尼罗替尼的合成  

Synthesis of Nilotinib

作　　者：陈永江[1] 王丽华[2] 周红[1] 王从站 

机构地区：[1]江苏恒瑞医药股份有限公司,江苏连云港222002 [2]连云港市第四人民医院,江苏连云港222023

出　　处：《中国医药工业杂志》2009年第6期401-403,411,共4页Chinese Journal of Pharmaceuticals

摘　　要：5-溴-3-三氟甲基苯胺和4-甲基-1H-咪唑在碳酸铯和碘化亚铜作用下缩合,得到3-三氟甲基-5-(4-甲基-1H-咪唑-1-基)苯胺(4)。另用3-氨基-4-甲基苯甲酸乙酯(5)与氨腈成胍6,6与3-二甲胺基-1-(3-吡啶基)-2-丙烯-1-酮环合得4-甲基-3-[[4-(3-吡啶基)-2-嘧啶基]氨基]苯甲酸乙酯(8),8经叔丁氧羰基保护、水解,再与4经酰胺化、脱保护后得到尼罗替尼,总收率40%(以5计)。The 5-bromo-3- （trifluoromethyl） phenylamine was reacted with 4-methyl- 1H-imidazole in presence of cesium carbonate and cuprous iodide to obtain 3-trifluoromethyl-5-（4-methyl-lH-imidazol-1- yl） phenylamine （4）. Ethyl 3-amino-4-methyl benzoate （5） was reacted with cyanamide to obtain the guanidine 6, which cyclized with 3-dimethylamino- 1- （3-pyridinyl） -2-propylene- 1-one to provide ethyl 4-methyl-3- [ [4- （3-pyridinyl） - 2-pyrimidinyl] amino] benzoate （8）. Compound 8 was subjected to Boc protection, hydrolysis, amidation and then condensation with compound 4 to give 4-methyl-N-[3-（4-methyl-1H-imidazol-l-yl）-5-（trifluoromethyl）phenyl]-3-[N- tert-butoxycarbonyl- [4- （3-pyridinyl） -2-pyrimidinyl] amino] benzamide （10）. After deprotection, the antitumor agent nilotinib was obtained with an overall yield of 40% based on compound 5.

关 键 词：尼罗替尼 酪氨酸激酶抑制剂 慢性粒细胞白血病 抗肿瘤药 合成 

分 类 号：R979.12[医药卫生—药品]