KR810001134B1 - Process for preparing thiadiazolylthio cephalosporins - Google Patents

Abstract

Cephalosporins(I; Ar = 2-thienyl, 3-thienyl, Ph, p-acyloxyphenyl; COB1 and COB2 are carboxyl, protected carboxyl; R = H, lower alkyl) were prepd. by the reaction of II and III. Thus, 235 mg 7α-methoxy-7β[α-(3-thienyl)-α-diphenylmethoxy-carbonylacetamido -3-(1,3,4-thiadiazol-2-yl) thiomethyl-1-dethia-1-oxa-3-cephem-4-4-carboxylate, 1 ml anisole and trifluoroacetic acid were reacted in 1.5 ml methylene chloride at 0oC for 1 hr to give 140 mg 7α-methoxy-7β-[α-carboxy-α-(3-thienyl)-acetamido -3-(1,3,4-thiadiazol-2-yl)thiomethyl-1-dethia-1-oxa-3-cephem-4-carboxylic acid.

Description

Manufacturing method of thiadiazolylthio cephalosporins

-메톡시-3-(임의로 알킬치환된 티아디아졸릴티오)-1-옥사데티아세파로스포린류 및 약학적으로 무독한 이들의 염이 제조 방법에 관한 것이다.The present invention provides 7β-arylmalonamido-7 of formula (I)

-Methoxy-3- (optionally alkyl-substituted thiadiazolylthio) -1-oxadethiacephalosporins and pharmaceutically toxic salts thereof relate to the preparation method.

In the above formula

Ar is 2-thienyl, 3-thienyl, phenyl, P-hydroxyphenyl, P-acyloxyphenyl or P-protected hydroxyphenyl group

COB ¹ and COB ² are carboxy or protected carboxy and R is hydrogen or lower alkyl.

Sepharoseporin derivatives having oxygen atoms instead of sulfur atoms in the benzene nucleus are already known (see JC Schahan and M. Dadick, Journal of Heterocyclic Chemitry, Vol. 5, p. 779 (1968); German Patent Application (LOS)). 2,219,601 (1972); S, Wolf et al., Canadian Jouranl of Chemistry, Vol. 52, 996 (1974); Bg Christensen et al. The Journal of the American Society, 96, 7582 (1974), and US Patent Application No. 303,905. And Japanese Patent Application No. 49-133,594, which claims priority to No. 395,662).

However, these documents do not specifically disclose the compound of formula (I). The present inventors have found the excellent antimicrobial activity of the compound of formula (I) to reach the present invention.

The compound of formula (I) is a novel antibacterial agent exhibiting the following properties when compared to other forms of 1-oxadetia cephalosporins and conventional cephalosporins.

1) Strong antimicrobial activity against gram-negative bacteria

2) high stability of β-lactam ring

3) Less dependence of antimicrobial activity on the range of bacterial β-lactamase products

4) Less dependence on inoculation size

5) high effects on bacteria that are resistant to other cephalosporins (e.g., Entrobacter, Serratia and Indole-positive Proteus)

6) high antimicrobial

7) Maintain high concentrations in the blood snack

8) high stability in blood

9) low binding to protein serum

Ar in the compound of formula (I) is 2-thienyl, 3-thienyl, phenyl, P-hydroxyphenyl, hydroxy-protected P-hydroxyphenyl or P-acyloxyphenyl.

In the last-mentioned P-acyloxyphenyls, the acyl residues are inorganic or organic acyl groups containing up to 20 carbons (especially C ₁ -C ₅ alkane oils, C ₈ -C ₁₀ aralkan oils, C ₇ -C ₁₀ aroyl, C ₂ -C ₅ alkoxycarbonyl, C ₈ -C ₂₀ aralkoxycarbonyl, carbamoyl, C ₂ -C ₆ N-alkylcarbamoyl or ureido carbonyl)

-메틸우레이도 카르바모일 등과 같은 아실을 포함한다.Specific examples of acyl groups include poromyl, acetyl, propionyl, butyryl, isobutyryl, bareryl, isovaleryl, phenylacetylphenyl, propionyl, benzoyl, toluoyl, carbomethoxycarbonyl, carboethoxy Carbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, carbamoyl, N-methylcarbamoyl, N-ethylcarbamoyl, N-propylcarbamoyl, N-isobutylcarbamoyl, N , N-dimethylcarbamoyl, carbamoylcarbamoyl, N

Methylureido also includes acyl such as carbamoyl and the like.

It is common to protect phenolhydroxys such as esters or ethers in the protected portion of the hydroxy-protected P-hydroxyphenols for Ar.

