拉戈利关键中间体的新合成方法

A Novel Synthetic Method of the Key Intermediate of Elagolix

本研究报道了拉戈利关键中间体(R)-[2-[5-(2-氟-3-甲氧基苯基)-3-[2-氟-6-(三氟甲基)苄基]-4-甲基-2,6-二氧代-3,6-二氢嘧啶-1(2H)-基]-1-苯乙基]氨基甲酸叔丁酯(1)的新合成路线。以3-氨基巴豆酸乙酯为原料,经氯甲酸苯酯活化后与(R)-叔丁基(2-氨基-1-苯乙基)氨基碳酸酯(4)缩合闭环得(R)-[2-[4-甲基-2,6-二氧代-3,6-二氢嘧啶-1(2H)-基]-1-苯乙基]氨基甲酸叔丁酯(6),6与2-氟-6-三氟甲基溴苄经缩合,得(R)-[2-[3-[2-氟-6-(三氟甲基)苄基]-4-甲基-2,6-二氧代-3,6-二氢嘧啶-1(2H)-基]-1-苯乙基]氨基甲酸叔丁酯(7),再经N-溴代琥珀酰亚胺溴化、与2-氟-3-甲氧基苯硼酸偶联等步骤制得1。从2到7的反应为原创路线,各中间体均未见文献报道。该工艺相对于原研工艺革除了易产生脱溴杂质的缩合反应步骤,原料价廉,并避免使用原研工艺中的危险性化学品,总收率由48%提高至71%,有利于工业化放大生产。

In this paper,the new synthetic route of the key intermediate of elagolix,tert-butyl(R)-[2-[5-(2-fluoro-3-methoxyphenyl)-3-[2-fluoro-6-(trifluoromethyl)benzyl]-4-methyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl]-1-phenylethyl]carbamate was reported.Innovatively,ethyl 3-aminocrotonate was used as a raw material,and after being activated by phenyl chloroformate,it was condensed with tert-butyl(R)-(2-amino-1-phenylethyl)-carbamate acetate(4),then cyclized to obtain tert-butyl(R)-[2-[4-methyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl]-1-phenylethyl]carbamate(6).The latter was condensed with 2-fluoro-6-trifluoromethylbenzyl bromide to give tert-butyl(R)-[2-[3-[2-fluoro-6-(trifluoromethyl)benzyl]-4-methyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl]-1-phenylethyl]-carbamate(7),brominated with N-bromosuccinimide,and coupled with 2-fluoro-3-methoxyphenylboronic acid to obtain the key intermediate 1.The synthetic route reduces the reaction steps,eliminates the condensation reaction step that easily produces debrominated impurities,greatly reduces the cost of raw materials,and avoids the use of hazardous chemicals.The total yield of 1 increased from 48%to 71%,which is more conducive to industrial scale-up production.