Optically active antifungal azoles. IX. An alternative synthetic route for 2-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol- 1-yl)propyl]-4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-3(2H,4H)1,2,4- triazolone and its analogs

Abstract

A new route for the synthesis of the optically active antifungal azole TAK-187, 2-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4- triazol-1-yl)propyl]-4-[4-(2,2,3,3-tetrafluoroptopoxy)phenyl]3(2H,4H)-1,2,4- triazolone, was established. The key synthetic intermediate, 2-[(1R)-2-(2,4- difluorophenyl)-2-oxo-1-methylethyl]-4-[4-(2,2,3,3- tetrafluoropropoxy)phenyl]-3(2H,4H)-1,2,4-triazolone (8), was prepared starting from the esters (11a, b) of (S)-lactic acid in a stereocontrolled manner. This optically active propiophenone derivative 8 was converted to the one carbon-elongated (1R,2S)-diol 7, which was then reacted with 1H-1,2,4- triazole to yield TAK-187. This newly developed route was applied to the synthesis of the analogs (25a, b - 28a, b) containing an imidazolone or imidazolidinone nucleus.