3,5-Bis(trifluoromethyl)benzoic acid → (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl) 4-[4-(3,3-dimethylmorpholino)-2-butynyl]piperazine dihydrochloride

Participants

Reaction Steps

1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide (0.22 ml) was added over 5 minutes to a mixture of (3R)-3-(3,4-dimethylbenzyl)-1-[4-(3,3-dimethylmorpholino)-2-butynyl]-piperazine trihydrochloride (0.48 g) and 3,5-bis(trifluoromethyl)benzoic acid (0.27 g), 1-hydroxybenzotriazole (0.15 g) and triethylamine (0.35 ml) in dichloromethane (10 ml). After 2 hours of stirring at room temperature, the reaction mixture was directly purified by column chromatography on silica gel using a mixed solvent of dichloromethane and methanol (40:1). The fractions containing the objective compound was collected and evaporated under reduced pressure. The residue was treated with 4N hydrogen chloride in ethyl acetate and recrystallized from a mixture of acetone and water to give colorless crystals of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[4-(3,3-dimethylmorpholino)-2-butynyl]-piperazine dihydrochloride (525 g).

Provenance & Evidence