboxyl. It can be prepared by reacting with a reaction derivative or heat at the acid (III) and carboxy position.

Starting compound (III) includes both known and novel compounds, and novel compound (III) can be prepared as described herein below.

Reaction derivatives at the amino group position of compound (II) are, for example, isocyanato, isothiocyanato, compound (II) silyl compound (e.g. trimethylsilylacetamide, bis (trimethylsilyl) acetamide, etc. ), Aldehyde compounds (e.g. acetaldehyde, isopentaldehyde, benzaldehyde, salicyaldehyde, phenylacetaldehyde, p-nitrobenzaldehyde, m-chlorobenzaldehyde, p-chlorobenzaldehyde, hydroxynaphthoaldehyde, furfuryl Carboaldehyde or the like or its corresponding hydrates, acetals, hemiacetals or enolates), ketone compounds (e.g. acetone, ethyl-ethyl ketone, ethyl isobutyl ketone, acetylacetone, ethyl acetoacetate, or the like ketals, hemiketal or Enolate), phosphorus compounds (e.g. phosphorus oxychloride, chlorinated phosphorus, etc.) or sulfur There are known reaction derivatives used in a wide range of amidation reactions, such as derivatives formed by reacting with percompounds (eg thionyl chloride, etc.).

Suitable salts of compound (II) include the salts exemplified for compound (I).

Reaction derivatives at the carboxy group position of compound (III) may include, for example, acid halides, acid anhydrides, activated amides, activated esters, and the like, preferably with acid anhydrides such as acid chlorides, acid bromide: Mixed acid anhydrides, dialkylphosphoric acids, sulfurous acid, thiosulfate, sulfuric acid, alkylcarboxes with acids such as phosphoric acid (e.g., dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid, dibenzyl phosphoric acid, halogenated phosphoric acid, etc.) Main acid, aliphatic carboxylic acid (e.g., pivalylic acid, pentanolic acid, isopentanoic acid, 2-ethylbutyric acid, trichloroacetic acid, etc.), aromatic carboxylic acid (e.g., benzoic acid, etc.): symmetric acid anhydride: imidazole Activated cyanides, with 4-substituted imidazoles, dimethylparasols, triazoles or tetrazole: activated esters (eg cyanomethyl esters, methoxymethyl esters, dimethyl mixed-methyl esters) , Vinyl ester, propargyl ester, p-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, mesylphenyl ester, phenylazo phenyl ester, phenylthio ester, p-nitro Phenyl thioester, p-cresylthio ester, carboxy methylthio ester, pyranyl ester, pyridyl ester, piperidyl ester, 8-quinolylthio ester, N, N-dimethylhydroxyamine, 1-hydroxy- N-hydroxy compounds such as 2- (1H) -pyridone, N-hydroxysuccinimide, N-hydroxyphthalamide, 1-hydroxybenzotriazole, 1-hydroxy-6-chlorobenzotriazole and the like Esters).

The reaction derivatives of the compounds (II) and (III) may be arbitrarily selected depending on the kind of the compounds (II) and (III) which can be actually used and the reaction conditions.

Suitable salts of compound (III) include inorganic base salts such as alkali metal salts (eg sodium salts, potassium salts, etc.) and alkaline earth metals (eg calcium salts, magnesium salts, etc.), tertiary amines (eg trimethylamine salts) , Salts having an organic base such as triethylamine salt, N, N-dimethylaniline salt, pyridine salt, and the like, salts having inorganic acids (eg, hydrochloride, hydrobromide and the like).

This reaction has an opposite effect on known solvents or reactions such as water, acetone, dioxane, acetonitrile, chloroform, benzene, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N, N-dimethylformamide, pyridine In other solvents or any mixtures thereof that do not provide

In the above reaction, when acylating agent (II) is used in the free or salt form, the reaction is carried out using a carbodiimide compound (e.g., N, N-dicyclohexylcarbodiimide, N-cyclohexyl-N'-morpholino). Ethyl carbodiimide, N-cyclohexyl-N '-(4-diethylaminocyclohexyl) carbodiimide, N, N'-diethylcarbodiimide, N, N'-diisopropylcarbodiimide, N Amine compounds, such as -ethyl-N '-(3-dimethylaminopropyl) -carbodiimide, etc., bisimidazole compounds (e.g., N, N'-carbonylbis (2-methylimidazole)) (E.g., pentamethyllanketene-N-cyclohexylamine, diphenylketene-N-cyclohexylimine, etc.), olepic or acetylenic ether compounds (e.g., ethoxyacetylene, β-chlorovinylethyl ether, etc.), 1 -(4-chlorobenzenesulfonyloxy) -6- (eg, polyphosphoric acid, trialkyl phosphite, ethylpolyphosphate, isopropyl polyphosphate, phosph Prepared by reacting ruus oxychloride, phosphorus trichloride, diethylchlorophosphite, orthophenylene chlorophosphite), thionyl chloride, oxalyl chloride, dimethylformamide with thionyl chloride, phosphorus oxychloride, phosgene, etc. It is preferably carried out in the presence of a condensing agent such as Vilsmeier reagent and the like.

의 그룹인 화합물(I)의 기하이성체에 있어서, 하기 설명된 대로, 신 이성체 및 안티 이성체 사이에는 입체적인 선택성이 존재하는 것으로 알려졌다.Structural formula A referred to below as "oxyimino compound" prepared by this process

For the geometric isomers of compound (I), which is a group of, it is known that there is a steric selectivity between the new isomers and the anti isomers, as described below.

의 그룹인 화합물(III)과 반응하여 진행될 경우 주 생성물로서 옥시미노 화합물(I)의 안티 이성체가 생성되며 해당 신 이성체는 옥시미노 아실화제(III)이 사용될 경우에도 본 반응 생성물에서 분리하기가 무척 어려워진다. 상기에서 설명한 방법으로 실시된 반응에 있어서, 상기 이성화 경향은 소위, 옥시미노 아실화제(III)의 활성화 단계로 불리는 상기 반응과정에서, 보다 불안정한 등이성체가 보다 안정한 해당 항 이성체로 부분 혹은 전체적으로 이성화하는 경향이 있기 때문인 것으로 풀이되며 따라서, 보다 안정한 이성체인 옥시미노 화합물(I)의 항 이성체가 반응 생성물로서 분리된다.The reaction is carried out in the presence of a condensate such as phosphorus pentachloride or thionyl chloride with the reaction derivative or salt of the structural formula (II) or amino group position in which A is referred to as " oxymino acylating agent (III) "

When reacted with compound (III), which is a group of, the anti-isomer of oxymino compound (I) is produced as a main product, and the corresponding isomer is very difficult to separate from the reaction product even when oxymino acylating agent (III) is used. Becomes difficult. In the reaction carried out by the method described above, the isomerization tendency is to partially or wholly isomerize the corresponding isomer to which the more unstable isomer is more stable in the course of the reaction, called the activation step of the oxymino acylating agent (III). The anti-isomer of oxymino compound (I), which is a more stable isomer, is separated as the reaction product.

Therefore, in order to selectively obtain a high quantity of new isomers of the oxymino compound (I), it is preferable to use the new isomers of the oxymino acylating agent (III), and to carry out the reaction under selected reaction conditions. That is, the isomers of the oxymino compound (I) are selectively reacted, for example, by reacting the compound (II) with the new isomer of the oxymino acylating agent (III), for example, in the presence of the aforementioned Vilsmeier reagent and in the ambient neutral conditions. And high yields.

The compound (I) and salts thereof are useful as antibacterial agents, and portions thereof may also be used as starting materials according to the following process.

Compounds obtained according to the processes described above can be isolated and purified by known methods.

When the desired compound (I) has the free carboxy of R ⁵ and / or the free amino of R ⁶ , it can be transformed into a pharmaceutically acceptable salt form by known methods.

Among the target compounds (I), the pharmaceutically acceptable salts and biological precursors of the compounds (I ') are useful as antibacterial agents as long as they exhibit high antimicrobial activity that interferes with the growth of pathogenic microorganisms, including Gram-positive and Gram-negative bacteria.

According to the above-mentioned process, the following compounds can be prepared.

Functionally regulated derivatives are as follows.

Corresponding salts are as follows.

Experimental data of representative compounds (I ′) are shown below to indicate the effectiveness of the active compound (I ′).

1. Antimicrobial Activity in Test Tubes

(1) Experiment Method

Antimicrobial activity in vitro is determined by the double structure agar-plate dilution method.

Platinum dilutions of 100-fold dilutions of each experimental strain cultured overnight in trypticase-peanut juice were lined on a heart infusionagar-HI (agar) containing different concentrations of the test compound and 37 ° C. Heated for 20 hours. The minimum when capability (MIC) is expressed in ug / ml.

(2) experimental compound

number

(3) experimental results

2. Protective effect against infectious disease in rats

(1) Experiment Method

Four-week-old male ICR strain mice weighing 18.5-21.5 g each are used in a group of ten mice. Experimental bacteria are incubated overnight at 37 ° C. on tryticase-whey agar and suspended in 5% mucin to obtain a suspension against each challenge cell. 0.5 ml suspension is injected intraperitoneally of the mouse, and after 1 hour, the solution containing the test compound is subcutaneously injected into the rat in various amounts. After 4 days of observation, the ED ₅₀ value is calculated as the number of mice surviving each sheep.

(2) experimental compound

number

(3) experimental results

^* 1: overnight culture

^* 2: 100-fold dilution of overnight incubation

^* 3: Treated in two different amounts after 1 and 3 hours after transmission

3. Acute Toxicity

(1) Experimental Method:

Ten female and 10 male rats 6 months old (JCL-SD week) are used in the group. Experimental compounds dissolved in distilled water are injected subcutaneously and intraperitoneally in rats. Observe for 7 days after dosing. LD ₅₀ values are calculated by the Litchfield-Wilcoxon method and are calculated from the number of animals killed.

(2) Experimental compound:

7- [2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -3-sephem-4-carboxylic acid (new isomer)

(3) experimental results

4. Absorbency

(1) Experimental Method:

The test compound is administered orally to a group of five fat rats (JCL-SD week, 6 week old male) and the Vail and trauma samples are collected 0-6 and 6-24 hours. The concentration of the test compound in the sample is determined by bioassay (disk method) using Bacillus subtilis ATCC-6633 as the test organism, and the recovery in bail and trauma is calculated.

(2) Experimental compound:

7- [2- (2-amino-4-thiazolyl) -2-pentyloxineiminoacetamido] -3-cepem-4-carboxylic acid (new isomer)

(3) experimental results

Total recovery in bile and urine is 22.8% over 24 hours.

In prophylactic and curative administration, the active compound (I ′) of the present invention is a pharmaceutically acceptable carrier such as an organic or inorganic solid or liquid excipient suitable for the oral, injectable or other dosage forms using the compound as an active ingredient. It is used in the form of a conventional medicine containing in a mixed form with. The agents may be in solid form such as capsules, tablets, dragee ointments or suppositories or in liquid form such as solutions, suspensions, emulsions. If necessary, the preparation may also include auxiliaries, stabilizers, humectants or emulsions, buffers and other commonly used additives.

The amount of compound varies in many ways and depends on the age and condition of the patient, the type and extent of the disease, and the type of active compound (I ′) used. In general, when 50 mg, 100 mg, 250 mg and 500 mg of the active compound (I ′) are used in an average dose, the infectious disease caused by pathogenic bacteria can be sufficiently treated. The active compound (I ′) can be administered in an amount of 1 mg / kg to 100 mg / kg, preferably in an amount of 5 mg / kg to 50 mg / kg.

Starting compound (III) can be prepared as follows.

Wherein R ² _a is an aliphatic hydrocarbon residue which may be substituted with halogen, carboxy or esterified carboxy.

R ² _a is a protective amino

X is halogen, Y is lower alkoxy carbonyl and Z is lower alkyl.

Example A

(1) A mixture of 34.6 g of ethyl 2-methoxyimino acet acetate (a mixture of new isomers and anti isomers) and 26.4 g of t-butoxycarbonyl hydrazine in 200 ml of ethanol was stirred at ambient temperature for 7 hours 30 minutes and left overnight. To precipitate the crystals.

The precipitate is collected by filtration, washed with ethanol and dried to afford 41.7 g of ethyl 2-methoxyimino-3-t-butoxy carbonyl hydrazonobutyrate (a mixture of neoisomers and antiisomers). Melting Point 144 ~ 145 ℃

(2) To 14.36 g of a solution of ethyl 2-methoxyimino-3-t-butoxycarbonyl hydrazobutyrate (a mixture of new isomers and anti isomers) containing 150 ml of methylene chloride, 15.9 ml of sulfur phosphate was stirred at ambient temperature. The mixture is stirred for 1 hour at ambient temperature.