-할로알칸오일(예,트리플루오로아세틸, 트리클로로아세틸, 모노클로로 아세틸), C₁∼C₆알칸오일(예, 포로밀, 아세틸, 프로피오닐, 부티릴),C₄-C₈의 β-케토카르복실아실(예, 아세토아세틸), C₂∼C₁₂알콕시카르보닐(예, 3급-부톡시카르보닐, 시클로프로필,메톡시카르보닐, 노르보르닐옥시카르보닐, 2,2,2-트리클로로에톡시카르보닐), C₈~C₁₅아르알콕시카르보닐(예, 벤질 옥시카르보닐, P-메톡 시벤질옥시카르보닐, P-니트로벤질옥시 카르보닐, P-메톡시벤질옥시카르보닐, 디페닐메톡시카르보닐)등과 같은 아실을 포함하여 에스케르를 형성하는 것과; C₁~C₆알킬(예, 메틸, 3급 부틸, 시클로프로필메틸, 이소보르닐, 테트라히드로피라닐, 메톡시메틸, 에톡시메틸, 메탄술포닐옥시메틸, 테트라히드로푸라닐), C₇~C₁₅아르알킬(예, 벤질, P-메톡시벤질, P-메틸벤질, m-메틸벤질, P-니트로벤질,디페닐메틸, 트리틸), C₃~C₈오르가노실릴(예, 트리메틸실릴; 트리에틸실릴)등과 같은 기를 함유하여 에테르를 형성하는 것을 포함한다.Particular examples of phenolic hydroxy-protecting groups are those of C ₁ to C ₆

-Halo alkanoyl (for example, as a trifluoroacetic acetyl, trichloro-acetyl, mono-chloro-acetyl), C ₁ ~C ₆ alkanoyl (e.g., captive wheat, acetyl, propionyl, butyryl), C ₄ -C ₈ a β Ketocarboxyacyl (eg acetoacetyl), C ₂ -C ₁₂ alkoxycarbonyl (eg tert-butoxycarbonyl, cyclopropyl, methoxycarbonyl, norbornyloxycarbonyl, 2,2, 2-trichloroethoxycarbonyl), C ₈ to C ₁₅ aralkoxycarbonyl (e.g. benzyl oxycarbonyl, P-methoxy cibenzyloxycarbonyl, P-nitrobenzyloxy carbonyl, P-methoxybenzyloxy Forming an escher including acyl such as carbonyl, diphenylmethoxycarbonyl), and the like; C ₁ to C ₆ alkyl (eg methyl, tertiary butyl, cyclopropylmethyl, isobornyl, tetrahydropyranyl, methoxymethyl, ethoxymethyl, methanesulfonyloxymethyl, tetrahydrofuranyl), C ₇ C ₁₅ aralkyl (e.g. benzyl, P-methoxybenzyl, P-methylbenzyl, m-methylbenzyl, P-nitrobenzyl, diphenylmethyl, trityl), C ₃ -C ₈ organosylyl (e.g. Forming a ether by containing a group such as trimethylsilyl; triethylsilyl) and the like.

COB ¹ and COB ² groups are usually carboxyl groups containing up to 20 carbon atoms or conventional protecting groups used in penicillin and cephalosporin chemistry.

Protected carboxyl groups are the same or different for COB ¹ and COB ² , respectively, in the same molecule. Typically, protecting groups are removed in the synthesis step of the compound of formula (I) to obtain free carboxy or salt. Thus, the structure of the carboxy protecting group can be adopted in various ways as long as it does not change the gist of the present invention. In other words, the structure of the protecting group has no specific properties other than forming a salt when protected, deprotected and included.

,

-디메틸프로파질, 테트라히드로피라닐, 프날이미도메틸,

,

-디메틸프로파질, 에톡시카르보닐옥시에틸, 메톡시카르 보닐옥시프포필 및 알릴에스테르 아르알킬에스테르류, 예를들면, 벤질펜에틸,톨릴메틸, 디메틸벤질, 니트로벤질, 할로벤질, 메톡시벤질, 트탈리딜, P-히드록시-디-3급-부틸벤질, 디페닐메틸, 트리틸, 펜아실, 클로로펜아실, 브로모펜아실, 니르로펜아실 및 메틸펜아실 에스테르; 다른 용이하게 제거될 수 있는지 방족 에스테르; 금속 에스테르류, 예를들면 트리메틸실릴, 디메틸메톡시실릴, 트리메틸주석 에스테르;방향족 에스테르류, 예를들면, 페닐, 나프릴, 톨릴, 디메틸페닐,니트로페닐, 메탄술포페닐, 클로로페닐, 펜타클로로페닐, 인다닐, 및 피리딜에스테르 등을 포함한다);히드라지드류, 아미드류, 또는 후술하는 약학적으로 무독한 염 또는 반응 또는 정제에 적합한 염을 형성하는 것이다.Particular examples of the aforementioned protected carboxys for COB ¹ and COB ² are those forming esters (optionally substituted C ₁ -C ₅ alkyl esters such as methyl, ethyl, isopropyl, n-butyl, tert- Butyl, pentyl, isopentyl, tert-pentyl, cyclopropylmethyl, monohydroxy tert-butyl, 2,2,2-trichloroethyl, chloromethyl, cyanomethyl, methanesulfonylethyl, acetylmethyl, Acetoxymethyl, propionyl, oxymethyl, fivaloyloxymethyl, benzoyloxymethyl, methylthiomethyl,

