Efficient Synthesis of NK1 Receptor Antagonist Aprepitant Using a Crystallization-Induced Diastereoselective Transformation
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- 作者：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
- 刊名：Journal of the American Chemical Society
- 出版年：2003
- 出版时间：February 26, 2003
- 年：2003
- 卷：125
- 期：8
- 页码：2129 - 2135
- 全文大小：137K
- 年卷期：v.125,no.8(February 26, 2003)
- ISSN：1520-5126
文摘
An efficient stereoselective synthesis of the orally active NK1 receptor antagonist Aprepitant isdescribed. 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 couplingwith 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-potprocess to the desired 
-(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 finalstep, a triazolinone side chain was appended to the morpholine core. The targeted clinical candidate wasthus obtained in 55% overall yield over the longest linear sequence.
-(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 finalstep, a triazolinone side chain was appended to the morpholine core. The targeted clinical candidate wasthus obtained in 55% overall yield over the longest linear sequence.