卡博替尼苹果酸盐的合成工艺改进

Improved synthesis of cabozantinib (S)-malate

以6,7-二甲氧基喹啉-4-醇2为起始原料,经三氯氧磷氯代得到中间体4-氯-6,7-二甲氧基喹啉3,再经醚化反应得到中间体6,7-二甲氧基-4-(4-氨基苯氧基)喹啉4;中间体4与1-(4-氟苯基氨基甲酰基)环丙烷羧酸5经过酰胺化反应制得卡博替尼6,6最后与(S)-苹果酸成盐得到目标化合物卡博替尼苹果酸盐1,总收率为75.4%,纯度为99.5%。其结构通过^(1)H NMR、^(13)C NMR及ESI-MS进行了表征,并探讨了中间体和目标化合物合成工艺的影响因素,该合成路线具有:反应条件温和,操作简单,污染小等优点,适合工业化生产。

Using 6,7-dimethoxyquinoline-4-ol 2 as the starting material,the intermediate 4-chloro-6,7-dimethoxyquinoline 3 was obtained by chlorination of phosphorus oxychloride,and then etherification reaction to obtain intermediate 6,7-dimethoxy-4-(4-aminophenoxy)quinoline 4;the intermediate 6 was obtained by chlorination,etherification,and amidation reactions,and finally salted with(S)-malic acid to obtain the target compound Cabozantinib(S)-malate 1.The total yield was 75.4% and the purity was 99.5%.Its structure was characterized by ^(1)H NMR,^(13)C NMR and ESI-MS,and the influencing factors of the synthesis process for intermediates and target compounds were discussed.The synthesis route has the advantages of mild reaction conditions,simple operation,and low pollution,which is suitable for industrial production.