,

Dimethylpropazyl, tetrahydropyranyl, franimidomethyl,

,

Dimethyl propazyl, ethoxycarbonyloxyethyl, methoxycarbonyloxypropofyl and allyl ester aralkyl esters such as benzylphenethyl, tolylmethyl, dimethylbenzyl, nitrobenzyl, halobenzyl, methoxybenzyl , Tetralidyl, P-hydroxy-di-tert-butylbenzyl, diphenylmethyl, trityl, phenacyl, chlorophenacyl, bromophenacyl, nitropenacyl and methylphenacyl esters; Aliphatic esters that may be readily removed; Metal esters such as trimethylsilyl, dimethylmethoxysilyl, trimethyltin esters; aromatic esters such as phenyl, naphthyl, tolyl, dimethylphenyl, nitrophenyl, methanesulfophenyl, chlorophenyl, pentachlorophenyl Hydrazides, amides, or pharmaceutically nontoxic salts described below or salts suitable for reaction or purification.

Pharmaceutically toxic salts of the carboxylic acids of formula (I) wherein COB ¹ and / or COB ² are carboxyl groups include alkali metal salts such as sodium and potassium salts; Alkaline earth metal salts such as magnesium, calcium, and alkanoyloxycalcium salts; and salts of organic bases such as procaine, xylocaine, dimethylaniline, triethylamine, and dicyclohexylamine And non-toxic salts.

Some carboxy-protecting groups are useful as drugs to alter the pharmaceutical properties of the product. In such cases it may be a group specifically known for drugs conventional for the preparation of β-lactam antibiotics. These groups are pharmaceutically harmless esters, such as those which increase absorption through digestion, the following pharmaceutically harmless esters such as phthalidyl, acetoxymethyl, propionyloxycetyl, and pivaloyl Esters such as oxymethyl, indanyl, phenyl, tolyl, dimethylphenyl, methoxyphenyl, methoxycarbonyloxyethyl, ethoxycarbonyloxymethyl, phenacyl and the like.

R group is hydrogen or lower alkali. Preferred lower alkyl at this time is C ₁ -C ₃ alkyl, such as methyl, ethyl, propyl and isopropyl.

Typically, the compound of formula (I) is administered parenterally to a human or animal in the form of a salt. The most preferred salts are salts of pharmaceutically toxic organic bases such as sodium or calcium salts or procaine or xylocaine salts. The function of this salt is selected from the viewpoint of stability, solubility and the like.

The compound of formula (I) exhibits strong antimicrobial activity against various Gram-positive and Gram-negative bacteria and is used as a drug, veterinary medicine and fungicide of human agents.

Pharmaceutically nontoxic salts of the compound of formula (I) are suitable for parenteral administration.

The compound of formula (I) in which the Ar group is P-acyloxyphenyl is easily hydrolyzed in serum and exhibits the same antimicrobial activity as that of the parent P-hydroxyphenyl compound.

Formula (I) compounds having carboxy well protected on COB ¹ and COB ² are useful for preparing deprotected antibiotics within or beyond the range of the formula (I) polymer.

Pharmaceutically toxic esters of the compounds of formula (I) are usually suitable for enteral administration.

Structural formula (I) compounds are commonly used to prevent or treat infectious diseases caused by bacteria, with a normal daily dose of 0.05 to 100 mg / kg body weight orally or parenterally for humans or animals. The dosage may be increased or decreased depending on the number of infected bacteria administered or the condition of the patient.

The compound of formula (I) may be administered alone in a variety of enteral or parenteral dosage forms conventional in the art, or in combination with other substances or carriers that work together. The pharmaceutical composition may be a mixture containing 0.01 to 99% of the compound of formula (I) and a pharmaceutical carrier which may be liquid or solid. The compound of formula (I) is dissolved, dispersed and suspended in a carrier. These may be in a single dosage form.

The compound of formula (I) is usually a vial, which is immediately solutioned before use. It may also contain excipients or diluents into formulations such as solutions, injections, ointments, tablets, powders, capsules and the like.

