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An efficient stereoselective synthesis of the orally active NK(1) 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 alpha-(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.


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 Tsou, James M McNamara, Paul J Reider. Efficient synthesis of NK(1) receptor antagonist aprepitant using a crystallization-induced diastereoselective transformation. Journal of the American Chemical Society. 2003 Feb 26;125(8):2129-35

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PMID: 12590540

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