反应详情

温度

85 °C

To a suspension of 1-(3-((4-amino-3-methoxyphenyl)amino)azetidin-1-yl)ethanone (14a, prepared according to the procedures described in WO 2012064706 A1 (April, 2012), Avila Therapeutics, Inc.) (120 mg, 0.51 mmol) and N-(3-(2-(methylsulfinyl)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide (51) (150 mg, 0.42 mmol) in 1 mL of dioxane and 1 mL of tBuOH at RT was added DIEA (0.22 mL, 1.27 mmol). The mixture was heated in an oil bath at 85° C. for 1 h. NMP (0.5 mL) was added to the reaction mixture and heating was continued 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 90% pure. This 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 MeOH, passed through a Silicycle (5 G) carbonate cartridge, rinsed with MeOH (20 mL). The fractions were collected and concentrated to give N-(3-(2-((4-((1-acetylazetidin-3-yl)amino)-2-methoxyphenyl)amino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide (14) (135 mg, 0.257 mmol, 60.7% yield) as a yellow crystalline solid. m/z (ESI, +ve ion) 526.0 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.42 (1H, br.), 8.74 (1H, s), 8.15 (1H, s), 7.91 (2H, d, J=9.4 Hz), 7.61 (1H, br.), 7.51 (1H, t, J=8.0 Hz), 7.18 (1H, br.), 7.02 (1H, d, J=8.0 Hz), 6.36-6.56 (2H, m), 6.23-6.36 (1H, m), 6.15 (2H, 5.71-5.87 (1H, m), 4.44 (1H, m), 4.18 (1H, 4.10 (1H, 3.75 (1H, m), 3.73 (3H, s), 3.58 (1H, m), 3.03 (1H, m), 1.80 (3H, s).

1. customprepared
2. temperatureheating
3. concentrationIt was concentrated under reduced pressure
4. 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)
5. customto give a material that
6. custompurified on a reverse phase HPLC
7. customDesired fractions were collected
8. dissolutionthe powdery residue was dissolved in MeOH
9. washrinsed with MeOH (20 mL)
10. customThe fractions were collected
11. concentrationconcentrated