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Practical Asymmetric Synthesis of Aprepitant, a Potent Human NK-1 Receptor Antagonist, via a Stereoselective Lewis Acid-Catalyzed Trans Acetalization Reaction

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journal contribution
posted on 28.08.2002, 00:00 by Matthew M. Zhao, James M. McNamara, Guo-Jie Ho, Khateeta M. Emerson, Zhiguo J. Song, David M. Tschaen, Karel M. J. Brands, Ulf-H Dolling, Edward J. J. Grabowski, Paul J. Reider, Ian F. Cottrell, Michael S. Ashwood, Brian C. Bishop
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.