一锅法制备抗肿瘤药对甲苯磺酸索拉非尼

One-pot synthesis of anticancer drug sorafenib tosylate

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。

Aim To develop a facile process for the molecular-targeted anticancer drug sorafenib tosylate（1）.Methods The target product was prepared from 4-chloro-3-trifluoromethylaniline（2）,which was transformed into the corresponding isocyanate（2′） in dichloromethane or 2-methyltetrahydrofunan solution of triphosgene in the presence of diisopropylethylamine.Then 2′ reacted with 4-（4-aminophenoxy）-N-methyl-2-pyridinecarboxamide（3） in the presence of diisopropylethylamine to give the unsymmetrical diaryl urea sorafenib（4） in one pot.Compound 4 was finally reacted with p-toluenesulfonic acid to deliver sorafenib tosylate（1）.Results Employing dichloromethane as the solvent and triphosgene as the safe and green substitute for highly toxic phosgene,sorafenib（4） was obtained in 84% yield,which was transformed into its tosylate 1 in 91% yield.The halogenated solvent was then successfully substituted in comparable yield of 85% by the green solvent 2-methyltetrahydrofunan to obtain 4,which was transformed into 1 in 96% yield.Conclusion This one-pot process of sorafenib（4） features simple operations,short reaction time,no separation of reactive intermediate,good yield and green chemistry.