Fosfluconazole, a phosphate prodrug of fluconazole (96),
was recently approved for intravenous use in Japan in
October 2003. The drug was developed as a water-soluble
prodrug by Pfizer as an enhancement to the injectable
infusion formulation of fluconazole (96), a very potent
antifungal agent, that could be used intravenously in bolus
doses requiring smaller volumes of fluid and sodium.
Synthesis
The
disclosed manufacturing route of synthesis utilized fluconazole (96) as a precursor and was prepared in two steps
using inexpensive starting materials. Fluconazole
was dissolved in dichloromethane with pyridine and was
treated sequentially with phosphorus trichloride at ¨C13??C
and reacted at 13??C for 2 hr followed by an addition of
benzyl alcohol at 14-16??C and reacted for 2 hrs at 10-15??C.
The mixture was then cooled to 0??C and 30% hydrogen
peroxide was added over three hours, maintaining the
temperature below 20??C. After stirring the reaction at 20??C
for 1hr, the intermediate 97 was isolated in 66% yield.
Hydrogenation of the benzyl phosphate at 60 psi in water
with 5% palladium on carbon gave the desired phosphate
prodrug, fosfluconazole (XI) in 88% yield.
