METHOD FOR PRODUCING CEPHEM-PRODROG ESTERS

摘要

The invention relates to a process for the preparation of cephem prodrug esters of the formula in which R<1> is C1-C5-alkanoyloxy-C1-C3-alkyl or C1-C5-alkoxycarbonyloxy-C1-C3-alkyl and X is an inorganic or organic anion, and in which the hydroxyimino group is present in the syn form, characterised in that a compound of the formula II in which R<2> is a protective group which can be eliminated by acid hydrolysis, is reacted with a bis(2-benzothiazolyl) disulphide of the formula VI in which R<3> is hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C3-C6-alkynyl, C1-C6-alkyloxy, C2-C6-alkenyloxy, C3-C6-alkynyloxy, hydroxyl, acetoxy, halogen, nitro, amino, carboxyl or the sulpho group, and triphenylphosphine in an inert solvent in the presence of a tertiary amine to give a compound of the formula V in which R<2> and R<3> have the abovementioned meanings, subsequently this compound is reacted with a 7-aminoceph-3-em-4-carboxylic ester of the formula III in which R<1> has the abovementioned meaning, in inert organic or dipolar aprotic solvents at temperatures between 0 DEG C and +80 DEG C, and the oxime-protected compound of the formula IV which is formed in which R<1> and R<2> have the abovementioned meanings, and in which the protected oxime group is present in the syn form, is treated with inorganic acids or with aliphatic or aromatic sulphonic acids in organic solvents at temperatures between +20 DEG and +110 DEG C to form the compound of the formula I.