Trimethyl orthoformate → 3-Chloro-2-dimethoxymethyl-4-fluorophenol

HRID 2095627Notes

Reaction equation

HRID 2095627 reaction equation
[Cl:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([OH:11])[C:3]=1C=O.CO[CH:14]([O:17][CH3:18])[O:15][CH3:16].[N+]([O-])([O-])=O.[NH4+].C(=O)([O-])[O-].[Na+].[Na+]>CO>[Cl:1][C:2]1[C:3]([CH:14]([O:15][CH3:16])[O:17][CH3:18])=[C:6]([OH:11])[CH:7]=[CH:8][C:9]=1[F:10]

Participants

6

Reactant 4

HCID 9005Trimethyl orthoformateHCID 10340Sodium CarbonateHCID 22985Ammonium nitrateHCID 534075972-Chloro-3-fluoro-6-hydroxybenzaldehyde

Product 1

HCID 670040603-Chloro-2-dimethoxymethyl-4-fluorophenolYield 65.2%

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Procedure

2-Chloro-3-fluoro-6-hydroxybenzaldehyde (79.0 g, 452 mmol) was taken in a single neck flask equipped with a condenser and a nitrogen inlet. To this, trimethylorthoformate (96.0 g, 99.0 mL, 905 mmol) and a solution of ammonium nitrate (3.6 g, 45 mmol) in methanol (40 mL) were added and heated to reflux for 16 hours. The reaction mixture was cooled to room temperature, poured into saturated aqueous sodium carbonate solution, stirred for few minutes, and extracted with ethyl acetate (300 mL, 200 mL). The combined organic layers were washed with water, dried over sodium sulfate, filtered and concentrated to give crude product. It was purified by column chromatography on silica gel using 10% ethyl acetate in hexane as eluent to give 65 g (64% yield) of the title compound. 1HNMR (CDCl3, 300 MHz): δ=8.52 (s, 1H), 7.04 (dd, J=9.0 Hz, 1H), 6.74-6.78 (m, 1H), 5.84 (s, 1H), 3.47 (s, 6H).

Workup

  1. customequipped with a condenser and a nitrogen inlet
  2. temperatureheated
  3. temperatureto reflux for 16 hours
  4. extractionextracted with ethyl acetate (300 mL, 200 mL)
  5. washThe combined organic layers were washed with water
  6. dry with materialdried over sodium sulfate
  7. filtrationfiltered
  8. concentrationconcentrated
  9. customto give crude product
  10. customIt was purified by column chromatography on silica gel using 10% ethyl acetate in hexane as eluent

Sources & evidence

ORD record
ord-3ac2401fe3f847488af93b316b9b9bdd
Source dataset
uspto-grants-2013_05
Patent number
US08445510B2

Reaction notes

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