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Efficient, Chemoenzymatic Process for Manufacture of the Boceprevir Bicyclic [3.1.0]Proline Intermediate Based on Amine Oxidase-Catalyzed Desymmetrization

2012; American Chemical Society; Volume: 134; Issue: 14 Linguagem: Inglês

10.1021/ja3010495

1943-2984

Tao Li, Jack Liang, Alexandre Ambrogelly, Timothy J. Brennan, Guy Gloor, Gjalt W. Huisman, James Lalonde, Azzeddine Lekhal, Ben Mijts, Sheela Muley, Lisa M. Newman, Matt Tobin, George S. K. Wong, A. S. Zaks, Xiyun Zhang,

HIV/AIDS drug development and treatment

The key structural feature in Boceprevir, Merck's new drug treatment for hepatitis C, is the bicyclic [3.1.0]proline moiety "P2". During the discovery and development stages, the P2 fragment was produced by a classical resolution approach. As the drug candidate advanced through clinical trials and approached regulatory approval and commercialization, Codexis and Schering-Plough (now Merck) jointly developed a chemoenzymatic asymmetric synthesis of P2 where the net reaction was an oxidative Strecker reaction. The key part of this reaction sequence is an enzymatic oxidative desymmetrization of the prochiral amine substrate.