Reacción #2175426

Ecuación de reacción

4-(2,3-difluorophenyl)cyclohexanone

sec-Butyllithium

ammonium chloride

3-Butoxy-1,2-difluorobenzene

→

1-butoxy-4-(4-(2,3-difluorophenyl)cyclohex-1-enyl)-2,3-difluorobenzene

Rendimiento 20.0%

Disolventes

THF

n-hexane

cyclohexane

ethyl acetate

THF

Condiciones de reacción

Tratamiento posterior

1. 1
   workup.ADDITION114 ml) was added dropwide
2. 2
   workup.ADDITIONwas added dropwise
3. 3
   workup.WAITin the temperature range of −75° C. to −70° C., and the stirring was continued for another 8 hours while the mixture
4. 4
   Otroto come to 25° C
5. 5
   workup.ADDITIONThe reaction mixture was poured into a vessel
6. 6
   workup.ADDITIONmixed with them
7. 7
   Otrohad separated into organic and aqueous phases
8. 8
   Extracciónthe extraction
9. 9
   LavadoThe combined organic phase was washed successively with water
10. 10
    Secadoa saturated aqueous solution of sodium hydrogencarbonate and water, and dried over anhydrous magnesium sulfate
11. 11
    workup.DISTILLATIONThen, the solvent was distilled off under the reduced pressure
12. 12
    workup.ADDITIONp-Toluenesulfonic acid (4.1 g) and toluene (300 ml) were added to the residue
13. 13
    Temperaturathe mixture was heated
14. 14
    Temperaturato reflux for 2 hours
15. 15
    workup.DISTILLATIONwhile distilled water
16. 16
    Otrowas removed
17. 17
    workup.ADDITIONwater (500 ml) and toluene (500 ml) were added to the mixture
18. 18
    workup.ADDITIONmixed with it
19. 19
    Otrohad separated into two phases of organic and aqueous phases
20. 20
    Extracciónthe extraction
21. 21
    LavadoThe combined organic phase was washed successively with a saturated aqueous solution of sodium hydrogencarbonate and water
22. 22
    Secadodried over anhydrous magnesium sulfate
23. 23
    OtroThe solution was purified by column chromatography
24. 24
    Otroa mixed solvent of toluene and heptane (1/1 by volume) as an eluent, and then by recrystallization from Solmix A-11

Procedimiento

3-Butoxy-1,2-difluorobenzene (s-18) (17.7 g) and THF (500 ml) were put in a reaction vessel under an atmosphere of nitrogen and cooled to −74° C. sec-Butyllithium (a 1.00 M solution in n-hexane and cyclohexane; 114 ml) was added dropwide thereto in the temperature range of −74° C. to −70° C., and the stirring was continued for another 2 hours. Then, 4-(2,3-difluorophenyl)cyclohexanone (s-19) (20.0 g) dissolved in THF (100 ml) was added dropwise thereto in the temperature range of −75° C. to −70° C., and the stirring was continued for another 8 hours while the mixture was allowed to come to 25° C. The reaction mixture was poured into a vessel containing an aqueous solution of ammonium chloride (3%; 200 ml) and ethyl acetate (200 ml), and mixed with them. The mixture was then allowed to stand until it had separated into organic and aqueous phases, and the extraction was carried out. The combined organic phase was washed successively with water, a saturated aqueous solution of sodium hydrogencarbonate and water, and dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under the reduced pressure. p-Toluenesulfonic acid (4.1 g) and toluene (300 ml) were added to the residue and the mixture was heated to reflux for 2 hours, while distilled water was removed. After the reaction mixture had been cooled to 30° C., water (500 ml) and toluene (500 ml) were added to the mixture, and mixed with it. The mixture was then allowed to stand until it had separated into two phases of organic and aqueous phases, and the extraction was carried out. The combined organic phase was washed successively with a saturated aqueous solution of sodium hydrogencarbonate and water, and dried over anhydrous magnesium sulfate. The solution was purified by column chromatography using silica gel as a stationary phase powder and a mixed solvent of toluene and heptane (1/1 by volume) as an eluent, and then by recrystallization from Solmix A-11 to give 1-butoxy-4-(4-(2,3-difluorophenyl)cyclohex-1-enyl)-2,3-difluorobenzene (s-20) (7.2 g). The yield based on the compound (s-18) was 20.0%.

Fuente