奥氮平原料药中相关杂质的合成及结构鉴定  

Synthesis and structure identification of impurities in bulk drugs olanzapine

作　　者：李玲[1] 赵世明[1] 张丹[2] 罗振福[1] 

机构地区：[1]天津药物研究院,天津300193 [2]天津理工大学化学化工学院,天津300384

出　　处：《中国药物化学杂志》2013年第3期194-196,202,共4页Chinese Journal of Medicinal Chemistry

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 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 E 2,3-b ] E 1,5 ] benzodiazepine hydro- chloride; 1-Chloromethyl-1 -methyl-4- （ 2-methyl-10H-benzo [ b ] thieno [ 2,3-e ] [ 1,4 ] diazepin-4-yl ） pipera- zin-l-ium chloride （ 2 ） was prepared by mixing olanzapine and dichloromethane; 2-Methyl-4-（ 4-meth- ylpiperazin-1 -yl） -10H-benzo [ b ] thieno [ 2,3-e ] E 1,4 ] diazepine 4＇-N-oxide （ 3 ） was obtained by oxidation of olanzapine. Their structures were confirmed by ~H-NMR, 13 C-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.

关 键 词：奥氮平 杂质 化学合成 结构鉴定 

分 类 号：R914[医药卫生—药物化学]