Acetonitrile → tert-butyl (3S,5R)-3-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

Participants

Reaction Conditions

Reaction Steps

tert-Butyl (3S,5R)-3-[(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate succinate (30.3 g, 62.2 mmol), acetonitrile (60.0 mL) and water (40.0 mL) were charged. Then, potassium carbonate (34.4 g, 0.249 mmol) was added, and the mixture was stirred for 10 min. 1-(4-Methoxybutyl)-2-trichloromethyl-1H-benzimidazole (20.0 g, 62.2 mmol) was added, and the mixture was stirred at 70-80° C. for 2 hr. Dimethyl sulfoxide (15.0 mL) was added, and the mixture was stirred at 70-80° C. for 6 hr. The reaction mixture was allowed to cool to 20-30° C. water (120 mL) and toluene (240 mL) were added, and the mixture was partitioned. The organic layer was washed successively with 10 w/v % brine (100 mL), 10 w/v % aqueous citric acid solution (100 mL) and 10 w/v % brine (100 mL). To the organic layer was added activated carbon Shirasagi A (1.0 g), and the mixture was stirred at 20-30° C. for 30 min. The activated carbon was filtered off and washed with toluene (40.0 mL), and the filtrate was concentrated under reduced pressure to 110 mL. After heating to 35-45° C., heptane (280 mL) was added dropwise tert-Butyl (3S,5R)-3-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate as crystals (10 mg) was added at 35-45° C., and the mixture was stirred at the same temperature for 1 hr. Heptane (140 mL) was added dropwise at 35-45° C., and the mixture was stirred for 30 min. The mixture was allowed to cool to 20-30° C. and stirred for 2 hr. The precipitated crystals were collected by filtration, washed with toluene-heptane (1:5, 40.0 mL), and dried under reduced pressure at 50° C. to give tert-butyl (3S,5R)-3-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate as a pale yellowish white crystalline powder (27.7 g, yield 74.2%).

Provenance & Evidence