反应详情

温度

90 °C

A mixture of (4R)-tert-butyl 4-(6-(5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yloxy)-6-azaspiro[2.5]octane-6-carboxylate (201.3 mg, 0.345 mmol), potassium isopropenyltrifluoroborate (Frontier Scientific, Inc., Logan, Utah; 61.1 mg, 0.413 mmol), PdCl2(dppf)-CH2Cl2 adduct (Acros Organics, Geel, Belgium; 14.28 mg, 17.48 μmol), and Et3N (0.048 mL, 0.350 mmol) in IPA (4.0 mL) was stirred under argon at 90° C. for 2 h. Additional potassium isopropenyltrifluoroborate (20.0 mg, 0.136 mmol) was added, and the resulting mixture was stirred at 90° C. for 1 h. The reaction was cooled to RT and diluted with EtOAc (150 mL). The resulting solution was sequentially washed with water (2×90 mL) and brine (60 mL), dried over Na2SO4, filtered, and concentrated onto silica gel. Chromatographic purification (ISCO, 12 g silica gel column, 0-30% EtOAc/hexanes, 15 min, 254 nm) provided (4R)-tert-butyl 4-(6-(5-(prop-1-en-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yloxy)-6-azaspiro[2.5]octane-6-carboxylate (175.4 mg, 0.321 mmol, 93% yield) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ ppm 9.05 (1 H, s), 8.45 (1 H, s), 8.19 (1 H, br. s.), 7.63-7.68 (1 H, m), 7.58-7.62 (1 H, m), 5.80 (1 H, d, J=8.6 Hz), 5.42 (1 H, s), 5.14 (1 H, s), 4.63 (1 H, br. s.), 4.47 (1 H, br. s.), 4.25 (1 H, d, J=8.4 Hz), 4.03 (1 H, d, J=11.2 Hz), 3.73-3.84 (1 H, m), 3.25 (1 H, d, J=13.7 Hz), 2.90-3.05 (1 H, m), 2.56-2.72 (1 H, m), 2.45 (1 H, br. s.), 2.24 (3 H, s), 2.21 (1 H, d, J=4.3 Hz), 2.12 (2 H, d, J=12.7 Hz), 1.75-1.87 (3 H, m), 1.11 (9 H, br. s.), 0.86 (2 H, br. s.), 0.72 (2 H, br. s.). MS (ESI, pos. ion) m/z: 546.3 (M+1).

1. stirringthe resulting mixture was stirred at 90° C. for 1 h
2. temperatureThe reaction was cooled to RT
3. washThe resulting solution was sequentially washed with water (2×90 mL) and brine (60 mL)
4. dry with materialdried over Na2SO4
5. filtrationfiltered
6. concentrationconcentrated onto silica gel
7. customChromatographic purification (ISCO, 12 g silica gel column, 0-30% EtOAc/hexanes, 15 min, 254 nm)