反应详情

A solution of 6-chloro-2-(4-(1,4-dimethylpiperidin-4-yl)phenylamino)-5-fluoronicotinamide (40 mg, 0.106 mmol), 3-phenyl-1-oxa-2,7-diazaspiro[4.5]dec-2-ene (42.1 mg, 0.127 mmol), and DIEA (0.074 mL, 0.425 mmol) in NMP (1 mL) was heated at 120° C. for 3 h and at 130° C. for 2 h. The reaction mixture was cooled, diluted with water. The resulting brown solid precipitate was filtered and purified by prep-HPLC. The product containing fractions were collected, basified with 1N NaOH, and extracted with methylene chloride twice. The combined organic factions were washed with water and concentrated to give 12 mg yellow solid. LC-MS: 3.04 min (RT). (M+H)+=557.28. 1H NMR (400 MHz, chloroform-d) δ ppm 10.66 (1H, s), 7.67 (2H, dd, J=6.81, 2.86 Hz), 7.50 (2H, d, J=8.79 Hz), 7.36-7.44 (3H, m), 7.22-7.25 (1H, m), 7.13 (2H, d, J=8.79 Hz), 5.43 (2H, br. s.), 3.79-3.90 (2H, m), 3.69-3.75 (1H, m), 3.57-3.67 (1H, m), 3.32 (1H, d, J=16.70 Hz), 3.05 (1H, d, J=16.70 Hz), 2.27-2.45 (4H, m), 2.22 (3H, s), 1.92-2.13 (4H, m), 1.57-1.79 (4H, m), 1.12 (3 H, s).

1. temperatureThe reaction mixture was cooled
2. filtrationThe resulting brown solid precipitate was filtered
3. custompurified by prep-HPLC
4. additionThe product containing fractions
5. customwere collected
6. extractionextracted with methylene chloride twice
7. washThe combined organic factions were washed with water
8. concentrationconcentrated