反应详情

温度

25 °C

To a pale yellow solution of N-tert-butyl-2-(1-(3-(3-cyanoazetidin-1-yl)propyl)-5-(difluoromethoxy)-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (45 mg, 68.9 μmol) in dichloromethane (4.00 mL) was added TFA (740 mg, 0.5 mL, 6.49 mmol, Eq: 94.1), the reaction mixture turned orange and was stirred at 25° C. for 18 h, mixture concentrated and the residue was re-dissolved in 5 mL of a solution of (dichloromethane/MeOH/ammonium hydroxide; 60:10:1) and stirred at 25° C. for 1 h, then evaporated to a yellow solid, which was dissolved in dichloromethane (added few drops of MeOH) and purified by chromatography (spherical silica 20-45 μm, 23 g, Versaflash Supelco) eluting with 0 to 5% over 20 min (MeOH containing 10% ammonium hydroxide)/dichloromethane. The pure product dissolved in dichloromethane and cyclohexane added to allow solid formation, light yellow flakes separated by decantation and dried under high vacuum to give N-tert-butyl-2-(1-(3-(3-cyanoazetidin-1-yl)propyl)-5-(difluoromethoxy)-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (33 mg, 63.2 μmol, 91.6%). MS (M+H)+=523; 1H NMR (DMSO-d6) δ: 12.80 (br. s., 1H), 9.06 (s, 1H), 8.37 (s, 1H), 8.19 (d, J=2.3 Hz, 1H), 7.81-7.96 (m, 2H), 7.39 (dd, J=9.1, 2.3 Hz, 1H), 7.19 (t, J=74.4 Hz, 1H), 4.53 (t, J=6.6 Hz, 2H), 3.35-3.57 (m, 3H), 3.16-3.25 (m, 2H), 2.38 (t, J=6.8 Hz, 2H), 1.78-2.02 (m, 2H), 1.49 (s, 9H).

1. concentrationmixture concentrated
2. dissolutionthe residue was re-dissolved in 5 mL of a solution of (dichloromethane/MeOH/ammonium hydroxide; 60:10:1)
3. stirringstirred at 25° C. for 1 h
4. customevaporated to a yellow solid, which
5. dissolutionwas dissolved in dichloromethane (added few drops of MeOH)
6. custompurified by chromatography (spherical silica 20-45 μm, 23 g, Versaflash Supelco)
7. washeluting with 0 to 5% over 20 min (MeOH containing 10% ammonium hydroxide)/dichloromethane
8. dissolutionThe pure product dissolved in dichloromethane
9. additioncyclohexane added
10. customseparated by decantation
11. customdried under high vacuum