5-chloro-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole → HCID 10439569, compound

Participants

Reaction Steps

The diastereoisomer mixture of (4-dimethylamino-4-phenylcyclohexylmethyl)-carbamic acid phenyl ester (705 mg, 2 mmole) was added to a solution of 5-chloro-3-(1,2,3,6-tetrahydropyridine-4-yl)-1H-indole (465.4 mg, 2 mmole) in dioxane (12 ml). The reaction mixture was then boiled under reflux for 20 hours. The reaction mixture was a suspension at RT. The solid was filtered off, washed with cold dioxane (3×2 ml) and dried. The solid was the polar diastereoisomer of 4-(5-chloro-1H-indol-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid-(4-dimethylamino-4-phenylcyclohexylmethyl)-amide (259 mg, m.p. 120°-130° C., 26%). The reaction solution (filtrate and wash phases) was concentrated by evaporation and water (10 ml) was added to the residue. The reaction mixture was adjusted to pH 11 with 5M NaOH and extracted with EE (3×20 ml). The combined EE extracts were washed with 1M NaOH (1×5 ml) and dried with Na2SO4. The solvent was distilled off in vacuo. The residue contained phenol and mainly the non-polar diastereoisomer of 4-(5-chloro-1H-indol-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid-(4-dimethylamino-4-phenylcyclohexylmethyl)-amide. The diastereoisomers were separated and purified by flash chromatography on silica gel (80 g). Ethanol (1000 ml) was used as eluent. The non-polar diastereoisomer of 4-(5-chloro-1H-indol-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid-(4-dimethylamino-4-phenylcyclohexylmethyl)-amide (304 mg, m.p. 216°-222° C., 31%) and a further part of the polar diastereoisomer of 4-(5-chloro-1H-indol-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid-(4-dimethylamino-4-phenylcyclohexylmethyl)-amide (85 mg, m.p. 108°-111° C., 9%) were thereby isolated.

Provenance & Evidence