title: Efficient synthesis of NK(1) receptor antagonist aprepitant using a crystallization-induced diastereoselective transformation.
abstract: 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.
authors.affiliation: Department of Process Research, Merck Research Laboratories, Rahway, New Jersey 07065, USA.
authors.forename: Karel M J
authors.initials: KM
authors.lastname: Brands
authors.forename: Joseph F
authors.initials: JF
authors.lastname: Payack
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Rosen
authors.forename: Todd D
authors.initials: TD
authors.lastname: Nelson
authors.forename: Alexander
authors.initials: A
authors.lastname: Candelario
authors.forename: Mark A
authors.initials: MA
authors.lastname: Huffman
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Zhao
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.forename: Bridgette
authors.initials: B
authors.lastname: Craig
authors.forename: Zhiguo J
authors.initials: ZJ
authors.lastname: Song
authors.forename: David M
authors.initials: DM
authors.lastname: Tschaen
authors.forename: Karl
authors.initials: K
authors.lastname: Hansen
authors.forename: Paul N
authors.initials: PN
authors.lastname: Devine
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Pye
authors.forename: Kai
authors.initials: K
authors.lastname: Rossen
authors.forename: Peter G
authors.initials: PG
authors.lastname: Dormer
authors.forename: Robert A
authors.initials: RA
authors.lastname: Reamer
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Welch
authors.forename: David J
authors.initials: DJ
authors.lastname: Mathre
authors.forename: Nancy N
authors.initials: NN
authors.lastname: Tsou
authors.forename: James M
authors.initials: JM
authors.lastname: McNamara
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Reider
mesh_terms: 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
chemical_list: D007769:Lactams; D009025:Morpholines; D064729:Neurokinin-1 Receptor Antagonists; D010078:Oxazines; D000077608:Aprepitant