title: Practical asymmetric synthesis of aprepitant, a potent human NK-1 receptor antagonist, via a stereoselective Lewis acid-catalyzed trans acetalization reaction.
abstract: 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.
authors.affiliation: Process Research, Merck Sharp & Dohme Research Laboratories, Hertford Road, Hoddesdon, Hertfordshire EN11 9BU, UK. matthew_ahao@merck.com
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Zhao
authors.forename: James M
authors.initials: JM
authors.lastname: McNamara
authors.forename: Guo-Jie
authors.initials: GJ
authors.lastname: Ho
authors.forename: Khateeta M
authors.initials: KM
authors.lastname: Emerson
authors.forename: Zhiguo J
authors.initials: ZJ
authors.lastname: Song
authors.forename: David M
authors.initials: DM
authors.lastname: Tschaen
authors.forename: Karel M J
authors.initials: KM
authors.lastname: Brands
authors.forename: Ulf-H
authors.initials: UH
authors.lastname: Dolling
authors.forename: Edward J J
authors.initials: EJ
authors.lastname: Grabowski
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Reider
authors.forename: Ian F
authors.initials: IF
authors.lastname: Cottrell
authors.forename: Michael S
authors.initials: MS
authors.lastname: Ashwood
authors.forename: Brian C
authors.initials: BC
authors.lastname: Bishop