反应详情

(S)-5-Bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide (Stage 169.1, (116 mg, 0.25 mmol) and pyrimidin-5-ylboronic acid (62 mg, 0.5 mmol) were dissolved in DME (1 mL). A solution of 2 M Na2CO3 (0.375 mL, 0.75 mmol) was added, the mixture was flushed with argon, PdCl2(dppf) (9 mg, 0.013 mmol) was added and the RM subjected to MW irradiation at 100° 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 under reduced pressure to give a residue that was purified flash chromatography (RediSep® Silica gel column, EtOAc/EtOAc-MeOH (98:2)), from 50% to 100% EtOAc-MeOH (98:2)) and treated with Si-Thiol (80 mg) in MeOH to afford the title compound as a white crystalline powder. HPLC (Condition 4) tR=4.71 min, HPLC Chiral (CHIRALPAK® AD-H, 250×4.6 mm, eluent: EtOH/MeOH (50:50), 0.5 mL/min, UV 210 nm) tR=60.52 min, UPLC-MS (Condition 3) tR=0.95 min, m/z=462.2 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.68-1.78 (m, 1H) 1.80-1.90 (m, 1H) 2.82-2.92 (m, 1H) 3.15-3.26 (m, 2H) 3.33-3.41 (m, 1H) 4.15-4.24 (m, 1H) 4.86 (d, J=3.52 Hz, 1H) 7.33 (d, J=8.21 Hz, 2H) 7.84 (d, J=9.38 Hz, 2H) 8.03-8.13 (m, 1H) 8.78 (m, J=2.35, 0.78 Hz, 1H) 8.87 (s, 2H) 9.18 (d, J=0.78 Hz, 1H) 10.16 (s, 1H).

1. additionwas added
2. customthe RM subjected to MW irradiation at 100° C. for 2 h
3. washwashed with brine
4. dry with materialThe organic phase was dried over Na2SO4
5. customevaporated under reduced pressure
6. customto give a residue that
7. customwas purified flash chromatography (RediSep® Silica gel column, EtOAc/EtOAc-MeOH (98:2))
8. additionfrom 50% to 100% EtOAc-MeOH (98:2)) and treated with Si-Thiol (80 mg) in MeOH