The Studies On The Synthesis Of Fosfluconazole And Its Impurities

Triazole antifungal drugs of fluconazole was developed by the Pfizer of U.S.company in 1980 and began to produce and used in clinic in China in 1992. Fosfluconazole is a phosphate ester prodrugs of fluconazole, it’s water-soluble and the antimicrobial effect is stronger than fluconazole. The infusion volume can be reduced when used in clinic and it can also reduce the burden on the circulatory system. This study was mostly focused on the phosphorylation of fluconazole,increaseing it’s solublity in water to get the water soluble prodrugs of fosfluconazole. The synthetic route is composed of two parts, the first step is the synthesis of fluconazole intermediate: 2-(2,4- difluorophenyl)-1,3- bis(1H-1,2,4- triazol- yl)-2- propyldibenzyl phosphate ester, the second step is the hydrogenation of the intermediate : 2-( 2,4- difluorophenyl)-1,3-bis(1H-1, 2,4- three-l- yl)-2- propyl dihydrogen phosphate. We finally determined the optimal synthesis route through analysis and discussions on various conditions, and the product was recognized as the fosfluconazole by the structure and purity analysis. The results may make adevelopment on the industrial synthesis of fosfluconazole. The main impurity of Fosfluconazole with purity of 95%,2-(2,4-difluoro-Phenyl)-1-(1H-1,2,4-triazol-1-yl)-3-(4H-1,2,4-triazol-4-yl)propan-2-yl-dihydrogen phosphateoxalate and 2-(2-fluorophenyl)-1,3-di(1H-1,2,4-triazol-1-yl)propan-2-yl dihydrogen phosphate, was synthesized by the Friedel-Crafts reaction, nucleophilic substitution, Corey-Chaykovskyreaction,Phosphorylation and catalytic hydrogenation, using1,3-difluorobenzene and 1-(2-fluorophenyl)ethan-1-one as starting material. The structure was confirmed by 1H NMR.