反应详情

温度

25 °C

In a 2-5 mL Biotage microwave vial were mixed N-tert-butyl-2-(6-fluoro-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (75 mg, 155 mmol), tert-butyl 3-(2-iodoethyl)azetidine-1-carboxylate (68 mg, 219 μmol.41) and Cs2CO3 (203 mg, 622 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, 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 (40 g column, 50 μm silica-gel from Analogix, 0 to 5% over 20 min (MeOH containing 10% ammonium hydroxide)/dichloromethane to give tert-butyl 3-(2-(3-(7-(tert-butylcarbamoyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)-6-fluoro-1H-indazol-1-yl)ethyl)azetidine-1-carboxylate (103 mg, 155 μmol, 99.5%) as a white solid. MS (M+Na)+=688; 1H NMR (CDCl3) δ: 9.24 (s, 1H), 8.56 (dd, J=8.7, 5.3 Hz, 1H), 8.37 (s, 1H), 8.09 (s, 1H), 6.98-7.16 (m, 2H), 5.75 (s, 2H), 4.46 (t, J=6.4 Hz, 2H), 4.02 (t, J=8.3 Hz, 2H), 3.49-3.72 (m, 5H), 2.49-2.69 (m, 1H), 2.33 (q, J=6.8 Hz, 2H), 1.65 (s, 9H), 1.48 (s, 2H), 1.45 (s, 9H), 0.92-1.03 (m, 2H), 0.00 (s, 9H); LCMS ESI+ TIC MS showed 100% purity, [M+Na]+=688.0.

1. temperaturethen heated to 100° C. in the Biotage microwave reactor for 30 min
2. filtrationfiltered through a celite pad, filtrate
3. concentrationconcentrated under high vacuum at 65° C.
4. dissolutionresidue dissolved in dichloromethane
5. custompurified by chromatography (40 g column, 50 μm silica-gel from Analogix, 0 to 5% over 20 min (MeOH containing 10% ammonium hydroxide)/dichloromethane