反应详情

Triethylamine (35.3 g) was added to a suspension of methyl 3-methyl-2-oxo-1-(piperidin-4-yl)-1,2-dihydropyridine-4-carboxylate hydrochoride (100 g) in THF (2.00 L) at room temperature. After being stirred at the same temperature for 30 minutes, 6-cyclopropyl-2,4′-difluoro-3-isopropoxybiphenyl-4-carbaldehyde (121 g) was added to the reaction mixture. The mixture was stirred at room temperature for 30 minutes. Sodium triacetoxyhydroborate (111 g) and acetic acid (20.9 g) were added to the reaction mixture. The mixture was stirred at room temperature for 16 hours. Aqueous saturated sodium hydrogen carbonate solution (1.30 L) and water (1.30 L) were added to the mixture at room temperature. The mixture was extracted with ethyl acetate (10 L). The organic layer was separated, washed with brine (4.00 L), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was dissolved in ethyl acetate (1.00 L). 4M hydrogen chloride (ethyl acetate solution, 87 ml) was added to the mixture at room temperature. Then crystalline seeds were added to the mixture. The mixture was diluted with diisopropyl ether (2.00 L) and stirred at room temperature for 1 hour. The precipitate was collected by filtration and washed with diisopropyl ether (1.50 L) to give the title compound (183.7 g).

1. stirringThe mixture was stirred at room temperature for 30 minutes
2. stirringThe mixture was stirred at room temperature for 16 hours
3. extractionThe mixture was extracted with ethyl acetate (10 L)
4. customThe organic layer was separated
5. washwashed with brine (4.00 L)
6. dry with materialdried over anhydrous sodium sulfate
7. concentrationconcentrated in vacuo
8. dissolutionThe residue was dissolved in ethyl acetate (1.00 L)
9. addition4M hydrogen chloride (ethyl acetate solution, 87 ml) was added to the mixture at room temperature
10. additionThen crystalline seeds were added to the mixture
11. additionThe mixture was diluted with diisopropyl ether (2.00 L)
12. stirringstirred at room temperature for 1 hour
13. filtrationThe precipitate was collected by filtration
14. washwashed with diisopropyl ether (1.50 L)