1-Bromo-3-fluorobenzene → HCID 178444323, compound

Temperature

30 °C

1-Bromo-3-fluorobenzene (s1) (60.0 g) and THF (1,000 ml) were placed in a reaction vessel under an atmosphere of nitrogen, and cooled to −74° C. n-Butyllithium (1.57M in n-hexane; 218 ml) was added dropwise in the temperature range of −74° C. to −70° C., and the stirring was continued for another 2 hours. 4-Pentylcyclohexanone (s2) (57.7 g) dissolved in THF (150 ml) was added dropwise 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 resulting reaction mixture was poured into a vessel containing an aqueous solution of ammonium chloride (500 ml) and ethyl acetate (500 ml), and mixed with them. The mixture was allowed to stand and separate into organic and aqueous layers, and the latter was extracted. The separated organic layers were washed with water, a saturated aqueous solution of sodium hydrogencarbonate and water, and dried over anhydrous magnesium sulfate. The solvent was distilled under reduced pressure. p-Toluenesulfonic acid (2.4 g) and toluene (250 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 (900 ml) were added and mixed with it. The mixture was allowed to stand and separate into two layers of organic and aqueous layers, and the latter was extracted. The separated organic layers were washed with a saturated aqueous solution of sodium hydrogencarbonate and water, and then dried over anhydrous magnesium sulfate. The resulting solution was purified by fractionation using column chromatography with heptane as an eluent and silica gel as a stationary phase powder, and dried. The product was dissolved in toluene (150 ml) and Solmix A-11 (150 ml), to which Pd/C (0.8 g) was added. The mixture was stirred at room temperature under a hydrogen atmosphere until hydrogen absorption had ceased. After the reaction had been completed, Pd/C was removed, and then solvent was distilled off. The resulting residue was purified by fractionation using column chromatography with heptane as an eluent and silica gel as a stationary phase powder, and by recrystallization from Solmix A-11, and then dried to give 1-fluoro-3-(trans-4-pentyl cyclohexyl)benzene (s3) (58.4 g). The yield based on the compound (s1) was 68.6%.

1. additionwas added dropwise in the temperature range of −74° C. to −70° C.
2. additionwas added dropwise in the temperature range of −75° C. to −70° C.
3. waitthe stirring was continued for another 8 hours while the mixture
4. customto come to 25° C
5. customThe resulting reaction mixture
6. additionwas poured into a vessel
7. additionmixed with them
8. customseparate into organic and aqueous layers
9. extractionthe latter was extracted
10. washThe separated organic layers were washed with water
11. dry with materiala saturated aqueous solution of sodium hydrogencarbonate and water, and dried over anhydrous magnesium sulfate
12. distillationThe solvent was distilled under reduced pressure
13. additionp-Toluenesulfonic acid (2.4 g) and toluene (250 ml) were added to the residue
14. temperaturethe mixture was heated
15. temperatureto reflux for 2 hours
16. distillationwhile distilled water
17. customwas removed
18. additionwater (500 ml) and toluene (900 ml) were added
19. additionmixed with it
20. customseparate into two layers of organic and aqueous layers
21. extractionthe latter was extracted
22. washThe separated organic layers were washed with a saturated aqueous solution of sodium hydrogencarbonate and water
23. dry with materialdried over anhydrous magnesium sulfate
24. customThe resulting solution was purified by fractionation
25. customsilica gel as a stationary phase powder, and dried
26. dissolutionThe product was dissolved in toluene (150 ml)
27. additionSolmix A-11 (150 ml), to which Pd/C (0.8 g) was added
28. customPd/C was removed
29. distillationsolvent was distilled off
30. customThe resulting residue was purified by fractionation
31. customsilica gel as a stationary phase powder, and by recrystallization from Solmix A-11
32. customdried

ORD record

ord-4b3095f84e0a4bf1ad9fb3bf65e09515

Source dataset

uspto-grants-2013_06

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08470199B2