反应详情

温度

92 °C

A mixture of (R)-methyl 5-bromo-6-(3-hydroxypyrrolidin-1-yl)nicotinate (Stage 9.6, 90 g, 299 mmol), 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-boronic acid pinacol ester (103.9 g, 373.6 mmol), K3PO4 (126.9 g, 597.7 mmol), Pd(PPh3)2Cl2 (6.29 g, 8.97 mmol) in toluene (900 mL) was stirred at 92° C. and for 16 h. After cooling the mixture to RT, the solution was washed with water (450 mL), 5% NaHCO3 solution (430 mL) and the solvent was evaporated off under reduced pressure to give a residue which was used without further purifications in the next step. HPLC (Condition 7) tR=6.929 min, LC-MS (Condition 8) tR=4.30 min, m/z=373.0 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.19-1.28 (m, 1H), 1.35-1.63 (m, 4H), 1.63-1.86 (m, 3H), 1.89 (br. s, 1H), 2.12-2.39 (m, 1H), 3.11 (br. s, 1H), 3.18-3.48 (m, 4H), 3.78 (s, 4H), 3.88 (d, J=11.54 Hz, 1H), 4.08-4.24 (m, 1H), 4.86 (dd, J=18.20, 2.89 Hz, 1H), 5.02 (d, J=8.28 Hz, 1H), 6.39 (br. s, 1H), 7.58 (d, J=1.25 Hz, 1H), 7.78 (br. s, 1H), 8.69 (t, J=2.01 Hz, 1H).

1. temperatureAfter cooling the mixture to RT
2. washthe solution was washed with water (450 mL), 5% NaHCO3 solution (430 mL)
3. customthe solvent was evaporated off under reduced pressure
4. customto give a residue which