反应详情

温度

80 °C

To a round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was added a solution of 4-(1-(5-(2-bromoacetyl)-4-cyclobutyl-2-methylbenzoyl)-4-fluoropiperidin-4-yl)benzonitrile (compound 236.1, 40 mg, 0.08 mmol, 1.00 equiv) in CH3CN (10 mL). Acetimidamide hydrochloride (7.6 mg, 0.08 mmol, 1.00 equiv) and potassium carbonate (33.4 mg, 0.24 mmol, 3.00 equiv) were added to the reaction. The resulting solution was stirred for 2 h at 80° C. in an oil bath, then cooled to ambient temperature and concentrated under reduced pressure. The residue was dissolved in 50 mL of ethyl acetate. The organic layer was washed with 2×20 mL of water, 2×20 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product (˜50 mg) was purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-001(SHIMADZU)): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05% TFA and CH3CN (29.0% CH3CN up to 43.0% in 8 min, up to 100.0% in 2 min, down to 29.0% in 2 min); Detector, Waters 2489 254&220 nm. The fractions containing pure compound were combined and lyophilized to yield 13 mg (35%) of the title compound as a white solid. m/z (ES+) 457 (M+H)+. 1H NMR (400 MHz, CD3OD): δ 7.78 (d, 2H), 7.65 (d, 2H), 7.50-7.46 (m, 2H), 7.35 and 7.23 (2 s, amide rotamers, 1H), 4.91-4.83 (m, 1H), 3.76-3.63 (m, 1H), 3.54-3.49 (m, 2H), 3.32-3.30 (m, 1H), 2.70 (s, 3H), 2.49 and 2.39 (2 singlets, amide rotamers, ArCH3, 3H), 2.34-2.28 (m, 7H), 1.98-1.80 (m, 3H).

1. customTo a round-bottom flask, which was purged
2. temperaturemaintained with an inert atmosphere of nitrogen
3. temperaturecooled to ambient temperature
4. concentrationconcentrated under reduced pressure
5. dissolutionThe residue was dissolved in 50 mL of ethyl acetate
6. washThe organic layer was washed with 2×20 mL of water, 2×20 mL of brine
7. dry with materialdried over anhydrous sodium sulfate
8. concentrationconcentrated under vacuum
9. customThe crude product (˜50 mg) was purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-001(SHIMADZU))
10. waitmobile phase, water with 0.05% TFA and CH3CN (29.0% CH3CN up to 43.0% in 8 min
11. waitup to 100.0% in 2 min
12. waitdown to 29.0% in 2 min)
13. additionThe fractions containing pure compound