盐酸吡西卡尼的合成工艺优化  

Improved Synthetic Method of Pilsicainide Hydrochloride

作　　者：张翅 潘德林 李瑞煜[1] 吴建国 朱雅宁 

机构地区：[1]华润三九(雅安)药业有限公司,四川雅安625000 [2]成都中医药大学中药资源系统研究与开发利用省部共建国家重点实验室培育基地,四川成都611137

出　　处：《中国医药工业杂志》2018年第3期309-311,共3页Chinese Journal of Pharmaceuticals

摘　　要：本研究对盐酸吡西卡尼(1)的合成工艺进行了优化。采用价廉易得的四氢-1H-吡咯里嗪-7a(5H)-乙酸盐酸盐(2)为起始原料,经酰氯化反应生成四氢-1H-吡咯里嗪-7a(5H)-乙酰氯盐酸盐(3),不经分离,直接与2,6-二甲基苯胺反应生成吡西卡尼(5)。化合物2的氮原子经盐酸保护后,可有效减少副反应的发生,提高化合物5的纯度(99%)。化合物5与盐酸成盐后,经无水乙醇/乙醚重结晶精制得到目标化合物1,总收率45.5%(以2计),纯度99.9%。优化后的工艺反应条件温和,成本低,收率高,革除了柱色谱的使用,操作简便,易于工业化生产。The synthetic process of pilsicainide hydrochloride （1） was improved. Tetrahydro-lH-pyrrolizine- 7a（5H）-acetic acid hydrochloride （2） reacted with thionyl chloride to give tetrahydro-lH-pyrrolizine-7a（5H）-acetyl chloride hydrochloride （3）. Then compound 3 was subjected to the condensation with 2,6-dimethylaniline directly to afford pilsicainide （5）. The nitrogen atom in compound 2 was protected by hydrochloric acid, which can effectively reduce the side reaction and improve the purity of compound 5 to 99 %. Finally, the target compound was obtained via salification of compound 5 and crystallization in ethanol/diethyl ether with an overall yield of 45.5 %, and a purity of 99.9 %. The improved synthetic route had some advantages, such as mild reaction conditions, low cost, high yield, and simple work-up, etc., which was more feasible for industrial production.

关 键 词：盐酸吡西卡尼 四氢-1H-吡咯里嗪-7a(5H)-乙酸盐酸盐 2 6-二甲基苯胺 工艺优化 

分 类 号：R972.2[医药卫生—药品] R914.5[医药卫生—药学]