Diisopropylethylamine → Benzamide

Participants

Reaction Conditions

Reaction Steps

1-(aminomethyl)-4,4-difluoro-N,N-dimethylcyclohexanamine represented by Formula 105 (190 mg, 0.99 mmol) was slowly added to a solution of 4-benzyloxy-3,4-dimethoxybenzoic acid represented by Formula 89 (327.66 mg, 1.14 mmol) and diisopropylethylamine (0.70 mL, 3.95 mmol) in DMF (7 mL) at room temperature. The reaction mixture was cooled to 0° C. and, after adding 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate methanaminium (HATU, 375.75 mg, 0.99 mmol) thereto, agitated at room temperature for 24 hours. The reaction solvent was removed under reduced pressure and chloroform (20 mL) was added to the remaining concentrate to prepare a solution. The solution was washed with a potassium carbonate solution, followed by separation to form an organic layer. After drying the organic layer with sodium sulfate (Na2SO4), the solvent was removed again under reduced pressure. The obtained vacuum-concentrated mixture was subjected to separation and purification through column chromatography (ethyl acetate/hexane/triethylamine, 2:1:0.1, v/v/v) using silica gel (SiO2), resulting in an alkalinized benzamide compound represented by Formula 11. HCl in MeOH (1.25 M, 0.75 mL, 0.93 mmol) was added to the alkalinized benzamide compound (360 mg, 0.78 mmol) in MeOH (5 mL) at room temperature. The reaction mixture was agitated at room temperature for 3 hours, the reaction solvent was removed under reduced pressure, and the remaining solids were filtered and washed with hexane to produce a benzamide salt compound represented by Formula 15 as a desired product (VVZ-016; 370 mg, 75% yield).

Provenance & Evidence