Cesium carbonate → (1S)-2,2-difluoro-1-(3'-fluoro-5'-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}biphenyl-4-yl)ethanol

HRID 530399Notes

Reaction equation

HRID 530399 reaction equation
[NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C@H:15]([OH:19])[CH:16]([F:18])[F:17])=[CH:11][CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:27]1[N:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[CH:29][N:28]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:17][CH:16]([F:18])[C@H:15]([C:12]1[CH:11]=[CH:10][C:9]([C:4]2[CH:3]=[C:2]([NH:1][C:27]3[N:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[CH:29][N:28]=3)[CH:7]=[C:6]([F:8])[CH:5]=2)=[CH:14][CH:13]=1)[OH:19]

Participants

5

Reactant 3

HCID 10796Cesium carbonateHCID 27739122-Chloro-4-(trifluoromethyl)pyrimidineHCID 118307581(1S)-1-(3'-amino-5'-fluorobiphenyl-4-yl)-2,2-difluoroethanol

Product 1

HCID 118307516(1S)-2,2-difluoro-1-(3'-fluoro-5'-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}biphenyl-4-yl)ethanol

Reagents, catalysts & solvents 1

HCID 167845palladium(II) acetateCatalyst

Conditions

Temperature
110 °C

Procedure

Palladium(II) acetate (33.5 mg, 0.149 mmol) was added to a mixture of (1S)-1-(3′-amino-5′-fluorobiphenyl-4-yl)-2,2-difluoroethanol (222 mg, 0.747 mmol), cesium carbonate (487 mg, 1.494 mmol), and 2-chloro-4-(trifluoromethyl)pyrimidine (143 mg, 0.784 mmol) in degassed (by sparging with Argon) dioxane (8 mL). The mixture was heated to 110° C. for 5 hours. Upon cooling to room temperature, the reaction mixture was diluted with saturated aqueous NaHCO3, extracted with ethyl acetate, washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate/toluene) to afford (1S)-2,2-difluoro-1-(3′-fluoro-5′-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}biphenyl-4-yl)ethanol. MS ESI calc'd. for C19H14F6N3O [M+H]+ 414, found 414. 1H NMR (500 MHz, Acetone-d6): δ 9.48 (s, 1H); 8.89 (d, J=4.9 Hz, 1H); 8.02 (d, J=2.1 Hz, 1H); 7.89 (dd, J=11.4, 2.4 Hz, 1H); 7.76 (d, J=8.0 Hz, 2H); 7.63 (d, J=8.0 Hz, 2H); 7.32 (d, J=4.9 Hz, 1H); 7.19-7.15 (m, 1H); 6.01 (td, J=55.9, 4.3 Hz, 1H); 5.37 (d, J=4.9 Hz, 1H); 5.00-4.93 (m, 1H).

Workup

  1. customin degassed (by sparging with Argon) dioxane (8 mL)
  2. temperatureUpon cooling to room temperature
  3. additionthe reaction mixture was diluted with saturated aqueous NaHCO3
  4. extractionextracted with ethyl acetate
  5. washwashed with brine
  6. dry with materialdried over sodium sulfate
  7. filtrationfiltered
  8. concentrationconcentrated in vacuo
  9. customThe residue was purified by silica gel column chromatography (ethyl acetate/toluene)

Sources & evidence

ORD record
ord-d1a448448c81421f80dda42c4b62d971
Source dataset
uspto-grants-2016_05
Patent number
US09353066B2

Reaction notes

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