The compound of formula (I) is prepared by reacting an amine of the following formula (II) or a reactive derivative thereof with an arylmalonic acid or a reactive derivative thereof of the following formula (II).

In the above formula

Ar, COB ¹ , COB ² and are as described above. The amine of formula (II) was prepared according to the method described in JP-A-49-133,594. Reactive derivatives thereof have 7-amino groups, wherein 7-amino groups are pretreated by conventional methods to allow silyl (e.g. trimethylsilyl, methoxydimethylsilyl), stannyl (e.g. trimethyl tin), carbonylalkenyl (e.g. acetone , Acetylacetone, acetoacetate, acetoacetonitrile, acetoacetamide, acetoacetyl yldir, cyclopentanedione, acetylbutyl to form an enamino with lactones or alkylidene (eg 1-haloalkylidene, 1-haloaralkylidene , 1-alkoxy-1-phenoxyalkylidene) derivative groups are obtained or acid addition salts (e.g., inorganic acids, carboxylic acids, sulfonic acids) are obtained.

Arylmalonic acid of formula (III) can be prepared by conventional methods, for example, Japanese Patent Application Laid-Open No. 51-1489; German Patent Application No. OLS 2,451,931 and Journal of American Chemical Society, 59,1909 (1937) and Copper 91: 8 2127 (1969). Can be prepared from known compounds. COB ¹ is the aforementioned protective carboxy. Reactive derivatives of arylmalonic acid of formula (III) include functional derivatives such as acid anhydrides, acid halides, reactive esters, reactive amides, azides, and the like. This reaction can be carried out as follows.

i) When using the free acid of formula (III) The amine of formula (II) or a reaction derivative thereof may be carbodiimide (e.g., N, N'-diethyl carbodiimine, N, N'-dicyclohexylcar Bodyimide), carbonyl compounds (e.g. carbonyldiimidazole), isoxazolinium salts, acylamino compounds (e.g. 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline), ami In the presence of a condensing agent such as a multidase, preferably in the presence of an aprotic solvent (eg halohydrocarbon, nitrile, ether, amide and mixtures thereof) with the compound of formula III. Compound (II): The molar ratio of the compound (III) is preferably 1: 2 and the molar ratio of the compound (II) is 1: 2.

ii) When the acid anhydride of formula (II) is used: The amine of formula (II) or a reactive derivative thereof is reacted with the acid anhydride of malonic acid of structure (III) in a conventional manner. Such anhydrides are alkoxy formic acid, Reactive anhydrides such as aralkyl formic acid, sulfuric acid, sulfurous acid, phosphoric acid, phosphorous acid, aliphatic or aromatic carboxylic acids or special intramolecular anhydrides such as sulfonic acid, ketene or nitrile oxides, symmetric anhydrides and the like. This reaction is based on inorganic bases (e.g. oxides, hydroxides, carbonates, bicarbonates, etc.) of alkali or alkaline earth metals; organic bases (e.g. tertiary amines, aromatic amines) oxirane (e.g. alkylene oxides, aralkylenes) In the presence of acid acceptors such as Drew (e.g., N, N-dimethylformamide, N, N-dimethylacetamide, hexamethylphosphotriamide), adsorbents (e.g. molecular sieves), and preferably aprotic solvents ( Eg halohydrocarbon, nitrile, ether, ketone, amide, ester or mixtures thereof). Preferred molar ratios are 2 moles of acid anhydride and 10 moles of acid acceptor relative to 1 mole of the structural formula (II) amine or reactive derivatives thereof.

iii) When using an acid halide of formula (III): Formula (II) amines or reactive derivatives thereof may be aprotic solvents (e.g., halolocarbons, nitriles, ethers, ketones, water, dialkyramides, or mixtures thereof). Constant) reacted with an acid halide or azide in the presence of an acid acceptor. Preferred molar ratios are 1: 2 acid halides and 1:10 acid acceptors relative to structural formula (II) amines or reactive derivatives thereof.

iv) When reactive esters and reactive amides are used: The structural formula (II) amines are prepared according to a conventional method by enolic esters (e.g. vinyl esters, isopropenyl esters) aryl esters (e.g. halophenyl esters, nitrophenyl esters). ), Reactive aromatic groups such as heteroaromatic esters (e.g. esters with 1-hydroxy-benzotriazole groups), esters with hydroxyl groups, esters with oxime or diacyl hydroxylamine: aromatic amides (e.g. Reactive amides such as amides, triazoles or 2-ethoxy-1,2-dihydroquinolines), diacylanilides, and the like, or other reactive derivatives (formimino groups such as N, N-dimethylformiminoester) And a) in the aprotic solvent described above. The preferred molar ratio of reactants is 1:10 reactive derivatives with respect to the amine of formula (II) or derivatives thereof.

