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目的研究分子靶向抗肿瘤药对甲苯磺酸索拉非尼(1)的简便合成工艺。方法以3-三氟甲基-4-氯苯胺(2)为起始原料,首先在三光气的二氯甲烷或2-甲基四氢呋喃溶液中,在二异丙基乙基胺存在下,制得相应的异氰酸酯(2′);然后在二异丙基乙基胺存在下,与4-(4-氨基苯氧基)-N-甲基-2-吡啶甲酰胺(3)成脲,一锅法合成索拉非尼(4);最后与对甲苯磺酸成盐得到目标化合物。结果以二氯甲烷为溶剂,使用安全易得的三光气,制得索拉非尼的收率为84%,目标物的收率为91%;以绿色溶剂2-甲基四氢呋喃替代二氯甲烷,制得索拉非尼的收率为85%,目标物的收率为96%。结论该工艺路线操作简便,反应时间短,无需分离高反应活性的中间体,收率较高,绿色环保。
Objective To study the simple and convenient synthesis of sorafenib tosylate (1). Methods Starting from 3-trifluoromethyl-4-chloroaniline (2), the title compound was prepared from triphosgene in dichloromethane or 2-methyltetrahydrofuran in the presence of diisopropylethylamine (2 ’); then with 4- (4-aminophenoxy) -N-methyl-2-pyridinecarboxamide (3) in the presence of diisopropylethylamine, Sorafenib (4) was synthesized by pot method. The target compound was obtained by salt formation with p-toluenesulfonic acid. The results showed that the yield of sorafenib was 84% and the yield of the target product was 91% using methylene chloride as solvent and triphosgene, which was safe and readily available. The methylene chloride , The yield of sorafenib was 85%, and the target yield was 96%. Conclusion The process route is easy to operate, the reaction time is short, without separation of high reactivity intermediate, high yield, green.