1-Hydroxybenzotriazole → tert-Butyl 4-(4-((4-(2-(1-amino-1-oxopropan-2-yl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate

Participants

Reaction Steps

1-Hydroxybenzotriazole (21.1 mg, 0.156 mmol), EDCl (30.0 mg, 0.156 mmol) and N,N-diisopropylethylamine (54.5 μL, 0.313 mmol) were added to a solution of lithium 2-(2-(2-(2-((4-(1-(tert-butoxycarbonyl)piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)propanoate (I54) (0.086 g, 0.142 mmol) in dry THF (6 mL) and dry DMF (1 mL) under an atmosphere of nitrogen. Ammonium carbonate (54.6 mg, 0.569 mmol) was added in one portion to the stirred reaction mixture after 10 minutes. The reaction was left stirred at room temperature for 18 hours. The volatiles were removed in vacuo and the residual solution was diluted with EtOAc (50 mL) then washed with saturated NaHCO3 (50 mL). The aqueous layer was extracted with EtOAc (2×50 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL) and dried over Na2SO4. After filtration the solvent was removed in vacuo to afford a pale yellow solid. The crude material was purified by column chromatography on silica gel (0-85% EtOAc in petroleum benzine 40-60° C.) to afford the title compound (I55) (65.2 mg, 77%) as a white foamy solid; 1H NMR (400 MHz, CDCl3) δ 8.54 (s, 1H), 7.51 (d, J=8.5 Hz, 2H), 7.47 (s, 1H), 7.40-7.36 (m, 1H), 7.30-7.17 (m, peaks obscured by CDCl3), 5.37 (s, 1H), 5.20 (s, 1H), 4.25 (b s, 2H), 4.01 (q, J=7.1 Hz, 1H), 3.17-3.02 (m, 4H), 2.80 (t, J=12.3 Hz, 2H), 2.64 (tt, J=12.3, 3.6 Hz, 1H), 1.83 (d, J=12.7 Hz, 2H), 1.67-1.59 (m, peaks obscured by water peak), 1.56 (d, J=7.2 Hz, 3H), 1.49 (s, 9H). LCMS Method C: rt 6.60 min; m/z 620 [M+Na]+, 598 [M+H]+, 542 [M-tButyl+2H]+, 498 [M-Boc+2H]+.

Provenance & Evidence