A new synthetic route to tenofovir disoproxil fumarate

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.