SU1024009A3 - Method of producing o-dethia-oxacephalosporines - Google Patents

Abstract

PURPOSE:To prepare 1-oxadethiacephalosporin useful as an antibiotic or its intermediate, economically, by eliminating 3-position eliminable group of 3-eliminable group-substituted 1-oxadethiacepham compound which is an intermediate of cephalosporin.

Description

The present invention relates to a method for producing new compounds — 1-children -1oxacephalosporins, which can be used as semi-products in the synthesis of cephalosporins, as well as substances with antimicrobial activity. A known method of obtaining 1-children is -1-oxacephalosporinosis ArCBiOKH-1-Y.: S l COfti L-x cH 2- where 2- or 3-thienylphenyl p xyphenyl yl alkanoyloxyphenyl; Ow. and, independently of one another, a free or protected carboxy group, by precipitation of y-amino-y-methoxy-3- (1-methyltetrazol-5-ylthiomethyl) -1-decya-1-oxa-3-cephem-1-carboxylic acid or its protected derivative with the corresponding arylmalonic acid derivative f1J. These compounds serve as semi-products in the synthesis of cephalosporins, and they themselves possess physiologically active properties. A known method for producing xycephalosporins is that the corresponding cephalospores are reacted with tert-butyl hypochlorite and lithium methylate in methanol in an inert solvent at a temperature of from -120 to t2. The aim of the invention is to obtain new compounds that expand the senal of the means of action on a living organism, as well as intermediates in their synthesis. This goal is achieved by the method of producing 1-child-1-oxaceph of losporins of the formula g: g ° 1 L-NV where Y is a divalent group of the formula: C crcn, 2.k, cov ..X sn-ssn. Sow cooft where SOOV is an esterified carboxyl group; X is a hydrogen or halogen atom; halogen atom or hydroxy- or acetsxy group and a free amino group or group of the formula ISONH-, where R is phenyl, cyano-, halo-, nitro or methyl-phenyl or benzyl, a compound of formula A4-fO jNy O where Y and A have the indicated values , is exposed to molecular chlorine or tert.-butyl hypochlorite as an N-halogenating reagent and lithium methylate or sodium, or potassium, or magnesium as a base in methanol in a halocarbon medium, for example dichloromethane, or an ether, for example tetrahydrofuran, or amide, for example K, N-dimethylformamide, in to honors the solvent at a temperature from -55 ° C to CPC within 5-70 minutes. When the compound N is treated with a nosing agent and a base, a corresponding imino compound is formed, the treatment of which with methanol leads to the formation of the desired compound I. Under the action of N-hydroylation. No other part of the molecule can be halogenated, but products can be recovered to remove the excess halogen atom introduced. The process involves the reaction of the starting compound E with a 1-halogenating reagent: molecular chlorine or tert.-butyl hypochloride, followed by exposure to lithium methylate, or sodium, or potassium, or magnesium in methanol. Typically, the amide of formula I is dissolved in 10-50 m of an inert solvent, mixed with 1-5 mol. eq. -halide agent for 2-10 minutes at a temperature from to, mixed with -Ceq. metal methylate in methanol and stirred at a temperature of from 5 to 70 minutes. The reaction mixture can be neutralized with acetic or mineral acid, after which the product is transferred to an organic solvent. The method allows to obtain a 95% yield of compounds 1. Compounds 1, obtained by methoxylation, can be isolated from the reaction mixture by removing the used solvent, unreacted by-products and similar contaminants by concentration, extraction, washing, drying, etc. and purified by re-precipitation, chromatography, crystallization, absorption or purification methods. The stereoisomers at positions 3 or 7 are separated by careful chromatography or fractional recrystallization. If desired, the stereoisomers can be further processed without being separated. Compounds I can be used as starting materials for the preparation of the known bactericidal 1-child-1-oxacephalosoprin in high yield. The choice of groups A, COOB and X in the starting materials and intermediates may depend on the ease of reaction, handling or use, stability under the conditions of the reaction and treatment, waste, costs and other practical factors. Compounds 1 or L, including a carboxyl group as a COOff, are bactericidal. Examples 1 - 2 (table). . 7j (unsubstituted-7o-amido-1 -dethia-1 oxaceph L is dissolved in a solvent and mixed in methanol with an H-halogenating agent and base in accordance with the conditions shown in Table 1, resulting in the corresponding H-methoxy -7 p amino compound. Experimental errors in IR spectra are within ± 10 cm, and experimental errors in NMR spectra are within ± 0.2 ppm. Melting points are uncorrected. Anhydrous sodium sulfate is used to dry the solution. Below examples 5 and 9. showing Experimental procedure for methoxylation. EXAMPLE 5. To a solution of 86 mg of diphenylmethyl 7 benzamido-CCC hydroxy-3 | -methyl-1-deethia-1-oxacepham-f cf-carboxylate in 20 ml of anhydrous dichloromethane was added 0.15 ml tert butyl hypochlorite and 1.1 ml of a 2N solution of lithium methylate in methanol at, and the mixture is stirred for 15 minutes, mixed with 1.2 ml of acetic acid, stirred for 5 minutes, diluted with ice-cold aqueous sodium bicarbonate solution, and extracted with dichloromethane. The extract is washed with an aqueous solution of sodium bicarbonate and water, dried and evaporated. The colorless foamy residue is purified by chromatography on silica gel to give 230 mg of diphenylmethyl-7E-benzamido-7od.-MeToxy-3a-goxy-3p-methyl-1-decyag-1-oxaiefam-vol carboxylate (yield: k8%). EXAMPLE 9 A solution of 187 mg of diphenylmethyl 7o-benzamido-3 Egbromo-3-bromoethyl-1-child-1-oxacephamo-o-carboxylate in 1 ml of anhydrous dichloromethane is added k6 µl tert, butyl hypochlorite and 0.17 ml of a 2 M solution of methylate lithium in methanol at and the mixture is stirred at the same temperature for 1 h. The physical constants of the compounds obtained are given in table. 2

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Claims (1)

METHOD FOR PRODUCING! -DETIA-1-OXACEFALOSPORINS of the formula I t ~ CHg -CH COOB ¹ or I ^d c-ch, x -c COOB ¹ where COOB * is an esterified carboxyl group; X is a hydrogen atom or a halogen on ‘, Σ is a halogen atom or an oxy or acetoxy group, a free amino group or a group of the formula R ¹ C0NH-, where ¹ is phenyl, cyano, halo, nitro or methyl phenyl or benzyl, characterized in that} 'is a compound of the formula P • g 0CH ₃ I where U and A have the indicated meanings, are exposed to molecular chlorine or tert.-butyl hypochlorite as an H-halogenating reagent where Y is a divalent group of the formula CZCH ₂ X, -Ch COOB ¹ and lithium or sodium, or potassium, or magnesium methylate as a base in methanol, in a medium of halocarbon, such as dichloromethane, or ether. for example tetrahydrofuran, or amide, for example N, N-dimethylformamide, as a solvent at a temperature of from ~ 55 ° C to 0 ° C for a period of 5–70 min.