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.
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.
Burgey
Christopher S
CS
Department of Medicinal Chemistry, Merck Research Laboratories, West Point, Pennsylvania 19486, USA. christopher_burgey@merck.com
Paone
Daniel V
DV
Shaw
Anthony W
AW
Deng
James Z
JZ
Nguyen
Diem N
DN
Potteiger
Craig M
CM
Graham
Samuel L
SL
Vacca
Joseph P
JP
Williams
Theresa M
TM
D001381:Azepines / Q000138:chemical synthesis*; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D007093:Imidazoles / Q000138:chemical synthesis*
D001381:Azepines; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D007093:Imidazoles; C525458:telcagepant