Ammonium Chloride → 1-(4-Ethoxy-2,3-difluorophenyl)-4-(4-butoxy-2,3-difluorophenyl)cyclohexan-1-ol

HRID 1511487Notes

Reaction equation

HRID 1511487 reaction equation
[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:5]=1[F:11])[CH3:2].C([Li])CCC.[CH2:17]([O:21][C:22]1[CH:27]=[CH:26][C:25]([CH:28]2[CH2:33][CH2:32][C:31](=[O:34])[CH2:30][CH2:29]2)=[C:24]([F:35])[C:23]=1[F:36])[CH2:18][CH2:19][CH3:20].[Cl-].[NH4+]>C1COCC1.C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:31]2([OH:34])[CH2:32][CH2:33][CH:28]([C:25]3[CH:26]=[CH:27][C:22]([O:21][CH2:17][CH2:18][CH2:19][CH3:20])=[C:23]([F:36])[C:24]=3[F:35])[CH2:29][CH2:30]2)=[C:6]([F:10])[C:5]=1[F:11])[CH3:2]

Participants

7

Reactant 4

HCID 25517Ammonium ChlorideHCID 27829281-Ethoxy-2,3-DifluorobenzeneHCID 581412471-(4-Butoxy-2,3-difluorophenyl)-cyclohexan-4-oneHCID 178418339Butyllithium

Product 1

HCID 669627671-(4-Ethoxy-2,3-difluorophenyl)-4-(4-butoxy-2,3-difluorophenyl)cyclohexan-1-olYield 97.5%

Reagents, catalysts & solvents 2

HCID 1140TolueneSolventHCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
30 °C

Procedure

1-Ethoxy-2,3-difluorobenzene (27) (7.0 g) and THF (200 ml) were added to a reaction vessel under a nitrogen atmosphere, and cooled to −74° C. n-Butyl lithium (1.57 M in n-hexane; 31.0 ml) was added dropwise in the temperature range of −74° C. to −70° C., and the stirring was continued for another 2 hours. Then, 1-(4-butoxy-2,3-difluorophenyl)-cyclohexane-4-one (28) (12.5 g) dissolved in THF (50 ml) was slowly added dropwise in the temperature range of 50° C. to 60° C., and stirring was continued for another 60 minutes. The obtained reaction mixture was cooled to 30° C., and then poured into a vessel containing an aqueous solution of ammonium chloride (3%; 400 ml) and toluene (200 ml) cooled to 0° C., and mixed. Then the mixture was allowed to separate into organic and aqueous phases, and the extraction into an organic phase was carried out. The organic phase obtained was washed sequentially with water, a saturated aqueous solution of sodium hydrogencarbonate and water, and dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure, giving 19.0 g of 1-(4-ethoxy-2,3-difluorophenyl)-4-(4-butoxy-2,3-difluorophenyl)cyclohexan-1-ol (29). The obtained compound (29) was yellow oil.

Workup

  1. additionwas added dropwise in the temperature range of −74° C. to −70° C.
  2. additionwas slowly added dropwise in the temperature range of 50° C. to 60° C.
  3. waitwas continued for another 60 minutes
  4. customThe obtained reaction mixture
  5. additionpoured into a vessel
  6. temperaturecooled to 0° C.
  7. additionmixed
  8. customto separate into organic and aqueous phases
  9. extractionthe extraction into an organic phase
  10. customThe organic phase obtained
  11. washwas washed sequentially with water
  12. dry with materiala saturated aqueous solution of sodium hydrogencarbonate and water, and dried over anhydrous magnesium sulfate
  13. distillationThen, the solvent was distilled off under reduced pressure

Sources & evidence

ORD record
ord-8217138fd5df40adb9a6b5092fde6243
Source dataset
uspto-grants-2012_07
Patent number
US08216489B2

Reaction notes

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