Methanol → Methyl 4-(benzylamino)-3,5-difluoro-2,6-dimethoxybenzoate

HRID 459939Notes

Reaction equation

HRID 459939 reaction equation
[CH2:1]([NH:8][C:9]1[C:18]([F:19])=[C:17](F)[C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11](F)[C:10]=1[F:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][O-:24].[Na+].[CH3:26][OH:27]>>[CH2:1]([NH:8][C:9]1[C:18]([F:19])=[C:17]([O:24][CH3:23])[C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11]([O:27][CH3:26])[C:10]=1[F:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1

Participants

4

Reactant 3

HCID 887MethanolHCID 10942334Sodium MethoxideHCID 14292030Methyl 4-(benzylamino)-2,3,5,6-tetrafluorobenzoate

Product 1

HCID 18444841Methyl 4-(benzylamino)-3,5-difluoro-2,6-dimethoxybenzoate

Procedure

Methyl 4-(benzylamino)-2,3,5,6-tetrafluorobenzoate (24.0 g, 76.6 mmol) was cooled to 5° C.–10° C. under a nitrogen atmosphere and a 25 weight % solution of sodium methoxide in methanol (53.5 mL, 234 mmol) was added dropwise over 5 minutes with continued cooling. The resulting mixture was stirred with ice bath cooling for another 10 minutes, the ice bath was removed and the mixture allowed to warm to 35° C.–40° C. It was recooled to room temperature and held for 4.5 hours before heating to 65° C.–70° C. where it was held for 3.5 hours. The mixture was cooled to room temperature and held overnight. Acetic acid (7.5 g) was added followed by methyl tert-butyl ether (250 mL) and water (100 mL). The lower aqueous layer was separated and the organic layer extracted with saturated, aqueous sodium bicarbonate solution (2×50 mL) followed by water (25 mL). The organic solution was concentrated under vacuum to give methyl 4-(benzylamino)-3,5-difluoro-2,6-dimethoxybenzoate as a yellow oil (24.5 g).

Workup

  1. temperaturecooling for another 10 minutes
  2. customthe ice bath was removed
  3. temperatureto warm to 35° C.–40° C
  4. customwas recooled to room temperature
  5. temperaturebefore heating to 65° C.–70° C. where it
  6. waitwas held for 3.5 hours
  7. waitheld overnight
  8. additionAcetic acid (7.5 g) was added
  9. customThe lower aqueous layer was separated
  10. extractionthe organic layer extracted with saturated, aqueous sodium bicarbonate solution (2×50 mL)
  11. concentrationThe organic solution was concentrated under vacuum

Sources & evidence

ORD record
ord-6affd4e07fc2473c9acd02fed66ed92a
Source dataset
uspto-grants-2007_03
Patent number
US07196090B2

Reaction notes

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