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.

Citation

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. Practical asymmetric synthesis of aprepitant, a potent human NK-1 receptor antagonist, via a stereoselective Lewis acid-catalyzed trans acetalization reaction. The Journal of organic chemistry. 2002 Sep 20;67(19):6743-7

PMID: 12227806

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