300 ml of ice water is added to the reaction mixture, and the methylene chloride layer is washed with water, a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride and then dried over magnesium sulfate. The solvent is distilled off to obtain an oil, which is stopped by column chromatography on silica gel using benzene and n-hexane (19: 1) as eluent to 1.8 g of ethyl 2-methoxyimino-. Obtain 2- (1,2,3-thiadiazol-4-yl) acetate (new isomer). Melting Point 77 ~ 79 ℃

From the fractional fraction an oil of ethyl 2-methoxyimino-2- (1,2,3-thiadiazol-4-yl) acetate (0.7 g of anti isomer) is obtained.

(3) 6.7 ml of sodium hydroxide 1N aqueous solution was added to 1.2 g of ethyl 2-methoxyimino-2- (1,2,3-thiadiazol-4-yl) acetate (new isomer) solution in 10 ml of methanol. The mixture is stirred for 1 hour 30 minutes at ambient temperature. Methanol is distilled off from the reaction mixture and water is added to the residue. The mixture is washed with ether, brought to pH1 by addition of 10% hydrochloric acid and extracted with ethyl acetate. The extract is washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The solvent is distilled off to obtain 0.7 g of 2-methoxyimino-2- (1,2,3-thiadiazol-4-yl) acetic acid prism. Melting Point 110 ~ 113 ℃

Example B

(1) To 152 g of a solution of ethyl 2-hydroxy iminoaceto acetate (a mixture of neoisomers and anti isomers) in 500 ml of acetone, 160 g of finely divided potassium carbonate are added. 130 g of dimethyl sulfate is stirred and added dropwise to the mixture at a temperature of 45 to 50 DEG C for 1 hour, and the mixture is further stirred for 2 hours. The insoluble material is filtered off and the filtrate is concentrated under reduced pressure. The filtered insoluble material is dissolved in 500 ml of water and the solution is added to the residue. The mixture is extracted twice with 300 ml of ethyl acetate. The molar extract is extracted twice with 200 ml of water, once 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 off under reduced pressure to obtain 145.3 g 3 g of a colorless oil, ethyl 2-methoxyimino acetoacetate (a mixture of neoisomers and anti isomers).

(2) To 500 g of ethyl 2-methoxyimino acetacetate solution (new isomer) in 500 ml of acetic acid, 235 ml of sulfuryl chloride was added dropwise while stirring with ice cooling for 20 minutes, and the mixture was cooled with water overnight. Nitrogen gas was introduced into the reaction mixture for 2 hours and then poured into 2.5 l of water. Extract once with 500 ml of methylene chloride and twice with 200 ml of methylene chloride and mix the extracts. The combined extracts were washed with saturated sodium chloride solution and adjusted to pH 6.5 by adding 800 ml of water and sodium bicarbonate. The methylene chloride layer is separated, washed with aqueous sodium chloride solution and dried over magnesium sulfate. The solvent is distilled off to yield 559 g of ethyl 2-methoxyimino-4-chloroaceto acetate (new isomer).

(3) To a solution of 18.4 g of thiourea and 19.8 g of sodium acetate in a mixture of 250 ml of methanol and 250 ml of water, 50 g of ethyl 2-methoxyimino-4-chloro acetoacetate (new isomer) was stirred for 3 min at main temperature Add. After stirring for 35 minutes at 40-45 ° C., the reaction mixture is cooled to ice and adjusted to pH6.3 by addition of saturated aqueous sodium bicarbonate solution. The mixture was stirred at the same temperature for 30 minutes, and the precipitate was collected by filtration, washed with 200 ml of water and 100 ml of diisopropyl ether, and then dried to give colorless crystalline ethyl 2-methoxyimino-2- (2-amino-1,3-thiazole- 4-yl) 37.8 g of acetate (new isomer) are obtained. Melting Point 161 ~ 162 ℃

(4) A suspension of 2.2 g of ethyl 2-methoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetate (new isomer) in 10 ml of ethanol in 12 ml of sodium hydroxide 1N aqueous solution The mixture is stirred at ambient temperature for 15 hours. 10% hydrochloric acid is added to the reaction mixture to adjust to pH 7.0 and ethanol is distilled off under reduced pressure. The residue aqueous solution was washed with ethyl acetate, adjusted to pH2.8 by addition of 10% hydrochloric acid, and stirred under cooling to precipitate the crystals. The crystals were collected by filtration, washed with acetone, and then recrystallized with ethanol to give colorless or needleless 2-methoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetic acid. (Neocrystalline) 1.1 g are obtained.

Example C

(1) To 48.9 g of an ethyl 2-ethoxyimino-3-oxobutyrate (new isomer) stirred solution contained in 49 ml of acetic acid at room temperature, 35.2 of sulfuryl chloride was added all at once and stirred at this temperature for 1 hour. The solution is added to 200 ml of water and extracted with methylene chloride. The extract is extracted with saturated aqueous sodium chloride solution, neutralized with aqueous sodium bicarbonate solution and washed with water. The solution is dried over sodium sulfate and concentrated under reduced pressure to give 53.8 g of ethyl 2-ethoxyimino-3-oxo-4-chlorobutyrate (new isomer) as a pale yellow oil.

(2) 38.7 g ethyl 2-ethoxyimino-3-oxo-4-chlorobutyrate (new isomer), 13.2 g thiourea, 14.3 g sodium acetate, 95 ml mixture of methanol and water are stirred at 48 ° C. for 40 minutes. The final solution was adjusted to pH6.5 by addition of aqueous sodium bicarbonate solution, the precipitate was collected by filtration, washed with diisopropyl ether, and then ethyl 2- (2-amino-4-thiazoline) -2-ethoxyimino acetate (New isomer) 14.7 g is obtained.

(3) 5 g of ethyl 2- (2-amino-4-thiazolyl) -2-ethoxyimino acetate (new isomer) is added to a mixture of 45.9 ml of 1N sodium hydroxide and 30 ml of ethanol and stirred for 5 minutes at room temperature. Ethanol was removed under reduced pressure, and the residue was dissolved in 60 ml of water, and then adjusted to pH 2.0 by addition of 10% hydrochloric acid. The solution is salted out and the precipitate is collected by filtration and dried to give 2.5 g of 2- (2-amino-4-thiazolyl) -2-ethoxyamino acetic acid (new isomer).

(4) 100 g of 2- (2-aminothiazol-4-yl) -2-ethoxyiminoacetic acid (neoisomer), 85.5 g of formic acid and 190.1 g of acetic anhydride were treated in a similar manner to F- (5) To 99.1 g of 2- (2-form amidothiazol-4-yl) -5-ethoxyiminoacetic acid (new isomer).

Example D

(1) To a suspension of 15 g of ethyl 2-hydroxyimino-3-oxobutyrate (new isomer) in 1 ml of 75 ml of acetone and 19.8 g of potassium carbonate, 16.2 g of propylated oxo is stirred and added dropwise to the mixture at ambient temperature 1 Stir for 30 minutes. The insoluble portion is collected by filtration and washed with acetone. Washes and filtrates are mixed, evaporated and dried under reduced pressure. The residue is added to water and the aqueous solution is extracted twice with chloroform. The extract is washed with an aqueous sodium chloride solution, dried over magnesium sulfate, evaporated and dried under reduced pressure to give 15.4 g of ethyl 3-oxo-2-propoxyiminobutyrate (new isomer) as an oil.

(2) 15.4 ml of ethyl 3-oxo-2-propoxyiminobutyrate (new isomer) and 10.6 g of sulfuryl chloride were dissolved in 15.4 ml of acetic acid, stirred and heated to 35-40 ° C. for 10 minutes, and further 4 hours at ambient temperature. Stir. The reaction mixture is poured into 200 ml of ice-water and then extracted twice with chloroform. The extract was washed once with aqueous sodium chloride solution, twice with aqueous sodium bicarbonate solution and once with water, evaporated and dried under reduced pressure to yield ethyl 4-chloro-3-oxo-2-propoxyiminobutyrate (new isomer). 15.4 g is obtained.

(3) 15.4 g of ethyl 4-chloro-3-oxo-2-propoxyiminobutyrate (new isomer), 4.97 g of thiourea and 8.89 g of sodium acetate hydrate were dissolved in a mixture of 40 ml of water and 50 ml of ethanol and 1 hour at 40 ° C. Stir. The saturated potassium carbonate aqueous solution was added to the reaction mixture under cooling to adjust the pH to 6.5 and then stirred at the same temperature for 30 minutes. The precipitated crystals are collected by filtration, washed with water and diisopropyl ether and dried to give 10.55 g of the crystals ethyl 2- (2-amino-4-thiazolyl) -2-propoxyimino acetate (new isomer). Melting Point 142 ~ 144 ℃

(4) 35 to 109 g of a solution of ethyl 2- (2-amino-4-thiazolyl) -2-propoxyimino acetate (new isomer) contained in a mixture of 39 ml of tetrahydrofuran, 39 ml of methanol and 75.8 ml of 1N sodium hydroxide, Stir at 40 ° C. for 5 hours. The solution is concentrated under reduced pressure and adjusted to pH 5.5 by addition of 10% hydrochloric acid. The precipitate is filtered, collected and dried to give 6.2 g of 2- (2-amino-4-thiazolyl) -2-propoxyimino acetic acid (new isomer). Melting Point 161 ° C (dec.)

(5) A method analogous to Example F- (5) using 21.8 g of 2- (2-aminothiazol 4-yl) -2-n-propoxyiminoacetic acid (neoisomer), 38.8 g of acetic anhydride and 17.5 g of formic acid The oil obtained by treatment with triisopropyl ether is triturated to give 19.2 g of 2- (2-formamido thiazol-4-yl) -2-n-propoxyiminoacetic acid (new isomer). Melting Point 164 ° C (dec.)

Example E

(1) 30 g of ethyl 2-hydroxyimino-3-oxobutyrate (new isomer), 32.5 g of isopropyl oxopropyl, 39.5 g of potassium carbonate and 150 ml of acetone were treated in a similar manner to Example D- (1) to give 35.4 g of ethyl 2-iso-propoxyimino-3-oxobutyrate (new isomer) are obtained.

(2) 35.4 g of ethyl 2-iso-propoxyimino-3-oxobutyrate (new isomer), 24.5 g of sulfuryl chloride and 35.4 ml of acetic acid were treated in a similar manner to Example D- (2) to give an oil of ethyl 4 41.5 g of -chloro-3-oxo-2-isopropoxyiminobutyrate is obtained.

(3) 41.5 g ethyl 4-chloro-3-oxo-2-iso-propoxyiminobutyrate (new isomer), 13.4 g thiourea, 14.4 g sodium acetate, 110 ml water and 110 ml ethanol, Example D- (3) Treatment was carried out in a similar manner to give 27.3 g of ethyl 2- (2-aminothiazol-4-yl) -2-iso propoxyimino acetate (isomer). Melting Point 162 ~ 164 ℃

(4) 26.8 g of ethyl 2- (2-aminothiazol-4-yl) -2-iso-propoxyimino acetate (new isomer), 156 ml of sodium hydroxide 1N aqueous solution, 156 ml of methanol, and 100 ml of tetrahydrofuran were carried out. Treatment in a similar manner to Example D- (4) gave 2- (2-aminothiazol-4-yl) -2-isopropoxyiminoacetic acid (15.3 g of neoisomer. Melting point 151 ° C. (dec.)

(5) 4 g of 5- (2-aminothiazol-4-yl) -2-iso-propoxyiminoacetic acid (neoisomer), 7.6 g of acetic anhydride and 3.4 g of formic acid were similar to those of Example F- (5) 3.75 g of 2- (2-formamido thiazol-4-yl) -2-iso-propoxyiminoacetic acid (new isomer) is treated with. Melting Point 168 ~ 169 ℃ (dec.)

Example F

(1) 46.9 g of oxo-ized n-butyl was added dropwise to a stirring solution of 40 g of ethyl 2-hydroxyimino-3-oxobutyrate (new isomer), 52.7 g of potassium carbonate and 200 ml of acetone under ice cooling for 5 minutes, and at room temperature Stir for time.

The solution is filtered and washed with acetone. The filtrate and washings are mixed and concentrated in vacuo. 300 ml of water is added to the residue, and the solution is extracted three times with methylene chloride. The solution is washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo to give 48.8 g of ethyl 2-n-butoxyimino-3-oxobutyrate (new isomer) as an oil.

