Cesium fluoride → 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

関与物質

反応手順

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.

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