Hydrochloric Acid → (2-Bromopyridin-3-yl)-(2-chlorophenyl)methanone

온도

-70 °C

Add n-butyllithium (21.7 mL, 34.8 mmol, 1.6 M in hexanes) to a −70° C. solution of diisopropylamine (4.9 mL, 34.8 mmol) in THF (75 mL). Allow the solution to cool back to −70° C., and add 2-bromopyridine (5.0 g, 31.6 mmol) to the solution while maintaining the temperature below −65° C. Rinse contents of vessel that contained 2-bromopyridine with THF (10 mL) and add this solution to the reaction mixture. Stir the resulting solution for 15 min, and then add a solution of 2-chlorobenzaldehyde (3.55 mL, 31.6 mmol) in THF (15 mL) in a single portion. Stir the resulting solution for approximately 5 h at −70° C. Add MeOH (3.0 mL) and remove cooling. Add 3 N HCl (30 mL) to the reaction mixture followed by toluene (25 mL). Separate the layers, and wash the organic layer with H2O (25 mL). Concentrate the organic layer to approximately 2 total volumes. Add toluene (50 mL) and concentrate the solution to approximately 2 total volumes. Add toluene (65 mL) again, and concentrate the solution to approximately 2 total volumes. Add DMSO (18 mL). Add N,N-diisopropylethylamine (14.5 mL, 83.1 mmol) to the resulting solution. In a separate reaction vessel, dissolve sulfur trioxide pyridine complex (11.6 g, 72.7 mmol) in DMSO (50 mL). Add a portion of the sulfur trioxide pyridine complex/DMSO solution (35 mL) to the reaction mixture and stir for 30 min. Add a second portion of the sulfur trioxide pyridine complex/DMSO solution (9 mL) to the reaction mixture and stir for 30 min. Add a third portion of the sulfur trioxide pyridine complex/DMSO solution (9 mL) and stir for 30 min. Add a final portion of the sulfur trioxide pyridine complex/DMSO solution (approximately 9 mL) and stir for 30 min. Add ethyl acetate (50 mL) and 1 N HCl (100 mL). Separate the layers and extract the aqueous layer with ethyl acetate (25 mL). Separate the layers and extract the combined organic layers with H2O (25 mL). Separate the layers and concentrate the organic layer to approximately 2 total volumes. Add isopropanol (50 mL) and concentrate the resulting solution to approximately 2 total volumes. Add isopropanol (50 mL) and concentrate the resulting solution to approximately 2 total volumes. Add isopropanol (5 mL), and then add heptane (40 mL) dropwise. Stir the resulting slurry for 15 min. Cool the slurry to 0° C. and stir for 1 h. Filter the slurry, rinse the filter cake with chilled heptane (20 mL), and dry to afford the title compound as an off-white solid: 1H NMR (500 MHz, CDCl3) δ 8.49 (dd, J=4.9, 2.0 Hz, 1H), 7.78 (dd, J=7.3, 2.0 Hz, 1H), 7.59 (dd, J=7.3, 1.5 Hz, 1H), 7.49-7.36 (m, 4H); 13C NMR (125 MHz, CDCl3) δ 193.8, 152.0, 139.5, 139.1, 137.7, 136.7, 133.6, 133.3, 131.8, 131.2, 127.4, 123.0. LRMS (ES+) calcd for C12H8BrClNO (M+H+) 295.9, found 295.8 m/z.

1. temperaturewhile maintaining the temperature below −65° C
2. customRinse contents of vessel that contained
3. stirringStir the resulting solution for approximately 5 h at −70° C
4. customAdd MeOH (3.0 mL) and remove
5. temperaturecooling
6. additionAdd 3 N HCl (30 mL) to the reaction mixture
7. customSeparate the layers
8. washwash the organic layer with H2O (25 mL)
9. concentrationConcentrate the organic layer to approximately 2 total volumes
10. concentrationAdd toluene (50 mL) and concentrate the solution to approximately 2 total volumes
11. concentrationAdd toluene (65 mL) again, and concentrate the solution to approximately 2 total volumes
12. customIn a separate reaction vessel
13. stirringstir for 30 min
14. stirringstir for 30 min
15. stirringstir for 30 min
16. stirringstir for 30 min
17. customSeparate the layers
18. extractionextract the aqueous layer with ethyl acetate (25 mL)
19. customSeparate the layers
20. extractionextract the combined organic layers with H2O (25 mL)
21. customSeparate the layers
22. concentrationconcentrate the organic layer to approximately 2 total volumes
23. concentrationAdd isopropanol (50 mL) and concentrate the resulting solution to approximately 2 total volumes
24. concentrationAdd isopropanol (50 mL) and concentrate the resulting solution to approximately 2 total volumes
25. stirringStir the resulting slurry for 15 min
26. temperatureCool the slurry to 0° C.
27. stirringstir for 1 h
28. filtrationFilter the slurry
29. washrinse the filter cake with chilled heptane (20 mL)
30. customdry

ORD 기록

ord-b3dd503d113d41c69b7ace085b4e4099

출처 데이터셋

uspto-grants-2008_06

DOI

10.6084/m9.figshare.5104873.v1

특허 번호

US07381826B2