A multigram chemical synthesis of the γ-secretase inhibitor LY411575 and its diastereoisomers

被引：61

作者：

Fauq, Abdul H. ^{[1
]}

Simpson, Katherine ^{[1
]}

Maharvi, Ghulam M. ^{[1
]}

Golde, Todd ^{[1
]}

Das, Pritam ^{[1
]}

机构：

[1] Mayo Clin Jacksonville, Dept Neurosci, Jacksonville, FL 32224 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2007年 / 17卷 / 22期

关键词：

LY411575; diastereomer; microwave; chiral chromatography; R-lactic acid;

D O I：

10.1016/j.bmcl.2007.07.062

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

An improved chemical synthesis of N-2((2S)-2-(3,5-difluorophenyl)-2-hydroxyethanoyl)-N1-((7S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-L-alaninamide (LY411,575, 9a), a known gamma-secretase inhibitor, is described. The key synthetic steps, which used no chiral chromatography in the entire sequence, involved (1) improved microwave-assisted synthesis of a seven-membered lactam (+/-)-(5.7-dihydro-6H-dibenz-[b,d]azepin-6-one 2, and (2) convenient isolation of pure LY411575 from a mixture of four diastereomers by simple flash silica gel chromatography. Starting from the resolved aminolactams 5a and 5b, all four diastereomers were produced in enantiomerically pure form. (C) 2007 Elsevier Ltd. All rights reserved.

引用

页码：6392 / 6395

页数：4

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