2-(2,4-DIFLUOROPHENYL)-1,3-BIS(1H-1,2,4-TRIAZOL-1-YL)PROPYL DIHYDROGEN PHOSPHATE

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.

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.