Ammonium Chloride → 1-Butoxy-4-(4-(2,3-difluorophenyl)cyclohex-1-enyl)-2,3-difluorobenzene

Temperatur

30 °C

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%.

1. addition114 ml) was added dropwide
2. additionwas added dropwise
3. waitin the temperature range of −75° C. to −70° C., and the stirring was continued for another 8 hours while the mixture
4. customto come to 25° C
5. additionThe reaction mixture was poured into a vessel
6. additionmixed with them
7. customhad separated into organic and aqueous phases
8. extractionthe extraction
9. washThe combined organic phase was washed successively with water
10. dry with materiala saturated aqueous solution of sodium hydrogencarbonate and water, and dried over anhydrous magnesium sulfate
11. distillationThen, the solvent was distilled off under the reduced pressure
12. additionp-Toluenesulfonic acid (4.1 g) and toluene (300 ml) were added to the residue
13. temperaturethe mixture was heated
14. temperatureto reflux for 2 hours
15. distillationwhile distilled water
16. customwas removed
17. additionwater (500 ml) and toluene (500 ml) were added to the mixture
18. additionmixed with it
19. customhad separated into two phases of organic and aqueous phases
20. extractionthe extraction
21. washThe combined organic phase was washed successively with a saturated aqueous solution of sodium hydrogencarbonate and water
22. dry with materialdried over anhydrous magnesium sulfate
23. customThe solution was purified by column chromatography
24. customa mixed solvent of toluene and heptane (1/1 by volume) as an eluent, and then by recrystallization from Solmix A-11

ORD-Eintrag

ord-7f9079abc02d42cbb77890ddc71ee4de

Quelldatensatz

uspto-grants-2013_05

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US08435422B2