吡仑帕奈原料药有关物质研究

A study of the potentially related substances of perampanel

目的研究吡仑帕奈原料药的有关物质来源与合成方法,为产品质量控制提供依据和有关物质对照品。方法根据文献公开报道的吡仑帕奈大规模制备工艺路线和吡仑帕奈分子结构特点,分析吡仑帕奈原料药生产和储存过程中可能存在的有关物质;以2-甲氧基-5-溴吡啶为原料合成有关物质A^G、以2-氰基氯苯为原料合成有关物质H;利用高效液相色谱法建立吡仑帕奈有关物质的分析方法。结果分析了吡仑帕奈原料药可能存在的10个有关物质(A^J),合成了9个有关物质(A^I),并利用1H-NMR和MS进行了结构确证,各有关物质的纯度在99.0%或以上,初步建立了吡仑帕奈原料药有关物质的高效液相色谱分析方法。结论本研究可为吡仑帕奈原料药有关物质的合成提供技术方法,所建立的有关物质分析方法可以为生产吡仑帕奈原料药的质量控制提供参考。

Perampanel,an orally active,noncompetitive,selective AM PA receptor antagonist,is a clinical drug for treatment of epilepsy.In this paper the potentially related substances of perampanel were analyzed and synthesized.Based on a large-scale synthetic route,10 related substances（A-J） of perampanel were proposed.The related substances E,F and I are intermediates of perampanel.A and B are the ammonolysis and hydrolysis products of perampanel respectively,while C and D are the oxidation and decyanation pro-ducts of perampanel.G is a methyl esterification product of related substance B.H is produced by a self-coupling reaction of 2-（1,3,2-dioxaborinan-2-yl） benzonitrile（J）.The synthetic routes were designed to prepare these related substances（A-I）.By using 5-bromo-2-methoxypyridine as the starting material,D,E,F,I and perampanel were prepared.A and B were obtained by a reaction of perampanel with a mixture of SOCl2 and H2O.Perampanel was oxidized by H2O2 in Ac OH to prepare the related substance C.The structures of all related substances were confirmed by1H-NM R and M S.A preliminary HPLC analysis method of perampanel and related substances was also developed.These results lay a foundation for the development of perampanel API and pharmaceutical preparation.