反应详情

(R)-5-Bromo-6-(3-(hydroxymethyl)pyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 75.1, 60 mg, 0.13 mmol), pyrimidin-5-ylboronic acid (24.2 mg, 0.196 mmol), Pd(PPh3)2Cl2 (9.15 mg, 0.013 mmol) and Na2CO3 (41.5 mg, 0.391 mmol) were added to a MW vial and treated with a mixture of DME (553 μL), water (158 μL) and EtOH (79 μL). The vial was sealed, evacuated/purged with argon and was subjected to MW irradiation at 80° C. for 2 h. The RM was diluted with THF (1 mL), treated with Si-Thiol (Silicycle, 1.27 mmol/g, 51.3 mg, 0.065 mmol), filtered and the filtrate was evaporated off under reduced pressure to give a residue which was purified by preparative HPLC (Condition 12, 25% for 0.2 min then 25% to 55% in 12 min) to yield the title compound as a white solid. UPLC-MS (condition 1) tR=2.13 min, m/z=460.1-461.1 [M+H]+, m/z=458.2 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.53-1.64 (m, 1H) 1.81-1.90 (m, 1H) 2.19-2.28 (m, 1H) 2.97 (dd, J=10.76, 6.85 Hz, 1H) 3.15-3.39 (m, 5H) 4.61 (t, J=5.01 Hz, 1H) 7.35 (d, J=8.80 Hz, 2H) 7.85 (d, J=9.05 Hz, 2H) 8.09 (d, J=2.20 Hz, 1H) 8.79 (d, J=2.20 Hz, 1H) 8.89 (s, 2H) 9.19 (s, 1H) 10.17 (s, 1H).

1. customThe vial was sealed
2. customevacuated/purged with argon
3. customwas subjected to MW irradiation at 80° C. for 2 h
4. additionThe RM was diluted with THF (1 mL)
5. filtrationfiltered
6. customthe filtrate was evaporated off under reduced pressure
7. customto give a residue which
8. customwas purified by preparative HPLC (Condition 12, 25% for 0.2 min