title: Synthesis of (1R,2S)-1-amino-2-vinylcyclopropanecarboxylic acid vinyl-ACCA) derivatives: key intermediates for the preparation of inhibitors of the hepatitis C virus NS3 protease.
abstract: (1R,2S)-1-Amino-2-vinylcyclopropanecarboxylic acid (vinyl-ACCA) is a key building block in the synthesis of potent inhibitors of the hepatitis C virus NS3 protease such as BILN 2061, which was recently shown to dramatically reduce viral load after administration to patients infected with HCV genotype 1. We have developed a scalable process that delivers derivatives of this unusual amino acid in >99% ee. The strategy was based on the dialkylation of a glycine Schiff base using trans-1,4-dibromo-2-butene as an electrophile to produce racemic vinyl-ACCA, which was subsequently resolved using a readily available, inexpensive esterase enzyme (Alcalase 2.4L). Factors that affect diastereoselection in the initial dialkylation steps were examined and the conditions optimized to deliver the desired diastereomer selectively. Product inhibition, which was encountered during the enzymatic resolution step, initially resulted in prolonged cycle times. Enrichment of racemic vinyl-ACCA through a chemical resolution via diastereomeric salt formation or the use of forcing conditions in the enzymatic reaction both led to improvements in throughput and the development of a viable process. The chemistry described herein was scaled up to produce multikilogram quantities of this building block.
authors: Research and Development, Boehringer Ingelheim (Canada), Ltd., 2100 Cunard Street, Laval, Québec H7S 2G5, Canada. pbeaulieu@lav.boehringer-ingelheim.com
authors: Pierre L
authors: PL
authors: Beaulieu
authors: James
authors: J
authors: Gillard
authors: Murray D
authors: MD
authors: Bailey
authors: Colette
authors: C
authors: Boucher
authors: Jean-Simon
authors: JS
authors: Duceppe
authors: Bruno
authors: B
authors: Simoneau
authors: Xiao-Jun
authors: XJ
authors: Wang
authors: Li
authors: L
authors: Zhang
authors: Karl
authors: K
authors: Grozinger
authors: Ioannis
authors: I
authors: Houpis
authors: Vittorio
authors: V
authors: Farina
authors: Heidi
authors: H
authors: Heimroth
authors: Thomas
authors: T
authors: Krueger
authors: Jürgen
authors: J
authors: Schnaubelt
mesh_terms: D000478:Alkylation; D000598:Amino Acids, Cyclic / Q000138:chemical synthesis* / Q000494:pharmacology; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000494:pharmacology; D008956:Models, Chemical; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D013237:Stereoisomerism; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D000598:Amino Acids, Cyclic; D000998:Antiviral Agents; D011480:Protease Inhibitors; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C023863:1-aminocyclopropane-1-carboxylic acid