No abstract

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 The initial six-step development route from 5-fluorouracil has been superseded by a four-step synthesis involving fluorination of methyl 3-oxopentanoate and cyclisation with formamidine acetate.

Theoretical chemistry Z 0350 Critical Assessment of Pharmaceutical Processes -A Rationale for Changing the Synthetic Route -[107 refs.]. -(BUTTERS*, M.; CATTERICK, D.; CRAIG, A.; CURZONS, A.; DALE, D.; GILLMORE, A.; GREEN, S. P.; MARZIANO, I.; SHERLOCK, J.-P.; WHITE, W.; Chem. Rev. (Washington, D. C.) 106 (2006) 7, 3002-3027; Proc. Res. Dev., AstraZeneca, Bristol BS10 7ZE, UK; Eng.) -Lindner 41-276