(2) Reaction with thiadiazolyl thio group:

-메톡시-3-치환메틸-1-옥사데티아-3-세펨-4-카르복실산 또는 유도체와 구조식(Ⅴ)의 1,3,4-디아티아졸-5-일 티올 또는 이의 반응성 유도체를 반응시켜서 만든다.7β-arylmalon amido-7 of structural formula (V)

-Methoxy-3-substituted methyl-1-oxadethia-3-cepem-4-carboxylic acid or derivative and 1,3,4-diathiazol-5-yl thiol of formula (V) or a reactive derivative thereof Is made by reacting

Where

Ar, COB ¹ , COB ² and are as described above.

X is a reactive group which may be substituted with a compound of formula (V) in a thiol group.

Representative X groups are acyloxy groups such as halogen or phosphoryloxy, dihaloacetoxy, and trihalo acetoxy. Reactive derivatives of the compounds of formula (V) are derivatives such as alkali metal salts, salts of organic bases (eg triethylamine salts) and the like.

The reaction of the above scheme is carried out in the presence of a base, preferably in a solvent (eg halohydrocarbon, ether ketone, or amide).

In a special case X can be a hydroxyl group formed of epoxy by the addition of a double bond of a ring. In other words, the compound of formula (VI) is a 7β aryl malon amido-7α-methoxy-3-epoxy metano-1-oxadetia-β-sefe-4-carboxylic acid derivative.

(3) Methoxylation: introducing 7α-methoxy group into 7α-hydrogen compound 7β-arylmalonamido-3- (1,3,4-thiadiazol-5-yl) thiomethyl- according to the following scheme 1-oxaderia-3-cepem-4-carboxylic acid or derivative thereof

In the above formula, Ar, COB ¹ , COB ² and R are as described above. This reaction can be carried out as follows.

a) Compound (VI) is treated with an N-halogenating agent (e.g. tertiary butylhypochlorite) and an alkali metal methoxide (e.g. sodium methoxide, potassium methoxide) in methanol to reduce the perhalogenated byproduct Is done by

b) The compound of formula (V) is treated with an N-halogenating agent in the presence of phenyllithium or sodium borate and reacted with a base in methanol.

c) alternatively using halogen and 1,5-diazabicyclounbecene (DBU) as the N-halogenating agent.

All these methods go through acylimino intermediates and add methanol to give the desired compound of formula (I).

(4) Removing protecting groups from carboxyl groups: Deprotection of protected carboxys for COB ¹ and COB ² affords compound of formula (I) with free carboxyl,

i) In the case of highly reactive esters, amides and anhydrides, deprotection is achieved by hydrolysis with an acid aqueous solution, base or buffer.

ii) haloethyl, benzyl, nitrobenzyl, dimethylbenzyl, diarylmethyl and triarylmethyl esters may be subjected to mild reducing conditions (e.g., acid and tin, zinc, secondary chromium salts, etc.) or side solvents (e.g. platinum palladium, nickel); ) Is cleaved to the corresponding free acid by means of side-effect hydrogenation or sodium dithionite reduction.

iii) Benzyl, methoxybenzyl, methylbenzyl, dimethoxybenzyl, tert-alkyl, trityl, diarylmethyl, cyclopropylmethyl, sulfonylethyl and cyclopropylmethyl esters are used for acids (e.g. inorganic acids, Lewis acids, Sonic acid, strong carboxylic acid) and, if necessary, treated in the presence of a cationic acceptor (e.g. anisole), solvated and decomposed to form free acid.

iv) Penacyl, ethynyl and p-hydroxy-3,5-di-3-tert-butylbenzyl esters are separated and reacted with bases or other nucleophiles to form free acids. The highly reactive phenacyl ester is removed by irradiation with light to form carboxylic acid.

(5) Deprotection in the phenol group of Ar: Representative deprotection is as follows.

i) esters and ethers as described above (particularly benzyl ethers and α-oxygenated ethers) include acids (e.g., inorganic acids, Lewis acids, strong carboxylic acids, sulfonic acids, other acids described above), If necessary, it is deprotected by reacting in the presence of a cationic receptor such as anisole. Hydrolysis conditions may also be applied.

ii) benzyloxyformester or benzylester is deprotected by catalytic hydrogenation using a catalyst such as platinum, palladium or nickel

Sometimes this reaction (5) takes place simultaneously with the reaction (4) described above. (6) Formation of Salts or Esters of Compounds of Formula (I): The compounds of formula (I) which receive free carboxy or phenol groups in conventional manner form salts by treatment with organic or inorganic salts. Typical esterification of the compound of formula (I) having free carboxy or phenol groups forms esters as described above.

