坡那替尼的合成

Synthesis of Ponatinib

2-甲基-5-硝基三氟甲苯(2)经溴代、取代、还原、成酰胺得到关键中间体3-碘-4-甲基-N-[4-[(4-甲基-1-哌嗪)甲基]-3-(三氟甲基)苯基]苯甲酰胺(6)。另外,3-溴咪唑并[1,2-b]哒嗪(7)经Sonogashira反应和脱保护得到3-乙炔咪唑并[1,2-b]哒嗪(9)。6与9经Sonogashira反应制得BCR-ABL酪氨酸激酶抑制剂坡那替尼,总收率约70%(以2计)。

N- [3- （trifluoromethyl） -4- [ （4-methylpiperazin- 1-yl） methyll phenyl] -3-iodo-4-methylbenzamide （6） was prepared from 2-methyl-5-nitro-trifluoromethylbenzene （2） via bromination, substitution, reduction and amidation. Meanwhile, 3-ethynylimidazo [ 1,2-b] pyridazine （9） was produced from 3-bromoimidazo [ 1,2-b] pyridazine （7） via Sonogashira reaction and deprotection. Finally, ponatinib was synthesized from 6 and 9 by Sonogashira reaction. The overall yield was about 70 % based on 2.