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Apr 4, 2012

Codexis, Merck & Co. Develop Prototype Enzyme-Based Method for Producing Boceprevir

  • Codexis and Merck & Co. report the development of a highly efficient, enzyme-based production method for a key intermediate in the production of boceprevir, the active ingredient in Merck's Vitrelis, approved for HCV. The companies point out that the biocatalyst can be used in the commercial-scale manufacturing of the boceprevir intermediate.

    “The Codexis technology has delivered solid results including the reduction in production costs for boceprevir,” says Peter Seufer-Wasserthal, Ph.D., svp, Codexis Pharmaceuticals. Codexis used its CodeEvolver™ directed evolution technology to develop this custom enzyme.

    The technique involves the creation and characterization of a custom enzyme that was capable of performing a key step in the synthesis of boceprevir. The new method increased chemical intermediate yield 150% over the previous process and reduced raw material use by 60%, water use by 61%, and overall process waste by 63%, the firms explain.

    "Incorporation of innovative environmentally sustainable means of manufacture is a key aspect of our research and development strategy," remarks Richard Tillyer, Ph.D., svp discovery and preclinical sciences, Merck Research Laboratories. "Enzymatic based methods can offer a biodegradable and renewable alternative to currently employed methods."

    The key structural feature in boceprevir 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 part of 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.


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