瑞卢戈利中间体的合成

Synthesis of Intermediates of Relugolix

以4-硝基苯丙酮(2)和氰基乙酸乙酯(3)为原料,经与硫粉环合、缩合、亲核取代、溴代反应、二甲胺取代和水解后得到瑞卢戈利的关键中间体2-[(2,6-二氟苄基)乙氧基羰基氨基]-4-二甲基氨基甲基-5-(4-硝基苯基)噻吩-3-甲酸(1),并对合成路线中反应条件及提纯方法进行优化,总收率51.5%,纯度98.7%以上,中间体的结构经~1H NMR和ESI-MS确证。优化后的工艺操作更加简便,更有利于工业化生产。

2-[(2,6-Difluorobenzyl)(ethoxycarbonyl)amino]-5-{4-{[(methoxycarbamoyl)amino]phenyl}-4-[(Dimethyl)amino]methyl]thiophene-3-carboxylic acid(1), a key intermediate of relugolix, was synthesized by a seven-step reaction of sulfur powder cyclization, condensation, nucleophilic substitution, bromination, dimethylamine substitution and hydrolysis from 4-nitrophenylacetone(2) and ethyl cyanoacetate3. Reaction conditions and purification methods in the synthetic route were optimized, in overall yield of 51.5% and>98.7% purity. Structures of intermediates and products were confirmed by ~1H NMR and ESI-MS. The optimized process is more simple and more conducive to industrial production.