Practical asymmetric synthesis of aprepitant, a potent human NK-1 receptor antagonist, via a stereoselective Lewis acid-catalyzed trans acetalization reaction.
A streamlined and high-yielding synthesis of aprepitant (1), a potent substance P (SP) receptor antagonist, is described. The enantiopure oxazinone 16 starting material was synthesized via a novel crystallization-induced dynamic resolution process. Conversion of 16 to the penultimate intermediate cis-sec-amine 9 features a highly stereoselective Lewis acid-catalyzed trans acetalization of chiral alcohol 3 with trichloroacetimidate 18 followed by inversion of the adjacent chiral center on the morpholine ring. The six-step process for the synthesis of 9 was accomplished in extremely high overall yield (81%) and with only two isolations.
Zhao
Matthew M
MM
Process Research, Merck Sharp & Dohme Research Laboratories, Hertford Road, Hoddesdon, Hertfordshire EN11 9BU, UK. matthew_ahao@merck.com
McNamara
James M
JM
Ho
Guo-Jie
GJ
Emerson
Khateeta M
KM
Song
Zhiguo J
ZJ
Tschaen
David M
DM
Brands
Karel M J
KM
Dolling
Ulf-H
UH
Grabowski
Edward J J
EJ
Reider
Paul J
PJ
Cottrell
Ian F
IF
Ashwood
Michael S
MS
Bishop
Brian C
BC