Oxalyl chloride → N-(2,6-Difluoro-3-hydroxy-phenyl)-5-(3,5-difluorophenyl)-2,3-dimethyl-benzamide

HRID 1771823Notes

Reaction equation

HRID 1771823 reaction equation
[F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([CH3:19])[C:12]([CH3:18])=[C:13]([CH:17]=2)[C:14]([OH:16])=O)[CH:5]=[C:6]([F:8])[CH:7]=1.C(Cl)(C(Cl)=O)=O.[NH2:26][C:27]1[C:28]([F:35])=[C:29]([OH:34])[CH:30]=[CH:31][C:32]=1[F:33].C([O-])(O)=O.[Na+]>C(Cl)Cl.CN(C=O)C.C1COCC1.O>[F:35][C:28]1[C:29]([OH:34])=[CH:30][CH:31]=[C:32]([F:33])[C:27]=1[NH:26][C:14](=[O:16])[C:13]1[CH:17]=[C:9]([C:4]2[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=2)[CH:10]=[C:11]([CH3:19])[C:12]=1[CH3:18]

Participants

9

Reactant 4

HCID 65578Oxalyl chlorideHCID 516892Sodium BicarbonateHCID 227559833-Amino-2,4-difluorophenolHCID 894437345-(3,5-Difluorophenyl)-2,3-dimethyl-benzoic acid

Product 1

HCID 89443518N-(2,6-Difluoro-3-hydroxy-phenyl)-5-(3,5-difluorophenyl)-2,3-dimethyl-benzamideYield 15.5%

Reagents, catalysts & solvents 4

HCID 6228DimethylformamideCatalystHCID 962WaterSolventHCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolvent2×

Procedure

To a solution of 5-(3,5-difluorophenyl)-2,3-dimethyl-benzoic acid (240 mg, 0.92 mmol, 1.1 eq) in CH2Cl2 (12 mL) was added (COCl)2 (348 mg, 2.75 mmol, 3.3 eq) and DMF (5 drops). The reaction mixture was stirred at room temperature for 1.5 h, then concentrated under reduced pressure to remove the organic solvent and excess reagent. The residue obtained was dissolved in THF (10 mL) and added dropwise to a solution of 3-amino-2,4-difluorophenol (intermediate X(a)) (121 mg, 0.83 mmol, 1.0 eq) and NaHCO3 (386 mg, 4.6 mmol, 5.0 eq) in THF (10 mL) at 0° C. After the addition, the reaction mixture was stirred at room temperature for 1 h. The resulting mixture was diluted with water and extracted with EtOAc. The organic extract was washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by column chromatography (CH2Cl2:MeOH, 500:1 to 200:1) to give the title compound as a yellow solid (50 mg, 15%).

Workup

  1. concentrationconcentrated under reduced pressure
  2. customto remove the organic solvent and excess reagent
  3. customThe residue obtained
  4. additionAfter the addition
  5. stirringthe reaction mixture was stirred at room temperature for 1 h
  6. extractionextracted with EtOAc
  7. extractionThe organic extract
  8. washwas washed with water and brine
  9. dry with materialdried (Na2SO4)
  10. filtrationfiltered
  11. customevaporated in vacuo
  12. customThe residue was purified by column chromatography (CH2Cl2:MeOH, 500:1 to 200:1)

Sources & evidence

ORD record
ord-18f87f714d2e48e6811e90850c357224
Source dataset
uspto-grants-2016_02
Patent number
US09249085B2

Reaction notes

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