Process development of voriconazole: A novel broad-spectrum triazole antifungal agent

In the synthesis of (2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoro-4-pyrimidiny l)-1-(1H-1,2,4-triazol-1-yl)-2-butanol (voriconazole), the relative stereoc hemistry 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 diastereo-control of this reaction has been examined by variation of p yrimidine substitution pattern and by changes in the metalation and reactio n conditions. Excellent diastereoselection (12: ii is obtained using an org anozinc derivative of 6-(1-bromoethyl)-4-chloro-5-fluoropyriminidine. lifte r removal cf the chlorine from the pyrimidine ring? the absolute stereochem istry of voriconazole is established via a diastereomeric salt resolution p rocess using (1R)-10 camphorsulfonic acid. Synthetic routes to the pyrimidi ne 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 The initial six-step development route from 5-fluorouracil has been superseded by a four-step synthesis involving fluorination of methyl 3-oxopentanoate and cyclisation with formamidine ac etate.