Water → HCID 178448048, compound

HRID 989585Notes

Reaction equation

HRID 989585 reaction equation
[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9][CH2:10][CH2:11][CH2:12][C@H:13]1[CH2:18][CH2:17][C@H:16]([C@H:19]2[CH2:24][CH2:23][C@H:22]([CH2:25][CH2:26][CH3:27])[CH2:21][CH2:20]2)[CH2:15][CH2:14]1.C([Li])(CC)C.[F:33][C:34]1[C:39]([F:40])=[CH:38][CH:37]=[CH:36][C:35]=1Br.O>C1COCC1.[Cl-].[Zn+2].[Cl-].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]1[C:7]([F:8])=[C:6]([C:38]2[CH:37]=[CH:36][CH:35]=[C:34]([F:33])[C:39]=2[F:40])[CH:5]=[CH:4][C:3]=1[O:9][CH2:10][CH2:11][CH2:12][C@H:13]1[CH2:18][CH2:17][C@H:16]([C@H:19]2[CH2:20][CH2:21][C@H:22]([CH2:25][CH2:26][CH3:27])[CH2:23][CH2:24]2)[CH2:15][CH2:14]1

Participants

8

Reactant 4

HCID 962WaterHCID 27332601-Bromo-2,3-difluorobenzeneHCID 178418400CID 53628100HCID 178448049HCID 178448049, compound

Product 1

HCID 178448048HCID 178448048, compoundYield 708.9%

Reagents, catalysts & solvents 3

HCID 3007855ZincchlorideCatalystHCID 178418397HCID 178418397, compoundCatalystHCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-70 °C

Procedure

Under nitrogen gas stream, 101 g (267 mmol) of the 3-(trans-4-(trans-4-propylcyclohexyl)cyclohexyl)propyl 2,3-difluorophenyl ether obtained by the procedures described above was dissolved in 1.0 l of THF and cooled down to −70° C. To this solution was added by drops 320 ml of sec-butyl lithium (1.0M, cyclohexane solution) while being maintained at the same temperature, and stirred at the same temperature for 2 hours. To the reaction mixture was added by drops 640 ml of zinc chloride (0.5M, THF solution), and stirred at the same temperature for 1 hour, the reaction temperature was gradually raised up to room temperature, and they were stirred for 1 hour. To the reaction mixture was added 1.00 g of tetrakis(triphenylphosphine)palladium (0), and a solution of 61.8 g (15.9 mmol) of 2,3-difluoro-1-bromobenzene in 600 ml of THF was added by drops thereto, and heated to reflux for 3 hours. The reaction mixture was added to 1.0 l of water to terminate the reaction, the solvent was distilled off under a reduced pressure, and the residue was extracted with 3.0 l of toluene. The organic layer was washed with 1.0 l of water thrice and dried over anhydrous magnesium sulfate. The solvent was distilled off under a reduced pressure, and the residue was subjected to silica gel column chromatography (eluent: toluene) to obtain 55.3 g of a crude 3-(trans-4-(trans-4-propylcyclohexyl)cyclohexyl)propyl 2,3-difluoro-4-(2,3-difluorophenyl)phenyl ether.

Workup

  1. temperaturewhile being maintained at the same temperature
  2. stirringstirred at the same temperature for 1 hour
  3. temperaturethe reaction temperature was gradually raised up to room temperature, and they
  4. stirringwere stirred for 1 hour
  5. temperatureheated
  6. temperatureto reflux for 3 hours
  7. customto terminate
  8. customthe reaction
  9. distillationthe solvent was distilled off under a reduced pressure
  10. extractionthe residue was extracted with 3.0 l of toluene
  11. washThe organic layer was washed with 1.0 l of water thrice
  12. dry with materialdried over anhydrous magnesium sulfate
  13. distillationThe solvent was distilled off under a reduced pressure

Sources & evidence

ORD record
ord-c54416837c254a3ca3cb7bb6da393a56
Source dataset
uspto-grants-2002_10
Patent number
US06458433B1

Reaction notes

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