反应详情

温度

100 °C

(R)-5-Bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 6.1, 60 mg, 0.134 mmol), 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole (45.4 mg, 0.202 mmol), Pd2(dba)3 (2.463 mg, 2.69 μmol), 2-dichlohexylphosphino-2′-6′-dimethoxybiphenyl (4.42 mg, 10.76 μmol) and K3PO4 (86 mg, 0.403 mmol) were added to a MW vial, which was sealed and evacuated/purged with argon. Dioxane was added and the RM was stirred at 100° C. for 16 h. Additional 2-methylthiasole-5-boronic acid pinacol ester (15.14 mg, 0.067 mmol) and Pd2(dba)3 (2.463 mg, 2.69 μmol) were added and RM was stirred at 100° C. overnight. The RM was diluted with THF (1 mL), treated with Si-Thiol (Silicycle, 1.44 mmol/g, 93 mg, 0.134 mmol), filtered and the filtrate was evaporated off under reduced pressure to give a residue which was purified by preparative HPLC (Condition 9, 30% for 0.2 min then 30% to 60% in 12 min) to yield the title compound as a white solid. UPLC-MS (Condition 1) tR=2.35 min, m/z=465.1-466.1 [M+H]+, m/z=463.1-464.2 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.71-1.80 (m, 1H) 1.81-1.92 (m, 1H) 2.70 (s, 3H) 3.03-3.09 (m, 1H) 3.25-3.40 (m, 2H) 3.45-3.55 (m, 1H) 4.20-4.27 (m, 1H) 4.88 (d, J=3.18 Hz, 1H) 7.34 (d, J=8.80 Hz, 2H) 7.60 (s, 1H) 7.85 (d, J=9.05 Hz, 2H) 8.04 (d, J=2.45 Hz, 1H) 8.76 (d, J=2.20 Hz, 1H) 10.18 (s, 1H).

1. customwas sealed
2. customevacuated/purged with argon
3. additionDioxane was added
4. stirringRM was stirred at 100° C. overnight
5. filtrationfiltered
6. customthe filtrate was evaporated off under reduced pressure
7. customto give a residue which
8. customwas purified by preparative HPLC (Condition 9, 30% for 0.2 min