Synthesis of (r)‐ and (s)‐1‐formyl‐6,7,8,9‐tetrahydro‐ N,N‐(dipropyl)‐3H‐benz[e]indol‐8‐amines: Potent and orally active 5‐ht_1a receptor agonists

Abstract

An efficient synthesis of the potent and orally active 5‐HT1A agonists, (R)‐(+)‐ and (S)‐(‐)‐1‐formyl‐6,7,8,9‐tetrahydro‐N,N‐dipropyl‐3H‐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‐4H‐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‐3H‐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.