新型止吐药枸橼酸马罗匹坦的合成  

Synthesis of a New Antiemetic Drug Maropitant Citrate

作　　者：崔俊然 朱明霞 王召卓 黄玮 甄丹宁 付德才[1] CUI Junran;ZHU Mingxia;WANG Zhaozhuo;HUANG Wei;ZHEN Danning;FU Decai(College of Chemical and Pharmaceutical Engineering,Hebei University of Science and Technology,Hebei Shijiazhuang 050018,China)

机构地区：[1]河北科技大学化学与制药工程学院,河北石家庄050018

出　　处：《河北师范大学学报（自然科学版）》2022年第2期182-187,共6页Journal of Hebei Normal University：Natural Science

基　　金：江苏省自然科学基金(BK20191296);中央高校业务费(2019B19114)。

摘　　要：以3奎宁酮盐酸盐和苯甲醛为原料,经羟醛缩合、迈克尔加成、构型转化,制备(2S)-二苯甲基奎宁-3-酮(6);化合物6与苄胺形成亚胺经铂碳催化氢化还原,用L-樟脑磺酸成盐纯化,钯碳催化氢化脱除苄基,制备关键中间体(2S,3S)-2-二苯甲基奎宁-3-胺(10).化合物10与2-甲氧基-5-叔丁基苯甲醛形成相应亚胺,经硼氢化试剂还原,得到马罗匹坦粗品,经L-樟脑磺酸成盐纯化,再与枸橼酸成盐制得枸橼酸马罗匹坦.优化了反应条件,对各步反应后处理、纯化步骤进行了改进,制备了高纯度的药用目标化合物,工艺操作简单,适合工业化生产.目标化合物结构经质谱和核磁共振氢谱确证,总收率约为20%,纯度为99.9%(HPLC).Using 3-quinone hydrochloride and benzaldehyde as raw materials,(2S)-benzhydrylquinine-3-one(6) was prepared through aldol condensation, Michael addition, and configuration transformation.The imine formed from compound 6 and benzylamine was reduced by Platinum-carbon catalytic hydrogenation, and then further purified by salting with L-camphorsulfonic acid.And the key intermediate(2S,3S)-2-benzhydryl-quinine-3-amine(10) was prepared by Palladium-carbon catalytic hydrogenation to remove benzyl group.The crude maropiptan was synthesised by reducing the imine which was formed by compound 10 and 2-methoxy-5-tert-butylbenzaldehyde.The high-purity maropitant citrateIt was obtained in the mixture of acetone, water and methyl tert-butyl ether after purifing by salt formation with L-camphorsulfonic acid.The synthetic route has been optimized to make the work-up process simple and more suitable for industrial production.The chemical structure of target compound was confirmed by ESI-MS and ^(1)HNMR,and the total yield was 20 % and the purity was 99.9 %(HPLC).

关 键 词：止吐药 枸橼酸马罗匹坦 3-奎宁酮盐酸盐 NK-1受体拮抗剂 

分 类 号：R914[医药卫生—药物化学]