GB1379465A - Cephem-4-carboxylic acids their 1-sulphoxides and methods of prepa ring them - Google Patents

Abstract

1379465 2 - Cephem - 4 - carboxylic acids MERCK & CO Inc 10 July 1972 [14 July 1971 10 Sept 1971 22 Nov 1971 14 April 1972] 32141/72 Heading C2C 2-Cephem-4-carboxylic acids of Formula I in which R is acyl, R<SP>1</SP> is hydrogen or methoxy, X is halogen, azido C 1-6 alkanoyloxy, aroyloxy, mono- or polyhydroxy-phenyl, 1-alkoxy-carbonyl-2-oxoalkyl, 1-(C 1-6 alkoxycarbonyl), 2- oxo - C 1-6 alkyl or 2,4 - dioxoalkyl and R<SP>2</SP> is a protecting group, are prepared by treating a compound II in which R<SP>3</SP> is hydrogen, amino or C 1-5 alkyl with either a hydrohalic acid or a compound containing an active hydrogen of formula HX, in the presence of a non-nucleophilic or Lewis acid as catalyst. Novel compounds V in which R is acyl, R<SP>2</SP> is hydrogen, or a protecting group and X<SP>2</SP> is hydrogen, halo, cyano, C 1-6 alkoxy, hydroxy, protected hydroxy, carbamoyloxy, C 1-6 alkanoyloxy, aroyloxy, mono- or polyhydroxyphenyl, 1-alkoxy-carbonyl-2- oxoalkyl heterocyclic-thio, heterocyclic-thiocarbonyl-thio or a tertiary amine are further reacted with an oxidizing agent to form the corresponding novel 1-sulphoxide. Compounds III in which R is acyl, R 2 is a protecting group, X<SP>1</SP> is C 1-6 alkoxy, cyano, hydroxy, C 1-6 alkanoyloxy, aroyloxy, carbamoyloxy, heterocyclic - thio, heterocyclic - thiocarbonyl - thio, or tertiary amine, m is 0 or 1 and the dotted line signifies a double bond in either the 2 or 3 position, comprises treating a compound of Formula III in which X<SP>1</SP> is halogen with a reagent M(X<SP>1</SP>) z where M is hydrogen or a cation from an alkali metal alkaline earth metal or Group IB metal and z is an integer equal to the valence of M; if the starting material is a #<SP>2</SP> cephem compound the product will be a mixture of both #<SP>2</SP> and #<SP>3</SP> isomers in which the #<SP>2</SP> predominates. X<SP>1</SP> is preferably carbamoyloxy and the reaction is carried out using sodium, potassium or calcium carbamate. Compounds VI in which R<SP>2</SP> is a protecting group and R and X<SP>2</SP> are as defined above are prepared by isomerization of the corresponding #<SP>2</SP> isomer by treatment with an alcohol, organic base or an adsorbent; treatment of compound VI with a reducing agent gives compound VII Compounds II are also prepared by isomerization of the corresponding pure #<SP>3</SP>-cephem compound using a base or with an adsorbent; the reaction goes to an equilibrium in which the #<SP>2</SP> isomer predominates. In the compounds prepared R is an acyl function (R 1 CO) in which R 1 is benzyl, α-amino-benzyl, 2-furylmethyl, 2- thienylmethyl, 4-amino 4-carboxy butyl (in which the amino and carboxy groups may be protected) or p-hydroxybenzyl, R<SP>2</SP> is trichloroethyl, t-butyl, benzoylmethyl, p-methoxybenzoyl, benzyl, benzhydryl or methoxymethyl and the amino protecting groups are trichloroethoxycarbonyl or t-butoxycarbonyl. Heterocyclicthio is 5 - methyl - 1,3,4 - thiadiazolyl - 2 - thio, heterocyclic - thiocarbonyl - thio is piperdinothiocarbonyl-thio and tertiary amine is pyridine. Starting materials are prepared from the sodium salt of 7-#-(D-5-amino-5-carboxy-valeramido) - 3 - carbamoyloxymethyl - 7α - methoxy- 3-cephem-4-carboxylic acid (prepared by fermentation procedure) which is treated successively with trichloroethoxycarbonyl chloride to protect the amino group and diphenyldiazomethane to protect the carboxy groups; reaction of this compound with 2-thienylacetylchloride produces the dibenzhydrylester of 7-#-[(D-5-trichloroethoxycarbonylamino - 5 - carboxyvaleryl) - (2- thienylacetyl)amino]- 3 - carbamoyloxymethyl- 7 - α - methoxy - 3 - cephem - 4 - carboxylic acid which is treated with zinc dust and acetic acid to form the benzhydryl ester of 3-carbamoyloxymethyl - 7 - α - methoxy - 7 - # - (2 - thienylacetamido) - 3 - cephem - 4 - carboxylic acid from which the #<SP>2</SP> isomer is obtained by isomerization. Trichloroethyl ester of 7-methoxy-3-carbamoyl oxymethyl - 7 - (2 - thienylacetamido) - 3 - cephem- 4-carboxylic acid is treated with zinc dust and acetic acid to form the free carboxylic acid.