Process Development and Pilot-Plant Synthesis of (2-Chlorophenyl)[2-(phenylsulfonyl)pyridin-3-yl]methanone

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• 作者：Michael E. Kopach ; Michael E. Kobierski ; D. Scott Coffey ; Charles A. Alt ; Tony Zhang ; Alfio Borghese ; William G. Trankle ; Dilwyn J. Roberts ; Humphrey Moynihan ; Kurt Lorenz ; Orla A. McNamara ; Marie Kissa
• 刊名：Organic Process Research & Development
• 出版年：2010
• 出版时间：September 17, 2010
• 年：2010
• 卷：14
• 期：5
• 页码：1229-1238
• 全文大小：327K
• 年卷期：v.14,no.5(September 17, 2010)
• ISSN：1520-586X

文摘

Routes to (2-chlorophenyl)[2-(phenylsulfonyl)pyridin-3-yl]methanone, 1, an intermediate in the manufacture of NK1-II inhibitor LY686017 are described which produce 1 in >75% yield and 95% purity. A highly selective telescoped ortho lithation/condensation/oxidation process was developed and successfully scaled to the clinical pilot plant to produce 25 kg of 1. For the pilot-plant campaign, the lithiation step was developed to operate at −50 °C using commercial lithium diisopropylamide (LDA), and the oxidation step employed catalytic TEMPO as the primary and NaOCl as the terminal oxidant. After completion of the pilot-plant campaign second-generation approaches to 1 were developed to improve process greenness where the lithiation and condensation step were operated as warm as −10 °C, the highly efficient AZADO catalyst was used as a substitute for TEMPO in the Anelli−Montanari oxidation, and process mass intensity was reduced 25%.