反应详情

(R)-3-Bromo-N-(4-(chlorodifluoromethoxy)phenyl)-4-(3-hydroxypyrrolidin-1-yl)benzamide (Stage 243.1, 80 mg, 0.173 mmol), pyrimidin-5-ylboronic acid (42.9 mg, 0.347 mmol), Pd(PPh3)2Cl2 (12.16 mg, 0.017 mmol) and Na2CO3 (73.5 mg, 0.693 mmol) were added to a MW vial and treated with a mixture of DME (735 μL), water (210 μL) and EtOH (105 μL). The vial was sealed, evacuated/purged with argon and subjected to MW irradiation at 125° C. for 15 min, diluted with DCM (2 mL), treated with Si-Thiol (Silicycle, 1.43 mmol/g, 72.2 mg, 0.104 mmol). The RM was centrifuged, the supernatant was filtered and the solvent was evaporated off under reduced pressure to give a residue which was purified by flash chromatography (RediSep® Silica gel column, 12 g, DCM/MeOH+1% NH4OH from 1% to 10% MeOH+1% NH4OH). Product was further purified by preparative SFC (Column DEAP, isocratic 6% in 6 min) to yield the title product as a white solid. UPLC-MS (Condition 3) tR=1.01 min, m/z=461.1 [M+H]+, m/z=459.1 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.66-1.81 (m, 1H) 1.82-1.94 (m, 1H) 2.68 (d, J=9.66 Hz, 1H) 2.98-3.10 (m, 2H) 3.18-3.27 (m, 1H) 4.17-4.26 (m, 1H) 4.89 (d, J=3.55 Hz, 1H) 6.99 (d, J=8.80 Hz, 1H) 7.33 (d, J=9.17 Hz, 2H) 7.82-7.90 (m, 3H) 7.95 (dd, J=8.80, 2.20 Hz, 1H) 8.87 (s, 2H) 9.17 (s, 1H) 10.12 (s, 1H).

1. customThe vial was sealed
2. customevacuated/purged with argon
3. customsubjected to MW irradiation at 125° C. for 15 min
4. additiondiluted with DCM (2 mL)
5. filtrationthe supernatant was filtered
6. customthe solvent was evaporated off under reduced pressure
7. customto give a residue which
8. customwas purified by flash chromatography (RediSep® Silica gel column, 12 g, DCM/MeOH+1% NH4OH from 1% to 10% MeOH+1% NH4OH)
9. customProduct was further purified by preparative SFC (Column DEAP, isocratic 6% in 6 min)