The Large-Scale Synthesis of (S)-N-Boc-bis(4-fluorophenyl)alanine

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• 作者：Robert B. Appell ; Lee T. Boulton ; Edward D. Daugs ; Matt Hansen ; Christopher H. Hanson ; Jerry Heinrich ; Christel Kronig ; Richard C. Lloyd ; David Louks ; Mark Nitz ; C茅line Praquin ; James A Ramsden ; Helen Samuel ; Mark Smit ; Matthew Willets
• 刊名：Organic Process Research & Development
• 出版年：2013
• 出版时间：January 18, 2013
• 年：2013
• 卷：17
• 期：1
• 页码：69-76
• 全文大小：338K
• 年卷期：v.17,no.1(January 18, 2013)
• ISSN：1520-586X

文摘

The synthesis of (S)-N-Boc-bis(4-fluorophenyl)alanine, an intermediate in the synthesis of denagliptin, is described from the synthesis of a 12 g proof of principle sample to a >900 kg cGMP manufacturing campaign. The chiral centre was established by the asymmetric hydrogenation of the sterically crowded precursor, ethyl 2-acetamido-3,3-bis(4-fluorophenyl)acrylate. The ability to isolate the various intermediates in a physical form that would readily allow filtration, washing, and ultimately purification underpinned the successful manufacturing campaign.