Process Development of Voriconazole: A Novel Broad-Spectrum Triazole Antifungal Agent

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• 作者：Mike Butters ; Julie Ebbs ; Stuart P. Green ; Julie MacRae ; Matthew C. Morland ; Charles W. Murtiashaw ; and Alan J. Pettman
• 刊名：Organic Process Research & Development
• 出版年：2001
• 出版时间：January 2001
• 年：2001
• 卷：5
• 期：1
• 页码：28 - 36
• 全文大小：88K
• 年卷期：v.5,no.1(January 2001)
• ISSN：1520-586X

文摘

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 ofpyrimidine 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 fromthe pyrimidine ring, the absolute stereochemistry of voriconazole is established via a diastereomeric salt resolution processusing (1R)-10-camphorsulfonic acid. Synthetic routes to thepyrimidine partner have also been evaluated. The initial six-step development route from 5-fluorouracil has been supersededby a four-step synthesis involving fluorination of methyl3-oxopentanoate and cyclisation with formamidine acetate.