Optically active antifungal azoles. XI. An alternative synthetic route for 1.
New routes for the synthesis of the optically active antifungal triazoles 1-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(1H-1-tetrazolyl)phenyl]-2-imidazolidinone (1b) and the 3-14-(1H-1,2,3-triazol-1-yl)phenyl]-2-imidazolidinone analog (1a) that possess an imidazolidine nucleus were established. The key synthetic intermediates, (2R,3R)-3-(2,2-diethoxvethyl)amino-2-(2,4-difluorophenyl)-1-(1H1,2,4-triazol-1-yl)-2-butanol (8) and (2R,3R)-2-(2,4-difiuorophenyl)-3-(2-h ydroxyethyl)amino-1-(1H-1,2,4-triazol-1-yl)-2-butanol (14), were prepared by the ring-opening reaction of the oxirane (2) with the corresponding 2-substituted ethylamines. The acetal (8) was converted to the imidazolidinones (1a, b) by condensation with the carbamates (10a, b) followed by treatment with hydrochloric acid and subsequent catalytic hydrogenation. The candidate selected for the clinical trials, 1b (TAK-456), was alternatively prepared from the hydroxyethylamino intermediate (14) via two reaction steps: condensation with the carbamate (10b) to the urea (15) and subsequent cyclization to the imidazolidinones. This newly developed synthetic route could be applied to a large scale preparation of 1b.
Ichikawa
T
T
Pharmaceutical Discovery Research Division, Takeda Chemical Indurstries, Ltd, Osaka, Japan. Ichikawa_Takashi@takeda.co.jp
Kitazaki
T
T
Matsushita
Y
Y
Hosono
H
H
Yamada
M
M
Mizuno
M
M
Itoh
K
K
D000935:Antifungal Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001393:Azoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002176:Candida albicans / Q000187:drug effects; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D009904:Optical Rotation; D013777:Tetrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D000935:Antifungal Agents; D001393:Azoles; D007093:Imidazoles; C423467:TAK 456; D013777:Tetrazoles