Cesium carbonate → 4-Amino-3'-chloro-6-fluoro-5-hydroxy-3-methylbiphenyl-3-carbonitrile

HRID 17599Notes

Reaction equation

HRID 17599 reaction equation
[NH2:1][C:2]1[C:9]([OH:10])=[C:8]([F:11])[C:7](Br)=[C:6](C)[C:3]=1[C:4]#[N:5].[Cl:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1.[C:24](=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O>[NH2:1][C:2]1[C:3]([CH3:24])([C:4]#[N:5])[CH2:6][C:7]([C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:14])[CH:20]=2)=[C:8]([F:11])[C:9]=1[OH:10]

Participants

6

Reactant 3

HCID 10796Cesium carbonateHCID 2734323(3-Chlorophenyl)boronic acidHCID 860975142-Amino-5-bromo-4-fluoro-3-hydroxy-6-methylbenzonitrile

Product 1

HCID 685854334-Amino-3'-chloro-6-fluoro-5-hydroxy-3-methylbiphenyl-3-carbonitrileYield 78%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

2-Amino-5-bromo-4-fluoro-3-hydroxy-6-methylbenzonitrile (I-75) (2.0 g, 8.16 mmol), 3-chlorophenylboronic acid (2.63 g, 16.3 mmol) and cesium carbonate (5.32 g, 16.3 mmol) were dissolved in 1,4-dioxane (90 ml)/water (10 ml), and at room temperature, (tetrakistriphenylphosphine)palladium(0) (943 mg, 0.82 mmol) was added. The solution was stirred in a nitrogen steam at 100° C. for 12 hours. After cooling to room temperature, the insoluble matter was separated by filtration with washing with ethyl acetate. The filtrate was concentrated under reduced pressure, and the residue was fractionated with ethyl acetate and saturated brine. The aqueous layer was separated, this was further extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The insoluble matter was separated by filtration, the solvent was evaporated away, and the resulting residue was purified by middle-pressure liquid chromatography (eluent, chloroform:ethyl acetate=95:5, v/v) to obtain the entitled compound (1.76 g, 78%) as a pale brown solid.

Workup

  1. temperatureAfter cooling to room temperature
  2. customthe insoluble matter was separated by filtration
  3. washwith washing with ethyl acetate
  4. concentrationThe filtrate was concentrated under reduced pressure
  5. customThe aqueous layer was separated
  6. extractionthis was further extracted twice with ethyl acetate
  7. washwashed with saturated brine
  8. dry with materialdried over anhydrous sodium sulfate
  9. customThe insoluble matter was separated by filtration
  10. customthe solvent was evaporated away
  11. customthe resulting residue was purified by middle-pressure liquid chromatography (eluent, chloroform

Sources & evidence

ORD record
ord-aa631540665a49e59cd3384132a16db5
Source dataset
uspto-grants-2010_06
Patent number
US07737166B2

Reaction notes

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