Di- tert -butyl Phosphonate Route to the Antiviral Drug Tenofovir.

Di- tert -butyl oxymethyl phosphonates were investigated regarding their suitability for preparing the active pharmaceutical ingredient tenofovir (PMPA). First, an efficient and simple access to the crystalline di- tert -butyl(hydroxymethyl)phosphonate was developed. O-Mesylation gave high yields of the active phosphonomethylation reagent. For the synthesis of tenofovir, a two-step sequence was developed using Mg(O t Bu) 2 as the base for the alkylation of ( R )-9-(2-hydroxypropyl)adenine. Subsequent deprotection could be achieved with aqueous acids. (Di- tert -butoxyphosphoryl)methyl methanesulfonate showed to be the most efficient electrophile tested, affording PMPA in 72% yield on a 5 g scale. The developed protocol could also be applied for the preparation of the hepatitis B drug adefovir (64% yield/1 g scale).