奥氮平原料药中相关杂质的合成及结构鉴定
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摘要
目的合成奥氮平原料药中的相关杂质并进行结构鉴定。方法分别以奥氮平的合成中间体4-氨基-2-甲基-10H-噻吩并[2,3-b][1,5]苯二氮杂艹卓盐酸盐和奥氮平为起始原料合成奥氮平的3个相关杂质:2-甲基-10H-噻吩并[2,3-b][1,5]苯二氮杂艹卓-4-(5H)-酮(1)、1-氯甲基-1-甲基-4-(2-甲基-10H-苯并[b]噻吩并[2,3-e][1,4]二氮杂艹卓-4-哌嗪基)-1-氯化物(2)和2-甲基-4-(4-甲基-1-哌嗪基)-10H-苯并[b]噻吩并[2,3-e][1,4]二氮杂艹卓4'-N-氧化物(3)。结果与结论合成并鉴定了奥氮平质量标准中提及的3种杂质,其结构经1H-NMR、13C-NMR谱及高分辨质谱确证;并且探讨了3种杂质可能的产生途径,以期为奥氮平的质量研究和相关杂质的控制提供帮助。
Three impurities of olanzapine related to pharmacopoeia of USP and EP were synthesized for quality control and research.2-Methyl-10H-thienobenzodiazepin-4(5H)-one(1) was prepared by alkaline hydrolysis of intermediate 4-amino-2-methyl-10H-thienebenzodiazepine hydrochloride;1-Chloromethyl-1-methyl-4-(2-methyl-10H-benzo[b]thienodiazepin-4-yl) piperazin-1-ium chloride(2) was prepared by mixing olanzapine and dichloromethane;2-Methyl-4-(4-methylpiperazin-1-yl)-10H-benzo[b]thienodiazepine 4′-N-oxide(3) was obtained by oxidation of olanzapine.Their structures were confirmed by 1H-NMR,13C-NMR and high resolution-MS.Based on the structures of the impurities,the possible routes to them were discussed to improve the quality of olanzapine.
Three impurities of olanzapine related to pharmacopoeia of USP and EP were synthesized for quality control and research.2-Methyl-10H-thienobenzodiazepin-4(5H)-one(1) was prepared by alkaline hydrolysis of intermediate 4-amino-2-methyl-10H-thienebenzodiazepine hydrochloride;1-Chloromethyl-1-methyl-4-(2-methyl-10H-benzo[b]thienodiazepin-4-yl) piperazin-1-ium chloride(2) was prepared by mixing olanzapine and dichloromethane;2-Methyl-4-(4-methylpiperazin-1-yl)-10H-benzo[b]thienodiazepine 4′-N-oxide(3) was obtained by oxidation of olanzapine.Their structures were confirmed by 1H-NMR,13C-NMR and high resolution-MS.Based on the structures of the impurities,the possible routes to them were discussed to improve the quality of olanzapine.
引文
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[5]GYORGYI K L,GABOR N,GYORGY K,et al.Process for the preparation of olanzapine:HU,20050001046[P].2005-11-11.
[2]LEYVA-PEREZ A,CABREEO-ANTONINO J R,CORMA A.Bifunctional solid catalysts for chemose-lective hydrogenation-cyclisation-amination cascadereactions of relevance for the synthesis of pharmaceu-ticals[J].Teteahedron,2010,66(41):8203-8209.
[3]ZBIGNIEW M,TOMASZ S.A process for the prepa-ration of a pharmaceutically pure polymorphic formⅡof olanzapine:AU,2003292452[P].2003-12-15.
[4]CALLIGARO D O,FAIRGURST J,HOTTEN T M,et al.The synthesis and biological activity of someknow n and putative metabolites of the atypicalantipsychotic agent olanzapine(LY170053)[J].Bioorg Med Chem Lett,1997,7(1):25-30.
[5]GYORGYI K L,GABOR N,GYORGY K,et al.Process for the preparation of olanzapine:HU,20050001046[P].2005-11-11.