Synthesis of a tetrahydropyran NK1 receptor antagonist via asymmetric conjugate addition.
Two asymmetric syntheses of the NK(1) receptor antagonist 1-[2-(R)-{1-(R)-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-3-(R)-(3,4-difluorophenyl)-4-(R)-tetrahydro-2H-pyran-4-ylmethyl]-3-(R)-methylpiperidine-3-carboxylic acid (1) were developed. In both routes, the core tetrahydropyran stereochemistry was established by asymmetric conjugate addition to an alpha,beta-unsaturated ester (6), using an amide of the chiral auxiliary pseudoephedrine. Selective ester reduction then allowed formation of lactone 2 with the thermodynamically preferred trans geometry. The chiral ether side chain (3) was attached by stereoselective acetal substitution. In the first route, the chiral piperidine ester fragment was installed at the end by N-alkylation. In the shorter second synthesis, this piece was appended to the Michael acceptor at the beginning.
Huffman
Mark A
MA
Department of Process Research, Merck & Co. Inc., P.O. Box 2000, Rahway, NJ 07065, USA. mark_huffman@merck.com
Smitrovich
Jacqueline H
JH
Rosen
Jonathan D
JD
Boice
Geneviève N
GN
Qu
Chuanxing
C
Nelson
Todd D
TD
McNamara
James M
JM
D000478:Alkylation; D020650:Combinatorial Chemistry Techniques; D015394:Molecular Structure; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011714:Pyrans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism
C501270:1-(2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(R)-(3,4-difluorophenyl)-4-(R)-tetrahydro-2H-pyran-4-ylmethyl)-3-(R)-methylpiperidine-3-carboxylic acid; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines; D011714:Pyrans