Hydrogen Bromide → 3-(4-Bromo-2-fluoro-phenoxy)-2,6-dimethyl-pyridine

HRID 889639Notes

Reaction equation

HRID 889639 reaction equation
N([O-])=O.[Na+].[CH3:5][C:6]1[C:11]([O:12][C:13]2[CH:18]=[CH:17][C:16](N)=[CH:15][C:14]=2[F:20])=[CH:10][CH:9]=[C:8]([CH3:21])[N:7]=1.C(=O)([O-])[O-].[K+].[K+].CCOC(C)=O.[BrH:34]>O.[Cu]Br>[Br:34][C:16]1[CH:17]=[CH:18][C:13]([O:12][C:11]2[C:6]([CH3:5])=[N:7][C:8]([CH3:21])=[CH:9][CH:10]=2)=[C:14]([F:20])[CH:15]=1

Participants

8

Reactant 5

HCID 260Hydrogen BromideHCID 8857Ethyl AcetateHCID 11430Potassium CarbonateHCID 23668193Sodium NitriteHCID 592873214-(2,6-Dimethyl-pyridin-3-yloxy)-3-fluoro-phenylamine

Product 1

HCID 592873113-(4-Bromo-2-fluoro-phenoxy)-2,6-dimethyl-pyridineYield 89%

Reagents, catalysts & solvents 2

HCID 24593copper(I) bromideCatalystHCID 962WaterSolvent

Procedure

A solution of sodium nitrite (4.57 g, 66.3 mmol) in water (75 ml) was added dropwise (over 45 minutes) to a cooled (at 0° C.) solution of intermediate D15 (7.7 g, 33.2 mmol) in 48% aqueous HBr (75 ml). The reaction mixture was warmed to room temperature and further stirred for 15 minutes, after which it was cooled again to 0° C. and copper(I) bromide (7.31 g, 49.8 mmol) was added portionwise. The mixture was allowed to reach room temperature, stirred for 15 minutes and finally it was heated at 140° C. for 1.5 hours. The reaction mixture was cooled to room temperature and neutralized with an aqueous saturated solution of potassium carbonate. EtOAc was added, the organic layer was separated and washed with brine, dried (Na2SO4) and the solvent evaporated in vacuo. The crude product was purified by column chromatography (silica gel; 0-10% EtOAc/heptane as eluent). The desired fractions were collected and evaporated in vacuo to yield D16 (8.75 g, 89%) as a pale brown oil.

Workup

  1. temperatureafter which it was cooled again to 0° C.
  2. customto reach room temperature
  3. stirringstirred for 15 minutes
  4. temperaturefinally it was heated at 140° C. for 1.5 hours
  5. temperatureThe reaction mixture was cooled to room temperature
  6. customthe organic layer was separated
  7. washwashed with brine
  8. dry with materialdried (Na2SO4)
  9. customthe solvent evaporated in vacuo
  10. customThe crude product was purified by column chromatography (silica gel; 0-10% EtOAc/heptane as eluent)
  11. customThe desired fractions were collected
  12. customevaporated in vacuo

Sources & evidence

ORD record
ord-e6c2ba6a655b4b4c920e6f84f0c1a746
Source dataset
uspto-grants-2012_08
Patent number
US08252937B2

Reaction notes

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