反应详情

温度

90 °C

(S)-5-Bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 33.1, 2.4. g, 5.38 mmol) and pyrimidin-5-ylboronic acid (1.33 g, 10.76 mmol) were dissolved in a mixture of DME (15 mL) and EtOH (2.1 mL). A solution of 2 M aq. NaHCO3 (8.07 mL, 16.14 mmol) was added, the RM was flushed with argon, then Pd(PPh3)2Cl2 (0.453 g, 0.645 mmol) was added and the RM was stirred under argon at 90° C. for 2 h. 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 purified by flash chromatography (Silica gel column, 200 g, DCM/MeOH from 2% to 5% MeOH). Treatment with Si-Thiol (1 g) in MeOH and a further purification by flash chromatography (RediSep® Silica gel column, EtOAc/MeOH from 0 to 20% MeOH) afforded the title compound as white crystalline solid. HPLC (Condition 4) tR=4.63 min, HPLC Chiral (CHIRALPAK® AD-H, 250×4.6 mm, eluent: EtOH, 0.5 mL/min, UV 210 nm) tR=31.72 min, UPLC-MS (Condition 3) tR=0.91 min, m/z=446.2 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.67-1.78 (m, 1H) 1.79-1.89 (m, 1H) 2.87 (d, J=11.73 Hz, 1H) 3.21 (m, J=11.10, 4.90 Hz, 2H) 3.37 (m, J=7.40 Hz, 1H) 4.19 (br. s, br. s, 1H) 4.87 (d, J=3.52 Hz, 1H) 7.33 (d, J=8.99 Hz, 2H) 7.75-7.89 (m, 2H) 8.08 (d, J=2.35 Hz, 1H) 8.70-8.83 (m, 1H) 8.87 (s, 2H) 9.18 (s, 1H) 10.16 (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. customThe residue was purified by flash chromatography (Silica gel column, 200 g, DCM/MeOH from 2% to 5% MeOH)
7. customTreatment with Si-Thiol (1 g) in MeOH and a further purification by flash chromatography (RediSep® Silica gel column, EtOAc/MeOH from 0 to 20% MeOH)