Tris(hydroxymethyl)aminomethane → N-[3,5-bis(trifluoromethyl)phenyl]-4-{3-[(pyridin-4-ylmethyl)oxy]pyridin-2-yl}piperazine-1-carboxamide

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Reaction Steps

The crude 1-[3-(Pyridin-4-ylmethoxy)pyridin-2-yl]-piperazine trifluoroacetic acid salt (˜500 mg) was dissolved in 25 mL of tetrahydrofuran along with 2 g of trisamine resin. The suspension was stirred for 1 hr and the resin was removed by filtration. The filtrate was concentrated under vacuum. The free-based material was dissolved in 5 mL of dichloromethane. To this solution was added triethylamine (150 μL, 1.08 mmol) and 3,5-bis(trifluoromethyl)phenyl isocyanate (150 μL, 0.864 mmol). The reaction was stirred at room temperature for 1 hr. The reaction mixture was concentrated under vacuum and re-dissolved in 25 mL ethyl acetate. The reaction mixture was washed 3 times each with 25 mL portions of water, 0.05 M HCl and saturated aqueous sodium chloride. The organic fraction was dried with magnesium sulfate and concentrated under vacuum. The residue was purified by flash chromatography with a gradient of 0% to 10% methanol in ethyl acetate with 5% triethylamine, giving N-[3,5-bis(trifluoromethyl)phenyl]-4-{3-[(pyridin-4-ylmethyl)oxy]pyridin-2-yl}piperazine-1-carboxamide (14 mg). 1H NMR (DMSO-d6) δ 9.24 (s, 1H), 8.60 (d, 2H), 8.22 (s, 2H), 7.84 (d, 1H), 7.58 (s, 1H), 7.46 (d, 2H), 7.33 (d, 1H), 6.92 (dd, 1H), 5.23 (s, 2H), 3.62-3.68 (m, 4H) 3.37-3.41 (m, 4H) ppm.

Provenance & Evidence