反应详情

To a solution of (2-chloro-phenyl)-(2-fluoropyridin-3-yl)methanol (140 g, 0.59 mol) in dichloromethane (1.1 L) under an argon atmosphere, add 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) (1.43 g, 9.15 mmol) and potassium bromide (10% w/w in water, 57.1 mL, 0.048 mol). To the resulting mixture add a solution of sodium hypochlorite (13% w/w active chlorine in water, 403 mL, 0.85 mol) and sodium bicarbonate (20.3 g, 0.24 mol) in water (403 mL) while stirring vigorously and while maintaining the temperature below 20° C. Continue stirring the reaction mixture for 30 min or until the reaction is complete. Separate the layers, and concentrate the organic layer to approximately 200 mL total volume. Add dimethylsulfoxide and concentrate until no dichloromethane remains in the solution. Add 4-acetylpyridine (107 g, 0.88 mol) and powdered lithium hydroxide (28.2 g, 1.17 mol) and stir at 60° C. for 2.5 h or until the reaction is complete. Cool to ambient temperature and add dichloromethane (1.4 L) and an aqueous solution of 10% sodium chloride (1.3 L) while maintaining the temperature between 20° C. and 24° C. Separate the layers and extract the aqueous layer with dichloromethane (1.4 L). Separate the layers and combine the organic layers. Wash the combined organic layers with an aqueous solution of 10% sodium chloride (3×2.6 L). Concentrate the organic layer to approximately 500 mL total volume, then add methanol (1.0 L). Concentrate under vacuum until the weight of the resulting residue is approximately 500 g, then add more methanol (207 mL). Heat the solution to 60° C. When the temperature reaches 45° C., add phosphoric acid (85% w/w in water, 67.4 g, 0.58 mol). Stir the resulting slurry at 22° C. for 16 h. Collect the resulting solid by filtration and wash with methanol (3×65 mL) and water (3×65 mL). Add the resulting solid to a solution of potassium carbonate (49.3 g, 0.356 mol) in water (714 mL) and stir for 4 h. Collect the resulting solid by filtration, wash with water (50 mL) and dry under vacuum at 50° C. to afford the title compound as an orange solid. 1H NMR (400 MHz, DMSO-D6) δ ppm 4.89 (s, 2H) 6.93 (d, J=7.33 Hz, 1H) 7.09 (s, 1H) 7.11-7.17 (m, 2H) 7.24 (dd, J=7.58, 5.31 Hz, 1H) 7.40-7.67 (m, 15H) 7.71-7.77 (m, 3H) 7.85 (d, J=7.83 Hz , 1H) 7.89 (d, J=6.06 Hz, 2H) 8.15 (d, J=7.58 Hz, 1H) 8.50 (d, J=3.79 Hz, 1H) 8.62 (d, J=3.79 Hz, 3H) 8.67 (d, J=5.81 Hz, 2H) 8.73 (dd, J=4.80, 1.52 Hz, 1H) 8.83 (d, J=5.81 Hz, 1H).

1. temperaturewhile maintaining the temperature below 20° C
2. stirringContinue stirring the reaction mixture for 30 min
3. customSeparate the layers
4. concentrationconcentrate the organic layer to approximately 200 mL total volume
5. concentrationAdd dimethylsulfoxide and concentrate until no dichloromethane
6. customSeparate the layers
7. extractionextract the aqueous layer with dichloromethane (1.4 L)
8. customSeparate the layers
9. washWash the combined organic layers with an aqueous solution of 10% sodium chloride (3×2.6 L)
10. concentrationConcentrate the organic layer to approximately 500 mL total volume
11. concentrationConcentrate under vacuum until the weight of the resulting residue
12. additionadd more methanol (207 mL)
13. temperatureHeat the solution to 60° C
14. customreaches 45° C.
15. stirringStir the resulting slurry at 22° C. for 16 h
16. customCollect the resulting solid
17. filtrationby filtration
18. washwash with methanol (3×65 mL) and water (3×65 mL)
19. stirringstir for 4 h
20. customCollect the resulting solid
21. filtrationby filtration
22. washwash with water (50 mL)
23. customdry under vacuum at 50° C.