title: Efficient large-scale synthesis of BILN 2061, a potent HCV protease inhibitor, by a convergent approach based on ring-closing metathesis.
abstract: A multistep scalable synthesis of the clinically important hepatitis C virus (HCV) protease inhibitor BILN 2061 (1) is described. The synthesis is highly convergent and consists of two amide bond formations, one etherification, and one ring-closing metathesis (RCM) step, using readily available building blocks 2-5. The optimization of each step is described at length. The main focus of the paper is the study of the RCM step and the description of the main problems faced when scaling up to pilot scale this highly powerful but very challenging synthetic operation. Eventually, the RCM reaction was smoothly scaled up to produce >400 kg of cyclized product.
authors.affiliation: Department of Chemical Development, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, P.O. Box 368, Ridgefield, Connecticut 06877, USA. nyee@rdg.boehringer-ingelheim.com
authors.forename: Nathan K
authors.initials: NK
authors.lastname: Yee
authors.forename: Vittorio
authors.initials: V
authors.lastname: Farina
authors.forename: Ioannis N
authors.initials: IN
authors.lastname: Houpis
authors.forename: Nizar
authors.initials: N
authors.lastname: Haddad
authors.forename: Rogelio P
authors.initials: RP
authors.lastname: Frutos
authors.forename: Fabrice
authors.initials: F
authors.lastname: Gallou
authors.forename: Xiao-Jun
authors.initials: XJ
authors.lastname: Wang
authors.forename: Xudong
authors.initials: X
authors.lastname: Wei
authors.forename: Robert D
authors.initials: RD
authors.lastname: Simpson
authors.forename: Xuwu
authors.initials: X
authors.lastname: Feng
authors.forename: Victor
authors.initials: V
authors.lastname: Fuchs
authors.forename: Yibo
authors.initials: Y
authors.lastname: Xu
authors.forename: Jonathan
authors.initials: J
authors.lastname: Tan
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.forename: Jinghua
authors.initials: J
authors.lastname: Xu
authors.forename: Lana L
authors.initials: LL
authors.lastname: Smith-Keenan
authors.forename: Jana
authors.initials: J
authors.lastname: Vitous
authors.forename: Michael D
authors.initials: MD
authors.lastname: Ridges
authors.forename: Earl M
authors.initials: EM
authors.lastname: Spinelli
authors.forename: Michael
authors.initials: M
authors.lastname: Johnson
authors.forename: Kai
authors.initials: K
authors.lastname: Donsbach
authors.forename: Thomas
authors.initials: T
authors.lastname: Nicola
authors.forename: Michael
authors.initials: M
authors.lastname: Brenner
authors.forename: Eric
authors.initials: E
authors.lastname: Winter
authors.forename: Paul
authors.initials: P
authors.lastname: Kreye
authors.forename: Wendelin
authors.initials: W
authors.lastname: Samstag
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002219:Carbamates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D003500:Cyclization; D016174:Hepacivirus / Q000187:drug effects / Q000201:enzymology*; D047028:Macrocyclic Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015394:Molecular Structure; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000998:Antiviral Agents; C479555:BILN 2061; D002219:Carbamates; D047028:Macrocyclic Compounds; D011480:Protease Inhibitors; D011804:Quinolines; D013844:Thiazoles