奥氮平原料药中相关杂质的合成及结构鉴定

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]苯二氮杂革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]苯二氮杂革-4-(5H)-酮(1)、1-氯甲基-1-甲基-4-(2-甲基-10H-苯并[b]噻吩并[2,3e][1,4]二氮杂革-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]二氮杂革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1HNMR、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 qua lity control and research.2-Methyl-10H-thieno [2,3-b] [1,5] benzodiazepin-4 (5H)-one (1) was prepared by alkaline hydrolysis of intermediate 4-amino-2-methyl-10H-thiene [2,3-b] [1,5] benzodiazepine hydrochloride; 1-Chloromethyl-1-methyl-4-(2-methyl-10H-benzo [b] thieno [2,3-e] [1,4] diazepin-4-yl) piperazin-l-ium chloride (2) was prepared by mixing olanzapine and dichloromethane; 2-Methyl-4-(4-methylpiperazin-1-yl)-10H-benzo [b] thieno [2,3-e] [1,4] diazepine 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.