反应详情

温度

100 °C

To a stirring solution of 1-(4-(methylsulfonyl)phenyl)-6-oxo-4-(piperidin-4-yloxy)-1,6-dihydropyridazine-3-carbonitrile HCl (example 47 step A) (41 mg, 0.10 mmol) in NMP (3 mL) at room temperature under argon was added DIPEA (38.8 mg, 0.30 mmol) and 5-(difluoromethoxy)-2-(methylsulfonyl)pyrimidine (22.4 mg, 0.1.0 mmol). The resulting reaction mixture was heated at 100° C. under argon overnight. After cooling to room temperature, 15 mL of EtOAc was added to the reaction mixture. The reaction mixture was washed with water (15 mL), and brine (15 mL). Organic phase was dried (MgSO4), filtered and concentrated. The crude product was dissolved in a small amount of DCM (˜3 ml) and loaded onto a 24 g ISCO silica gel column which was eluted with a 20 min gradient from 20% to 100% EtOAc/Hexanes. 8 mg (15% for two steps) of 4-(1-(5-(difluoromethoxy)pyrimidin-2-yl)piperidin-4-yloxy)-1-(4-(methylsulfonyl)phenyl)-6-oxo-1,6-dihydropyridazine-3-carbonitrile was obtained as a tan solid 1H NMR (400 MHz, CDCl3) δ ppm 1.75-2.27 (m, 4H) 3.08 (s, 3H) 3.66-3.97 (m, 2H) 3.97-4.24 (m, 2H) 4.54-4.95 (m, 1H) 6.34 (s, 1H) 7.84 (d, J=8.79 Hz, 2H) 8.07 (d, J=8.79 Hz, 2H) 8.24 (s, 2H). MS (ESI) 519 (M+H).

1. customThe resulting reaction mixture
2. temperatureAfter cooling to room temperature
3. washThe reaction mixture was washed with water (15 mL), and brine (15 mL)
4. dry with materialOrganic phase was dried (MgSO4)
5. filtrationfiltered
6. concentrationconcentrated
7. dissolutionThe crude product was dissolved in a small amount of DCM (˜3 ml)
8. washwas eluted with a 20 min gradient from 20% to 100% EtOAc/Hexanes