1. The Large-Scale Synthesis of (S)-N-Boc-bis(4-fluorophenyl)alanine
- Author
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Christel Kronig, Mark R. Smit, Daugs Edward D, Christopher H. Hanson, Richard C. Lloyd, James A. Ramsden, Robert B. Appell, Matthew Willets, Mark A. Nitz, Matt Hansen, Céline Praquin, Lee T. Boulton, Louks David H, Helen Samuel, and Jerry Heinrich
- Subjects
Steric effects ,Alanine ,Acrylate ,chemistry.chemical_compound ,Chemistry ,Stereochemistry ,Organic Chemistry ,Asymmetric hydrogenation ,Physical form ,Physical and Theoretical Chemistry - Abstract
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.
- Published
- 2012
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