(2) Stir 48.8 g of ethyl 2-n-butoxyimino-3-oxobutyrate (new isomer), 31.5 g of salt sulphuryl and 48.8 ml of acetic acid at 40 ° C. for 10 minutes, and further stir at room temperature for 5 hours 30 minutes. . The solution is added 300 ml of water under ice cooling and extracted three times with methylene chloride. The extract is washed sequentially with water, aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solution is concentrated in vacuo to give 52.1 g of ethyl 2-n-butooxy imino-4-chloro-3-oxobutyrate (new isomer) as an oil.

(3) A solution of 51.1 g of ethyl 2-n-butoxyimino-4-chloro-3-oxobutyrate (new isomer), 15.9 g of thiourea, 28.4 g of sodium acetate trihydrate, 130 ml of water, and 180 ml of ethanol at 40 ° C Stir for 1 hour and 15 minutes. To the solution is added an aqueous sodium carbonate solution under ice cooling to adjust to pH6.6 and stirred for 20 minutes under ice cooling. The precipitate is filtered, collected and washed sequentially with water and diisopropyl ether to give 36.1 g of ethyl- (2-aminothiazol-4-yl) -2-butoxyimino acetatecin (isomer), melting point 126- 128 ℃

(4) 35 g of ethyl 2- (2-aminothiazol-4-yl) -2-n-butoxyimino acetate (new isomer), 133 ml of methanol, 133 ml of tetrahydrofuran and 133 ml of sodium hydroxide 2N aqueous solution Stir at 30 ° C. for 5 hours. The solution is concentrated in vacuo and the residue is dissolved in water. The solution is adjusted to pH7 by adding 10% hydrochloric acid and treated with activated carbon. 10% hydrochloric acid was added to the solution to adjust the pH to 2.0, and 25.4 g of 2- (2-aminothiazol-4-yl) -2-n-butoxyiminoacetic acid (new isomer) was added for 20 minutes under ice cooling. Get

(5) 18.95 g of formic acid was stirred and added dropwise to 42.0 g of anhydrous acidic acid at room temperature for 5 minutes, and stirred at 50 ° C for 1 hour. To the solution was added 25 g of 2- (2-aminothiazol-4-yl) -2-n-butoxyiminoacetic acid (new isomer) under ice cooling and stirred at room temperature for 3 hours, followed by another 1 hour at 30 ° C. Stir. The solution is concentrated in vacuo and the residue is dissolved in diethyl ether. The solution is washed in the order of water and saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo. The resulting oil was triturated with a solution of n-hexane (1 part) and diisopropyl ether (1 part), and then collected by filtration to obtain 2- (2-formamidothiazol-4-yl) -2-n-butoxy. 20.1 g of minoacetic acid (new isomer) is obtained.

Example G

(1) 40 g of ethyl 2-hydroxyimino-3-oxobutyrate (new isomer), 200 ml of N, N-dimethylformamide, 52.7 g of potassium carbonate and 34.94 g of iso-butylbromide were similar to Example F- (1) The process gives 42 g of ethyl 2-iso-butoxyimino-3-oxo-butyrate (new isomer).

(2) 42 g of ethyl 2-iso-butoxyimino-3-oxobutyrate (new isomer), 42 ml of acetic acid and 27.1 g of sulfuryl chloride were treated in a similar manner to F- (2) to give ethyl 2-iso-part 31.9 g of oxyimino-4-chloro-3-oxobutyrate (new isomer) are obtained.

(3) Example F-, 31.9 g ethyl 2-iso-butoxyimino-4-chloro-3-oxobutyrate (new isomer), 9.72 g thiourea, 17.4 g sodium acetate 3-hydrate, 120 ml ethanol and 80 ml water Treatment in a similar manner to (3) yields 17.6 g of ethyl 2- (2-aminothiazol-4-yl) -2-iso-butoxyimino acetate (new isomer). Melting Point 122 ~ 124 ℃

(4) 19.6 g of ethyl 2- (2-aminothiazol-4-yl) -2-iso-butoxyimino acetate (new isomer), 72.2 ml of sodium hydroxide 2N aqueous solution, 72.2 ml of methanol and 72.2 ml of tetrahydrofuran Was treated in a similar manner to Example F- (4) to give 16.1 g of 2- (2-aminothiazol-4-yl) -2-dis-butoxyiminoacetic acid (new isomer). Melting Point 180 ° C (dec.)

(5) 11.5 g of 2- (2-aminothiazol-4-yl) -2-iso-butoxyiminoacetic acid (neoisomer), 19.3 g of acetic anhydride and 8.7 g of formic acid were prepared with Example F- (5). Treatment in a similar manner yields 11.15 g of 2- (2-formamidothiazol-34-yl) -2-iso-butoxyiminoacetic acid (new isomer). Melting Point 163 ° C (dec.)

Example H

(1) 30 g of ethyl 2-hydroxyimino-3-oxobutyrate (new isomer), 100 ml of N, N-dimethylformamide, 39.5 g of potassium carbonate, and 31.1 g of cyclohexylbromide were similar to those of Example F- (1) Treatment to give 41.8 g of ethyl 2-cyclohexyloxyimino-3-oxobutyrate (new isomer) as an oil.

(2) 41.3 g of 2-ethylcyclohexyloxyimino-3-oxobutyrate (new isomer), 41.3 ml of acetic acid and 23.8 g of sulfuryl chloride were treated in a similar manner to Example P- (2) to give an oil of ethyl 4- 27.8 g of chloro-2-cyclohexyloxyimino-3-oxobutyrate (new isomer) are obtained.

(3) Example F- (27.8 g of ethyl 4-chloro-2-cyclohexyloxyimino-3-oxobutyrate (new isomer), 7.7 g of thiourea, 13.7 g of sodium acetate 3-hydrate, 70 ml of water and 140 ml of ethanol Treatment in a similar manner to 3) yields 3.6 g of ethyl 2- (2-aminothiazol-4-yl) -2-cyclohexyloxyaminoacetate (new isomer). Melting point 125 ~ 126 ℃

(4) 3.5 g of ethyl 2- (2-aminothiazol-4-yl) -2-cyclohexyloxyiminoacetate (new isomer), 11.8 ml of sodium hydroxide 2N aqueous solution, 11.8 ml of methanol and 11.8 ml of tetrahydrofuran Treatment in a similar manner to Example F- (4) yields 2.1 g of 2- (2-aminothiazol-4-yl) -2-cyclohexyloxyiminoacetic acid (new isomer). Melting Point 148 ° C (dec.)

(5) 1.5 g of 2- (2-aminothiazol-4-yl) -2-cyclohexyloxyiminoacetic acid (new isomer), 2.27 g of acetic anhydride and 1.03 g of formic acid were prepared in a similar manner to Example F- (5). The sludge obtained by treatment with is suspended in an aqueous sodium bicarbonate solution. Adjusted by adding 10% hydrochloric acid to the suspension. The precipitate is filtered, collected, washed with water and dried to give 1.0 g of 2- (2-formaminothiazol-4-yl) -2-cyclohexyloxyiminoacetic acid (new isomer). Melting Point About 230 ℃

Example I

(1) Ethyl 2-hydroxyimino-3-oxobutyrate (59.7 g of neoisomers, 280 ml of N, N-dimethylformamide, 72.3 g of potassium carbonate and 43 g of propargyl bromide similar to Example F- (1)) Treatment with 71.2g of ethyl 2-propargyloxyimino-3-oxobutyrate (new isomer).

(2) 71.2 g of ethyl 2-propargyloxyimino-3-oxobutyrate (new isomer), 81 ml of acetic acid, and 50.2 g of sulfuryl chloride were treated in a similar manner to Example F- (2) to give an oil of ethyl 4- 61.6 g of chloro-3-oxo-2-propargyloxyiminobutyrate (new isomer) are obtained.

(3) Example F- (3), 61 g of ethyl 4-chloro-3-oxo-2-propargylminobutyrate (new isomer), 20 g of thiourea, 35.8 g of sodium acetate 3-hydrate, 150 ml of water and 180 ml of ethanol Treatment was carried out in a similar manner to give 35.6 g of ethyl 2- (2-aminothiazol-4-yl) -2-propyryloxyiminoacetate (new isomer).

(4) 2.8 g of ethyl 2- (2-aminothiazol-4-yl) -2-propargyloxyaminoacetate (new isomer), 23 ml of methanol, 20 ml of tetrahydrofuran and 22.17 ml of sodium hydroxide 1N aqueous solution were carried out. Treatment in a similar manner to Example F- (4) yields 1.924 g of 2- (2-aminothiazol-4-yl) -2-propargyloxyiminoacetic acid (new isomer).

Example J

(1) 40 g of ethyl 2-hydroxyimino-3-oxobutyrate (new isomer), 200 ml of N, N-dimethylformamide, 52 g of potassium carbonate and 41.4 g of n-hexylbromide were similar to those of Example F- (1) To give 60.7 g of ethyl 2-n-hexyloxyimino-3-oxobutyrate (new isomer) as an oil.

(2) 60.7 g of ethyl 2-n-hexyloxyimino-3-oxobutyrate (new isomer), 61 ml of acetic acid and 34.7 g of sulfuryl chloride were treated in a similar manner to Example F- (2) to give ethyl 2-n- 55.6 g of hexyloxyimino-4-chloro-3-oxobutyrate (new isomer) are obtained.

(3) 55.6 g of ethyl 2-n-hexyloxyimino-4-chloro-3-oxobutyrate (new isomer), 27.2 g of sodium acetate 3-hydrate, 280 ml of ethanol and 140 ml of water were similar to Example F- (3) The process gives 29.3 g of ethyl 2- (2-aminothiazol-4-yl) -2-n-hexyloxyiminoacetate (new isomer). Melting Point 77 ~ 78 ℃

(4) 29.1 g of ethyl 2- (2-aminothiazol-4-yl) -2-n-hexyloxyiminoacetate (new isomer), 97.2 ml of methanol, 97.2 ml of sodium hydroxide 2N aqueous solution and 50 ml of tetrahydrofuran Treatment in a similar manner to Example F- (4) yields 24.0 g of 2- (2-aminothiazol-4-yl) -2-n-hexyloxyiminoacetic acid (new isomer). Melting Point 174 ° C (dec.)

Example K

(1) 40 g of ethyl 2-hydroxyimino-3-oxobutyrate (new isomer), 200 ml of N, N-dimethylformamide, 52 g of potassium carbonate and 37.9 g of pentylbromide were treated in a similar manner to Example F- (1) To give 57.5 g of ethyl 2-pentyloxyimino-3-oxobutyrate (new isomer) as an oil.

(2) 57.5 g of ethyl 2-pentyloxyimino-3-oxobutyrate (new isomer), 58.5 ml of acetic acid, and 20.9 ml of sulfuryl chloride, were treated in a similar manner as in Example F- (2) to obtain ethyl 2-pentyloxy. 51.1 g of mino-4-chloro-3-oxobutyrate (new isomer) are obtained.

(3) 51.1 g of ethyl 2-pentyloxyimino-4-chloro-3-oxobutyrate (new isomer), 14.7 g of thiourea, 26.4 g of sodium acetate trihydrate, 175 ml of ethanol and 125 ml of water were obtained in Example F- (3). 28.7 g of ethyl 2- (2-aminothiazol-4-yl) -2-pentyloxyiminoacetate (isomer) is treated in a similar manner to. Melting point 86 ~ 88 ℃

(4) Example F-, ethyl 2- (2-aminothiazol-4-yl) -2-pentyloxyiminoacetate (23.6 g of neoisomer, 100.2 ml of sodium hydroxide 2N aqueous solution, 100 ml of ethanol and 100 ml of tetrahydrofuran) Treatment in a similar manner to (4) yields 22.4 g of 2- (2-aminothiazol-4-yl) -2-pentyloxyiminoacetic acid (new isomer), melting point 176 ° C (dec.)

(5) 15 g of 2- (2-aminothiazol-4-yl) -2-pentyloxyiminoacetic acid (new isomer), 23.8 g of acetic anhydride and 10.7 g of formic acid were treated in a similar manner to Example F- (5) To obtain 14.7 g of 2- (2-formamidothiazol-4-yl) -2-pentyloxineiminoacetic acid (new isomer). Melting point 125 ℃ (dec.)

