Study On The Synthetic Process Of 7-AVCA And 7-ACCA

Nowadays, cephalosporin antibiotics have been widely used in clinical treatment of disease which were caused by pathogenic bacteria, and they have been developed into the fourth-generation. Cefdinir and Cefixime belong to the third-generation cephalosporins, and they are widely used for their potent antibiotic activity with broad spectrum and resistance to beta-lactamases. Cefaclor belongs to the second-generation cephalosporins, and it is also in great demand for its potent biological activity. 7-amino-3-vinyl-4-cephalo- sporanic acid (7-AVCA) is the key intermediate in preparation of Cefdinir and Cefixime, 7-amino-3-chloro-3-cephem-4-carboxylic acid (7-ACCA) is the intermediate in the synthesis of Cefaclor. The synthetic methods of 7-AVCA and 7-ACCA were investigated in this paper.7-phenylacetamide-3-vinyl-4–cephalosporanic acid p-methoxybenzyl ester (GVNE) , which was an intermediate of 7-AVCA was synthesized from 7-phenylacetamide-3-chloro- methyl-4–cephalosporanic acid p-methoxybenzyl ester (GCLE) by the Wittig reaction. Then GVNE was hydrolyzed with phenol solution catalyzed by phosphoric acid to remove the carboxyl protecting group, and 7-phenylacetamide-3-vinyl-4–cephalosporanic acid was synthesized, not separated, 7-phenylacetamide-3-vinyl-4–cephalosporanic acid was enzymatic hydrolyed to remove the amino protecting group, and 7-AVCA was obtained. The total yield was 75% and the purity of the product was higher than 99.1%(HPLC).7-phenylacetamide-3-hydroxy-3-cephem-4–carboxylic acid diphenylmethyl ester (3-hydroxycephem) was synthesized from ENM by bromination, hydrolysis and cyclization. The complex of 3-hydroxycephem and toluene was obtained by the recrystallization of 3-hydroxycephem in toluene solution. 3-hydroxycephem toluene complex was further chlorined with PCl3 in DMF solution to give 7-phenylacetamide-3- chloro-3-cephem-4–carboxylic acid diphenylmethyl ester. The obtained product was hydrolyzed and enzymatic hydrolyed to deprotect the carboxyl protecting group and the amino protecting group, and 7-ACCA was obtained. The total yield was 63% and the purity of the product was higher than 98.6%(HPLC).The chemical structures of 7-AVCA and 7-ACCA had been characterized by IR and 1H-NMR.