囊性纤维化治疗新药Ivacaftor的合成

Synthesis of Ivacaftor-A Cystic Fibrosis Drug

Ivacaftor是被FDA批准用于由G551D基因突变引起的囊性纤维化的治疗药物。以2,4-二叔丁基苯酚为原料,经酯化保护、硝化、水解脱保护、硝基还原得到关键中间体2,4-二叔丁基-5-氨基苯酚;苯胺和乙氧亚甲基丙二酸二乙酯经Gould-Jacobs反应得到4-氧代-1,4-二氢喹啉-3-羧酸。2,4-二叔丁基-5-氨基苯酚与4-氧代-1,4-二氢喹啉-3-羧酸缩合得到Ivacaftor,总收率约13%(以苯胺计)。

Ivacaftor （1） has been approved by FDA for the treatment of cystic fibrosis caused by G551D gene mutation. It was synthesized by the reaction of 4-oxo-1,4-dihydroquinoline-3-carboxylic acid （5_） with 5- amino-2,4-di-tert-butylphenol （12） in overall yield of 13% （based on aniline）. 5_ was prepared via Gould- Jacobs reaction from aniline and diethyl-2- （ethoxymethylene） malonate. 12 was obtained from 2,4-di-tertbutylphenol via ester formation, nitration, ester hydrolysis and the reduction of the nitro group.