Efficient Synthesis of NK 1 Receptor Antagonist Aprepitant Using a Crystallization-Induced Diastereoselective Transformation
2003; American Chemical Society; Volume: 125; Issue: 8 Linguagem: Inglês
10.1021/ja027458g
ISSN1943-2984
AutoresKarel M. J. Brands, Joseph F. Payack, Jonathan D. Rosen, Todd D. Nelson, A. Candelario, Mark A. Huffman, Matthew M. Zhao, Jing Li, Bridgette Craig, Zhiguo J. Song, David M. Tschaen, Karl B. 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,
Tópico(s)Asymmetric Synthesis and Catalysis
ResumoAn 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.
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