反应详情

温度

90 °C

Into a flame-dried reaction vessel under argon was placed 4-(8-bromo-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridin-7-yl)benzonitrile (49 mg, 0.1 mmol), phenylboronic acid (37 mg, 0.3 mmol), K3PO4 (64 mg, 0.3 mmol), Pd(dppf)Cl2.CH2Cl2 (8.0 mg, 0.01 mmol) and anhydrous THF (1.5 mL). The suspension was degassed with argon bubbling, and the reaction vessel was sealed and stirred at 90° C. for 4.5 h. Analysis by HPLC/MS indicated the reaction was not complete. Additional palladium catalyst (3 mg) and THF (0.5 mL) was added, and the suspension was degassed again. The reaction mixture was stirred at 90° C. for 16 h more. After cooling to room temperature, the reaction mixture was partitioned between EtOAc and water. The EtOAc layer was washed with water, then saturated aqueous NaCl, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified using a silica gel cartridge (12 g) eluted with a gradient of EtOAc (0-70%) in hexanes to afford the desired product (90% pure). The product was further purified by preparative reverse phase HPLC (Phenomenex Luna 5 μm C-18 21.2×100 mm column eluted with a linear gradient of 70% to 100% B over 10 min (A=90% water, 10% methanol and B=90% methanol, 10% water) with flow rate at 20 mL/min and UV detection at 220 nm). The desired fractions were concentrated under reduced pressure. The residue obtained was dissolved in acetonitrile, frozen and lyophilized to afford 19.5 mg of the title compound as a light yellow powder. HPLC/MS: retention time=3.69 min, [M+H]+=486.7.

1. customInto a flame-dried reaction vessel under argon
2. customThe suspension was degassed with argon bubbling
3. customthe reaction vessel was sealed
4. additionAdditional palladium catalyst (3 mg) and THF (0.5 mL) was added
5. customthe suspension was degassed again
6. stirringThe reaction mixture was stirred at 90° C. for 16 h more
7. temperatureAfter cooling to room temperature
8. customthe reaction mixture was partitioned between EtOAc and water
9. washThe EtOAc layer was washed with water
10. dry with materialsaturated aqueous NaCl, dried over Na2SO4
11. filtrationfiltered
12. concentrationconcentrated under reduced pressure
13. customThe crude product was purified
14. washeluted with a gradient of EtOAc (0-70%) in hexanes