Study On The Synthetic Technology Of Mehyoxy Cephalosporins7-MAC

Cephamycin antibiotics have been widely used in clinical treatment of diseases whichwere caused by pathogenic bacteria. Because of7α-methoxylation group on the cephemnucleus, these drugs were resistant to β-lactamase and belonged to the enzyme-resistantantibiotics. The development of Cephamycin antibiotics was described in the paper. Thesynthetic processes of the key intermediate7β-Amino-7α-Methoxy-3-[(1-methyl-1H-tetrazo-5-yl)thiomethyl]-3-Cephem-4-carboxylic acid diphenylmethyl ester(7-MAC) inpreparation of Cephamycin antibiotics was researched. After investigation of a series ofsynthetic routes of7-MAC, the synthetic processes were improvement. Based on thecompleted experiments of small-scale and pilot-scale amplification, the best syntheticprocesses had been determined which was easy to operate on industrial scale.The reported synthetic methods of7-MAC were analyzed and discussed in this study.The synthetic processes of7-MAC was determined and established by small-scaleexperiments.7-Amino-3-[(1-methyl-1H-tetrazo-5-yl)thiomethyl]-3-Cephem-4-carboxylicacid(7-TMCA) was synthesized by7-Aminocephalosporanic acid (7-ACA) by nucleo-philic-substitution of3-acyloxyl group in cephem nucleus with5-mercapto-1-methyl-1H-tetrazole.7-Methylsulfeninmine-3-[(1-methyl-1H-tetrazo-5-yl)thiomethyl]-3-Cephem-4-carboxylic acid diphenylmethyl ester(intermediateⅠ) was synthesized from7-TMCAby substituted-elimination of7-amino to form the structure of sulfeninmine precursors inthe presence of methylsulfenyl bromide, esterification of4-carboxylic acid withdiphenyldiazomethane. Finally7-MAC was obtained from intermediateⅠ after the groupof methloxy was introduced in the presence of triphenylphosphine and aluminumtrimethoxide. The total yield was over60%, higher than the literature reported; the purityof the product was higher than99%(HPLC), the transmitance was higher than75%. Thechemical structure of7-MAC had been characterized by means of1H-NMR and IR.Based on the results of the small-scale experiments, the synthesis process of thepilot-scale experiments were followed and it was proved to be validated. The stability andmaneuverability of the synthesis process in industrial scale production was further toverified in a plant trial production, the results proved feasible and laid technicalfoundation for the commercial batch production of7-MAC.