A multigram chemical synthesis of the gamma-secretase inhibitor LY411575 and its diastereoisomers.
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.
Fauq
Abdul H
AH
Department of Neuroscience, Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, FL 32224, USA. fauq.abdul@mayo.edu
Simpson
Katherine
K
Maharvi
Ghulam M
GM
Golde
Todd
T
Das
Pritam
P
D000409:Alanine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D001381:Azepines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000528:radiation effects; D002850:Chromatography, Gel; D007769:Lactams / Q000138:chemical synthesis / Q000737:chemistry / Q000528:radiation effects; D008872:Microwaves; D015394:Molecular Structure; D058428:Silica Gel; D012822:Silicon Dioxide / Q000737:chemistry; D013237:Stereoisomerism
C527770:5,7-dihydro-6H-dibenz-(b,d)azepin-6-one; D001381:Azepines; D007769:Lactams; C484278:N2-((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; D058428:Silica Gel; D012822:Silicon Dioxide; D053829:Amyloid Precursor Protein Secretases; D000409:Alanine