瑞戈非尼合成工艺研究  

Synthesis Research of Regorafenib

作　　者：汤君 何广卫 张强 刘为中 刘毅[2] TANG Jun;HE Guang-wei;ZHANG Qiang;LIU Wei-zhong;LIU Yi(Hefei Industrial Pharmaceutical Institute Co., Ltd., Hefei 230601, China;Anqing Medical and Pharmaceutical College, Anqing 246052, China)

机构地区：[1]合肥医工医药股份有限公司,安徽合肥230601 [2]安庆医药高等专科学校,安徽安庆246052

出　　处：《合成化学》2022年第5期400-406,共7页Chinese Journal of Synthetic Chemistry

基　　金：国家“重大新药创制”科技重大专项(2012ZX09401006)。

摘　　要：4-氨基-3-氟苯酚(2)和4-氯-N-甲基吡啶-2-甲酰胺(3)经亲核取代反应制得4-(4-氨基-3-氟苯氧基)-N-甲基吡啶-2-甲酰胺(4);4与4-氯-3-三氟甲基异氰酸苯酯(5)缩合得4-[4-[[[4-氯-3-(三氟甲基)苯基]氨甲酰基]氨基]-3-氟苯氧基]-N-甲基吡啶-2-甲酰胺(6);6再用丙酮/水重结晶制得瑞戈非尼(1),其结构经^(1)H NMR、^(13)C NMR、MS(ESI)和元素分析确证,晶型与原研一致。按优化后的合成工艺进行公斤级规模放大,产品总收率48.5%(以3计),纯度99.86%。4-Amino-3-fluorophenol(2)reacted with 4-chloro-N-methylpyridine-2-formamide(3)to obtain 4-(4-amino-3-fluorophenoxy)-N-methylpyridine-2-formamide(4)through nucleophilic substitution.4-[4-[[[4-Chloro-3-(trifluoromethyl)phenyl]carbamoyl]amino]-3-fluorophenoxy]-N-methylpyridine-2-carboxamide(6)was obtained by condensation between compound 4 and 4-chloro-3-(trifluoromethyl)phenyl isocyanate(5),which was used to prepare the regorafenib(1)via recrystallization by acetone/H_(2)O.The structure was confirmed by ^(1)H NMR,^(13)C NMR,MS(ESI),and elemental analysis,and the crystalline form was consistent with the original research.According to the optimized synthetic process,kilogram-scale production has been achieved with total yield of 48.5%(based on compound 3),and purity of 99.86%.

关 键 词：瑞戈非尼 激酶抑制剂 合成 工艺研究 甲酰胺 亲核反应 

分 类 号：O62[理学—有机化学] R914.5[理学—化学]