title: Efficient, chemoenzymatic process for manufacture of the Boceprevir bicyclic [3.1.0]proline intermediate based on amine oxidase-catalyzed desymmetrization.
abstract: 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.
authors.affiliation: Merck & Co., Inc., 126 East Lincoln Avenue, Rahway, New Jersey 07065, USA. li.tao@epa.gov
authors.forename: Tao
authors.initials: T
authors.lastname: Li
authors.forename: Jack
authors.initials: J
authors.lastname: Liang
authors.forename: Alexandre
authors.initials: A
authors.lastname: Ambrogelly
authors.forename: Tim
authors.initials: T
authors.lastname: Brennan
authors.forename: Guy
authors.initials: G
authors.lastname: Gloor
authors.forename: Gjalt
authors.initials: G
authors.lastname: Huisman
authors.forename: James
authors.initials: J
authors.lastname: Lalonde
authors.forename: Azzeddine
authors.initials: A
authors.lastname: Lekhal
authors.forename: Ben
authors.initials: B
authors.lastname: Mijts
authors.forename: Sheela
authors.initials: S
authors.lastname: Muley
authors.forename: Lisa
authors.initials: L
authors.lastname: Newman
authors.forename: Matt
authors.initials: M
authors.lastname: Tobin
authors.forename: George
authors.initials: G
authors.lastname: Wong
authors.forename: Aleksey
authors.initials: A
authors.lastname: Zaks
authors.forename: Xiyun
authors.initials: X
authors.lastname: Zhang
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology; D002384:Catalysis; D020134:Catalytic Domain; D002626:Chemistry, Pharmaceutical / Q000379:methods; D015195:Drug Design; D006526:Hepatitis C / Q000188:drug therapy; D006801:Humans; D007700:Kinetics; D008995:Monoamine Oxidase / Q000737:chemistry*; D010100:Oxygen / Q000737:chemistry; D011392:Proline / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry; D015203:Reproducibility of Results; D013696:Temperature
chemical_list: D000998:Antiviral Agents; C512204:N-(3-amino-1-(cyclobutylmethyl)-2,3-dioxopropyl)-3-(2-((((1,1-dimethylethyl)amino)carbonyl)amino)-3,3-dimethyl-1-oxobutyl)-6,6-dimethyl-3-azabicyclo(3.1.0)hexan-2-carboxamide; D011392:Proline; D008995:Monoamine Oxidase; D010100:Oxygen