反应详情

温度

85 °C

To a suspension of N1-(1-(2-fluoroethyl)azetidin-3-yl)-3-methoxybenzene-1,4-diamine (11c) (135 mg, 0.56 mmol) and N-(3-(2-(methylsulfinyl)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide (11b) (230 ing, 0.65 mmol) in 1 mL of dioxane and 1 mL of tBuOH at RT was added DIEA (0.29 mL, 1.69 mmol). The mixture was heated in an oil bath at 85° C. for 3 h. It was concentrated under reduced pressure. The residue was purified on a silica gel column (5% MeOH in DCM followed by 2-6% of 2 M NH3 in MeOH in DCM) to give a material that was about 95% pure. The material was dissolved in 10 mL of DMSO and purified on a reverse phase HPLC, using a gradient of 10-90% of (0.1% TFA in CH3CN) in (0.1% TFA in water). Desired fractions were collected, lyophilized and the powdery residue was dissolved in 2 mL of MeOH, passed through a Silicycle (5 G) carbonate cartridge, rinsed with MeOH (20 mL). The fractions were collected and concentrated to give the title compound (95 mg, 31% yield) as a brown crystalline solid. m/z (ESI, +ve ion) 530.0 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.40 (1H, br.), 8.73 (1H, br.), 8.10 (1H, br.), 7.90 (1H, d, J=9.4 Hz), 7.83 (1H, br.), 7.64 (1H, s), 7.51 (1H, t, J=8.0 Hz), 7.15 (1H, br.), 7.02 (1H, d, J=8.6 Hz), 6.44 (2H, m), 6.29 (1H, m), 6.16 (1H, d, J=2.0 Hz), 5.86 (1H, br.), 5.78 (1H, m), 5.57 (1H, br.), 4.49 (1H, t, J=4.8 Hz), 4.37 (1H, t, J=4.9 Hz), 3.90 (1H, br.), 3.72 (3H, s), 3.70 (2H, m), 2.83 (2H, m), 2.74 (1H, 1, J=4.8 Hz), 2.67 (1H, t, J=4.8 Hz).

1. concentrationIt was concentrated under reduced pressure
2. customThe residue was purified on a silica gel column (5% MeOH in DCM followed by 2-6% of 2 M NH3 in MeOH in DCM)
3. customto give a material that
4. custompurified on a reverse phase HPLC
5. customDesired fractions were collected
6. dissolutionthe powdery residue was dissolved in 2 mL of MeOH
7. washrinsed with MeOH (20 mL)
8. customThe fractions were collected
9. concentrationconcentrated