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 |
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Authors: | Matthew L 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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Institution: | 1. AMRI, Singapore Research Centre, Singapore Science Park II, Singapore 117525, Singapore;2. AMRI, 26 Corporate Circle, PO Box 15098, Albany, NY 12212-5098, USA |
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Abstract: | (7S,10R)-5-Methyl-2-((3-(trifluoromethyl)phenyl)sulfonyl)-5,6,7,8,9,10-hexahydro-7,10-epiminocycloheptab]indole 1a is a potent 5-HT6 antagonist (h5-HT6 Ki = 1.5 nM) which is derived from an epiminocycloheptb]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-epiminocycloheptab]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-epiminocycloheptab]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. |
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