反应详情

温度

2.5 °C

To a 50 L three-neck round-bottom flask equipped with a mechanical stirrer, thermocouple, and nitrogen inlet, was added dry THF (35 L) and cooled to 0-5° C. To the flask was added Iron (III) chloride (2.7 kg, 0.15 eq) portion wise over 30-60 min. and stirred for 15-30 min. resulting in a clear greenish solution. Under a nitrogen atmosphere in a dry 100 gallon glass lined reactor was added THF (87.5 L) and magnesium turnings (4.05 kg, 1.5 eq), and cooled to 0-5° C. To the THF and magnesium mixture was added the solution of FeCl3 in THF at a rate to maintain the internal temperature below 10° C. To the resulting yellow/green mixture was added TMEDA (15.5 kg, 1.2 eq) at a rate to maintain the internal temperature below 20° C. The resulting reaction mixture was heated to 40-45° C. for 1 hour and a mixture of 1 bromo-2-(trifluoromethyl)benzene (25 kg, 1.0 eq) and bromocyclopentane (19.9 kg, 1.2 eq) was added to the reaction mixture at a rate to maintain an internal temperature below 25° C. The resulting reaction mixture was allowed to stir at room temperature overnight and subsequently cooled to an internal temperature of 0-5° C. To the resulting mixture was added 6 N HCl (100 L, 1.5 h) at such a rate as to maintain the internal temperature below 15° C. (caution, very exothermic). After the quench, MTBE (200 L) was added and the reactor contents was stirred for 30 min. The phases were separated and the aqueous layer back extracted with MTBE (75 L). The combined organic layers were washed with H2O (50 L), brine (50 L) and dried (MgSO4). The mixture was filtered through an in-line (1 micron) filter cartridge followed by an additional in-line (0.45 micron) filter cartridge into a clean dry reactor. The solvent was evaporated under vacuum (jacket ≦30° C.) and co-evaporated with heptanes (2×25 L) to provide a viscous liquid. The viscous liquid was dissolved in heptanes (100 L) and passed through a silica plug (25 kg). The silica plug was eluted with heptanes (TLC, Rf˜0.8, silica gel, heptanes) and the fractions containing the product were evaporated to provide the title compound as a yellow liquid, 11.7 kg (49.2%), purity as determined by HPLC was 94.1%. 1H NMR conforms to reference standard.

1. customTo a 50 L three-neck round-bottom flask equipped with a mechanical stirrer
2. customresulting in a clear greenish solution
3. temperaturecooled to 0-5° C
4. temperatureto maintain the internal temperature below 10° C
5. temperatureto maintain the internal temperature below 20° C
6. customThe resulting reaction mixture
7. temperaturewas heated to 40-45° C. for 1 hour
8. additionwas added to the reaction mixture at a rate
9. temperatureto maintain an internal temperature below 25° C
10. customThe resulting reaction mixture
11. stirringto stir at room temperature overnight
12. temperaturesubsequently cooled to an internal temperature of 0-5° C
13. temperatureto maintain the internal temperature below 15° C. (caution, very exothermic)
14. stirringthe reactor contents was stirred for 30 min
15. customThe phases were separated
16. extractionthe aqueous layer back extracted with MTBE (75 L)
17. washThe combined organic layers were washed with H2O (50 L), brine (50 L)
18. dry with materialdried (MgSO4)
19. filtrationThe mixture was filtered through an in-line (1 micron)
20. filtrationfilter cartridge
21. filtrationfilter cartridge into a clean dry reactor
22. customThe solvent was evaporated under vacuum (jacket ≦30° C.)
23. customto provide a viscous liquid
24. washThe silica plug was eluted with heptanes (TLC, Rf˜0.8, silica gel, heptanes)
25. additionthe fractions containing the product
26. customwere evaporated