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Bioorg Med Chem Lett. 2007 Nov 15;17(22):6392-5. Epub 2007 Aug 30.

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

Author information

1
Department of Neuroscience, Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, FL 32224, USA. fauq.abdul@mayo.edu

Abstract

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.

PMID:
17897827
PMCID:
PMC2962444
DOI:
10.1016/j.bmcl.2007.07.062
[Indexed for MEDLINE]
Free PMC Article

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