4-Fluorophenol → HCID 86590293, compound

HRID 497525Notes

Reaction equation

HRID 497525 reaction equation
[CH2:1]([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][CH:11]([C:16]1[C:24]([F:25])=[CH:23][C:19]([C:20]([NH2:22])=[O:21])=[C:18](Cl)[N:17]=1)[CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:27][C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH2:1]([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][CH:11]([C:16]1[C:24]([F:25])=[CH:23][C:19]([C:20]([NH2:22])=[O:21])=[C:18]([O:34][C:31]3[CH:32]=[CH:33][C:28]([F:27])=[CH:29][CH:30]=3)[N:17]=1)[CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1

Participants

5

Reactant 3

HCID 97324-FluorophenolHCID 10796Cesium carbonateHCID 86590294HCID 86590294, compound

Product 1

HCID 86590293HCID 86590293, compoundYield 66.7%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

Exo-N-(8-Benzyl-8-aza-bicyclo[3.2.1]oct-3-yl-2-chloro-5-fluoro-nicotinamide (7.9 g, 21 mmol) (see Preparation 33), 4-fluorophenol (2.6 g, 23 mmol) and caesium carbonate (13.8 g, 42 mmol) were stirred in N,N-dimethylformamide (200 ml) at 70° C. under an atmosphere of nitrogen for 20 hours. The reaction mixture was then partitioned between ethyl acetate (300 ml) and water (300 ml) and the organic layer separated. The organic phase was then washed with a saturated aqueous solution of sodium chloride (3-fold 200 ml), concentrated in vacuo and the residue purified by flash column chromatography on silica gel eluting with a solvent gradient of 20:80 changing to 100:0, by volume, ethyl acetate:pentane. The product was triturated with pentane (30 ml) giving exo-N-(8-benzyl-8-aza-bicyclo[3.2.1]oct-3-yl-5-fluoro-2-(4-fluoro-phenoxy)-nicotinamide (6.3 g) as a white solid.

Workup

  1. customThe reaction mixture was then partitioned between ethyl acetate (300 ml) and water (300 ml)
  2. customthe organic layer separated
  3. washThe organic phase was then washed with a saturated aqueous solution of sodium chloride (3-fold 200 ml)
  4. concentrationconcentrated in vacuo
  5. customthe residue purified by flash column chromatography on silica gel eluting with a solvent gradient of 20:80 changing to 100:0, by volume, ethyl acetate
  6. customThe product was triturated with pentane (30 ml)

Sources & evidence

ORD record
ord-062f3c894f874b28ba02305dcbfb4159
Source dataset
uspto-grants-2005_09
Patent number
US06949573B2

Reaction notes

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