Example L

(1) 2.91 g of allyl bromide is 10 g of methyl 2- (2-tritylaminothiazol-4-yl) -2-hydroxyiminoacetate (new isomer), 100 ml of N, N-dimethylformamide and 4.54 g of potassium carbonate 5 minutes was added dropwise to the suspension of the suspension under ice cooling and then stirred at the temperature for 4 hours. 200 ml of water is added to the solution and extracted twice with diethyl ether. The extract is washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solution is concentrated in vacuo and the residue is triturated with n-hexane and diethylether solution. The precipitate is filtered and collected to give 9.4 g of ethyl 2- (2-tritylaminothiazol-4-yl) -2-allyloxyiminoacetate (new isomer). Melting Point 130 ~ 132 ℃

(2) 8.7 g of ethyl 2- (2-tritylaminothiazol-4-yl) -2-allyloxyiminoacedate (isomer), 42.5 ml of 50% formic acid, and 42.5 ml of tetrahydrofuran were heated to 60 ° C. Stir for 40 minutes. The solution is concentrated in vacuo and the residue is dissolved in ethyl acetate, washed in this order of aqueous sodium carbonate solution and saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solution was concentrated in vacuo, and the residue was then column chromatographed on silica gel using benzene and ethyl acetate to give ethyl 2- (2-aminothiazol-4-yl) -2-allyloxyiminoacetate (sin). Isomer) 3.7 g. Melting point 102 ~ 104 ℃

(3) 3.6 g of ethyl 2- (2-aminothiazol-4-yl) -2-allyloxyiminoacetate (new isomer), 14.1 ml of sodium hydroxide 2N aqueous solution, 14.1 ml of tetrahydrofuran and 15 ml of methanol were 40 ° C. Stir for 1 hour 30 minutes. The solution is concentrated in vacuo and then the residue is dissolved in water. Under ice cooling, the mixture was adjusted to pH 2.8 by adding 10% hydrochloric acid, and the precipitate was filtered, collected, washed in the order of water and acetone, and then dried to give 2- (2-aminothiazol-4-yl) -2-allyl. 1.91 g of oxyiminoacetic acid (new isomer) is obtained. Melting Point 187 ° C (dec.)

Example M

(1) 4.16 g of propargyl bromide was dissolved in 10 g of ethyl 2- (2-tritylaminothiazol-4-yl) -2-hydroxyiminoacetate (new isomer) under nitrogen gas atmosphere, 4.84 g of potassium carbonate, and N Add to 22 ml suspension of N-dimethylformamide and stir to room temperature for 100 minutes. The undissolved material is filtered off and washed with a small amount of N, N-dimethylformamide, and then 400 ml of water is added to the mixed solution of the filtrate and the washing solution. The suspension is extracted with 400 ml of ethyl acetate and the extract is washed with saturated aqueous sodium chloride solution and then dried over magnesium sulfate. The solution is treated with activated charcoal and then concentrated in vacuo and the residue is triturated with diisopropyl ether. The precipitate is filtered, collected and washed with diisopropylether to give 8.34 g of ethyl 2- (2-triphylaminothiazol-4-yl) -2-propargyloxyiminoacetate (new isomer).

(2) 50% formic acid 41m1 was added to 8.2 g of ethyl 2- (2-tritylaminothiazol-4-yl) -2-propargyloxyiminoacetate (new isomer) and 41 ml of tetrahydrofuran and The mixture is stirred for 1 hour. The solution is concentrated under reduced pressure to 1/2 volume of initial volume and the precipitate is collected by filtration and washed with diisopropyl ether. The filtrate and washings are mixed and concentrated in vacuo. The residue is added by stirring 200 ml of ethyl acetate. The undissolved material is collected by filtration and washed with diethyl ether to give 0.3 g of ethyl 2- (2-aminothiazol-4-yl) -2-propargylminooxyacetatecin (isomer). The filtrate and ethyl acetate washing solution are mixed, washed once with saturated aqueous sodium bicarbonate solution, twice with saturated aqueous sodium chloride solution and then dried over magnesium sulfate. The solution is treated with activated charcoal and concentrated in vacuo. The residue is added to benzene and then dried in vacuo. The residue is column chromatographed on silica gel using benzene and ethyl acetate in turn. The eluate is concentrated in vacuo and the residue is triturated with diisopropyl ether. The precipitate is filtered, collected and washed with diisopropyl ether to afford 2.658 g of the same compound (new isomer) as described above. The infrared spectrum and nuclear magnetic resonance spectrum are the same as in the case of the compound obtained in Example I- (3).

Example N

A solution is prepared by adding 0.84 g sodium bicarbonate to a suspension of 2 g 2- (2-formamidothiazol-4-yl) hydroxide and 120 ml of water. 4.56 g of ethyl 2-aminooxyacetate hydrochloride is added to the solution, and sodium bicarbonate is added to adjust the pH to 6 while stirring at room temperature for 3 hours. Hydrochloric acid was added to the solution to adjust the pH to 1.5, salted and extracted three times with ethyl acetate. The extract is dried over magnesium sulfate and concentrated in vacuo. The residue was triturated with diethyl ether, and the precipitate was collected by filtration and dried to obtain 1.44 g of 2- (2-formamidothiazol-4-yl) -2-ethoxycarbonylmethoxyiminoacetic acid (new isomer). . Melting point 112 ° C (dec.)

Example O

(1) Example F- (60g of ethyl 2-hydroxyimino-3-oxobutyrate (new isomer), 54.1g of 1-bromo-2-chloroethane, 78g of potassium carbonate and 200ml of N, N-dimethylformamide Treatment in a similar manner to 1) yields 83.6 g of ethyl 2- (2-chloroethoxyimino) -3-oxobutyrate (new isomer).

(2) 83.6 g of ethyl 2- (2-chloroethoxyimino) -3-oxobutyrate (new isomer), 52.4 g of sulfuryl chloride and 83.6 ml of acetic acid were treated in a similar manner to Example P- (2) to give an oil. 68 g of phosphorus ethyl 2- (2-chloroethoxyimino) -3-oxo-4-chlorobutyrate (new isomer) is obtained.

(3) Example F of 68 g of ethyl 2- (2-chloroethoxyimino) -3-oxo-4-chlorobutyrate (new isomer), 20.2 g of thiourea, 36.2 g of sodium acetate trihydrate, 270 ml of ethanol and 170 ml of water Treatment in a similar manner to-(3) yields 33.7 g of ethyl 2- (2-aminothiazol-4-yl) -2- (2-chloroethoxyimino) acetate (new isomer). Melting point 126 ~ 128 ℃

(4) Ethyl 2- (2-aminothiazol-4-yl) -2- (2-chloroethoxyimino) acetate (30.5 g of neoisomers, 220 ml of sodium hydroxide 1N aqueous solution, 110 ml of methanol and 140 ml of tetrahydrofuran) Treatment in a similar manner to Example F- (4) gave 23.4 g of 2- (2-aminothiazol-4-yl) -2- (2-chloroethoxyimino) acetic acid (new isomer). (dec.)

(5) Examples of 15 g of 2- (2-aminothiazol-4-yl) -2- (2-chloroethoxyimino) acetic acid (new isomer), 24.5 g of acetic anhydride, 11.0 g of formic acid, and 50 ml of tetrahydrofuran Treatment in a similar manner to F- (5) yields 13.4 g of 2- (2-formamidothiazol-4-yl) -2- (2-chloroethoxyimino) acetic acid (new isomer). Melting Point 155 ° C (dec.)

Example P

To 3.0 g of 2- (2-formamidothiazol-4-yl) hydroxide suspension contained in 60 ml of methanol and 60 ml of water, sodium hydroxide 1N aqueous solution was stirred and adjusted to pH 8. 2.24 g of 2,2,2-trifluoroethoxyamine hydrochloride is added to the solution, and an aqueous solution of sodium hydroxide 1N is added to adjust the pH to 2.5 to 3. The solution is stirred at room temperature for 1 hour 30 minutes and then the methanol is removed under reduced pressure. 1N aqueous sodium hydroxide solution was added to the concentrated aqueous solution, adjusted to pH 7, and washed with ethyl acetate. Ethyl acetate is added to the aqueous solution, and then adjusted to pH 1.5 by addition of 10% hydrochloric acid, followed by extraction with ethyl acetate. The aqueous layer is extracted again with ethyl acetate. The extracts are mixed, then washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solution is concentrated in vacuo to give 2.4 g of 2- (2-formamidothiazol-4-yl) -2- (2,2,2-trifluoroethoxyimino) acetic acid (new isomer). Melting Point 162 ~ 163 ℃ (dec.)

Example Q

Oil obtained by treating 10 g of 2- (2-pramidothiazol-4-yl), 4.2 g of sodium bicarbonate and 8.1 g of tert-butyl 2-aminooxyacetate in a similar manner to Example N was converted to n-hexane. After milling, the precipitate was collected by filtration and dried to give 11.3 g of 2- (2-formamidothiazol-4-yl) -2-tert-butoxycarbonylmethoxyiminoacetic acid (new isomer). Melting Point 117 ° C (dec.)

Example I

2- {2- (2,2,2-trifluoroacetamido) -4-thiazolyl} -2-methion in Vilsmeier reagent prepared with dimethylformamide and oxychloride arsenic acid in 10 ml of ethyl acetate. 0.65 g of oxyiminoacetic acid (new isomer) is added at 0 ° C., and the mixture is stirred at the same temperature for 40 minutes to obtain an activated acid solution. The activated acid solution was added dropwise to 0.5 g of 7-amino-2,3-dimethyl-3-cepem-4-carboxylic acid and 1.73 g of trimethylsilyl acetamide in -30 ° C in 30 ml of ethyl acetate. The mixture is stirred for 40 minutes at the same temperature.

To the mixture is added 10 ml of water and the ethyl acetate layer is separated and washed with water.

30 ml of water is added to the solution, and sodium bicarbonate is adjusted to pH 7.5 by addition under ice cooling.

After shaking the mixture, the aqueous layer was separated and 50 ml of ethyl acetate was added to the aqueous solution.

Dilute hydrochloric acid is adjusted to pH 2 by stirring, the ethyl acetate layer is separated, washed with water and saturated aqueous sodium chloride solution in this order, treated with activated charcoal and dried over magnesium sulfate. The residue concentrated under reduced pressure was powdered with diisopropyl ether to obtain 7- [2- {2- (2,2,2-trifluoroaceamido) -4-thiazolyl} -5-methoxyiminoacet. Amido] 0.9 g of -2,3-dimethyl-3-cepem-4-carboxylic acid (new isomer) is obtained.

Example 2

2.14 g of dry pyridine is added to a suspension of 10.50 g of P-nitrobenzyl 7-phenylacetamido-3-cef-4-carboxylate in 100 ml of dry dichloromethane. 5.50 g of pentachloride arsenic acid is added to the solution and -10 ° C, and the mixture is stirred at -5 ° C for 45 minutes, and then further to 10 ° C for 1 hour. 520 g of methanol are added and stirred at -20 ° C for 1 hour 30 minutes. The precipitate is collected by filtration, washed with 120 ml of dichloromethane and 130 ml of diethyl ether, followed by drying to give 7.90 g of P-nitrobenzyl 7-amino-3-cepem-4-carboxylate. Melting Point 182 ℃ (dec)

Example 3

Vilsmeier reagent prepared with 0.43 g of dimethylformamide and 0.92 g of oxychloride lean acid is suspended in 10 ml of dry ethyl acetate.

To the suspension was added 1.15 g of 2- (2-formamido-4-thiazolyl) -2-methoxyimino acetic acid (isomer) under stirring with ice cooling, and the mixture was stirred at the same temperature for 30 minutes to activate. Prepare an acid solution. Dissolve 1.79 g of P-nitrobenzyl 7-amino-43-cefe-4-carboxylate hydrochloride and 5.0 g of trimethylsilylacetamide in 40 ml of ethyl acetate and add the activated acid solution at −20 ° C. to the solution at once. Then, the mixture was stirred at the same temperature for 2 hours 30 minutes. To the solution was added 60 ml of water and 200 ml of ethyl acetate to separate the ethyl acetate layer, washed with 10 ml of 10% hydrochloric acid, 60 ml of saturated aqueous sodium bicarbonate solution and 50 ml of aqueous sodium chloride solution, dried over magnesium sulfate and treated with activated carbon. Evaporate under reduced pressure.

Diethyl ether was added to the residue, and the precipitate was collected by filtration to obtain P-nitrobenzyl 7- {2- (2-formamido-4-thiazolyl) -2-methoxyiminoacetamido} -3- 1.30 g of 4-carboxylate (new isomer) are obtained. Melting Point 210 ~ 212 ℃ (dec)

Example 4

1.04 g of sodium bicarbonate was added to 100 ml of water under ice cooling, and 7- [2- (2-amino-4-thiazolti) -2-methoxyiminoacetamido] -3-cepem-4-carboxylic acid hydro Add 2.6 g of chloride (new isomer) solution and stir to room temperature. The solution is lyophilized to give sodium 7- [2- (2-amino-4-thiazolyl) -2-methoxyaminoacet amido] -3-cepem-4-carboxylate (new isomer).

