雷迪帕韦及其关键中间体的合成研究

乙醛酸甲酯与R(+)-α-甲基苄胺缩合、与环戊二烯通过aza-Diels–Alder反应，产物经氢化、上Boc保护、水解、缩合得到苯并咪唑衍生物，继续与联硼酸频哪醇酯反应得到雷迪帕韦关键中间体：(1R,3S,4S)-3-[6-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-苯并咪唑-2-基]-2-氮杂双环[2.2.1]庚烷-2-羧酸叔丁酯，总收率40.6%（以乙醛酸甲酯计），关键中间体经过三步反应得到雷迪帕韦丙酮合物，纯度99.7%，ee值达100%。

An improved synthesis of ledipasvir and its key intermediate

After the condensation of methyl aldehyde and D(+)-alpha-methylbenzylamine, followed by an aza-Diels-Alder reaction with cyclopentadiene, a benzimidazole derivative compound was prepared via hydrogenation, Boc protection, hydrolysis and condensation, followed by reacting with coupling boric acid ester to obtain the key intermediate of (1R,3S,4S)-3-[6-(4,4,5,5-Tetra-methyl-1,3,2-dioxaborolan-2-yl)-1H-benzimidazol-2-yl]-2-azabicyclo[2.2.1]heptane-2-carboxylic acid 1,1-dimethylethyl ester. Ledipasvir could be prepared by using this key intermediate via three steps and its HPLC purity and ee value could reach to 99.9% and 100%, respectively.