Water → Darifenacin

Participants

Reaction Steps

A slurry of potassium hydroxide (48.7 g, 0.87 moles) in 2-methylbutan-2-ol (175 mL) is heated at 50-60° C. After 1 hour (S)-2-{1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]-3-pyrrolidinyl}-2,2-diphenylacetonitrile hydrobromide (VI) (25.0 g, 0.051 moles) is added and the resulting mixture is heated at reflux for 20 hours. The reaction mixture is cooled to ambient temperature and water (125 mL) is added maintaining the temperature below 30° C. The mixture is stirred for 15 minutes, then allowed to settle and the organic phase is separated. The organic phase is washed with aqueous sodium chloride (125 mL of 5% w/w solution) to provide a solution of (S)-2-{1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]-3-pyrrolidinyl}-2,2-diphenylacetamide as a solution in 2-methylbutan-2-ol (VII). The solution is heated at reflux in the presence of Amberlite® resin (37.5 g) for 22 hours then cooled to ambient temperature. The Amberlite® resin is removed by filtration and washed with 2-methylbutan-2-ol (25 mL). The combined 2-methylbutan-2-ol phases are concentrated and essentially replaced by toluene to a final volume of approximately 140 mL. The toluene solution is cooled to 0° C. during which time crystallisation occurs. (S)-2-{1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]-3-pyrrolidinyl}-2,2-diphenylacetamide toluene solvate (VIII) is collected by filtration, washed with chilled toluene (25 mL) and dried at 35° C. under vacuum. Yield (22.2 g, 84%).

Provenance & Evidence