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

(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-HT6Ki = 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.

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(7S,10R)-11-tert-Butyl 5-((1R,2S,5R)-2-isopropyl-5-methylcyclohexyl) 2-bromo-7,8,9,10-tetrahydro-7,10-epiminocyclohepta[b]indole-5,11(6H)-dicarboxylateC29H39BrN2O4[α]D20=-100.0 (c, 1.0, CHCl3)Absolute configuration: (7S,10R)

(7S,10R)-tert-Butyl 2-bromo-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole-11-carboxylateC18H21BrN2O2[α]D20=-100.4 (c, 0.9, DMSO)Absolute configuration: (7S,10R)

(7S,10R)-tert-Butyl 2-bromo-5-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole-11-carboxylateC19H23BrN2O2[α]D20=+121.8 (c, 1.1, CHCl3)Absolute configuration: (7S,10R)

(7S,10R)-tert-Butyl 5-methyl-2-((3-(trifluoromethyl)phenyl)sulfonyl)-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole-11-carboxylateC26H27F3N2O4S[α]D20=-64.6 (c, 1.3, CHCl3)Absolute configuration: (7S,10R)

(7S,10R)-5-Methyl-2-((3-(trifluoromethyl)phenyl)sulfonyl)-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole hydrochlorideC21H20CIF3N2O2S[α]D20=+36.6 (c, 0.8, MeOH)Absolute configuration: (7S,10R)