In the synthesis of (2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoro-4-pyrimidinyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol (voriconazole), the relative stereochemistry is set in the addition of a 4-(1-metalloethyl)-5-fluoropyrimidine derivative to 1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)-1-ethanone. The diastereocontrol of this reaction has been examined by variation of pyrimidine substitution pattern and by changes in the metalation and reaction conditions. Excellent diastereoselection (12:1) is obtained using an organozinc derivative of 6-(1-bromoethyl)-4-chloro-5-fluoropyrimidine. After removal of the chlorine from the pyrimidine ring, the absolute stereochemistry of voriconazole is established via a diastereomeric salt resolution process using (1R)-10-camphorsulfonic acid. Synthetic routes to the pyrimidine partner have also been evaluated. The initial six-step development route from 5-fluorouracil has been superseded by a four-step synthesis involving fluorination of methyl 3-oxopentanoate and cyclisation with formamidine acetate.

Process Development of Voriconazole: A Novel Broad-SpectrumTriazole Antifungal Agent.-A novel approach for the large-scale preparation of the title compound (VII) is developed. The pure enantiomer is obtained in 40% yield from the racemate (VII) by recrystallization of a salt with (1R)-10-camphorsulfonic acid and subsequent hydroxide treatment. -(BUTTERS, MIKE; EBBS, JULIE; GREEN, STUART P.; MACRAE, JULIE; MORLAND, MATTHEW C.; MURTIASHAW, CHARLES W.; PETTMAN, ALAN J.; Org. Process Res. Dev. 5 (2001) 1, 28-36; Process Res. Dev., Pfizer Cent. Res., Sandwich, Kent CT13 9NJ, UK; EN)