盐酸罂粟碱降解有关物质的合成  

Synthesis of Impurities from Degradation of Papaverine Hydrochloride

作　　者：郑志波 彭朋[1] 李颖 胡江渊 张福利[4] 赵传猛[4] ZHENG Zhibo;PENG Peng;LI Ying;HU Jiangyuan;ZHANG Fuli;ZHAO Chuanmeng(Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals,Zhejiang University of Technology,Hangzhou 310014;School of Pharmacy,Fudan University,Shanghai 201203;Shisenhai(Hangzhou)Biopharmaceutical Co.,Ltd.,Hangzhou 311404;Shanghai Institute of Pharmaceutical Industry Co.,Ltd.,China State Institute of Pharmaceutical Industry Co.,Ltd.,Shanghai 201203)

机构地区：[1]浙江工业大学长三角绿色制药协同创新中心,浙江杭州310014 [2]复旦大学药学院,上海201203 [3]时森海(杭州)生物制药有限公司,浙江杭州311404 [4]中国医药工业研究总院有限公司,上海医药工业研究院有限公司,上海201203

出　　处：《中国医药工业杂志》2023年第9期1330-1336,共7页Chinese Journal of Pharmaceuticals

摘　　要：在考察盐酸罂粟碱原料药稳定性的过程中,经强制降解试验发现了6种有关物质,其中有关物质1~4未被各药典收录。以相应的去甲基胺或酸为起始原料,经缩合、环合、还原、脱氢4步反应,分别可得罂粟碱中4个甲氧基分别脱去1个甲基的产物:1-(3,4-二甲氧基苄基)-6-羟基-7-甲氧基异喹啉(有关物质1)、1-(3,4-二甲氧基苄基)-6-甲氧基-7-羟基异喹啉(有关物质2)、1-(3-羟基-4-甲氧基苄基)-6,7-二甲氧基异喹啉(有关物质3)、1-(3-甲氧基-4-羟基苄基)-6,7-二甲氧基异喹啉(有关物质4)。另外合成了《欧洲药典》收录的(6,7-二甲氧基异喹啉-1-基)-(3,4-二甲氧基苯基)甲酮(IMP-D)和(6,7-二甲氧基异喹啉-1-基)-(3,4-二甲氧基苯基)甲醇(IMP-B)。这6个化合物均经^(1)H NMR、^(13)C NMR和HRMS确证结构。In the process of stability investigation of papaverine hydrochloride,6 compounds were founded in forced degradation experiment.Among them,the related substances 1-4 were not indexed in pharmacopoeias.1-(3,4-Dimethoxybenzyl)-6-hydroxy-7-methoxyisoquinoline(related substance 1),1-(3,4-dimethoxybenzyl)-6-methoxy-7-hydroxyisoquinoline(related substance 2),1-(3-hydroxy-4-methoxybenzyl)-6,7-dimethoxyisoquinoline(related substance 3),and 1-(3-methoxy-4-hydroxybenzyl)-6,7-dimethoxyisoquinoline(related substance 4)were obtained via condensation,cyclization,reduction and dehydrogenation with the corresponding demethylamine or acid as starting materials.Besides,two compounds,as the impurities indexed in European pharmacopoeia,(6,7-dimethoxy-1-isoquinolyl)-(3,4-dimethoxyphenyl)ketone(IMP-D)and(6,7-dimethoxy-1-isoquinoline)-(3,4-dimethoxyphenyl)methanol(IMP-B)were synthesized.The structures of these 6 compounds were confirmed by^(1)H NMR,^(13)C NMR and HRMS.

关 键 词：盐酸罂粟碱 强制降解 有关物质 

分 类 号：TQ460.6[化学工程—制药化工]