Journal
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
Volume 17, Issue 22, Pages 6392-6395Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2007.07.062
Keywords
LY411575; diastereomer; microwave; chiral chromatography; R-lactic acid
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Funding
- NIA NIH HHS [P01 AG025531, P01 AG020206, P01 AG025531-01A1, P01 AG025531-03, P01 AG025531-02, P01 AG 20206] Funding Source: Medline
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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.
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