反应详情

温度

4 °C

A solution of diisopropylamine (101.2 g, 140.2 mL, 1.000 mol) in tetrahydrofuran (1.148 L) was cooled to between −25° C. and −20° C. Butyllithium (2.5M in hexanes) (400 mL of 2.5 M, 1.000 mol) was added at such a rate as to maintain the reaction temperature below −20° C. (addition 20 minutes). The mixture was then allowed to warm to 4° C. over 1 hour, then re-cooled to −78° C. 3-bromo-5-fluoro-pyridine (153.0 g, 869.6 mmol) in tetrahydrofuran (382.5 mL) was added over 40 minutes. The mixture was stirred for 90 minutes, then a solution of 1,1,1,2,2,2-hexachloroethane (205.9 g, 869.6 mmol) in tetrahydrofuran (350.0 mL) was added dropwise over 40 minutes. Once the addition was complete the mixture was allowed to warm to ambient overnight. The mixture was cooled to 0° C. then transferred into cold water (2 L), stirred for 20 mins then MTBE (2.5 L) added and stirred vigorously for 30 mins then transferred to separating funnel and organic layer separated. Aqueous was transferred back to reaction vessel and further extracted with MTBE (2.5 L), stirred for 10 mins vigorously then transferred to separating funnel and organic layer separated. Organics were combined, dried (MgSO4), filtered and concentrated to a brown oil. The oil was dissolved in pentane (500 ml) and ether (300 ml). HCl (2M in ether) (434.8 mL of 2 M, 869.6 mmol) was added slowly with stirring. On complete addition the mixture was stirred for 20 mins then solid collected by filtration, washed with ether and dried under vacuum for 1 h to leave product 18 as a beige solid (148.9 g, 69%); 1H NMR (500 MHz, DMSO-d6) δ 8.77 (2H, s); 19F NMR (500 MHz, DMSO-d6) δ −124.8; MS 210.8.

1. temperatureto maintain
2. additionthe reaction temperature below −20° C. (addition 20 minutes)
3. temperaturere-cooled to −78° C
4. additionOnce the addition
5. temperatureto warm to ambient overnight
6. temperatureThe mixture was cooled to 0° C.
7. stirringstirred for 20 mins
8. stirringstirred vigorously for 30 mins
9. customto separating funnel
10. customorganic layer separated
11. customAqueous was transferred back to reaction vessel
12. extractionfurther extracted with MTBE (2.5 L)
13. stirringstirred for 10 mins vigorously
14. customto separating funnel
15. customorganic layer separated
16. dry with materialdried (MgSO4)
17. filtrationfiltered
18. concentrationconcentrated to a brown oil
19. dissolutionThe oil was dissolved in pentane (500 ml)
20. stirringwith stirring
21. additionOn complete addition the mixture
22. stirringwas stirred for 20 mins
23. filtrationsolid collected by filtration
24. washwashed with ether
25. customdried under vacuum for 1 h