Example 5

(1) 5 g of 7- [2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -3-cef-4-carboxylic acid (new isomer) at 35 to 40 ° C To 30 ml of an aqueous solution of 1.04 g of sodium bicarbonate was added and stirred at 50 to 53 ° C for 30 minutes. The insoluble material is removed, the filtrate is treated with 0.3 g of activated carbon and then filtered. The filtrate is lyophilised to give 4.2 g of sodium 7- [2- (2-amino-4-thiazolyl) -2-methoxyimino acetamido] -3-cepem-4-carboxylate (new isomer).

(2) 1.15 g of 7- [2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3-cef-4-carboxylic acid (neoisomer) in 100 ml of water To 0.111 g of aqueous calcium hydroxide solution was added, the solution was stirred for 10 minutes at room temperature. The solution was filtered and the filtrate was lyophilised to yield calcium 7- [2- (2-aminothiazol-4-yl) -2-methoxyimino acetamido] -3-cepem-4-carboxylate (syn) Isomer) 1.2 g.

(3) 100 ml of 1.15 g of 7- [2- (2-aminotaazol-4-yl) -2-methoxyiminoacetamido] -3-cepem-4-carboxylic acid (neoisomer) To 0.088 g of magnesium hydroxide contained in the suspension was added and the mixture was stirred at 70 ° C. for 30 minutes to form a solution. The final solution was filtered and the filtrate was lyophilised to give magnesium 7- [2- (2-aminothiazol-4-yl) -2-methoxyimino acetamido] -3-cepem-4-carboxylate ( Neoisomer) 1.1 g.

(4) 1.15 g of 7- [2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido) -3-cef-4-carboxylic acid (neoisomer) in 50 ml of water Add 0.523 g of arginine solution, and stir the solution to room temperature for 10 minutes. The final solution was filtered and the filtrate was lyophilised to give 7- [2- (2-aminothiazol-4-yl) -2-ethoxyimino acetamido] -3-cepem-4-carboxylic acid arginine salt ( 1.35 g of neoisomers).

(5) 12 ml of 1.21 g of sodium 7- [2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3-cepem-4-carboxylate (new isomer) Was added to a solution of 0.55 g of lysine hydrochloride in lysine, and the solution was lysed to give 7- [2- (2-aminothiazol-4-yl) -2-methoxyimino acetamido] -3-sefem- 1.6 g of 4-carboxylic acid (new salt isomers) are obtained.

(6) A room temperature of 7- [2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido containing 20% aqueous sodium hydride solution in a mixture of 8 ml of ethanol and 8 ml of water. ] -3-4-cepem-carboxylic acid (new isomer) is added to a suspension of pH 7.5 to make a solution of pH 7.5. Filtrate, wash, mix the filtrate and wash solution (containing 18.3 ml of water), add 46 ml of ethanol at 20-25 ° C. with stirring dropwise, and stir at the same temperature for 30 minutes.

28 ml of ethanol was added dropwise to the mixture for 30 minutes, and the mixture was stirred at the same temperature for 2 hours. The precipitate was collected by filtration, washed with 20 ml of ethanol and dried in vacuo at room temperature to give sodium 7- [2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3-cefem. 13.5 g of a plate (new isomer) of 4-carboxylate dihydrate are obtained. Melting Point 260 ° C (dec.)

(7) 35-45 g of 15-sodium 7- [2- (2-aminothiazol-4-yl) -2-methoxy iminoacetamido] -3-cef-4-carboxylate (new isomer) It is dissolved by stirring in 13 ml of water. 52 ml of heated ethanol (30 ° C.) was added to the stirred solution, stirred at the same temperature for 5 minutes, and then stirred at room temperature for 2 hours. The precipitate was collected by filtration, washed with ethanol and dried under reduced pressure to give sodium 7- [2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3-cepem-4 13.45 g of a plate (neoisomer) of carboxylate dihydrate are obtained.

(8) 7- [2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3-sefem- containing 4 N aqueous sodium hydroxide solution in 100 ml of water at 5 DEG C or lower. Carefully add to a stirred suspension of 52 g of 4-carboxylic acid (new isomer) to make a solution of pH 7.0-7.5. Filtration, washing, and 200 ml of the filtrate and washing solution were mixed and added dropwise to 2 L of ethanol for 30 minutes, and then stirred at room temperature for 15 minutes and then stirred at 5 to 10 ° C. for 1 hour. The precipitate was collected by filtration, washed with 200 ml of ethanol and then dried in vacuo at 30 ° C. to give amorphous sodium 7- [2- (2-aminothiazol-4-yl) -2-methoxyimino acet amido ] 4,3 g of cefe-4-carboxylate (new isomer) is obtained.

(9) Sodium 7- [2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3-cepem-4-carboxylate) cin isomer in 250 ml of methanol) 10 g of the suspension is treated with an ultrasonic device to make a clean solution.

The solution is left at room temperature and then stirred at the same temperature for 3 hours. The precipitate was filtered, collected and washed with methanol to give amorphous sodium 7- [2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3-cepem-4-carboxylate (Neoisomer) is obtained.

(10) The crystals obtained in the above example were dried on P ₂ O ₅ of Becuo for 1 day at room temperature to give sodium 7- [2- (2-aminothiazole) -2-methoxyiminoacetamido] -3 Obtain a plate (new isomer) of cefem-4-carboxylate.

Example 6

A Vilsmeier reagent solution is prepared from 0.39 g of dry dimethylformamide, 1.2 ml of dry ethyl acetate and 0.84 g of oxychloride arsenic acid. To the solution was activated acid by adding 0.93 g of a 2- (1,2,3-thiadiazol-4-yl) -2-methoxyiminoacetic acid (new isomer) solution in 10 ml of ethyl acetate at -15 ° C. Get a solution.

1.5 g of P-nitrobenzyl 7-amino- 3-cepm-4-carboxylate in 50 ml of dry ethyl acetate, 4.6 g of trimethylsilylacetamide and 1 ml of bis (trimethylsilyl) acetamide, stirred for 5 hours at -45 ° C. To make a solution. The activated acid solution prepared above was added to the solution by stirring at −10 ° C. all at once, and the mixed solution was stirred at −5 ° C. for 1 hour 30 minutes. Water was added to the reaction mixture, the insoluble product was filtered off, washed with ethyl acetate and water and dried to give a pale yellow powder of P-nitrobenzyl 7- {2- (1,2,3-thiadiazole. 1.9 g of 4--4-yl) -2-methoxyimino acetamido} -3-cefe-4-carboxylate (new isomer) are obtained. Melting Point 243 ~ 245 ℃ (dec.)

Example 7

1.7 g of 7-amino-3-cepem-4-carboxylic acid and 2.84 g of sodium bicarbonate are dissolved in a mixture of 35 ml of water and 35 ml of acetone. To a suspension of 3.42 g of 2- (2-amino-4-thiazolyl-2-methoxyiminoacetic acid (isomer) in 34 ml of dry ethyl acetate, 1.95 ml of oxychloride alinic acid was added dropwise at 0? 6 占 폚 for 10 minutes. Stir at the same temperature for 30 minutes Add dropwise 2.3 g solution of trimethyl silylacetamide in 5 ml of ethyl acetate to the solution at 0-6 ° C. for 20 minutes and stir the mixture for 20 minutes. To the mixture was added dropwise 1.95 ml of oxychloride lean acid for 10 minutes, followed by stirring for 30 minutes.

At this temperature, 1.29 ml of dimethylformamide is added dropwise to the reaction mixture for 10 minutes and stirred for 1 hour to obtain a clear solution. The solution is added dropwise to the pH 6.5-7.5 and 7-amino-3-cepem-4-carboxylic acid solution at -5 to 5 ° C for 30 minutes, and the reaction mixture is stirred at the same temperature for 1 hour. 200 ml of ethyl acetate is added to the solution, the aqueous layer is separated, washed with methylene chloride, and nitrogen gas is introduced to foam. The pH is adjusted to 4 by the addition of acetic acid, followed by column chromatography on a porous nonionic absorbent resin “Diion HP-20” (trade name: manufactured by Mitsubishi Chemical Corporation), and then eluted with a 20% aqueous solution of isopropyl alcohol. The eluate was concentrated under reduced pressure, and lyophilized to obtain 2.0 g of 7- [2- (2-amino-4-thiazolyl) -2-methoxyimino acetamido] -3-cepem-4-carboxylic acid (new isomer). Get Compare the product with a true sample in the infrared and nuclear magnetic resonance spectra.

Example 8

1.2 g of oxychloride arynic acid were added all at once to a suspension of 1.23 g of 2- (2-amino-4-thiazolyl) -2-methoxyiminoacetic acid (new isomer) in 12 ml of ethyl acetate at 5 ° C. Stir at 30 ° C.

1.0 g of trimethyl silyl acetamide is added, and the mixture is temporarily added at 4-6 ° C. and stirred for 40 minutes to form a clean solution. To 30 ml of tetrahydrofuran and 10 ml of acetone, 1.9 g of P-nitrobenzyl 7-amino-3-cepem-4-carboxylate hydrochloride is added, followed by 20 ml of an aqueous solution of 0.6 g of sodium bicarbonate.

The solution obtained above at pH 8.0 was added dropwise at 0-5 ° C., stirred at −2-2 ° C. at pH 8.0 for 30 minutes, and the undissolved material was filtered off. The filtrate is extracted with ethyl acetate and the extract is washed with saturated aqueous sodium chloride solution, then dried over magnesium sulfate and concentrated under reduced pressure. Powdered with diisopropyl ether as a residue, p-nitrobenzyl 7- [2- (2-amino-4-thiazolyl) -2-methoxy iminoacetamido] -3-cepem-4-carboxylate ( Neoisomer) 1.6 g.

Example 9

Suspension 3.4 g of P-nitrobenzyl 7-amino-43-cefe-4-carboxylate in 60 ml of tetrahydrofuran and add 20 ml of an aqueous solution of 1.2 g of sodium bicarbonate to the suspension. 30 ml of 1N aqueous sodium hydroxide is added dropwise to the solution at 3-4 ° C. and stirred for 20 minutes.

10% hydrochloric acid is added to the solution to adjust to pH 7.0 and concentrated under reduced pressure. Insoluble material is filtered off and the filtrate is washed with ethyl acetate. 30 ml of acetone are added to the filtrate and cooled to -5 ° C.

Prepared in a similar manner to Example 7 in 2.2 g of oxychloride alinic acid, dimethylformamide, trimethylsilylacetamide and 2- (2-amino-4-thiazolyl) -2-methoxy iminoacetic acid (new isomer) The solution is added to the solution obtained above at pH 7.5-8.5 at -5 ° C to 0 ° C. The mixture is stirred for 2 h at 3-7 ° C. at pH 7.5-8.5 and the insoluble material is filtered off. The aqueous layer was separated from the filtrate, washed with ethyl acetate and adjusted to pH 3.0 to 7- [2- (2-amino-4-thiazolyl) -2-methoxyaminoacetamido] -3-cepem-4 1.1 g of carboxylic acids (new isomers) are obtained.

Example 10

To a suspension of 1.0 g of 2- (2-amino-4-thiazolyl) -2-ethoxyiminoacetic acid (new isomer) contained in 10 ml of tetrahydrofuran, 1.764 g of phosphoryl chloride was added at a temperature of 5 ° C. or lower, and Stir for 20 minutes.

0.4 g of trimethylsilyl acetamide and 0.4 g of N, N-dimethylformamide are added to the solution, and the mixture is stirred at a temperature of 5 ° C. or lower for 40 minutes. [Solution A] 3.5 g of trimethylsilylacetamide was added to a suspension of 1.5 g of 4-nitrobenzyl 7-amino-3-cepem-4-carboxylate in 1 ml of tetrahydrofuran and stirred at room temperature for 1 hour 30 minutes. . The solution A is added to the solution at -20 ° C at a time and stirred at -5 ~ 0 ° C for 1 hour.

20 ml of water is added to the solution at −20 ° C., and the pH is adjusted to 7.5 by addition of aqueous sodium bicarbonate solution.

70 ml of tetrahydrofuran and 50 ml of saturated aqueous sodium chloride solution are added to the solution, and the solution is sufficiently shaken. The aqueous layer is separated and extracted with tetrahydrofuran, then the tetrahydrofuran layer and the extract are mixed and washed with saturated aqueous sodium chloride solution. The solution was dried over magnesium sulfate and concentrated under reduced pressure, then the residue was triturated with diisopropyl ether to give 4-nitrobenzyl 7- [2- (2-amino-4-thiazolyl) -2-ethoxyiminoamino acetami 2.5 g of 3-cefe-4-carboxylate (new isomer) is obtained.

