盐酸乌拉地尔的新合成工艺研究
Study on the Synthetic Process of Urapidil Hydrochloride
王栋 1蒋海婷 1罗鹏 1陆俊 2王玲 2李友军 1金悦1
作者信息
- 1. 江苏润安制药有限公司研发部,江苏淮安 223299
- 2. 江苏正大清江制药有限公司研究所,江苏淮安 223001
- 折叠
摘要
以3-[(叔丁氧羰基)氨基]丙酸(2)和1-(2-甲氧基苯基)哌嗪盐酸盐(3)为起始原料,通过活性酯法进行酰胺合成,得[3-[4-(2-甲氧基苯基)哌嗪-1-基]-3-氧代丙基]氨基甲酸叔丁酯(4),再经脱保护得3-[4-(2-甲氧基苯基)哌嗪-1-基]丙胺三盐酸盐(6盐酸盐),最后与6-氯-1,3-二甲基尿嘧啶-2,4(1H,3H)-二酮(7)缩合得盐酸乌拉地尔(1盐酸盐).目标产物经HPLC、1H NMR、13C NMR、MS和元素分析确证.总收率达61.2％(以2计),纯度99.95％.改进后的工艺解决了关键中间体6国产化的技术难题,适合工业化生产.
Abstract
With 3-[(tert-butoxycarbonyl)amino]propanoic acid(2)and 1-(2-methoxyphenyl)piperazine hydrochloride(3)as starting materials,tert-butyl[3-[4-(2-methoxyphenyl)piperazin-1-yl]-3-oxopropyl]carbamate(4)was obtained by active ester method.3-[4-(2-Methoxyphenyl)piperazin-1-yl]propylamine trihydrochloride(6 hydrochloride)was prepared by the reduction of 4 followed by removing the Boc protective group.Finally,6 was condensed with 6-chloro-1,3-dimethylpyrimidine-2,4(1H,3H)-dione(7)to obtain the title compound with an overall yield of above 61.2％(based on 2)and a purity of 99.95％.The target product was confirmed by HPLC,1H NMR,13C NMR,MS and elemental analysis.The improved process is suitable for industrial production as it solves the technical problem of localization of key intermediate 6.
关键词
乌拉地尔/a受体阻滞剂/N,N-羰基二咪唑/合成Key words
urapidil/α receptor blocker/N,N-carbonyldiimidazole/synthesis引用本文复制引用
出版年
2024
NETL
NSTL
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