Efficient Synthesis of NK1 Receptor Antagonist Aprepitant Using a Crystallization-Induced Diastereoselective Transformation
| Autor: | Jing Li, David J. Mathre, Joseph F. Payack, James M. McNamara, Nancy N. Tsou, David M. Tschaen, Karel M. J. Brands, Karl B. Hansen, Paul J. Reider, Bridgette Craig, Peter G. Dormer, Mark A. Huffman, Philip J. Pye, Todd D. Nelson, Kai Rossen, Robert A. Reamer, Alexander Candelario, Jonathan D. Rosen, Christopher J. Welch, Zhiguo J. Song, Paul N. Devine, Matthew M. Zhao |
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| Rok vydání: | 2003 |
| Předmět: |
Trifluoromethyl
Lactams Molecular Structure Stereochemistry Chemistry Morpholines Acetal Total synthesis Stereoisomerism General Chemistry Crystallography X-Ray Condensation reaction Biochemistry Catalysis chemistry.chemical_compound Colloid and Surface Chemistry Enantiopure drug Neurokinin-1 Receptor Antagonists Morpholine Oxazines Lewis acids and bases Aprepitant Glyoxylic acid |
| Zdroj: | Journal of the American Chemical Society. 125:2129-2135 |
| ISSN: | 1520-5126 0002-7863 |
| DOI: | 10.1021/ja027458g |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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