Example 11

4.12 g of 4-ethyltrobenzyl 7- (2-phenylacetamido) -3-hydroxy-3-cefe-4-car contained 2.12 g of triethylamine and 7.12 g of dimethylaniline and 3.93 g of trimethylsilyl chloride in 200 ml of methyl chloride. It is added to a stirred suspension of 10 g of carboxylate and the solution is stirred for 1 hour to room temperature. 4.88 g of pentachloride arsenic acid is added to the solution at -30 to -25 ° C and stirred at -25 to -50 ° C for 3 hours. 42 ml of methanol is added to the solution at -25 to -20 ° C, stirred for 1 hour, and then 35 ml of water at -25 to -20 ° C, and stirred to room temperature.

The precipitate was collected by filtration, washed with methylene chloride and diethyl ether, followed by drying to find 4-nitrobenzyl 7-amino-3-hydroxy-3-cepem-4-carboxylate 5.2 at a melting point of 148 ° C. (dec.) 5.2. get g

Example 12

2.87 g of phosphoryl chloride was added dropwise to a solution of 1.37 g of N, N-dimethyl formamide in 10 ml of ethyl acetate at 5-10 ° C., 40 ml of ethyl acetate was added, followed by stirring for 40 minutes under ice cooling. The solution was added 5 g of 4-nitrobenzyl 7-amino-3-hydroxy-3-cefe-4-carboxylate, 50 ml of ethyl acetate, 14.3 g of trimethylsilylacetamide and bis (trimethylsilyl) acetamide at -15 ° C. It is added to the mixture of g all at once and stirred for 1 hour and 12 minutes at -20 ~ -15 ℃. Add 50 ml of water to the solution at -25--20 ° C and stir until the temperature rises to 5 ° C. The aqueous layer is separated and extracted with ethyl acetate. Ethyl acetate and extracts are mixed and washed with saturated aqueous sodium chloride solution and then dried over magnesium sulfate. The solution was concentrated to a volume of 50 ml under reduced pressure and the precipitate was collected by filtration and then washed with ethyl acetate to give 4-nitrobenzyl 7-2- (2-formamido-4-thiazolyl) -2-methoxyiminoacet. 3.5 g of amido-3-hydroxy-3-cepem-4-carboxylate (new isomer) are obtained. Melting Point 163 ° C (dec.)

Example 13

2- (2-amino-4-thiazolyl) -2-isopropoxyimino acetate in 25 ml of tetrahydrofuran containing 4.6 g trimethylsilylacetamide chloride and 0.9 g of N, N-dimethylformamide (New isomer) To 5.8 g of a stirred suspension is added at a temperature of 3 ° C or less for 30 minutes. [Solution A] 10.5 g of trimethyl silyl acetamide is added to a suspension of 3.9 g of 4-nitrobenzyl 7-amino-3-cepem-4-carboxylate in 50 ml of tetrahydrofuran and stirred at room temperature for 1 hour 30 minutes. . To the solution was added once as solution A of -20 ° C and stirred for 40 minutes at -2 ~ 0 ° C. At -20 ° C, 70 ml of water and 100 ml of tetrahydrofuran are added to the solution, the pH is adjusted to 7.5 by the addition of an aqueous sodium bicarbonate solution, followed by stirring for 1 hour. 200 ml of saturated aqueous sodium chloride solution is added and the organic layer is separated, the remaining aqueous layer is extracted with tetrahydrofuran and the extract and the organic layer are mixed. Washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, concentrated under reduced pressure, the residue was triturated with diisopropyl ether, and the precipitate was collected by filtration to obtain 4-nitrobenzyl 7- [2- (2-amino-4-thiazolyl). 6.0 g of 2-isopropoxyimino acetamido] -3-cepem-4-carboxylate (neomer) is obtained.

Example 14

2- (2-amino-4-thiazolyl) -2-propoxyiminoacetic acid containing 4.6 g of phosphoryl chloride, 0.95 g of trimethylsilylacetamide and 1.2 g of N, N-dimethylformamide in 20 ml of tetrahydrofuran ( New isomer) to 2.8 g of a stirred suspension at a temperature of 5 ° C. or less and stirred for 20 minutes. The solution was added dropwise to a suspension of 3.9 g of 4-nitrobenzyl 7-amino-3-cepem-4-carboxylate in a mixture of 20 ml of tetrahydrofuran 20 ml of water and 20 ml of acetone at a temperature of -5 ° C to 5 ° C. At this time, 20% aqueous solution of sodium carbonate was added to maintain pH6.9-7.1. The solution is stirred at -5 ~ 5 ° C for 30 minutes, and further stirred at 10 ° C for 1 hour and then adjusted to pH7.5. 100 ml of tetrahydrofuran and 200 ml of saturated aqueous sodium chloride solution are added to the solution, the insoluble material is filtered off, the organic layer is separated from the filtrate and washed with saturated aqueous sodium chloride solution. After drying over magnesium sulfate and concentration under reduced pressure, the residue was triturated with diisopropyl ether and the precipitate was collected by filtration to obtain 4-nitrobenzyl 7- [2- (2-amino-4-thiazolyl) -2-propoxyiminoa. 5.8 g of cetamido] -3-cefe-4-carboxylate (new isomer) are obtained.

Example 15

13.2 g of phosphoryl chloride is added dropwise to a stirring solution of 6.3 g of N, N-dimethylformamide and 24.7 ml of tetrahydrofuran at -5 ° C, and stirred at this temperature for 30 minutes. To the solution was added 120 ml of tetrahydrofuran and 19.5 g of 2- (2-formamidothiazol-4-yl) -2-n-butoxyiminoacetic acid (new isomer) at -5 ° C and 30 minutes at the same temperature. Stir. The solution was added dropwise to a stirring suspension of 24.7 g of 4-nitrobenzyl 7-amino-3-cepem-4-carboxylate, 60 ml of tetrahydrofuran 120 ml acetone and 60 ml of water at -5 to 5 ° C. at this time 20% sodium carbonate. Aqueous solution was added to adjust pH to 7-7.5, and then stirred for 30 minutes. The undissolved material is filtered off and to the filtrate is added saturated aqueous sodium chloride solution and then extracted twice with tetrahydrofuran. The extract was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, concentrated in vacuo and the residue was triturated with diisopropyl ether to 4-nitrobenzyl 7- [2- (2-formamidothiazol-4-yl 34.6 g of) -2-n-butoxyiminoacetamido] -3-cepem-4-carboxylate (new isomer) is obtained.

Example 16

2- (2-formamidothiazol-4-yl) -2-isobutoxyiminoacetic acid (neoisomer) 4.48 g, N, N-dimethylformamide 2.10 g, phosphorine chloride 4.40 g tetrahydrofuran 110 ml, 4 8.23 g of nitrobenzyl 7-amino-3-cepem-4-carboxylate, 16 ml of acetone and 16 ml of water were treated in a similar manner to Example 15 (1) to give 4-nitrobenzyl 7- [2- (2-form Amidothiazol-4-yl) 2-isobutoxyiminoacet amido] -3-cepem-4-carboxylate (new isomer) 12.8 g is obtained.

Example 17

2- (2-formamidothiazol-4-yl) -2-cyclohexyloxyiminoacetic acid (0.9 isomer isomer, N, N-dimethylformamide 266mg phosphotyl chloride 557mg, tatrahydrofuran 20ml-nitrobenzyl 3-nitroben 7- [2- (2-gilformamido) was treated with 3 ml of 7-amino-3-cepem-4-carboxylate and 3 ml of acetone and 3 ml of water in a similar manner to Example 15- (1). 1.69 g of thiazol-4-yl) -2-cyclohexyloxyiminoacetamido] -3-cefecarboxylate (new isomer) is obtained.

Example 18

0.84 g of phosphoryl chloride was added dropwise to a stirred suspension of 10 g of 2- (2-aminothiazol-4-yl) -9-allyloxyiminoacetic acid (new isomer) 1.0 g tetrahydrofuran and 0.05 ml of water at 5 ° C, Stir at the same temperature for 20 minutes. To the solution, 0.66 g of trimethylsilylacetamide 0.84 g of phosphoryl chloride and 0.45 g of N, N-dimethylformamide were added and stirred at 5 ° C. for 1 hour to obtain an activated acid solution. 4.0 g of trimethylsilylacetamide is added to a suspension of 0.88 g of 7-amino-3-cepem-4-carboxylic acid in 10 ml of tetrahydrofuran at 40 ° C. and stirred for 30 minutes. The activated acid solution obtained above is added to the solution at -20 ° C in one portion and stirred at 0 ° C for 1 hour. 20 ml of water is added to the solution at −20 ° C., the pH is adjusted to 7.5 by the addition of an aqueous sodium bicarbonate solution and then ethyl acetate is added to separate the aqueous layer. The solution is washed with ethyl acetate and diisopropyl ether, adjusted to pH 5.0 and treated with activated charcoal. The solution was adjusted to 3.0 and the precipitate was collected by filtration, washed with water and dried over phenic acid pentoxide to give 7- [2- (2-aminothiazol-4-yl) -2-allyloxyiminoacet 0.8 g of amido] -3-cefe-4-carboxylic acid (isomer) is obtained.

Example 19

14 g of phosphoryl chloride was added dropwise to a suspension of 1.7 g of 2- (2-aminothiazol-4-yl) -2-propargyloxyiminoacetic acid (isomer) in 15 ml of tetrahydrofuran at a temperature of 7 ° C. or lower. And stirred for 10 minutes at the temperature. To the solution was added 1.3 g of phosphoryl chloride 1.4 g trimethylsilylacetamide and 0.76 g of N, N-dimethylformamide and stirred for 20 minutes to obtain an activated acid solution. To a suspension of 1.5 g of 7-amino-3-cepem-4-carboxylic acid in 20 ml of tetrahydrofuran, 7.8 g of trimethylsilylacetamide is added and stirred at 40 ° C. for 30 minutes. The activated acid solution is added to the solution at -20 ° C in one portion and stirred at 0 ° C for 30 minutes. 20 ml of water is added to the solution at −20 ° C., adjusted to pH 7.5 by addition of an aqueous sodium bicarbonate solution, the aqueous layer is separated, washed with ethyl acetate and diisopropyl ether and treated with activated carbon at pH 5.5. The solution was adjusted to pH 3.0, and the precipitate was collected by filtration and dried under reduced pressure on phenic acid pentoxide to give 7- [2- (2-aminothiazol-4-yl) -2-propargyloxyiminoacet. 1.47 g of amido] -3-cepem-4-carboxylic acid (new isomer) is obtained.

Example 20

To a suspension of 23 g of 2- (2-formamidothiazol-54-yl) -2-methoxyiminoacetic acid (new isomer) in 230 ml of thionyl chloride, add 3 drops of N, N-dimethylformamide and add 60 drops. Stir at 5 ° C. for 5 hours. Concentrated in vacuo, added benzene to the residue, collected the precipitate, collected by filtration, washed three times with 30 ml of benzene and diethyl ether to give 2- (2-formamidothiazol-4-yl) -2-methoxyimino. 19 g of acetyl chloride (anti isomer) are obtained. 46 g of trimethylsilyl acetamide is added to a suspension of 16.8 g of 4 nitrobenzene 7-amino-3-cefe-4-carboxylate in 168 ml of methylene chloride and stirred at 40 ° C. for 1 hour. 13.6 g of 2- (2-formamidothiazol-4-yl) -2-methoxy iminochloride (antiisomer) is added to the suspension at 5-0 ° C. and stirred at the same temperature for 1 hour. 150 ml of water is added to the solution and stirred for 15 minutes. The precipitate was collected by filtration, washed with water, and then dried under reduced pressure and dried over 4-nitrobenzyl 7- [2- (2-formamidothiazol-4-yl) -2-methoxyiminoacet on pentoxide arsenic. Amido] -3-cepem-4-carboxylate (anti isomer) 25.7 g.

Example 21

3 g of 2- (2-aminothiazol-4-yl) -2-n-hexyloxyiminoacetic acid (new isomer), 0.15 g of water, 3.8 g of phosphoryl chloride, 10.7 g of trimethyl silylacetamide, N, N-dimethylform 50 ml of amide 1.0 g tetrahydrofuran and 2.0 g of 7-amino-3-cepem-4-carboxylic acid were treated in a similar manner to Example 18 to obtain 7-2- (2-aminothiazol-4-yl) -2. 1.1 g of -n-hexyloxy minoacetamido-3-cepem-4-carboxylic acid (new isomer) is obtained.

