对甲苯磺酸索拉非尼的合成

Synthesis of sorafenib tosylate

目的改进对甲苯磺酸索拉非尼的合成工艺,提高反应收率并简化操作。方法以吡啶-2-甲酸甲酯为起始原料,经氯代、甲胺化反应得到4-氯-N-甲基吡啶-2-甲酰胺,随后在氢氧化钾作用下于DMF溶剂中与对氨基苯酚钾盐反应生成4-(4-氨基苯氧基)-N-甲基吡啶-2-甲酰胺,最后与4-氯-3-(三氟甲基)苯胺在羰基二咪唑的作用下反应得到索拉非尼,再经成盐得到对甲苯磺酸索拉非尼。结果与结论目标化合物的总收率约为71.6%,其结构经核磁共振氢谱、质谱确证。该路线操作简便、条件温和、有利于工业化生产。

Sorafenib tosylate is marketed as Nexavar by Bayer for the treatment of advanced renal cell carcinoma. The synthetic route to sorafenib tosylate for industrial manufacturing was optimized. Methyl picolinate was transformed to 4-chloro-N-methylpicolinamide by chlorination and methylamination. The reaction of 4- chloro-N-methylpicolinamide with potassium 4-aminophenolate in DMF using KOH as the base produced 4- （4-aminophenoxy）-N-methylpicolinamide, which was transformed to sorafenib base after the reaction with 4-chloro-3-（trifluoromethyl） aniline in the presence of CDI. Sorafenib tosylate was finally synthesized after salt formation with an overall yield of about 71.6%. The structure of sorafenib tosylate was characterized by 1H-NMR and ESI-MS. The purity was determined by HPLC. The procedure developed has several advanta- ges such as high yields and mild reaction conditions.