Synthesis Of The Intermediate Of Cephalosporins-Cefditoren Pivoxil

Cefditoren pivoxil is an oral third generation cephalosporin with broad-spectrum against bacteria.It is stable to ?-lactam enzyme and especially has obvious activity to entero-bacteriaceae.7-Amino-3-[Z-2-(4-methylthiazol-5-yl)vinyl]-3-cephen-4-carboxylic acid(abbreviated as 7-ATCA),which is the key intermediate of Cefditoren pivoxil,was researched in this paper.The aim of this paper was to optimize pivotal steps by a series of experiments including solvent and temperature of Wittig reaction,the amount of sodium iodide,the amount of 4-methyl-5-thiazolaldehyde,reagents of removing protection group,the system of enzyme reaction and to reach the optimal condition at last.In addition,the key point in this paper was to remove the p-methoxybenzyl ester of 4-position by hydrolyzation and some reagents such as anhydrous aluminum trichloride,phenol,methanesulfonic acid,tirfluoroacetic acid,trichloroacetic acid,anhydrous formic acid and the like were tried.Finally trichloroacetic acid was the best choice due to gaining a good yield and being easy to recycle for further use,the recovery of trichloroacetic acid was 89%.The whole route had lower cost and fewer pollution to environment.7-Phenylacetamide-3-[2-(4-methyl-5-thiazolyl)vinyl]-3-cephem-4-carboxylic acid p-methoxybenzyl ester(abbreviated as MPMC)was synthesized from 7-phenylacetamide-3-chloromethyl-4-cephalospranic acid p-methoxybenzyl ester(GCLE)by Wittig reaction to introduce 4-methyl-5-thiazolyl.Then MPMC was hydrolyzed with trichloroacetic acid to remove 4-position protective group of p-methoxybenzyl alcohol to give 7-phenylacetamide-3-[2-(4-methyl-5-thiazolyl)vinyl]-3-cephem-4-carboxylic acid(abbreviated as 7-PMCA).7-PMCA was transformed to a salt with dicyclohexylamine and the salt was hydrolyzed by penicillin acylase enzyme(abbreviated as PGA)to remove the phenylacetic acid to obtain 7-ATCA.The total yield was 55%.7-ATCA was characterized by 1H NMR.The purity of Z-isomer of 7-ATCA was 97%and E-isomer was 1.0%according to HPLC(peak area normalization method).4-Methyl-5-thiazolaldehyde was synthesized from 2-ethanoyl-?-butyrolactone by a series of experiments.The yield was 20%.The purity was 99.3%by GC(peak area normalization method).