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

被引：128

作者：

Brands, KMJ ^{[1
]}

Payack, JF ^{[1
]}

Rosen, JD ^{[1
]}

Nelson, TD ^{[1
]}

Candelario, A ^{[1
]}

Huffman, MA ^{[1
]}

Zhao, MM ^{[1
]}

Li, J ^{[1
]}

Craig, B ^{[1
]}

Song, ZGJ ^{[1
]}

Tschaen, DM ^{[1
]}

Hansen, K ^{[1
]}

Devine, PN ^{[1
]}

Pye, PJ ^{[1
]}

Rossen, K ^{[1
]}

Dormer, PG ^{[1
]}

Reamer, RA ^{[1
]}

Welch, CJ ^{[1
]}

Mathre, DJ ^{[1
]}

Tsou, NN ^{[1
]}

McNamara, JM ^{[1
]}

Reider, PJ ^{[1
]}

机构：

[1] Merck Res Labs, Dept Proc Res, Rahway, NJ 07065 USA

来源：

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY | 2003年 / 125卷 / 08期

关键词：

D O I：

10.1021/ja027458g

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

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-1,4oxazin-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.

引用

页码：2129 / 2135

页数：7

共 72 条

[1] N-BOC 2-ACYLOXAZOLIDINES - USEFUL PRECURSORS TO ENANTIOPURE 1,2-DIOLS VIA HIGHLY DIASTEREOSELECTIVE NUCLEOPHILIC ADDITIONS [J].