Efficient synthesis of NK1 receptor antagonist aprepitant using a crystallization-induced diastereoselective transformation

Karel M.J. Brands, Joseph F. Payack, Jonathan D. Rosen, Todd D. Nelson, Alexander Candelario, Mark A. Huffman, Matthew M. Zhao, Jing Li, Bridgette Craig, Zhiguo J. Song, David M. Tschaen, Karl Hansen, Paul N. Devine, Philip J. Pye, Kai Rossen, Peter G. Dormer, Robert A. Reamer, Christopher J. Welch, David J. Mathre, Nancy N. TsouJames M. McNamara, Paul J. Reider

Research output: Contribution to journalArticle

134 Scopus citations

Abstract

An efficient stereoselective synthesis of the orally active NK1 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 α-(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.

Original languageEnglish (US)
Pages (from-to)2129-2135
Number of pages7
JournalJournal of the American Chemical Society
Volume125
Issue number8
DOIs
StatePublished - Feb 26 2003
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Catalysis
  • Chemistry(all)
  • Biochemistry
  • Colloid and Surface Chemistry

Fingerprint Dive into the research topics of 'Efficient synthesis of NK<sub>1</sub> receptor antagonist aprepitant using a crystallization-induced diastereoselective transformation'. Together they form a unique fingerprint.

  • Cite this

    Brands, K. M. J., Payack, J. F., Rosen, J. D., Nelson, T. D., Candelario, A., Huffman, M. A., Zhao, M. M., Li, J., Craig, B., Song, Z. J., Tschaen, D. M., Hansen, K., Devine, P. N., Pye, P. J., Rossen, K., Dormer, P. G., Reamer, R. A., Welch, C. J., Mathre, D. J., ... Reider, P. J. (2003). Efficient synthesis of NK1 receptor antagonist aprepitant using a crystallization-induced diastereoselective transformation. Journal of the American Chemical Society, 125(8), 2129-2135. https://doi.org/10.1021/ja027458g