反应详情

温度

25 °C

In a 2-5 mL Biotage microwave vial were mixed N-tert-butyl-2-(5-(difluoromethoxy)-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (50 mg, 94.2 μmol), 1-(3-chloropropyl)azetidine-3-carbonitrile (44.8 mg, 283 μmol, Eq: 3.0) and Cs2CO3 (123 mg, 377 μmol) in DMF (2.00 mL). The mixture was stirred ˜10 min at 25° C. then heated to 100° C. in the Biotage microwave reactor for 30 min. LCMS showed complete reaction, diluted with 10 mL of dichloromethane and filtered through a celite pad, filtrate concentrated under high vacuum at 65° C. and residue dissolved in dichloromethane 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 to give 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, 73.2%) as a white solid. MS (M+H)+=653.1; 1H NMR (CDCl3) δ: 9.22 (s, 1H), 8.36 (s, 1H), 8.31 (d, J=2.3 Hz, 1H), 8.04 (s, 1H), 7.58 (d, J=9.1 Hz, 1H), 7.36 (dd, J=8.9, 2.1 Hz, 1H), 6.56 (t, J=73.7 Hz, 1H), 5.75 (s, 2H), 4.57 (t, J=6.6 Hz, 2H), 3.24-3.40 (m, 3H), 2.50 (t, J=6.6 Hz, 2H), 2.08 (quin, J=6.5 Hz, 2H), 1.65 (s, 9H), 0.91-1.03 (m, 2H), 0.00 (s, 9H).

1. temperaturethen heated to 100° C. in the Biotage microwave reactor for 30 min
2. customreaction
3. filtrationfiltered through a celite pad, filtrate
4. concentrationconcentrated under high vacuum at 65° C.
5. dissolutionresidue dissolved in dichloromethane
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