Study On Synthesis Of Several Pazufloxacin Impurities

Pazufloxacin, marketed in 2002 in Japan at first, was jointly developed by Mitsubishi Pharma Corporation and Toyama Chemical Co., Ltd.. It was one kind of broad-spectrum and efficient fluoroquinolones. There was a wide range of application for its antibacterial effect. In recent years, the systems of new drug approval and old drug review were gradually improved in China. Thus it has become necessary to study the Production and Quality management to decrease adverse drug reactions.This paper mainly aimed at serial synthetic researches of pazufloxacin impurities. These impurities were might yielded in production, storage and application of pazufloxacin. Based on the research literature about pazufloxacin synthesis, this paper mainly focused on the studies of pazufloxacin and key intermediates P-1 and P-2. We designed several synthetic routes of pazufloxacin impurities. Faced with multifarious reaction steps, we screened different reaction conditions:kinds and amounts of the solvent, reaction temperature, form and equivalent of the additives, etc. Reaction system were optimized to obtain the best technics.1) Pazufloxacin, the starting material, was transformed into impurity B-4, by acetylation reaction.2) The key intermediate P-B was prepared through acid hydrolysis reaction of intermediate P-1. With intermediate P-B in hand, the key intermediate P-A was obtained via oxidative hydrolysis reaction. The target impurity P-1’was finally yielded via Hofmann degradation reaction from intermediate P-A.3) Starting from intermediate P-2, the key intermediate P-3 was prepared via cyano nucleophilic substitution reaction. With intermediate P-3 as raw material, impurities D-9, D-7 and D-1 were obtained through various degrees of hydrolysis reactions.According to screened reaction conditions, we got appropriate amounts of pazufloxacin impurities samples. This would provide raw materials and scientific bases for the following researches.