反应详情

温度

25 °C

To a pale yellow solution of 2-(5-(difluoromethoxy)-1-methyl-1H-indazol-3-yl)-N-(1-hydroxy-2-methylpropan-2-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (34.4 mg, 61.4 μmol) in dichloromethane (1.44 mL) was added TFA (426 mg, 288 μL, 3.74 mmol, Eq: 60.9), the reaction mixture turned orange and was stirred at 25° C. overnight then concentrated. 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 3 h, then evaporated to a light yellow solid, dissolved in dichloromethane (containing a few drops of MeOH) 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 to give a mixture of 2 compounds, no pure compound obtained. Mixture combined again and purified by preparative TLC (Silica GF 1000 μm, 20×40 cm (Gypsum Binder, Fluorescent Indicator)) to give the desired 2-(5-(difluoromethoxy)-1-methyl-1H-indazol-3-yl)-N-(1-hydroxy-2-methylpropan-2-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (20 mg, 46.5 μmol, 75.7%) as white needles. MS (M+H)+=431; 1H NMR (DMSO-d6) δ: 9.07 (s, 1H), 8.37 (s, 1H), 8.21 (d, J=1.9 Hz, 1H), 7.80-7.90 (m, 2H), 7.35-7.42 (m, 1H), 7.18 (t, J=74.4 Hz, 1H), 4.95 (t, J=5.7 Hz, 1H), 4.19 (s, 3H), 3.62 (d, J=5.7 Hz, 2H), 1.42 (s, 6H).

1. concentrationthen 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 3 h
4. customevaporated to a light yellow solid
5. dissolutiondissolved in dichloromethane (containing a few drops of MeOH)
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. customto give
9. additiona mixture of 2 compounds
10. customno pure compound obtained
11. custompurified by preparative TLC (Silica GF 1000 μm, 20×40 cm (Gypsum Binder, Fluorescent Indicator))