富马酸泰诺福韦酯新合成路线

A new synthetic route to tenofovir disoproxil fumarate

摘要: 对富马酸泰诺福韦酯的新合成路线进行研究。以R-环氧氯丙烷为起始原料，通过常压氢化制得R-1-氯-2-丙醇（ 7 ），化合物 7 与多聚甲醛和氯化氢气体反应得R-1-氯-2-氯甲基丙烷（ 6 ），化合物 6 与亚磷酸三乙酯反应得R-(2-甲基-1-氯乙基)氧甲基膦酸二乙酯（ 5 ），化合物 5 与腺嘌呤缩合后再经脱酯反应得到关键中间体R-9-(2-膦酸甲氧基丙基)-腺嘌呤（ 3 ，泰诺福韦）。化合物 3 经酯化、成盐得到最终产物富马酸泰诺福韦酯。合成富马酸泰诺福韦酯的总收率为8.4%，其结构经MS、¹H NMR和IR确证。

Abstract: The preferred route to tenofovir disoproxil fumarate involves hydrogenation of R-epichlorohydrin under normal pressure.The resulting product R-1-chloro-2-propanol( 7 ) was converted to R-1-chloro-2-chloromethylpropane( 6 ) by reaction with paraformaldehyde and hydrogen chloride gas.R-diethyl (2-methyl-1-chloroethyl)oxymethylphosphoante( 5 ) was synthesized by condensation of 6 with triethyl phosphite.The key intermediate R-9-［2-(phosphonomethoxy)propyl］adenine( 3 ,tenofovir) was prepared from 5 via condensation and deesterification.The target product tenofovir disoproxil fumarate( 1 ) was obtained sequentially through esterification and salifying.The total yield of 1 was 8.4%,and its structure was confirmed by MS,¹H NMR and IR.