Succinic Acid → tert-Butyl 4-(4-(trifluoromethyl)-1-(2-pyrrolidin-1-ylethyl)-1H-imidazol-2-yl)piperidine-1-carboxylate succinate

Participants

Reaction Conditions

Reaction Steps

Add 1-(2-chloro-ethyl)-pyrrolidinium chloride (73.50 g, 1.15 eq) to a mixture of tert-butyl 4-(4-(trifluoromethyl)-1H-imidazol-2-yl)piperidine-1-carboxylate (120.00 g, 375.79 mmol) and potassium hydroxide (54.82 g, 2.60 eq) in dimethyl sulfoxide (1.1 L). Stir the resulting suspension at 50° C. overnight. Cool the reaction mixture to room temperature and add ice/water (1.50 l). Extract with ethyl acetate (3×500 mL). Wash the organics with water (2×300 mL) and saturated aqueous sodium chloride (300 mL), dry over anhydrous sodium sulfate. Purify by silica gel chromatography, eluting with 5% to 15% isopropyl alcohol in dichloromethane, to give a mixture of tert-butyl 4-(4-(trifluoromethyl)-1-(2-pyrrolidin-1-ylethyl)-1H-imidazol-2-yl)piperidine-1-carboxylate (122.00 g, 78%) and tert-butyl 4-(5-(trifluoromethyl)-1-(2-pyrrolidin-1-ylethyl)-1H-imidazol-2-yl)piperidine-1-carboxylate (14.00 g, 9%). Add isopropyl alcohol (470 mL) and heat to 70° C. Add a solution of butanedioic acid (35 g, 1 eq) in isopropyl alcohol (350 mL) preheated at 75° C. Stop heating and let stir at room temperature overnight. Filter the solid and wash with isopropyl alcohol (300 mL). Suspend the solid in isopropyl alcohol (500 mL) and stir 15 minutes. Filter and stir the solid in isopropyl alcohol (500 mL) 15 minutes one more time, then filter to give the title compound (124.00 g, 82%) as a white solid. MS (ES) m/z=417 [M]+.

Provenance & Evidence