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Synthesis of ( r )‐ and ( s )‐1‐formyl‐6,7,8,9‐tetrahydro‐ N,N ‐(dipropyl)‐3 H ‐benz[ e ]indol‐8‐amines: Potent and orally active 5‐ht 1a receptor agonists
Author(s) -
Lin ChiuHong,
Ennis Michael D.,
Hoffman Robert L.,
Phillips Gillian,
HaadsmaSvensson Susanne R.,
Ghazal Nabil B.,
Chidester Connie G.
Publication year - 1994
Publication title -
journal of heterocyclic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.321
H-Index - 59
eISSN - 1943-5193
pISSN - 0022-152X
DOI - 10.1002/jhet.5570310123
Subject(s) - chemistry , medicinal chemistry
An efficient synthesis of the potent and orally active 5‐HT 1A agonists, ( R )‐(+)‐ and ( S )‐(‐)‐1‐formyl‐6,7,8,9‐tetrahydro‐ N,N ‐dipropyl‐3 H ‐benz[ e ]indol‐8‐amines 1a and 1b , is described. This synthesis was accomplished in twelve steps from commercially available 1,5,6,7‐tetrahydro‐4 H ‐indol‐4‐one ( 5 ). The key step involved a regio‐controlled Friedel‐Crafts acylation of 1‐( p ‐toluenesulfonyl)indol‐4‐acetyl chloride with ethylene to yield a versatile synthon, 3‐( p ‐toluenesulfonyl)‐6,7,8,9‐tetrahydro‐3 H ‐benz[ e ]indol‐8‐one ( 10 ). Subsequent coupling of this ketone with chiral α‐methylbenzylamine under reductive amination conditions yielded a mixture of diastereomers. These diastereomers were efficiently separated by either chromatography or fractional recrystallization of the derived hydrochloride salts. Debenzylation of the pure diastereomers was followed by alkylation and formylation to yield ( R )‐(+)‐ and ( S )‐(‐)‐enantiomers 1a and 1b with >99% purity.