title: A Synthesis of a Spirocyclic Macrocyclic Protease Inhibitor for the Treatment of Hepatitis C.
abstract: The development of a convergent and highly stereoselective synthesis of an HCV NS3/4a protease inhibitor possessing a unique spirocyclic and macrocyclic architecture is described. A late-stage spirocyclization strategy both enabled rapid structure-activity relationship studies in the drug discovery phase and simultaneously served as the basis for the large scale drug candidate preparation for clinical use. Also reported is the discovery of a novel InCl3-catalyzed carbonyl reduction with household aluminum foil or zinc powder as the terminal reductant.
authors.affiliation: Department of Process Chemistry, Merck Research Laboratories, Merck & Co., Inc. , Rahway, New Jersey 07065, United States.
authors.forename: Cheol K
authors.initials: CK
authors.lastname: Chung
authors.affiliation: Department of Process Chemistry, Merck Sharp and Dohme Ltd. , Hertford Road, Hoddesdon EN11 9BU, United Kingdom.
authors.forename: Ed
authors.initials: E
authors.lastname: Cleator
authors.affiliation: Department of Process Chemistry, Merck Sharp and Dohme Ltd. , Hertford Road, Hoddesdon EN11 9BU, United Kingdom.
authors.forename: Aaron M
authors.initials: AM
authors.lastname: Dumas
authors.affiliation: Department of Process Chemistry, Merck Research Laboratories, Merck & Co., Inc. , Rahway, New Jersey 07065, United States.
authors.forename: Jacqueline D
authors.initials: JD
authors.lastname: Hicks
authors.affiliation: Department of Process Chemistry, Merck Research Laboratories, Merck & Co., Inc. , Rahway, New Jersey 07065, United States.
authors.forename: Guy R
authors.initials: GR
authors.lastname: Humphrey
authors.affiliation: Department of Process Chemistry, Merck Research Laboratories, Merck & Co., Inc. , Rahway, New Jersey 07065, United States.
authors.forename: Peter E
authors.initials: PE
authors.lastname: Maligres
authors.affiliation: Department of Process Chemistry, Merck Research Laboratories, Merck & Co., Inc. , Rahway, New Jersey 07065, United States.
authors.forename: Andrew F
authors.initials: AF
authors.lastname: Nolting
authors.affiliation: Department of Process Chemistry, Merck Research Laboratories, Merck & Co., Inc. , Rahway, New Jersey 07065, United States.
authors.forename: Nelo
authors.initials: N
authors.lastname: Rivera
authors.affiliation: Department of Process Chemistry, Merck Research Laboratories, Merck & Co., Inc. , Rahway, New Jersey 07065, United States.
authors.forename: Rebecca T
authors.initials: RT
authors.lastname: Ruck
authors.affiliation: Department of Process Chemistry, Merck Research Laboratories, Merck & Co., Inc. , Rahway, New Jersey 07065, United States.
authors.forename: Michael
authors.initials: M
authors.lastname: Shevlin
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D055808:Drug Discovery; D016174:Hepacivirus / Q000187:drug effects*; D006526:Hepatitis C / Q000188:drug therapy*; D006576:Heterocyclic Compounds, 4 or More Rings / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D047028:Macrocyclic Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D013141:Spiro Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*
chemical_list: D000998:Antiviral Agents; D006576:Heterocyclic Compounds, 4 or More Rings; C000609755:MK-8831; D047028:Macrocyclic Compounds; D013141:Spiro Compounds; D017361:Viral Nonstructural Proteins