Sulfuric Acid → 5-Bromo-3-[(2,6-difluorobenzyl)oxy]pyridine-2-amine

HRID 2401633Notes

Reaction equation

HRID 2401633 reaction equation
[F:1][C:2]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:3]=1[CH2:4][O:5][C:6]1[C:7]([NH2:12])=[N:8][CH:9]=[CH:10][CH:11]=1.S(=O)(=O)(O)O.[Br:23]Br>C(O)(=O)C.C(OCC)(=O)C>[Br:23][C:10]1[CH:11]=[C:6]([O:5][CH2:4][C:3]2[C:13]([F:17])=[CH:14][CH:15]=[CH:16][C:2]=2[F:1])[C:7]([NH2:12])=[N:8][CH:9]=1

Participants

6

Reactant 3

HCID 1118Sulfuric AcidHCID 24408BromineHCID 102634983-(2,6-Difluoro-benzyloxy)-pyridin-2-ylamine

Product 1

HCID 211114885-Bromo-3-[(2,6-difluorobenzyl)oxy]pyridine-2-amine

Reagents, catalysts & solvents 2

HCID 176Acetic AcidSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
0 °C

Procedure

32.6 g of 3-[(2,6-difluorobenzyl)oxy]pyridine-2-amine (Example 1A; 138 mmol, 1 equivalent) were suspended in 552 ml of 10% strength aqueous sulphuric acid, and the mixture was cooled to 0° C. 8.5 ml of bromine (165 mmol, 1.2 equivalents) were dissolved in 85 ml of acetic acid and then, over a period of 90 min, added dropwise to the ice-cooled reaction solution. After the dropwise addition had ended, the mixture was stirred at 0° C. for 90 min and then diluted with 600 ml of ethyl acetate, and the aqueous phase was separated off. The aqueous phase was re-extracted with ethyl acetate. The organic phases were combined, washed with saturated aqueous sodium bicarbonate solution, dried and concentrated. The residue was dissolved in dichloromethane and chromatographed on silica gel (petroleum ether/ethyl acetate gradient as mobile phase). This gave 24 g (55% of theory) of the title compound.

Workup

  1. temperaturecooled
  2. customreaction solution
  3. additionAfter the dropwise addition
  4. customthe aqueous phase was separated off
  5. extractionThe aqueous phase was re-extracted with ethyl acetate
  6. washwashed with saturated aqueous sodium bicarbonate solution
  7. customdried
  8. concentrationconcentrated
  9. dissolutionThe residue was dissolved in dichloromethane
  10. customchromatographed on silica gel (petroleum ether/ethyl acetate gradient as mobile phase)

Sources & evidence

ORD record
ord-4aec98b41526402089357da770ac17ac
Source dataset
uspto-grants-2014_08
Patent number
US08796305B2

Reaction notes

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