反应详情

温度

90 °C

(R)-5-Bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 35.1, 89 mg, 0.2 mmol) and (6-(hydroxymethyl)pyridin-3-yl)boronic acid (61.2 mg, 0.4 mmol) were dissolved in DME (0.8 mL). A solution of 2 M NaHCO3 (0.3 mL, 0.6 mmol) was added, the RM was flushed with argon, heated to 90° C. and treated with Pd(PPh3)2Cl2 (14.0 mg, 0.02 mmol). The RM was stirred under argon at 95° C. for 2 h in a sealed pressure safe tube. After cooling to RT, the RM was dissolved in EtOAc and washed with brine. The organic phase was dried over Na2SO4 and evaporated to dryness under reduced pressure. The residue was diluted in MeOH, treated with Si-Thiol (100 mg), the resin was filtered off and the solvent was evaporated off under reduced pressure to give a residue which was purified by flash chromatography (Silica gel column, EtOAc/MeOH, from 0 to 20% MeOH) afforded the title compound as an off-white amorphous solid. HPLC (Condition 4) tR=4 min, UPLC-MS (Condition 3) tR=0.87 min, m/z=475.3 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.63-1.76 (m, 1H) 1.77-1.86 (m, 1H) 2.86 (d, J=11.34 Hz, 1H) 3.11-3.26 (m, 2H) 3.33-3.43 (m, 1H) 4.12-4.22 (m, 1H) 4.61 (d, J=5.87 Hz, 2H) 4.84 (d, J=3.13 Hz, 1H) 5.47 (t, J=5.87 Hz, 1H) 7.33 (d, J=8.99 Hz, 2H) 7.53 (d, J=8.21 Hz, 1H) 7.74-7.88 (m, 3H) 8.00 (d, J=2.35 Hz, 1H) 8.51 (d, J=2.35 Hz, 1H) 8.74 (d, J=2.35 Hz, 1H) 10.15 (s, 1H).

1. customthe RM was flushed with argon
2. temperatureAfter cooling to RT
3. washwashed with brine
4. dry with materialThe organic phase was dried over Na2SO4
5. customevaporated to dryness under reduced pressure
6. additionThe residue was diluted in MeOH
7. additiontreated with Si-Thiol (100 mg)
8. filtrationthe resin was filtered off
9. customthe solvent was evaporated off under reduced pressure
10. customto give a residue which
11. customwas purified by flash chromatography (Silica gel column, EtOAc/MeOH, from 0 to 20% MeOH)