An efficient synthesis of (7S,10R)-2-bromo-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole: application in the preparation and structural confirmation of a potent 5-HT6 antagonist

Matthew Isherwood, Peter R. Guzzo, Alan J. Henderson, Ming Min Hsia, Jagjit Kaur, Kassoum Nacro, Venkateswara R. Narreddula, Shailaja Panduga, Rashmi Pathak, Bharat Shimpukade, Valentina Tan, Kai Xiang, Zhu Qiang, Animesh Ghosh

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Abstrakt

(7S,10R)-5-Methyl-2-((3-(trifluoromethyl)phenyl)sulfonyl)-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole 1a is a potent 5-HT6 antagonist (h5-HT6 Ki = 1.5 nM) which is derived from an epiminocyclohept[b]indole scaffold. In order to synthesize 1a on a multi-gram scale to support advanced biological testing, an efficient chiral resolution of the intermediate tert-butyl 2-bromo-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole-11-carboxylate 2 was developed. After derivatizing 2 with (1R)-()-menthyl chloroformate it was found that a single diastereomer 7a could be isolated by selective precipitation from n-hexane. The absolute stereochemistry of 7a was determined by X-ray crystallography and the structure was confirmed as (7S,10R)-tert-butyl 2-bromo-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole-11-carboxylate. Removal of the chiral auxiliary under basic conditions afforded intermediate 2a in >99% enantiomeric purity and with 80% yield based on recovery from the racemic compound 2. Intermediate 2a was used successfully to synthesize 5-HT6 antagonist 1a on a multi-gram scale.
OriginalsprogEngelsk
TidsskriftTetrahedron: Asymmetry
Vol/bind23
Udgave nummer22
Sider (fra-til)1522-1527
ISSN0957-4166
DOI
StatusUdgivet - 2012

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