对甲苯磺酸索拉非尼的合成工艺改进  

Improvement of the Synthesis Technology of Sorafenib Tosylate

作　　者：赵泉[1] 罗兰[2] 杨逸[2] 甘勇军[3] 王以武[3] 

机构地区：[1]重庆医科大学附属大学城医院,重庆401331 [2]重庆医科大学药学院,重庆401331 [3]重庆医科大学实验教学管理中心,重庆401331

出　　处：《中国药房》2015年第34期4795-4797,共3页China Pharmacy

摘　　要：目的:改进对甲苯磺酸索拉非尼(Ⅰ)的合成工艺。方法:以2-吡啶甲酸为原料,经卤化、酰胺化得N-甲基-4-氯吡啶-2-甲酰胺(Ⅳ);4-氯-3-(三氟甲基)苯胺(Ⅴ)在引发剂三乙胺作用下活化后直接与对氨基苯酚反应得N-[4-氯-3-(三氟甲基)-苯基]-N′-4-(羟基苯基)脲(Ⅶ);在叔丁醇钾作用下,Ⅳ与Ⅶ反应得索拉非尼,再成盐得目标化合物,并对其进行核磁共振(1H-NMR)表征。结果:表征确证制得目标化合物Ⅰ,总收率约74%[以4-氯-3-(三氟甲基)苯胺计],色谱纯度为94%。工艺优化后提高了收率,简化了多步中间体减压蒸馏纯化过程,添加引发剂缩短了反应时间。结论:成功合成Ⅰ,且原料易得、操作简便、收率较高。OBJECTIVE：To improve the synthesis technology of sorafenib tosylate（Ⅰ）. METHODS：The intermediate Nmethyl-（4-chlorpyridin-2-yl）carboxamide（Ⅳ）was obtained by chlorination and amidation with 2-picolinic acid as the starting compound. Meanwhile,N-[4-chloro-3-（triflouromethyl）phenyl]-N′-（4-hydroxyphenyl）urea（Ⅶ） was prepared from aminophenol and4-chloro-3-trifluoromethyl phenyl isocyanate,which was obtained from 4-chloro-3-（trifluoromethyl）aniline（Ⅴ）by reaction with initiator triethylamine. Sorafenib tosylate was synthesized from Ⅳ and Ⅶ with potassium tert-butoxide by condensation and salt formation. The target compound was characterized by1H-NMR. RESULTS：The target compound was confirmed as Ⅰ,with the overall yield of 74% [based on 4-chloro-3-（trifluoromethylanilin）]. The purification of chromatogram was 94%. Optimized technology improves yield and simplifies multi-step intermediate decompression,distillation and purification process;the application of initiator shortens the duration of reaction. CONCLUSIONS：Ⅰ is prepared successfully,and raw material can be obtained easily and is easy to operate with high yield.

关 键 词：甲苯磺酸索拉非尼 合成 改进 核磁共振 

分 类 号：R413[医药卫生—临床医学]