Water → 1-(Cyclohexylmethyl)-7-methoxyindole-3-carboxylic acid

Participants

Reaction Conditions

Reaction Steps

The damp solid was suspended in 4 M aqueous sodium hydroxide (1700 ml) and heated to reflux with stirring for 2 h. The mixture was cooled and washed with diethyl ether (2×400 ml). The aqueous phase was then acidified to pH 1 using 5 M hydrochloric acid and the resulting fine precipitate filtered off, washed with water to neutrality and dried to afford 7-methoxy-1H-indole-3-carboxylic acid as a pink solid (42.7 g). To a solution of 7-methoxy-1H-indole-3-carboxylic acid (42.7 g, 224 mmol) in di-methylformamide (1250 ml) at 10° C. under nitrogen was added sodium hydride (60% dispersion in mineral oil, 23.0 g, 575 mmol) portionwise over 20 minutes, maintaining the temperature below 15° C. The cooling bath was removed and the suspension stirred for 90 minutes. Cyclohexylmethyl bromide (64.7 ml, 464 mmol) was added. The mixture was heated at 60° C. with stirring for 3 h. The mixture was cooled to 10° C. and poured into water (3600 ml). The emulsion was washed with diethyl ether (3×500 ml). The aqueous phase was acidified to pH 1 using 5 M hydrochloric acid and the precipitate filtered off, washed with water to neutrality and dried to afford 1-(cyclohexyl)methyl-7-methoxy-1H-indole-3-carboxylic acid (55 g) as a white solid. Oxalyl chloride (12.4 g, 97.4 mmol) was added dropwise to a mixture of 1-(cyclohexyl)methyl-7-methoxy-1H-indole-3-carboxylic acid (7.0 g, 24.4 mmol) and dichloromethane (150 ml) under ice-water cooling and the resulting mixture was stirred at room temperate for 18 h. Dichloromethane and excess oxalyl chloride were removed by evaporation and the obtained residue was mixed with dichloromethane (150 ml). Ammonia gas was bubbled into the resulting mixture for 30 min under ice-water bath cooling. The reaction mixture was concentrated in vacuo, then the obtained solid was triturated sequentially with 0.5 M hydrochloric acid, 5% aqueous sodium carbonate, and water, and dried under reduced pressure to afford 1-(cyclohexyl)methyl-7-methoxy-1H-indole-3-carboxylic acid amide (5.1 g) as a brown solid.

Provenance & Evidence