反应详情

To a solution of 2-(5-(difluoromethoxy)-1-methyl-1H-indazol-3-yl)-N-(4-(hydroxymethyl)tetrahydro-2H-pyran-4-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (40 mg, 66.4 μmol) in acetonitrile (6 mL) was added CsF (50.4 mg, 332 μmol, Eq: 5.00) and 18-crown-6 (17.5 mg, 66.4 μmol), the reaction mixture was heated to reflux for 72 h, then diluted with dichloromethane (20 mL), filtered over celite and concentrated. The residue was dissolved in dichloromethane and purified by chromatography (spherical silica 20-45 μm, 23 g, Versaflash Supelco) eluting with 0 to 5% over 15 min (MeOH containing 10% ammonium hydroxide)/dichloromethane. The pure product dissolved in dichloromethane/MeOH and cyclohexane added to allow solid formation, which was separated by filtration and dried to give 2-(5-(difluoromethoxy)-1-methyl-1H-indazol-3-yl)-N-(4-(hydroxymethyl)tetrahydro-2H-pyran-4-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (16 mg, 33.9 μmol, 51.0%) as an off-white solid. MS (M+H)+=473 (>90% purity); 1H NMR (DMSO-d6) δ: 9.07 (s, 1H), 8.40 (s, 1H), 8.04 (d, J=1.9 Hz, 1H), 7.78-7.88 (m, 2H), 7.37-7.43 (m, 1H), 7.21 (t, J=74.4 Hz, 1H), 4.92 (t, J=5.7 Hz, 1H), 4.19 (s, 3H), 3.73 (d, J=5.7 Hz, 2H), 3.50-3.69 (m, 4H), 2.21 (d, J=13.6 Hz, 2H), 1.70-1.89 (m, 2H). Unreacted starting material (11 mg, 27%) was also recovered.

1. temperaturethe reaction mixture was heated
2. temperatureto reflux for 72 h
3. filtrationfiltered over celite and
4. concentrationconcentrated
5. dissolutionThe residue was dissolved in dichloromethane
6. custompurified by chromatography (spherical silica 20-45 μm, 23 g, Versaflash Supelco)
7. washeluting with 0 to 5% over 15 min (MeOH containing 10% ammonium hydroxide)/dichloromethane
8. dissolutionThe pure product dissolved in dichloromethane/MeOH
9. additioncyclohexane added
10. customwas separated by filtration
11. customdried