Practical Asymmetric Synthesis of Aprepitant, a Potent HumanNK-1 Receptor Antagonist, via a Stereoselective LewisAcid-Catalyzed Trans Acetalization Reaction
A streamlined and high-yielding synthesis of aprepitant (1), a potent substance P (SP) receptorantagonist, is described. The enantiopure oxazinone 16 starting material was synthesized via anovel crystallization-induced dynamic resolution process. Conversion of 16 to the penultimateintermediate 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 chiralcenter on the morpholine ring. The six-step process for the synthesis of 9 was accomplished inextremely high overall yield (81%) and with only two isolations.
