瑞戈非尼的合成工艺优化  

Synthetic Process Improvement of Regorafenib

作　　者：甘勇军[1] 王以武[1] 张量 徐启贵[2] GAN Yongjun;WANG Yiwu;ZHANG Liang;XU Qigui(Experimental Teaching Center,Chongqing Medical University,Chongqing 401331;College of Pharmacy,Chongqing Medical University,Chongqing 400016)

机构地区：[1]重庆医科大学实验教学中心,重庆401331 [2]重庆医科大学药学院,重庆400016

出　　处：《中国医药工业杂志》2020年第2期196-199,共4页Chinese Journal of Pharmaceuticals

基　　金：重庆医科大学实验教学管理中心“MTS”项目(LTMC201906)给予资助.

摘　　要：本研究对抗肿瘤药瑞戈非尼(1)的合成工艺进行优化。4-氯吡啶-2-甲酸甲酯(3)与甲胺反应得4-氯-N-甲基吡啶-2-甲酰胺(4)。以四丁基溴化铵为催化剂,4与4-氨基-3-氟苯酚(5)在二(口恶)烷中反应得4-(4-氨基-3-氟苯氧基)-N-甲基吡啶-2-甲酰胺(6)。三光气与4-氯-3-三氟甲基苯胺(7)在甲苯和吡啶中反应得4-氯-3-(三氟甲基)苯异氰酸酯(8)。6与8在乙酸乙酯中缩合得瑞戈非尼无水物(2),2在氯化氢的乙酸乙酯溶液作用下成盐酸盐,再在丙酮/水中加入碳酸氢钠转化为1,纯度99.8%。优化后的工艺反应条件温和,操作简单,总收率65%(以3计),较适合工业生产。An improved synthetic process of regorafenib(1), an antineoplastic drug, was reported. Methyl 4-chloropyridine-2-carboxylate(3) reacted with methylamine to obtain 4-chloro-N-methylpyridine-2-formamide(4). Compound 4 reacted with 4-amino-3-fluorophenol(5) in 1,4-dioxane with tetrabutylammonium bromide as the catalyst to give 4-(4-amino-3-fluorophenoxy)-N-methylpyridine-2-formamide(6). Triphosgene reacted with 4-chloro-3-(trifluoromethyl)aniline(7) in toluene and pyridine to give 4-chloro-3-(trifluoromethyl)phenyl isocyanate(8). Condensation of 6 and 8 in ethyl acetate gave regorafenib anhydrous(2). Compound 2 was treated with hydrogen chloride in ethyl acetate solution, followed by transformation in acetone/water mixture by adding NaHCO3 to give 1 with a purity of 99.8%. This improved process had mild reaction conditions and simple operations, and the total yield was 65%(based on compound 3). It could be more suitable for industrial production.

关 键 词：瑞戈非尼 抗肿瘤药 合成 工艺优化 

分 类 号：R979.1[医药卫生—药品]