Sulfuric Acid → 3-Amino-2,4-difluorophenol

HRID 1771592Notes

Reaction equation

HRID 1771592 reaction equation
[F:1][C:2]1[C:10]([O:11][Si](C(C)C)(C(C)C)C(C)C)=[CH:9][CH:8]=[C:7]([F:22])[C:3]=1C(O)=O.C(Cl)(C(Cl)=O)=O.[N-:29]=[N+]=[N-].[Na+].OS(O)(=O)=O>C(Cl)Cl.CN(C=O)C.CC(C)=O.O.CCO>[NH2:29][C:3]1[C:2]([F:1])=[C:10]([OH:11])[CH:9]=[CH:8][C:7]=1[F:22]

Participants

10

Reactant 4

HCID 1118Sulfuric AcidHCID 33557Sodium AzideHCID 65578Oxalyl chlorideHCID 894436202,6-Difluoro-3-triisopropylsilyloxy-benzoic acid

Product 1

HCID 227559833-Amino-2,4-difluorophenolYield 50%

Reagents, catalysts & solvents 5

HCID 6228DimethylformamideCatalystHCID 180AcetoneSolvent2×HCID 702EthanolSolventHCID 962WaterSolvent3×HCID 6344DichloromethaneSolvent

Procedure

To a solution of 2,6-difluoro-3-triisopropylsilyloxy-benzoic acid (18.4 g, 0.056 mol, 1.0 eq) in DCM (180 mL) and DMF (3 drops) at 0° C. was added (COCl)2 (21.19 g, 0.167 mmol, 3.0 eq) dropwise. The mixture was warmed to room temperature and stirred for 1 h. The reaction mixture was evaporated in vacuo and the residue obtained dissolved in acetone (100 mL). The resultant solution was added dropwise to a cooled solution of NaN3 (14.5 g, 0.223 mol, 4.0 eq) in acetone (160 mL) and water (100 mL) at 0° C. The reaction was stirred for 1 h at 0° C. Further water was then added (200 mL) and the reaction heated at 70° C. overnight. The acetone was removed under reduced pressure and the aqueous layer extracted with EtOAc. The combined organic extracts were washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue obtained dissolved in EtOH (94 mL) and water (30 mL). Concentrated H2SO4 (30 mL) was added and the reaction heated at 110° C. overnight. The ethanol was removed under reduced pressure and the aqueous layer extracted with EtOAc. The combined organic extracts were dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by column chromatography (petroleum ether: EtOAc, 20:1 to 6:1) to give the title compound as a white solid (4.0 g, 50%).

Workup

  1. customThe reaction mixture was evaporated in vacuo
  2. customthe residue obtained
  3. stirringThe reaction was stirred for 1 h at 0° C
  4. temperaturethe reaction heated at 70° C. overnight
  5. customThe acetone was removed under reduced pressure
  6. extractionthe aqueous layer extracted with EtOAc
  7. washThe combined organic extracts were washed with water and brine
  8. dry with materialdried (Na2SO4)
  9. filtrationfiltered
  10. customevaporated in vacuo
  11. customThe residue obtained
  12. temperaturethe reaction heated at 110° C. overnight
  13. customThe ethanol was removed under reduced pressure
  14. extractionthe aqueous layer extracted with EtOAc
  15. dry with materialThe combined organic extracts were dried (Na2SO4)
  16. filtrationfiltered
  17. customevaporated in vacuo
  18. customThe residue was purified by column chromatography (petroleum ether: EtOAc, 20:1 to 6:1)

Sources & evidence

ORD record
ord-ace0d82c18ea47a4a56626a0cf2cdbef
Source dataset
uspto-grants-2016_02
Patent number
US09249085B2

Reaction notes

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