4-Amino-3-fluorophenol → 4-[(2-Fluoro-4-hydroxy-phenylamino)-methyl]-2-methyl-benzoic Acid Methyl Ester

HRID 424818Notes

Reaction equation

HRID 424818 reaction equation
[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].[CH3:10][O:11][C:12](=[O:22])[C:13]1[CH:18]=[CH:17][C:16]([CH:19]=O)=[CH:15][C:14]=1[CH3:21].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C>[CH3:10][O:11][C:12](=[O:22])[C:13]1[CH:18]=[CH:17][C:16]([CH2:19][NH:1][C:2]2[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=2[F:9])=[CH:15][C:14]=1[CH3:21]

Participants

5

Reactant 3

HCID 27359194-Amino-3-fluorophenolHCID 5049666Sodium triacetoxyborohydrideHCID 20134203Methyl 4-formyl-2-methylbenzoate

Product 1

HCID 667041774-[(2-Fluoro-4-hydroxy-phenylamino)-methyl]-2-methyl-benzoic Acid Methyl EsterYield 95.2%

Reagents, catalysts & solvents 1

HCID 176Acetic AcidSolvent

Procedure

A mixture of 4-amino-3-fluoro-phenol (900 mg, 7.08 mmol) and 4-formyl-2-methyl-benzoic acid methyl ester (1.23 g, 6.90 mmol) in 35 mL acetic acid is stirred for two hours at room temperature. Sodium triacetoxyborohydride (3.20 g, 15.1 mmol) is added and stirred at room temperature. Upon completion, the mixture is concentrated under reduced pressure and partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The aqueous layer is separated and extracted with ethyl acetate (3×). The combined ethyl acetate layers are dried (MgSO4) and concentrated under reduced pressure. The residue is purified on 120 g silica eluting with a gradient of ethyl acetate in heptane (10% to 60%) to provide the title compound (1.9 g, 93%) as a yellow oil. ES/MS m/e 290.0 (M+1).

Workup

  1. stirringstirred at room temperature
  2. concentrationUpon completion, the mixture is concentrated under reduced pressure
  3. custompartitioned between ethyl acetate and saturated aqueous sodium bicarbonate
  4. customThe aqueous layer is separated
  5. extractionextracted with ethyl acetate (3×)
  6. dry with materialThe combined ethyl acetate layers are dried (MgSO4)
  7. concentrationconcentrated under reduced pressure
  8. customThe residue is purified on 120 g silica eluting with a gradient of ethyl acetate in heptane (10% to 60%)

Sources & evidence

ORD record
ord-03a046ca22e6447a913c3fcd79f4f240
Source dataset
uspto-grants-2012_01
Patent number
US08106077B2

Reaction notes

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