Hydrochloric Acid → HCID 86667324, compound

HRID 2039405Notes

Reaction equation

HRID 2039405 reaction equation
[F:1][C:2]1[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:3]=1[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[C:8]([F:19])[C:7]=1[F:20].C([Li])(CC)C.[F:31][C:32]1[C:37]([F:38])=[C:36]([O:39][CH2:40][CH3:41])[CH:35]=[CH:34][C:33]=1[CH:42]1[CH2:47][CH2:46][C:45](=O)[CH2:44][CH2:43]1.Cl>C(OCC)(=O)C.C1COCC1>[F:20][C:7]1[C:8]([F:19])=[C:9]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:10]=[CH:11][C:6]=1[CH2:5][CH2:4][C:3]1[CH:21]=[CH:22][C:23]([C:45]2[CH2:46][CH2:47][CH:42]([C:33]3[CH:34]=[CH:35][C:36]([O:39][CH2:40][CH3:41])=[C:37]([F:38])[C:32]=3[F:31])[CH2:43][CH:44]=2)=[C:24]([F:25])[C:2]=1[F:1]

Participants

7

Reactant 4

HCID 313Hydrochloric AcidHCID 111611214-(4-Ethoxy-2,3-difluorophenyl)cyclohexanoneHCID 68008782HCID 68008782, compoundHCID 178418400CID 53628100

Product 1

HCID 86667324HCID 86667324, compound

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolvent2×HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
30 °C

Procedure

1-(2,3-Difluorophenethyl)-2,3-difluoro-4-(hexyloxy)benzene (s-24) (3.6 g) and THF (100 ml) were placed in a reaction vessel under an atmosphere of nitrogen, and cooled to −74° C. sec-Butyllithium (1.00M; n-hexane and cyclohexane solution; 12 ml) was added dropwise in the temperature range of −74° C. to −70° C., and the stirring was continued for another 2 hours. 1-(2,3-Difluoro-4-ethoxyphenyl)-cyclohexan-4-one (s-25) (2.6 g) in a THF (50 ml) solution was added dropwise in the temperature range of −75° C. to −70° C., and the stirring was continued for 8 hours while the mixture was allowed to return to 25° C. The resulting reaction mixture was poured into a vessel containing a 1N-HCl aqueous solution (100 ml) and ethyl acetate (100 ml) and mixed with them. The mixture was then allowed to stand until it had separated into organic and aqueous layers, and the extraction was carried out. The resulting organic layers were separated, and washed with a saturated aqueous solution of sodium hydrogencarbonate and water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. p-Toluenesulfonic acid (0.19 g) and toluene (100 ml) were added, and the mixture was heated to reflux for 2 hours, while distilled water was removed. After the reaction solution had been cooled to 30° C., water (200 ml) and toluene (100 ml) were added and mixed with it. The mixture was then allowed to stand until it had separated into two layers of organic and aqueous layers, and the extraction into an organic layer was carried out. The resulting organic layers were separated, and washed with a saturated aqueous solution of sodium hydrogencarbonate and water, and then dried over anhydrous magnesium sulfate. The resulting solution was purified by column chromatography using silica gel as a stationary phase powder and toluene as an eluent, and further purified by recrystallization from a mixed solvent of Solmix A-11 and heptane (Solmix A-11:heptane=1:2 by volume) and dried to give 1-(2,3-difluoro-4-(hexyloxy)phenethyl)-4-(4-(4-ethoxy-2,3-difluorophenyl)cyclohex-1-enyl)-2,3-difluorobenzene (No. 487) (3.1 g). The yield based on the compound (s-24) was 33.8%.

Workup

  1. additionwas added dropwise in the temperature range of −74° C. to −70° C.
  2. waitthe stirring was continued for 8 hours while the mixture
  3. customto return to 25° C
  4. customThe resulting reaction mixture
  5. additionwas poured into a vessel
  6. additionmixed with them
  7. customhad separated into organic and aqueous layers
  8. extractionthe extraction
  9. customThe resulting organic layers were separated
  10. washwashed with a saturated aqueous solution of sodium hydrogencarbonate and water
  11. dry with materialdried over anhydrous magnesium sulfate
  12. distillationThe solvent was distilled off under reduced pressure
  13. additionp-Toluenesulfonic acid (0.19 g) and toluene (100 ml) were added
  14. temperaturethe mixture was heated
  15. temperatureto reflux for 2 hours
  16. distillationwhile distilled water
  17. customwas removed
  18. additionwater (200 ml) and toluene (100 ml) were added
  19. additionmixed with it
  20. customhad separated into two layers of organic and aqueous layers
  21. extractionthe extraction into an organic layer
  22. customThe resulting organic layers were separated
  23. washwashed with a saturated aqueous solution of sodium hydrogencarbonate and water
  24. dry with materialdried over anhydrous magnesium sulfate
  25. customThe resulting solution was purified by column chromatography
  26. customfurther purified by recrystallization from a mixed solvent of Solmix A-11 and heptane (Solmix A-11:heptane=1:2 by volume)
  27. customdried

Sources & evidence

ORD record
ord-5740bb03ae644d04a6361dd8461284cb
Source dataset
uspto-grants-2013_11
Patent number
US08580147B2

Reaction notes

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