Stereoselective preparation of a cyclopentane-based NK1 receptor antagonist bearing an unsymmetrically substituted sec-sec ether.
A highly efficient synthesis of the potent and selective NK-1 receptor antagonist 1 is described. The key transformation involved the etherification reaction between cyclopentanol 12 and chiral imidate 30 which was catalyzed by HBF4 to initially give ether 14 as a 17:1 mixture of diastereomers and in 75% combined yield. The diastereoselectivity was upgraded to 109:1 by crystallization of the triethylamine solvate 44 which was isolated in 54% yield from 12. Mechanistic studies confirmed that the etherification reaction proceeds through an unprecedented S(N)2 reaction pathway under typical S(N)1 reaction conditions.
Kuethe
Jeffrey T
JT
Department of Process Research, Merck and Company, Incorporated, P.O. Box 2000, Rahway, New Jersey 07065, USA. Jeffrey_Kuethe@Merck.com
Marcoux
Jean-Francois
JF
Wong
Audrey
A
Wu
Jimmy
J
Hillier
Michael C
MC
Dormer
Peter G
PG
Davies
Ian W
IW
Hughes
David L
DL
D003517:Cyclopentanes / Q000138:chemical synthesis* / Q000737:chemistry; D004987:Ethers; D015394:Molecular Structure; D064729:Neurokinin-1 Receptor Antagonists
D003517:Cyclopentanes; D004987:Ethers; D064729:Neurokinin-1 Receptor Antagonists