反应详情

To a solution of (S)-1-methyl-piperidin-3-yl amine (120 mg, 1.05 mmol) in THF (8.0 mL), under nitrogen, was added 2N trimethylaluminium in hexanes (1.0 mL, 2.0 mmol), and the reaction mixture was allowed to stir at room temperature for 1.5 hours. After this time, a THF (5.0 mL) solution of 1-(3-fluorophenyl)-4-ureido-1H-pyrrole-3-carboxylic acid ethyl ester (291 mg, 1.0 mmol), was added and the reaction mixture was heated at 65-70° C. for a period of 18 hours. After this time, the reaction mixture was allowed to cool to room temperature and was then quenched by addition of a saturated solution of Rochelle's salt. After 0.5 hours, the mixture was extracted with DCM (3×10 mL) and EtOAc (1×10 mL). The combined organic layer was dried (MgSO4) and concentrated in vacuo. The resultant residue was then purified by flash chromatography (silica, 5 g column, Isolute, 0-20% MeOH in DCM) to afford the title compound (60 mg, 0.17 mmol, 17%). LCMS (method A), RT=5.13 min, M+H+=360; 1H NMR (DMSO-D6, 400 MHz): 8.97 (s, 1H), 8.05 (d, J=2.6 Hz, 1H), 7.68 (d, J=7.8 Hz, 1H), 7.56 (d, J=2.6 Hz, 1H), 7.55-7.48 (m, 1H), 7.39 (dt, J=10.6, 2.3 Hz, 1H), 7.36-7.33 (m, 1H), 7.12 (td, J=8.5, 2.4 Hz, 1H), 6.29 (s, 2H), 3.95-3.88 (m, 1H), 2.85-2.77 (m, 1H), 2.65-2.57 (m, 1H), 2.18 (s, 3H), 1.92-1.73 (m, 3H), 1.74-1.67 (m, 1H), 1.58-1.46 (m, 1H), 1.33-1.19 (m, 1H).

1. temperaturethe reaction mixture was heated at 65-70° C. for a period of 18 hours
2. temperatureto cool to room temperature
3. customwas then quenched by addition of a saturated solution of Rochelle's salt
4. waitAfter 0.5 hours
5. extractionthe mixture was extracted with DCM (3×10 mL) and EtOAc (1×10 mL)
6. dry with materialThe combined organic layer was dried (MgSO4)
7. concentrationconcentrated in vacuo
8. customThe resultant residue was then purified by flash chromatography (silica, 5 g column, Isolute, 0-20% MeOH in DCM)