Example 22

0.506 g of 2- (2-formamidothiazol-34-yl) -2-propargyloxyiminoacetic acid (neoisomer), 0.161 g of N, N-dimethylformamide 0.337 g of phosphochloride chloride and 7.9 ml of ethyl acetate Is treated in a similar manner to Example 15 to obtain an activated acid solution. A suspension of 0.703 g of 4-nitrobenzyl-7-amino-3-hydroxy-3-cefe-4-carboxylate in 10 ml of ethyl acetate in 1.85 g of trimethylsilyl acetamide and 1.60 g of bis (trimethylsilyl) acetamide Is added and stirred at room temperature for 1 hour. An acid solution activated at −10 ° C. was added to the solution at once and stirred at this temperature for 1 hour. 20 ml of water and 20 ml of ethyl acetate are added to the solution, and the organic layer is separated, washed with 15 ml of a saturated aqueous sodium bicarbonate solution of 8 ml of sodium chloride, and dried over magnesium sulfate. The solution was concentrated in vacuo, the residue was triturated with diethyl ether and the precipitate was filtered and collected by 4-nitrobenzyl 7- [2- (2-formamidothiazol-4-yl) -2-pro 0.71 g of pargilloxyiminoacetamido] -3-hydroxy-3-cepem-4-carboxylate (new isomer) is obtained.

Example 23

0.515 g of 2- (2-formamidothiazol-4-yl) -2-propoxyiminoacetic acid (neoisomer), 0.16 g of N, N-dimethylformamide, 0.337 g of phosphoryl chloride and 7.9 ml of ethyl acetate were carried out. Treatment is performed in a similar manner to Example 15 to obtain an activated acid solution. 1.85 g of trimethylsilylacetamide and 1.60 g of bis (trimethylsilyl) acetamide were added to a suspension of 0.703 g of 4-nitrobenzyl 7-amino-3-hydroxy-3-cefe-4-carboxylate in 10 ml of ethyl acetate. Add and stir to room temperature for 1 hour. The activated acid solution was added to the solution at -10 ° C at once and stirred at this temperature for 1 hour. 20 ml of water and 20 ml of ethyl acetate are added to the solution, the organic layer is separated, washed with 8 ml of saturated aqueous sodium bicarbonate solution and 14 ml of water, and dried over magnesium sulfate. The solution was concentrated in vacuo, the residue was triturated with diethyl ether, and the precipitate was collected by filtration to obtain 4-nitro 7- [2- (2-formamidothiazol-4-yl) -2-propoxy. 0.75 g of iminoacetamido] -3-hydroxy-3-cefe-4-carboxylate (new isomer) is obtained.

Example 24

2- (2-formamidothiazol-4-yl) -2-isobutoxyiminoacetic acid (isomer) 0.54 g N, N-dimethylformamide 0.16 g 0.34 g phosphoryl chloride and 10 ml of ethyl acetate Example 15 It is treated in a similar manner to to obtain an activated acid solution. 1.85 g of trimethylsilylacetamide and 1.62 g of bis (trimethylsilyl) acetamide were added to a suspension of 0.7 g of 4-nitrobenzyl 7-amino-3-hydroxy-3-cefe-4-carboxylate in 10 ml of ethyl acetate. Add and stir at 40 ° C. for 30 minutes. The acid solution activated at the solution -20 ℃ is added at once, and stirred at the same temperature for 1 hour. 10 ml of water is added to separate the organic layer, washed with water, sodium bicarbonate, aqueous solution and saturated aqueous sodium chloride solution, dried and concentrated in vacuo, and the residue is triturated with diisopropyl ether. The precipitate is filtered off, collected, washed with diisopropyl ether and dried to 7- [2- (2-formamidothiazol-4-yl) -2-isobutoxyaminoacetamido] -3-hydro 1.09 g of oxy-3-cepem-4-carboxylate (new isomer) are obtained.

Example 25

0.114 g of N, N-dimethylformamide 0.240 g of phosphoryl chloride and 0.5 ml of ethyl acetate are reacted by a known method to obtain a Vilsmeier reagent. 5 ml of ethyl acetate and 0.35 g of 2- (2-formamidothiazol-4-yl) -2-ethoxyiminoacetic acid (new isomer) are added at this temperature for 30 minutes to obtain an activated acid solution. 1.31 g of trimethylsilyl acetamido and 1.14 g of bis (trimethylsilyl) acetamide were prepared in 0.50 g of 4-nitrobenzyl 7-amino-3-hydroxy-3-cefe-4-carboxylate in 17.5 ml of ethyl acetate. Add to the suspension and stir to room temperature for 1 hour, then add the activated acid solution to the solution at −10 ° C. and stir to room temperature for 30 minutes. 15 ml of water and 15 ml of ethyl acetate are added, the organic layer is separated, washed with 15 ml of saturated aqueous sodium bicarbonate solution and 10 ml of water, dried over magnesium sulfate and concentrated in vacuo. The residue was triturated with diethyl ether and the precipitate was filtered off to obtain 4-nitrobenzyl 7- [2- (2-formamidothiazol-4-yl) -2-ethoxyiminoacetamido] -3-hydroxy. 0.634 g of 3-cefem-4-carboxylate (new isomer) are obtained.

Example 26

2- (2-formamidothiazol-4-yl) -2-pentyloxyiminoacetic acid (neoisomer) 414 g 4-nitrobenzyl 7-amino-3-cepem-4-carboxate 4.5 g N, N- Dimethylformamide 1.41 g Phosphoryl chloride 2.96 g and tetrahydrofuran 72 ml acetone 15 ml 15 ml of water were treated in a similar manner as in Example 15- (1) to 4-nitrobenzyl 7- [2- (2-formamidotia Zol-4-yl) -2-pentyloxyiminoacetamido] -3-cepem-4-carboxylate (new isomer) is obtained.

Example 27

15 g of 7-phenylacetamido-3-tosyloxy-ε-cepm-carboxylic acid at room temperature containing 10.3 g of N, N-dimethylphenylamine and 5.64 g of trimethylchlorosilin in 150 ml of methyl chloride. Is added to a stirred solution, and the solution is stirred at room temperature for 1 hour. To the solution at -35 ° C, 7.03 g of penta chloride phosphate is added and stirred at -25 to -20 ° C for 1 hour 30 minutes, and then 61 ml of methanol is added and the temperature is stirred for 40 minutes. 50 ml of water is added at -20 to -10 ° C, the organic layer is separated, washed twice with water, the aqueous layer and the washing solution are mixed, washed twice with methylene chloride and once with diethyl ether.

The solution was adjusted to pH 4.7 by addition of 10% aqueous sodium hydroxide, and the precipitate was collected by filtration, washed with water, acetone and diethyl ether, dried over arsenic acid pentoxide, and 7-amino having a melting point of 172 ° C (dec.). 5.01 g of 3-tosyloxy-3-cepem-4-carboxylic acid is obtained.

Example 28

0.76 g of 2- (2-aminothiazol-4-yl) -2-methoxyiminoacetic acid (new isomer), 0.33 g of N, N-dimethylformamide 0.33 g of phosphoryl chloride 1.46 g of 0.5 g of trimethylsilylacetamide, and ethyl acetate 10 ml is treated by a known method to obtain an activated acid solution. 3.7 g of trimethylsilylacetamide was added to a suspension of 1.0 g of 7-amino-3-tosyloxy-3-cepem-4 -carboxylic acid in 15 ml of ethyl acetate, stirred at room temperature, and the activated acid solution was added. Add at -15 ℃ at once and stir at -5 ~ 5 ℃ for 1 hour. The solution is cooled to -20 [deg.] C., 30 ml of water is added and the pH is adjusted to 6.5 by the addition of aqueous sodium bicarbonate solution, which is then filtered off and the aqueous layer separated. The pH was adjusted to 3.0 by adding hydrochloric acid, and the precipitate was filtered and collected, and then dried to dry 7- [2- (2-aminothiazol-4-yl) -2-methoxyinoacetamido) -3-tosyloxy. 1.0 g of 3-cefe-4-carboxylic acid (new isomer) are obtained.

Example 29

2- (2-formaminothiazol-4-yl) -2-ethoxycarbonylmethoxy iminoacetic acid (new isomer) 1.35 g 4-nitrobenzyl 7-amino-3-cepem-4-carboxylate 1.54 g, N, N-dimethylformamide 393 mg, phosphoryl chloride 825 mg tetrahydrofuran 21.2 ml acetone 3.9 ml and water 3.9 ml were treated in a similar manner to Example 15- (1) to give 4-nitrobenzyl 7- [2- 2.52 g of (2-formaminothiazol-4-yl) -2-ethoxycarbonylmethoxyiminoacetamido] -3-cef-4-carboxylate (new isomer) is obtained.

Example 30

Vilsmeier reagent was prepared by a known method in 0.32 g of N, N-dimethylformamide and 0.67 g of phosphoryl chloride, and the suspension was suspended in 10 ml of ethyl acetate, followed by 2- (2-formamidothiazole-4- 1.2 g of I) -2- (2,2,2-trifluoroethoxyimino) acetic acid (new isomer) is added to form a stirred suspension under ice cooling, and the solution is stirred at the same temperature for 30 minutes. The solution was added to a solution of 0.8 g of 7-amino-3-cepem-4-carboxylic acid and 4.2 g of trimethylsilylacetamide in 20 ml of ethyl acetate at -25 deg. C and 1 hour at -20--10 deg. After stirring, water and ethyl acetate are added and the ethyl acetate layer is separated. The aqueous layer was extracted again with ethyl acetate, water was added to the mixed extract, and then saturated sodium bicarbonate aqueous solution was adjusted to pH 7.5 and the aqueous layer was separated. Ethyl acetate was added to the aqueous layer, hydrochloric acid was added, pH1.5 The ethyl acetate layer is separated and the aqueous layer is extracted again with ethyl acetate. The extracts are mixed, washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, concentrated in vacuo and the residue is triturated with diethyl ether. The precipitate was filtered, collected and dried to 7- [2- (2-formamidothiazol-4-yl) -2- (2,2,2-trifluoroethoxyimino) acetamido] -3 1.55 g of cefem-4-carboxylic acid (new isomer) is obtained.

Example 31

2-47- (2-formamidothiazol-4-yl) -2- (2-chloroethoxyimino) acetic acid (new isomer) in 47 ml of ethyl acetate 1.1 g of N, N-dimethylformamide and chloride A solution of 2.3 g of phosphoyl and 2.5 g of 7-amino-3-cefe-4-carboxylic acid and 12.7 g of bis (trimethylsilyl) acetamide in 25 ml of ethyl acetate were prepared in a similar manner to Example 15- (1). 7- [2- (2-formamidothiazol-4-yl) -2- (2-chloroethoxyimino-acetamido-3-cepem-4-carboxylic acid (new isomer) Obtain 1.85 g.

Example 32

2- (2-formamidothiazol-4-yl) -2- (tert-butoxycarbonylmethoxyimino) acetic acid (new isomer) 3.2 g N, N dimethylformamide 0.852 g in 34 ml of ethyl acetate And a solution of 1.79 g of phosphoryl chloride and 1.95 g of 7-amino-3-cepem-4-carboxylic acid and 9.9 g of bis (trimethylsilyl) acetamide in 19.5 ml of ethyl acetate were prepared in Example 15- (1). 7- [2- (2-formamidothiazol-4-yl) -2- (tert-butoxycarbonylmethoxyimino) -acetamido) -3-cefe-4- 2.9 g of carboxylic acid (new isomer) are obtained.

Example 33

7- [2- (2-formamidothiazol-4-yl) -2- (tert-bucooxycarbonylmethoxyimino) acetamido] -3-cepem-4-carboxylic acid (new isomer) 2.8 g A mixture of 2.8 ml of anisole and 11.2 ml of trifluoroacetic acid is stirred for 1 hour to room temperature. To the solution was added ethyl acetate and water, adjusted to pH7.0 by addition of sodium bicarbonate, the crystal layer was separated and the ethyl acetate layer was washed with water. The aqueous extracts are mixed, washed with ethyl acetate and diethyl ether and adjusted to pH 2,0 by addition of 10% hydrochloric acid under ice cooling. The precipitate is filtered, collected, washed with water and dried to 7- [2- (2-formamidothiazol-4-yl) -2-carboxymethyliminoacetamido] -3-cef-4- 1.43 g of carboxylic acids (new isomers) are obtained.

