盐酸乌拉地尔的新合成工艺研究  

Study on the Synthetic Process of Urapidil Hydrochloride

作　　者：王栋 蒋海婷 罗鹏 陆俊 王玲[2] 李友军 金悦 WANG Dong;JIANG Haiting;LUO Peng;LU Jun;WANG Ling;LI Youjun;JIN Yue(Research and Development Dept.,Jiangsu Run’an Pharmaceutical Co.,Ltd.,Huai’an 223299;Research Institute,Jiangsu Chiatai Qingjiang Pharmaceutical Co.,Ltd.,Huai’an 223001)

机构地区：[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

出　　处：《中国医药工业杂志》2024年第4期501-505,共5页Chinese Journal of Pharmaceuticals

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、^(1)H NMR、^(13)C 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。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,^(1)H NMR,^(13)C 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 Α受体阻滞剂 N N-羰基二咪唑 合成 

分 类 号：R972.4[医药卫生—药品]