2-(4-Bromophenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol → 1,1,1,3,3,3-Hexafluoro-2-(4-(2-((6-methoxy-2-pyridinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol

HRID 1972666Notes

Reaction equation

HRID 1972666 reaction equation
[CH3:1][O:2][C:3]1[N:8]=[C:7]([CH2:9][CH:10]2[NH:15][CH2:14][CH2:13][N:12]([S:16]([C:19]3[S:20][CH:21]=[CH:22][CH:23]=3)(=[O:18])=[O:17])[CH2:11]2)[CH:6]=[CH:5][CH:4]=1.Br[C:25]1[CH:30]=[CH:29][C:28]([C:31]([OH:40])([C:36]([F:39])([F:38])[F:37])[C:32]([F:35])([F:34])[F:33])=[CH:27][CH:26]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.[NH4+].[Cl-].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:33][C:32]([F:34])([F:35])[C:31]([C:28]1[CH:27]=[CH:26][C:25]([N:15]2[CH2:14][CH2:13][N:12]([S:16]([C:19]3[S:20][CH:21]=[CH:22][CH:23]=3)(=[O:17])=[O:18])[CH2:11][CH:10]2[CH2:9][C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[N:8]=2)=[CH:30][CH:29]=1)([OH:40])[C:36]([F:37])([F:39])[F:38]

Participants

7

Reactant 3

HCID 232335702-(4-Bromophenyl)-1,1,1,3,3,3-hexafluoropropan-2-olHCID 23676156Sodium t-butoxideHCID 665833823-((6-Methoxy-2-pyridinyl)methyl)-1-(2-thiophenylsulfonyl)piperazine

Product 1

HCID 569330491,1,1,3,3,3-Hexafluoro-2-(4-(2-((6-methoxy-2-pyridinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanolYield 75.4%

Reagents, catalysts & solvents 3

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 1140TolueneSolventHCID 25517Ammonium ChlorideSolvent

Conditions

Temperature
100 °C

Procedure

To a 50-mL round-bottomed flask was added 3-((6-methoxy-2-pyridinyl)methyl)-1-(2-thiophenylsulfonyl)piperazine (115 mg, 0.325 mmol), 2-(4-bromophenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (126 mg, 0.390 mmol, Bioorg. Med. Chem. Lett. 2002, 12, 3009), dicyclohexyl(2′,4′,6′-triisopropyl-[1′,1′-biphenyl]-2-yl)phosphine (RuPhos)(62 mg, 0.13 mmol, Strem, Newburyport, Mass.), tris(dibenzylideneacetone)dipalladium (30 mg, 0.033 mmol, Strem, Newburyport, Mass.) and sodium tert-butoxide (94 mg, 0.98 mmol, Aldrich, St. Louis, Mo.) in toluene (5 mL). The reaction mixture was stirred at 100° C. for 18 h and then allowed to cool to room temperature and then diluted with saturated NH4Cl (5 mL) and extracted with EtOAc (2×40 mL). The organic extract was washed with saturated NaCl (5 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material as a light-yellow oil. The crude product was purified by silica gel chromatography, eluting with 30% EtOAc/hexanes to give 1,1,1,3,3,3-hexafluoro-2-(4-(2-((6-methoxy-2-pyridinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol (146 mg) as a light-yellow tar (mixture of enantiomers).

Workup

  1. temperatureto cool to room temperature
  2. extractionextracted with EtOAc (2×40 mL)
  3. extractionThe organic extract
  4. washwas washed with saturated NaCl (5 mL)
  5. dry with materialdried over Na2SO4
  6. filtrationThe solution was filtered
  7. concentrationconcentrated in vacuo
  8. customto give the crude material as a light-yellow oil
  9. customThe crude product was purified by silica gel chromatography
  10. washeluting with 30% EtOAc/hexanes

Sources & evidence

ORD record
ord-bbf58c90a8814026a1f0b9453db147a7
Source dataset
uspto-grants-2013_04
Patent number
US08431563B2

Reaction notes

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