反应详情

温度

100 °C

A microwave tube was charged with N-(3-(5-methyl-2-(methylsulfinyl)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide (5b; 210 mg, 0.57 mmol), 4-(4-methylpiperazino)aniline (136 mg, 0.71 mmol) and DIEA (0.20 mL, 1.14 mmol) in tert-butanol (5.5 mL). The tube was sealed and the mixture was heated to 100° C. for 3 d. The mixture was concentrated and then the brown solid was suspended in Et2O and collected by filtration. The brown solid was washed with Et2O to afford 270 mg of crude material. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (12 g), eluting with a gradient of 0-20% MeOH in DCM. This enriched product was repurified on a Gilson preparatory HPLC (Gemini Phenomenex; 30×150 mm, 5μ, 10-95% 0.1% TFA/CH3CN in 0.1% TFA/water). The product containing fractions were combined and concentrated. A saturated solution of aqueous NaHCO3 was added and the mixture was extracted with 3:1 CHCl3/IPA (3×30 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated to provide N-(3-(5-methyl-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide (52 mg, 0.11 mmol, 18% yield) as a yellow solid. m/z (ESI, +ve ion) 496.1 (M+H)+. NMR (400 MHz, DMSO-d6) δ ppm 10.35 (1H, s), 8.82 (1H, s), 7.93 (1H, d, J=8.61 Hz), 7.57-7.56 (1H, m), 7.53 (1H, t, J=8.12 Hz), 7.17-7.19 (2H, m), 6.95-7.02 (1H, m), 6.53-6.56 (1H, m), 6.37-6.48 (1H, m), 6.31 (1H, d, J=0.39 Hz), 6.21-6.28 (1H, m), 5.72-5.80 (1H, m), 2.91-3.02 (4H, m), 2.46 (3H, s), 2.39-2.44 (4H, m) 2.21 (3H, s).

1. customThe tube was sealed
2. concentrationThe mixture was concentrated
3. filtrationcollected by filtration
4. washThe brown solid was washed with Et2O
5. customto afford 270 mg of crude material
6. customThe crude material was absorbed onto a plug of silica gel
7. custompurified by chromatography through a Redi-Sep pre-packed silica gel column (12 g)
8. washeluting with a gradient of 0-20% MeOH in DCM
9. customThis enriched product was repurified on a Gilson preparatory HPLC (Gemini Phenomenex; 30×150 mm, 5μ, 10-95% 0.1% TFA/CH3CN in 0.1% TFA/water)
10. additionThe product containing fractions
11. concentrationconcentrated
12. additionA saturated solution of aqueous NaHCO3 was added
13. extractionthe mixture was extracted with 3:1 CHCl3/IPA (3×30 mL)
14. dry with materialThe combined organic layers were dried over anhydrous Na2SO4
15. filtrationfiltered
16. concentrationconcentrated