All reactions of these reactions (1) to (6) can be carried out at a temperature of about -30 ° C to 100 ° C, preferably -20 ° C to 50 ° C. The solvent is halocarbons (e.g. dichloromethane, chloroform, dichloroethane, trichloroethane, chlorobenzene), ethers (e.g. diethyl ether, tetrahydrofran, petrahydropyran, anisole), ketones ( Acetone, methyl ethyl ketone, methyl isoputyl ketone, cyclohexanone, acetophenone), esters (e.g. ethyl acetate, butyl acetate, methylbenzoate), nitrohydrocarbons (e.g. nitromethane), nitriles (E.g. acetonitrile, benzonitrile), amides (e.g. formamide, acetamide, dimethylformamide, dimethylacetamide, hexamethylphosphortriamide), sulfoxides, acids (e.g. formic acid, acetic acid) , Bases (eg butylamine, triethylamine, pyridine, picoline, quinoline), alcohols (eg methanol, ethanol, pentanol, benzyl alcohol), and the like. As the solvent, a solvent or a mixture of two or more solvents may be used.

This reaction can be stirred while releasing water under an inert gas to speed up the reaction rate.

The desired product can be separated from the reaction mixture by removing solvents, unreacted products, by-products and other impurities used by conventional methods such as concentration, extraction, adsorption, elution, washing, chromatography, recrystallization and the like.

The following examples illustrate the invention. These embodiments do not reduce the scope of the invention.

Example 1

(1) A solution obtained by suspending 375 mg of α- (4-p-methoxybenzyloxyphenyl) -α-p-methoxybenzyloxycarbonyl acetic acid in 5 ml of methylene chloride is stirred at -15 ° C under nitrogen pressure. Triethylamine (90 μl) and oxaryl chloride (55 μl) were added thereto, and the reaction mixture was stirred for 1 hour under ice cooling, and 228 ml of 5α-methoxy-7β- in 5 ml of methylene chloride containing 52 μl of pyridine. Amino-3- (2-methyl-1,3,4-thiadiazol-5-yl) thiomethyl-1-dethia-1-oxa-3-cepem-4-carboxylate is mixed with a solution of Stir for 30 minutes under ice-cooling, and carry out under reduced pressure. The residue is dissolved in ethyl acetate, washed with 2N hydrochloric acid, water, 5% sodium bicarbonate and water in this order, dehydrated and concentrated. The residue was purified by chromatography on a 20 g silica gel column to give 212 mg of diphenylmethyl 7α-methoxy-7β- [α- (4-p-methoxybenzyloxyphenyl) -α-p-methoxybenzyloxycarbonyl Acetamido] -3-2 (2-methyl-1,3,4-thiadiazol-5-yl) thiomethyl-dethia-1-oxa-3-cefe-4-carboxylate is obtained ( Yield: 52%)

(2) 1 ml of anisole and 0.5 ml of trifluoroacetic acid were added to a solution of 212 mg of the product prepared in (1) in 2 ml of methylene chloride with stirring under nitrogen pressure at 0 ° C., and then the distillate was mixed at 0 ° C. 30 Stir for minutes and concentrate under reduced pressure. Ether residues. 7α-methoxy-7β- (α-p-hydroxyphenyl-α-carboxacetamido) -3- (2-methyl-1,3,4-thiadiazole-51) -thiomethyl-1 after washing -Dethia-1-oxa-3-cepem-4-carboxylic acid is obtained. Yield 94% Melting Point 118 ° C (Decomposition)

Example 2

-(3-티에닐)-

-디페닐메톡시카르보닐아세트산을 현탁시킨 액을 냉각시키면서 79㎕의 트리에틸아민과 49㎕의 옥사릴 클로라이드를 가한 다음 이 혼합물을 20분간 교반하고 46㎕의 피리딘을 함유하는 4ml의 메틸렌크로라이드에 200mg의 디페닐메틸 7α-메톡시-7-아미노-3-(2-메틸-1,3,4-티아디아졸-5-일) 티오메틸-1-데티아-1-옥사-3-세펨-4-카르복실레이트를 녹인 용액과 합한 다음 빙냉하 15분간 교반한다. 반응 혼합물을 에틸아세레이트로 희석하고 2N,염산, 물, 5%중탄산나트륨수용액 및 물의 순서로 세척하고 탈수한 후 감압하 농축시킨다. 잔유물을 10%물을 함유하는 실리카겔상 크로마토그라피하여 정제하면 302mg의 디페닐메틸 7α-메톡시-7β-[α-(3-티에닐)-α-디페닐메톡시카르보닐 아세트아미도]-3-(2-메틸티-1,3,4-아디아졸-5-일) 티오메틸-메티아-1-옥사-3-세펨-4-카르복실레이트가 수득된다. 수율 93%(1) 268 mg in 4 ml methylene chloride

