Bromotrimethylsilane → Tenofovir

Participants

Reaction Conditions

Reaction Steps

(R)-9-[2-(hydroxy)propyl]adenine (HPA) (20.0 g, 0.104 mol) was suspended in DMF (44.5 ml) and heated to 65° C. Magnesium t-butoxide (14.2 g, 0.083 mol), or alternatively magnesium isopropoxide, was added to the mixture over one hour followed by diethyl p-toluenesulfonyloxymethylphosphonate (66.0 g, 0.205 mol) over two hours while the temperature was kept at 78° C. The mixture was stirred at 75° C. for 4 hours. After cooling to below 50° C., bromotrimethylsilane (73.9 g, 0.478 mol) was added and the mixture heated to 77° C. for 3 hours. When complete, the reaction was heated to 80° C. and volatiles were removed via atmospheric distillation. The residue was dissolved into water (120 ml) at 50° C. and then extracted with ethyl acetate (101 ml). The pH of the aqueous phase was adjusted to pH 1.1 with sodium hydroxide, seeded with authentic (R)-PMPA, and the pH of the aqueous layer was readjusted to pH 2.1 with sodium hydroxide. The resulting slurry was stirred at room temperature overnight. The slurry was cooled to 4° C. for three hours. The solid was isolated by filtration, washed with water (60 ml), and dried in vacuo at 50° C. to yield 18.9 g (63.5%) of crude (R)-9-[2-(phosphonomethoxy)propyl]adenine (PMPA) as an off-white solid.

Provenance & Evidence