Efficient synthesis of NK(1) receptor antagonist aprepitant using a crystallization-induced diastereoselective transformation.
An efficient stereoselective synthesis of the orally active NK(1) receptor antagonist Aprepitant is described. A direct condensation of N-benzyl ethanolamine with glyoxylic acid yielded a 2-hydroxy-1,4-oxazin-3-one which was activated as the corresponding trifluoroacetate. A Lewis acid mediated coupling with enantiopure (R)-1-(3,5-bis(trifluoromethyl)phenyl)ethan-1-ol afforded a 1:1 mixture of acetal diastereomers which was converted into a single isomer via a novel crystallization-induced asymmetric transformation. The resulting 1,4-oxazin-3-one was converted via a unique and highly stereoselective one-pot process to the desired alpha-(fluorophenyl)morpholine derivative. Interesting and unexpected [1,2]-Wittig and [1,3]-sigmatropic rearrangements were identified during the optimization of these key steps. In the final step, a triazolinone side chain was appended to the morpholine core. The targeted clinical candidate was thus obtained in 55% overall yield over the longest linear sequence.
Brands
Karel M J
KM
Department of Process Research, Merck Research Laboratories, Rahway, New Jersey 07065, USA.
Payack
Joseph F
JF
Rosen
Jonathan D
JD
Nelson
Todd D
TD
Candelario
Alexander
A
Huffman
Mark A
MA
Zhao
Matthew M
MM
Li
Jing
J
Craig
Bridgette
B
Song
Zhiguo J
ZJ
Tschaen
David M
DM
Hansen
Karl
K
Devine
Paul N
PN
Pye
Philip J
PJ
Rossen
Kai
K
Dormer
Peter G
PG
Reamer
Robert A
RA
Welch
Christopher J
CJ
Mathre
David J
DJ
Tsou
Nancy N
NN
McNamara
James M
JM
Reider
Paul J
PJ
D000077608:Aprepitant; D018360:Crystallography, X-Ray; D007769:Lactams / Q000138:chemical synthesis / Q000737:chemistry; D015394:Molecular Structure; D009025:Morpholines / Q000138:chemical synthesis* / Q000737:chemistry; D064729:Neurokinin-1 Receptor Antagonists; D010078:Oxazines / Q000737:chemistry; D013237:Stereoisomerism
D007769:Lactams; D009025:Morpholines; D064729:Neurokinin-1 Receptor Antagonists; D010078:Oxazines; D000077608:Aprepitant