Practical asymmetric synthesis of aprepitant, a potent human NK-1 receptor antagonist, via a stereoselective Lewis acid-catalyzed trans acetalization reaction

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

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62 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)6743-6747
Number of pages5
JournalJournal of Organic Chemistry
Volume67
Issue number19
DOIs
StatePublished - Sep 20 2002
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Organic Chemistry

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    Zhao, M. M., McNamara, J. M., Ho, G. J., Emerson, K. M., Song, Z. J., Tschaen, D. M., Brands, K. M. J., Dolling, U. H., Grabowski, E. J. J., Reider, P. J., Cottrell, I. F., Ashwood, M. S., & Bishop, B. C. (2002). Practical asymmetric synthesis of aprepitant, a potent human NK-1 receptor antagonist, via a stereoselective Lewis acid-catalyzed trans acetalization reaction. Journal of Organic Chemistry, 67(19), 6743-6747. https://doi.org/10.1021/jo0203793