抗白血病药普纳替尼合成路线改进

Improved Synthesis of anti-leukemia drug ponatinib

对抗白血病新药普纳替尼(1)的合成工艺进行改进。以3-溴咪唑并[1,2-b]哒嗪(3)为起始原料,采用"一锅法"经与三甲基硅基乙炔的Sonogashira偶联、脱保护基、与3-碘-4-甲基-N-[4-[(4-甲基-1-哌嗪基)甲基]-3-(三氟甲基)苯基]苯甲酰胺(9)的第二次Sonogashira偶联得终产物1。关键中间体9的合成,以3-三氟甲基-4-[(4-甲基哌嗪-1-基)甲基]-苯胺(6)与3-碘-4-甲基苯甲酸(7)在EDCI/HOBt/Et3N催化下直接缩合,代替文献使用二氯亚砜酰化后再缩合的两步反应。改进后的路线反应条件温和,操作简便,减少了昂贵的钯催化剂的用量,反应总收率由44.5%提高至80%(以3计)。

The synthetic route of anti-leukemia drug ponatinib （1） was optimized. The target compound was prepared via Sonogashira coupling with trimethylsilylacetylene, deprotection and Sonogashira coupling with 3-iodo-4-methyl-N- ~4- E （4-methylpiperazin- 1-yl） methyl]-3- （trifluoromethyl） phenyl~ benzamide （9） by ＇one-pot＇ method with 3-bromoimidazo [ 1,2-b] pyridazine （3） as the starting material. In the synthesis of the key intermediate 9, 3- （trifluoromethyl） -4- E （4-methylpiperazin- 1-yl） methyll aniline （6） and 3-iodo-4-methylbenzoic acid （7） was coupled directly in the presence of EDCI/HOBt/TEA. The improved method has several advantages including mild conditions, simple operations, high yield （80 %）, and the amount of the expensive palladium catalyst has been cut down to half.