反应详情

3-Carbamoyl-pyrrolidine-1-carboxylic acid tert-butyl ester (0.22 g, 1.03 mmol) is dissolved in DCM (5 mL). TFA (2 mL, 26.0 mmol) is added and the reaction is allowed to stir at rt overnight. The solvent is removed in vacuo and THF (5.0 mL) is added followed by methanesulfonic acid 6-[1-(3-trifluoromethyl-phenylcarbamoyl)-1H-indol-5-yloxy]-pyrimidin-4-ylmethyl ester (0.347 g, 0.685 mmol) and DIEA (0.60 mL, 3.42 mmol). The reaction is heated at 60° C. for 19 h. The solvent is removed in vacuo and the residue separated by FCC (0-15%, 10% NH3MeOH/DCM) to provide (±)-5-[6-(3-carbamoyl-pyrrolidin-1-ylmethyl)-pyrimidin-4-yloxy]-indole-1-carboxylic acid (3-trifluoromethyl-phenyl)-amide. MS (ESI) m/z 524.9 (M+1); 1H NMR (400 MHz, DMSO-d6) δ ppm 10.41 (s, 1H), 8.72 (s, 1H), 8.30 (d, J=8.84 Hz, 1H), 8.14 (d, J=3.79 Hz, 1H), 8.10 (s, 1H), 7.97 (s, 1H), 7.65 (t, J=8.08 Hz, 1H), 7.51 (d, J=2.53 Hz, 2H), 7.16 (dd, J=8.84, 2.27 Hz, 1H), 7.12 (s, 1H), 6.81 (d, J=3.54 Hz, 1H), 3.63 (br. S., 1H), 3.14 (d, J=7.33 Hz, 1H), 2.94 (br. S., 1H), 1.99 (br. S., 1H), 1.25 (d, J=6.06 Hz, 6H).

1. customThe solvent is removed in vacuo and THF (5.0 mL)
2. additionis added
3. temperatureThe reaction is heated at 60° C. for 19 h
4. customThe solvent is removed in vacuo
5. customthe residue separated by FCC (0-15%, 10% NH3MeOH/DCM)