-(3-thienyl)-

79 μl of triethylamine and 49 μl of oxarylyl chloride were added while cooling the suspension of diphenylmethoxycarbonyl acetic acid, and then the mixture was stirred for 20 minutes, and 4 ml of methylene chloride containing 46 μl of pyridine. 200 mg diphenylmethyl 7α-methoxy-7-amino-3- (2-methyl-1,3,4-thiadiazol-5-yl) thiomethyl-1-dethia-1-oxa-3- Combine the fem-4-carboxylate solution and stir for 15 minutes under ice-cooling. The reaction mixture is diluted with ethyl acetate, washed with 2N hydrochloric acid, water, 5% aqueous sodium bicarbonate solution and water, dehydrated and concentrated under reduced pressure. Purification of the residue by chromatography on silica gel containing 10% water yielded 302 mg of diphenylmethyl 7α-methoxy-7β- [α- (3-thienyl) -α-diphenylmethoxycarbonyl acetamido]-. 3- (2-Methylthi-1,3,4-adiazol-5-yl) thiomethyl-methia-1-oxa-3-cepem-4-carboxylate is obtained. Yield 93%

(2) To 4 ml of methylene chloride, 0.5 ml of anisole and 0.4 ml of trichloroacetic acid were added to a solution of 302 mg of the product prepared in (1) at 0 ° C. under nitrogen pressure, and the mixture was stirred at the same temperature for 30 minutes. And concentrated under reduced pressure. The residue was washed with ether, 180 mg of 7α-methoxy-7β- [α- (3-thienyl) -α-carboxacetamido] -3- (2-methyl-1,3,4-thiadiazole- 5-yl) thiomethyl-1-dedia-1-oxa-3-cefe-4-carboxylic acid is obtained. Yield 97%

Melting Point> 105 ° C (Decomposition)

Example 3

(1) 6 ml of 0.565 M sodium methoxide / methanol was added to a solution of 400 mg of 1,3,4-thiadiazole-2-thiol in 6 ml of methanol, and the mixture was stirred for 20 minutes and concentrated. The residue was taken up in 5 ml of dimethylformamide and 1.50 g of diphenyl methyl 7β-benzamido-7α-methoxy-3-chloromethyl-1-dethia-1-oxa-3-cepem-4-carboxylate Pour with ice-cooling solution, stir at the same temperature for 20 minutes, pour in water and extract with ethyl acetate. The extract is washed with water, dehydrated and concentrated under reduced pressure. The residue is chromatographed on a column of 50 g silica gel containing 10% water and eluted with a mixture of benzene and ethyl acetate (2: 1). The eluate was concentrated to give 1.25 g of diphenylmethyl 7β-benzado 7α-methoxy-3- (1,3,4-thiadiazol-2-yl) thiomethyl-1-dethia-1-oxa. Obtain 3-cepem-4-carboxylate. Yield: 72.6%

용적으로 농축한다. 이 잔유물에 붓고 에틸아세테이트로 추출한다. 이 잔유물을 10%의 물을 함유하는 실리카겔의 컬럼상에 크로마토 그라피하고 벤젠과 에틸아세테이트의 혼합물로 용출하면 676mg의 디페닐메틸 7β-아미노-7α-메톡시-3- (1,3,4-티아디아졸-5-일)티오메틸-1-데티아-1-옥사-3-세펨-4-카르복실레이트를 수득한다. 수율 65%(2) To a solution of 1.25 g of the above-prepared product in 3 ml of methylene chloride, 327 µl of pyridine and 762 µl of phosphorus pentachloride were added while stirring under nitrogen atmosphere at 8 ° C., and the mixture was stirred at room temperature for 2 hours. The mixture was cooled to −30 ° C., mixed with 14 ml of methanol, stirred at 0 ° C. for 90 minutes, stirred at room temperature for 30 minutes, and cooled to freezing again. The reaction mixture was mixed with 1.9 ml of diethylamine and stirred for 10 minutes, then under reduced pressure.

