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

Abdul H. Fauq, Katherine Simpson, Ghulam M. Maharvi, Todd Golde, Pritam Das

Research output: Contribution to journalArticle

52 Scopus citations

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 γ-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.

Original languageEnglish (US)
Pages (from-to)6392-6395
Number of pages4
JournalBioorganic and Medicinal Chemistry Letters
Volume17
Issue number22
DOIs
StatePublished - Nov 15 2007

Keywords

  • Chiral chromatography
  • Diastereomer
  • LY411575
  • Microwave
  • R-lactic acid

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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