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.
作者
王栋
蒋海婷
罗鹏
陆俊
王玲
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)
出处
《中国医药工业杂志》
EI
CAS
CSCD
2024年第4期501-505,共5页
Chinese Journal of Pharmaceuticals
