比特拉韦关键中间体的合成工艺改进

Improvement of Synthetic Process for the Key Intermediate Bictegravir

本研究以N-叔丁氧羰基-D-丙氨酸(2)为起始原料,经缩合得N-叔丁氧羰基-D-丙氨肟酸(3),3与环戊二烯经氧化和Diels-Alder反应得[(R)-1-[(1S,4R)-2-氧杂-3-氮杂双环[2.2.1]庚-5-烯-3-基]-1-氧代丙基-2-基]氨基甲酸叔丁酯(4),4经催化氢化得到[(R)-1-[(1S,4R)-2-氧杂-3-氮杂双环[2.2.1]庚-3-基]-1-氧代丙基-2-基]氨基甲酸叔丁酯(5),5再经水解、Boc保护、催化氢化和脱保护成盐制得比特拉韦关键中间体(1R,3S)-3-氨基环戊醇盐酸盐(1),总收率43%,产品纯度99.65%,ee 99.74%。其中,化合物5未见文献报道,5到叔丁基[(1S,3R)-3-羟基环戊基]氨基甲酸酯(7)的合成路线亦未见文献报道。该路线中,2作为手性辅基对于Diels-Alder反应表现出很好的底物诱导作用,实现了不对称合成;反应条件温和,避免了原研工艺中易燃易爆等危险试剂的使用。

In this report,N-(tert-butoxycarbonyl)-D-aminoprohydroxamic acid(3)was obtained by condensation from N-(tert-butoxycarbonyl)-D-alanine(2).Then,compound 3 reacted with cyclopentadiene to give[(R)-1-[(1S,4R)-2-oxa-3-azabicyclo[2.2.1]hept-5-en-3-yl]-1-oxopropan-2-yl]tert-butyl carbamate(4)via oxidation and Diels-Alder reaction.Then[(R)-1-[(1S,4R)-2-oxa-3-azabicyclo[2.2.1]hept-3-yl]-1-oxopropan-2-yl]tert-butyl carbamate(5)was obtained by catalytic hydrogenation.And the key intermediate of bictegravir,(1R,3S)-3-aminocyclopentanol hydrochloride(1)was obtained by hydrolysis,Boc protection,catalytic hydrogenation,and deprotection,with a total yield of 43%,a purity of 99.65%,and ee value of 99.74%.Compound 5 has not been found in the literature before,nor the route from 5 to tert-butyl[(1S,3R)-3-hydroxycyclopentyl]carbamate(7).Compound 2 had a good induction effect on Diels-Alder reaction,achieving asymmetric synthesis.The reaction conditions are mild,avoiding the use of inflammable,explosive and other dangerous reagents.