title: Synthesis of the (3R,6S)-3-amino-6-(2,3-difluorophenyl)azepan-2-one of telcagepant (MK-0974), a calcitonin gene-related peptide receptor antagonist for the treatment of migraine headache.
abstract: Two novel routes have been developed to the (3 R,6 S)-3-amino-6-(2,3-difluorophenyl)-1-(2,2,2-trifluoroethyl)azepan-2-one 2 of the CGRP receptor antagonist clinical candidate telcagepant (MK-0974, 1). The first employs a ring-closing metathesis of the styrene 7 as the key reaction, while the second makes use of a highly diastereoselective Hayashi-Miyaura Rh-catalyzed arylboronic acid addition to nitroalkene 16. The latter route has been implemented to produce multigram quantities of telcagepant for extensive preclinical evaluation.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, West Point, Pennsylvania 19486, USA. christopher_burgey@merck.com
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Burgey
authors.forename: Daniel V
authors.initials: DV
authors.lastname: Paone
authors.forename: Anthony W
authors.initials: AW
authors.lastname: Shaw
authors.forename: James Z
authors.initials: JZ
authors.lastname: Deng
authors.forename: Diem N
authors.initials: DN
authors.lastname: Nguyen
authors.forename: Craig M
authors.initials: CM
authors.lastname: Potteiger
authors.forename: Samuel L
authors.initials: SL
authors.lastname: Graham
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Vacca
authors.forename: Theresa M
authors.initials: TM
authors.lastname: Williams
mesh_terms: D001381:Azepines / Q000138:chemical synthesis*; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D007093:Imidazoles / Q000138:chemical synthesis*
chemical_list: D001381:Azepines; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D007093:Imidazoles; C525458:telcagepant