Manufacture of cefalosporins and intermediates

Abstract

There is described a process for the preparation of 3-disubstituted cepham-4-carboxylic acid derivatives of formula Iwherein R″ is 4-methoxybenzyl, X is the residue of a thioether and Z is a residue of a nucleophilic compound, such as 2-furoylthio, acetoxy or 1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-1,2,4-triazin-3-ylthio, by reaction of a functional derivative of α-(2-chloroacetamido)thiazol-4-yl-α-methoxyiminoacetic acid with 7β-amino-3-methylenecepham-4-carboxylic acid 4-methoxybenzyl ester, subsequent treatment of the obtained 4-methoxybenzyl 7β-[α-(2-chloroacetamido)thiazol-4-yl-α-methoxyimino]acetamido-3-methylenecepham-4-carboxylate with a S-chloromercaptan of formula X—S—Cl, such as methanesulfenyl chloride, and final treatment of the corresponding 4-methoxybenzyl 7β-[α-(2-chloroacetamido)thiazol-4-yl-α-methoxyimino]acetamido-3-thio-3-chloromethylcepham-4-carboxylate thus obtained of formula Vwherein R″ and X are as defined above, with a compound of formula M-Z, in which M is an alkaline metal or a hydrogen atom and Z is as defined above. These novel intermediates may be converted into the corresponding 3-cephem derivatives by oxidative cleavage of the mercaptan X—SH. By suitable deprotection, these 3-cephem derivatives afford cephalosporins such as ceftiofur, cefotaxime and ceftriaxone.