反应详情

3-Bromo-1-(1-methylethyl)-6-phenyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (93 mg, 0.258 mmol), 3-(aminomethyl)-4,6-dimethyl-2(1H)-pyridinone hydrochloride (64 mg, 0.336 mmol), HOBT (60 mg, 0.387 mmol) and EDC (74 mg, 0.387 mmol) were suspended in DMSO (14 mL) and stirred at room temperature for 10 minutes, after which time DIEA (0.9 ml, 5.16 mmol) was added. After stirring for 2 h, 4-methylmorpholine (1 ml, 9.04 mmol) was added. The reaction mixture was stirred first at room temperature for 21 h, and then at 80° C. (aluminum heating block) for 31 h. The reaction mixture was cooled to room temperature and then added dropwise to a cold, slightly basic solution (pH˜8-10) of water (100 mL) and 1N Na2CO3 (8 mL). After stirring for 20 min., the contents were extracted with EtOAc (2×100 mL). The combined organic layers are washed with brine, dried over Na2SO4, filtered, and concentrated to a residue. The crude residue was dissolved in 10% MeOH/DCM and purified by silica gel chromatography (eluent: 10-95% gradient EtOAc/Hexanes and then 10% (5% NH4OH/MeOH)/DCM and EtOAc, 10-90% gradient). The product was collected as an off-white solid. (35 mg, 27%). LCMS E-S (M+H)=494.1/496.0. 1H NMR (400 MHz, CHLOROFORM-d) δ 11.58 (br. s., 1H), 8.11 (dd, J=1.89, 7.71 Hz, 2H), 7.68 (br. s., 1H), 7.60 (br. s., 1H), 7.44-7.53 (m, 3H), 5.92 (s, 1H), 5.42 (quin, J=6.69 Hz, 1H), 4.63 (br. s., 1H), 2.41 (br. s., 3H), 2.11 (br. s., 3H), 1.62 (d, J=6.57 Hz, 6H).

1. stirringAfter stirring for 2 h
2. stirringThe reaction mixture was stirred first at room temperature for 21 h
3. temperatureThe reaction mixture was cooled to room temperature
4. stirringAfter stirring for 20 min.
5. extractionthe contents were extracted with EtOAc (2×100 mL)
6. washThe combined organic layers are washed with brine
7. dry with materialdried over Na2SO4
8. filtrationfiltered
9. concentrationconcentrated to a residue
10. dissolutionThe crude residue was dissolved in 10% MeOH/DCM
11. custompurified by silica gel chromatography (eluent
12. customThe product was collected as an off-white solid