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

doi:10.1016/j.bmcl.2007.07.062

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

Neuroscience

Research output: Contribution to journal › Article › peer-review

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 language	English (US)
Pages (from-to)	6392-6395
Number of pages	4
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	17
Issue number	22
DOIs	https://doi.org/10.1016/j.bmcl.2007.07.062
State	Published - 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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10.1016/j.bmcl.2007.07.062

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title = "A multigram chemical synthesis of the γ-secretase inhibitor LY411575 and its diastereoisomers",

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.",

keywords = "Chiral chromatography, Diastereomer, LY411575, Microwave, R-lactic acid",

author = "Fauq, {Abdul H.} and Katherine Simpson and Maharvi, {Ghulam M.} and Todd Golde and Pritam Das",

note = "Funding Information: The financial support provided for this synthetic project by National Institutes of Health (NIH Grant No. P01 AG20206) is gratefully acknowledged. ",

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doi = "10.1016/j.bmcl.2007.07.062",

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AU - Fauq, Abdul H.

AU - Simpson, Katherine

AU - Maharvi, Ghulam M.

AU - Golde, Todd

AU - Das, Pritam

N1 - Funding Information: The financial support provided for this synthetic project by National Institutes of Health (NIH Grant No. P01 AG20206) is gratefully acknowledged.

PY - 2007/11/15

Y1 - 2007/11/15

N2 - 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.

AB - 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.

KW - Chiral chromatography

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KW - LY411575

KW - Microwave

KW - R-lactic acid

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

Abstract

Keywords

ASJC Scopus subject areas

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