Concentrate to volume. Pour into this residue and extract with ethyl acetate. The residue was chromatographed on a column of silica gel containing 10% water and eluted with a mixture of benzene and ethyl acetate to give 676 mg of diphenylmethyl 7β-amino-7α-methoxy-3- (1,3,4- Thiadiazol-5-yl) thiomethyl-1-dethia-1-oxa-3-cefe-4-carboxylate is obtained. Yield 65%

(3) 262 mg of α-p-methoxybenzyloxycarbonyl-α- (4-p-methoxybenzyloxyphenyl) acetic acid suspended in 3 ml of methylene chloride. After adding ethylamine and 39 µl of oxaryl chloride, the mixture was stirred under ice cooling for 1 hour, and the mixture was stirred for 1 hour under ice cooling to obtain a corresponding acid halide group.

To a solution of 150 mg of the product prepared in (2) above was added 2 ml of methylene chloride, 36 µl of pyridine and the acid halide prepared above were added. The mixture was stirred for 20 minutes, mixed with 2 ml of water and concentrated under reduced pressure. The residue is extracted with ethyl acetate. The extract was washed in the order of 2N hydrochloric acid, 5% aqueous sodium bicarbonate solution, and water, then dehydrated and concentrated under reduced pressure. The residue was chromatographed on a column of 10 g silica gel containing 10% water and eluted with a mixture of benzene and ethacetate (4: 1) to 153 mg of diphenylmethyl 7β- [α-p-methoxybenzyloxycarbonyl -α- (4-p-methoxybenzyloxyphenyl) -acetamino] -7α-methoxy-3- (1,3,4-thiadiazol-2-yl) thiomethyl-1-dethia-oxa Obtain 3-cefem-4-carboxylate.

Yield 55%

(4) 2 ml of methylene chloride was added to acetic acid with 0.7 ml of anisole and 0.5 ml of trifluo, ice-cooled in a solution of 150 mg of the product prepared in (3) above, and the mixture was stirred for 25 minutes. Concentrate. This residue was washed with ether and 78 mg of 7α-methoxy-7β- (α-p-hydroxyphenyl-α-carboxacetamido) -3- (1,3,4-thiadiazol-5-yl) Obtain thiomethyl-1-dethia-1-oxa-3-cefe-4-carboxylic acid. Yield 92%

Melting Point> 120 ° C1 (Decomposition)

Example 4

(1) To a solution of 212 mg of α-diphenyl methoxycarbonyl-α- (3-thienyl) acetic acid in 3 ml of methylene chloride, 79 μl of triethylamine and 49 μl of oxaryl chloride were added with ice cooling. Stir the mixture for 20 minutes to give the corresponding acid halide. 150 ml diphenylmethyl 7β-amino-7α-methoxy-3- (1,3,4-thiadiazol-2-yl) thiomethyl-1-dethia-1-oxa-3- in 2 ml methylene chloride To the solution of cefe-4-carboxylate was added to the solution of the above-mentioned acid halide and 36 μl of pyridine under ice-cooling, the mixture was stirred for 20 minutes, extracted with ethyl acetate, 2N hydrochloric acid and 50% aqueous sodium bicarbonate solution. After washing in order of water, dehydration and concentration under reduced pressure. This residue was subjected to chromatography on silica gel of 10 g of silica gel containing 10% of water to obtain 235 mg of diphenylmethyl 7α-methoxy-7β- [α- (3-thienyl) -α-diphenylmethoxycarbonylacetate. Amido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-1-dethia-1-oxa-3-cepem-4-carboxylate is obtained. Yield 93%

(2) To 1.5 ml of methylene chloride, 1 ml of anisole and 0.5 ml of tripuluoacetic acid were added to a solution of 235 mg of the product prepared in (1), with stirring at 0 ° C., and the mixture was stirred at the same temperature for 1 hour. And concentrated under reduced pressure. When this residue is washed with ether, this crude oil is washed with ether to give 140 mg of 7α-methoxy-7β- [α-carboxy-α (3-thienyl) -acetamido] -3- (1,3,4 -Thiadiazol-2-yl) thiomethyl-1-oxa-3-cefe-4-carboxylic acid is obtained. Yield 98%

Melting point 110 ℃

Example 5

The products from Examples 1 to 4 were dissolved on 0.001 N-sodium bicarbonate and the antibacterial activity was measured on the resulting sodium salt. These compounds exhibited a minimum inhibitory concentration of less than 1.0 μg / ml for this, Clahlich, (EcoliH.).

Claims (1)

The amine of formula (II) or a reactive derivative thereof is reacted with an arylmalonic acid of formula (III) or a reactive derivative thereof at -30 ° C to 100 ° C in the presence of a condensed system and an acid acceptor. Separosporins and a method for producing the salt thereof.

In the above formula Ar is 2-thienyl, 3-thienyl, phenyl, P-hydroxyphenyl, P-acyloxyphenyl or P-protected hydroxyphenyl group, COB ¹ and COB ² are each a carboxyl group or a protected carboxyl group, R is hydrogen or a lower alkyl group.