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.
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-tria zol-1- yl)propyl]-4-[4-(2,2,3,3-tetrafluoropropoxy)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.
Kitazaki
T
T
Medicinal Chemistry Laboratories, Takeda Chemical Industries, Ltd., Osaka, Japan.
Tasaka
A
A
Hosono
H
H
Matsushita
Y
Y
Itoh
K
K
D000935:Antifungal Agents / Q000138:chemical synthesis*; D002851:Chromatography, High Pressure Liquid; D002855:Chromatography, Thin Layer; D009682:Magnetic Resonance Spectroscopy; D013055:Spectrophotometry, Infrared; D013237:Stereoisomerism; D014230:Triazoles / Q000138:chemical synthesis*; D005466:Fluorocarbons
D000935:Antifungal Agents; D014230:Triazoles; C105227:TAK 187; D005466:Fluorocarbons