Example 34

2- (2-formamidothiazol-4-yl) -2- (2,2,2-trifluoroethoxyimino) acetic acid (new isomer) 0.9 g N, N-dimethyl in 10 ml of ethyl acetate A solution of 0.24 g of formamide and 0.5 g of phosphotyl chloride and 1.23 g of 4-nitrobenzyl-7-amino-3-chloro-3-cepem-4-carboxylate hydrochloride in 20 ml of ethyl acetate and trimethylsilylacetamide 2.8 g solution was treated in a similar manner to the original Example 51- (1) to give 4-nitrobenzyl 7- [2- (2-formamidothiazol-4-yl) -2- (2,2,2- 1.9 g of trifluoroethoxyimino) acetamido] -3-chloro-3-cepem-4 -carboxylate (new isomer) are obtained.

Example 35

5 g of 4-nitrobenzyl 7-amino-3-cepem-4-carboxylate are dissolved in a solution of 13.8 g of trimethylsilylacetamido and 10 ml of bis (trimethylsilyl) acetamide in 50 ml of dry ethyl acetate and Stir for 1:30 minutes. 2.88 g solution of boromine in 7 ml of methylene chloride was added dropwise at -40 ° C. to a diketene 1.5 g solution in 7 ml of methylene chloride for 20 minutes and stirred at -30 ° C. for 1 hour, followed by 4-nitrobenzyl 7- To the amino-3-cepem-4-carboxylate solution was added dropwise at -15 ° C. under ice cooling and stirred at the same temperature for 30 minutes. 50 ml of water was added to the solution, followed by washing with ethyl acetate. The etaacetate extract was washed with water, dried over magnesium sulfate and concentrated under reduced pressure to give 4-nitrobenzyl 7- [2- (2-bromoacetyl) acetic as an oil. 6.15 g of amido] -3-cepem-4-carboxylate is obtained.

Example 36

A solution of 43.0 g bromine in 30 ml of methylene chloride was added dropwise to a diketene 22.6 g solution in 30 ml of methylene chloride at -30 ° C. for 35 minutes, stirred at this temperature for 30 minutes, and then the solution was stirred at -15 ° C. for tetrahydrofuran. To a stirring solution of 75.1 g of 4-nitrobenzyl 7-amino-3-cepem-4-carboxylate and 68.4 g of bis (trimethylsilyl) acetamide in 1.5 liter was added dropwise for 10 minutes and stirred at this temperature for 50 minutes. While maintaining the solution at pH 2.0, add 35 ml of water and 35 ml of aqueous solution of 18.6 g of sodium nitrite, stir at 10-15 ° C. for 15 minutes, adjust the pH to 4.5 by adding saturated aqueous sodium bicarbonate solution, and 17.1 g of thiourea 150 ml of aqueous solution is added. Saturated aqueous sodium bicarbonate solution was adjusted to pH6.0, stirred for 20 minutes to separate the organic layer, concentrated under reduced pressure, the residue was dissolved in 1.5 liter of ethyl acetate and washed three times with water. The solution was dried over magnesium sulfate, treated with activated charcoal, concentrated under reduced pressure, and the residue was triturated with 200 ml of diethyl ether. The precipitate was collected by decantation to obtain a mixture of 300 ml of ether acetate, 500 ml of tetrahydrofuran at 60 ° C. and 1 liter of ethyl acetate. And 100 ml of ethyl acetate, washed three times, and dried to give 4-nitrobenzyl 7- [2- (2-amino-4-thiazolyl) -2-hydroxyiminoacetamido] -3-sefe-4- 55.5 g of carboxylate (new isomer) are obtained.

Example 37

2.54 g of 7-amino-3-cepem-4-carboxylic acid is dissolved in 11.7 g of trimethylsilyl acetamide and 15 ml of bis (trimethylsilyl) acetamide in 50 ml of dry ethyl acetate. 2.43 g solution of bromine in 10 ml of dry methylene chloride was added dropwise to -28 DEG solution in 1.28 g of diketene in 25 ml of dry methylene chloride at -30 ° C for 10 minutes, and stirred at the temperature for 1 hour and 30 minutes. To a solution containing amino-3-cepem-4-carboxylic acid is added at -15 ° C for 10 minutes and stirred at -15-10 ° C for 1 hour 30 minutes. 50 ml of water was added to the solution, the ethyl acetate layer was separated, washed with an aqueous sodium bicarbonate solution, and then adjusted to pH 2.0 by addition of 10% hydrochloric acid to the aqueous extract, followed by extraction with ethyl acetate. The ethyl acetate extracts are washed with water, dried over magnesium sulfate and concentrated under reduced pressure to give 2.82 g of 7- [2- (2-bromoacetyl) acetamido] -3-cepem-4-carboxyl phase.

Example 38

The following compounds can be prepared in a similar manner as in Example 35.

(1) 4-nitrobenzyl 7- [2- (2-aminothiazol-4-yl) -ethoxyiminoacetamido] -3-cepem-4-carboxylate (neoisomer).

(2) 4-nitrobenzyl 7- [2- (2-aminothiazol-4-yl) -2-propoxyiminoacetamido] -3-cepem-4-carboxylate (neoisomer).

(3) 4-nitrobenzyl 7- [2- (2-aminothiazol-4-yl) -2-isopropoxyiminoacetamido] -3-cepem-4-carboxylate (new isomer).

Example 39

704 mg of phosphoryl chloride was added dropwise to 336 mg of N, N-dimethylformamide in 8 ml of ethyl acetate at a temperature of 5 ° C. or lower, stirred at this temperature for 30 minutes, and then 2- (2-formamidothiazol-4-yl 1 g of) -5-methoxyiminoacetic acid (new isomer) is added and stirred at 5-10 ° C. for 1 hour. The solution was added dropwise to a solution of 872 mg of 7-amino-3-hydroxycefe-4-carboxylic acid and 1.05 g of trimethylsilylacetamide in 20 ml of ethyl acetate at -20 ° C for 5 minutes, and then -20 ° to -25 ° C. After stirring for 1 hour, 50 ml of water is added and sodium bicarbonate is adjusted to pH 7.0. The aqueous layer is separated, the ethyl acetate layer is extracted again with 10 ml of water, the aqueous extract is mixed and adjusted to 6 and absorbed on a porous nonionic absorbent resin Dion HP-20 (trademark: 50 ml manufactured by Mitsubishi Chemical Corporation). The column was washed with 50 ml of water and eluted with 30% aqueous isopropyl alcohol. The eluate containing the target compound was adjusted to pH 6.5 and concentrated under reduced pressure. The residue was lyophilised to give sodium 7-2-2- (2 1.1 g of -formamidothiazol-4-yl) -2-methoxyiminoacetamido-3-hydroxycefe-4-carboxylate (new isomer) is obtained.

Example 40 (Preparation of lysification for inoculation)

The sodium salt of Compound A (20 g, potency) is dissolved in 200 ml of water and 5 ml of the solution is filled in 10 ml vials respectively, and the bottle is cooled to dry in vacuo (lyophilization).

Example 41 (Suspension Step for Inoculation)

The aqueous suspension is suitable for intramuscular injection.

Example 42 (Tablets for Oral Administration)

The mixture produces tablets that are used orally for the treatment of infectious diseases caused by pathogenic bacteria.

Example 43 (Capsules for Oral Administration)

The mixture produces capsules that are used orally for the treatment of infectious diseases caused by pathogenic bacteria.

Example 44

1.27 g of 5- (2-formamidothiazol-4-yl) -2-propargyloxyimino) acetic acid (neoisomer), 843 mg of N, N-dimethylformamide, 843 mg of phosphoryl chloride and 11.2 ml of ethyl acetate Treatment is carried out in a known manner to obtain an activated acid solution. A mixture of 1.33 g of 7-amino-3-methoxy-3-cepem-4-carboxylic acid hydrochloride, 4 g of trimethylsilylacetamide, 2 ml of bis (trimethylsilyl) acetamide and 20 ml of ethyl acetate was brought to 40-45 ° C. After stirring for an hour, the activated acid solution at −15 ° C. was added to the solution at once, followed by stirring at −5˜−10 ° C. for 1 hour 30 minutes. 30 ml of water are added, filtered to separate the organic layer, and then the filtered insoluble material is dissolved in saturated aqueous sodium bicarbonate solution and the solution is added to the organic layer. The solution is adjusted to pH 7.5, the aqueous solution is separated and extracted with ethyl acetate to pH 2.0, then the extract is washed with water, dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo to give a yellow powder of 7- [2- (2-formamidothiazol-4-yl) -2-propargyloxyiminoacetamido] -3-methoxy-3-cepem 1.0 g of 4-carboxylic acids (new isomers) are obtained.

Example 45

1.27 g of 2- (2-formamidothiazol-4-yl) -2-propargyloxyiminoacetic acid (neoisomer), N, N-dimethylformamide 400 mg phosphoryl chloride 850 mg and 11.2 ml ethyl acetate are known Treated by an external method to obtain an activated acid solution. The activated acid solution was added to 2 g of 7-amino-3-chloro-3-cepem-4-carboxylic acid hydrochloride in 40 ml of ethyl acetate, 6 g of trimethylsilylacetamide and 3 ml of bis (trimethylsilyl) acetamide. It adds temporarily at 15 and stirred at -5-10 degreeC for 1 hour 30 minutes. 30 ml of water are added, the ethyl acetate layer is separated, extracted with saturated aqueous sodium bicarbonate solution, and ethyl acetate is added to the aqueous extract. The pH is adjusted to 2.0 by addition of 10% hydrochloric acid, the ethyl acetate layer is separated, washed with water, dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was determined as a mixture of ethyl acetate and diisopropyl ether, and then the precipitate was filtered, collected and dried to give 7- [2- (2-formamidothiazole-4 as a yellow powder. -Yl) -2-propargyloxyiminoacetamido] -3-chloro-3-cepem-4-carboxylic acid (1.5 g of new isomer is obtained).

Example 46

7.52 g of 2- (2-formaminothiazol-4-yl) -2-n-octyloxyiminoacetic acid (new isomer) in 16 ml of tetrahydrofuran prepared in a similar manner to Example 30, phosphoryl chloride 5.4 g and a solution of 4 g of 7-amino-3-cefe-4-carboxylic acid contained in a mixture of 2.58 g of N and N, N-dimethylformamide and 20 ml of acetone, 20 ml of water and 20 ml of tetrahydrofuran were prepared in Example 30- (1 7- [2- (2-formamidothiazol-4-yl) -2-octyloxyiminoacetamido] -3-cepem-4-carboxylic acid (new isomer) Get 8.1 g.

Example 47

The following compounds were obtained by methods analogous to those of the above examples.

(1) 7- [2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -3-cepem-4-carboxylic acid hydrochloride (new isomer).

(2) 7- [2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3-cepem-4-carboxyl-sodium (neoisomer).

(3) 7- [2- (2-formamido-34-thiazolyl) -2-methoxyiminoacetamido] -3-cepem-4-carboxylic acid (new isomer).

(4) n-hexanoyloxymethyl 7- [2- (2-amino-4-thiazolyl) -2-methoxyimino-acetamido] -3-cepem-4-carboxylate (new isomer)

Claims (1)

Reacting a 7-amino-3-cepem (or cepam) compound of formula (II), a reaction derivative thereof at its amino position, or a salt thereof with a carboxylic acid of formula (III), a reaction derivative thereof at its carboxy position, or a salt thereof To prepare a compound of formula (I) and salts thereof.

In the above formula, R ¹ is thiadiazolyl or R ⁶ is amino, protective amino

Is a thiazolyl or haloacetyl group, and A is an aliphatic hydrocarbon moiety that methylene or R ² may be substituted with hydrogen or halogen, carboxy or esterified carboxy

R ³ is hydrogen or lower alkyl, R ⁴ is hydrogen, halogen, lower alkyl or R ⁷ is a group of the formula -OR ⁷ wherein R ⁷ is hydrogen, lower alkyl or acyl, and R ⁵ is carboxyl or functionally controlled. carboxy, and the dashed line represents the 3-cephem nucleus and sepam as a whole, but i) R ³ is hydrogen when R ⁴ is a group of the -OR ⁷ as hydrogen, halogen or R ⁷ defined above, ii) R ³ is a lower When alkyl, R ⁴ is lower alkyl and iii) a structural formula wherein R ¹ is thiadiazolyl or R ⁶ is as defined above

When the thiazolyl, A has the structural formula as R ² have the above-defined

And iv) when R ¹ is haloacetyl, the dotted line represents the 3-cepm nucleus and R ⁴ represents hydrogen, halogen, -OR ⁷ . v) R ² is neither hydrogen nor lower alkyl when R ⁴ is halogen or a group of —OR ⁷ where R ⁷ is lower alkyl.