Ethyl Acetate → 1-[4-(Tetrahydropyran-2-yloxy)phenyl]-4-(4-trifluoromethoxyphenoxy)piperidine

HRID 856103Notes

Reaction equation

HRID 856103 reaction equation
[F:1][C:2]([F:18])([F:17])[O:3][C:4]1[CH:16]=[CH:15][C:7]([O:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:6][CH:5]=1.Br[C:20]1[CH:32]=[CH:31][C:23]([O:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.O>[O:26]1[CH2:27][CH2:28][CH2:29][CH2:30][CH:25]1[O:24][C:23]1[CH:31]=[CH:32][C:20]([N:12]2[CH2:11][CH2:10][CH:9]([O:8][C:7]3[CH:15]=[CH:16][C:4]([O:3][C:2]([F:1])([F:17])[F:18])=[CH:5][CH:6]=3)[CH2:14][CH2:13]2)=[CH:21][CH:22]=1

Participants

9

Reactant 4

HCID 8857Ethyl AcetateHCID 10796Cesium carbonateHCID 46464362-(4-Bromophenoxy)tetrahydro-2H-pyranHCID 161154394-[4-(Trifluoromethoxy)phenoxy]piperidine

Product 1

HCID 160991421-[4-(Tetrahydropyran-2-yloxy)phenyl]-4-(4-trifluoromethoxyphenoxy)piperidineYield 64.2%

Reagents, catalysts & solvents 4

HCID 167845palladium(II) acetateCatalystHCID 634876Binap, (A+-)-CatalystHCID 962WaterSolventHCID 1140TolueneSolvent

Procedure

A mixture of 4-(4-trifluoromethoxyphenoxy)piperidine (30.3 g, 0.116 mol) prepared in Reference Example 190, 2-(4-bromophenoxy)tetrahydropyran (30 g, 0.116 mol), palladium acetate (1.0 g, 4.64 mmol), BINAP (4.3 g, 6.96 mmol) and cesium carbonate (49 g, 0.151 mol) in toluene (300 ml) was refluxed under a nitrogen atmosphere for 30 hours. Ethyl acetate and water were added to the reaction mixture, which was stirred for a while. The insoluble substances were removed by filtration through Celite, and the filtrate was then extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=20/1) to afford 1-[4-(tetrahydropyran-2-yloxy)phenyl]-4-(4-trifluoromethoxyphenoxy)piperidine (32.6 g, yield 64%) as a yellow powder.

Workup

  1. temperaturewas refluxed under a nitrogen atmosphere for 30 hours
  2. customThe insoluble substances were removed by filtration through Celite
  3. extractionthe filtrate was then extracted with ethyl acetate
  4. washThe extract was washed with brine
  5. dry with materialdried over magnesium sulfate
  6. filtrationfiltered
  7. concentrationThe filtrate was concentrated under reduced pressure
  8. customthe residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=20/1)

Sources & evidence

ORD record
ord-e3cfcaec0fdb490da7d92ba52509d53b
Source dataset
uspto-grants-2007_08
Patent number
US07262212B2

Reaction notes

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