Potassium Carbonate → 2-Fluoro-N-(6-fluoro-3-hydroxy-2-methyl-phenyl)-3-(3-fluorophenyl)-5-methyl-benzamide

HRID 1771784Notes

Reaction equation

HRID 1771784 reaction equation
[F:1][C:2]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)=[CH:9][C:8]([CH3:18])=[CH:7][C:3]=1[C:4]([OH:6])=O.C(Cl)(=O)C(Cl)=O.[NH2:25][C:26]1[C:27]([CH3:34])=[C:28]([OH:33])[CH:29]=[CH:30][C:31]=1[F:32].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.CN(C=O)C.C1COCC1.O>[F:1][C:2]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)=[CH:9][C:8]([CH3:18])=[CH:7][C:3]=1[C:4]([NH:25][C:26]1[C:31]([F:32])=[CH:30][CH:29]=[C:28]([OH:33])[C:27]=1[CH3:34])=[O:6]

Participants

9

Reactant 4

HCID 11430Potassium CarbonateHCID 65578Oxalyl chlorideHCID 177757273-Amino-4-fluoro-2-methylphenolHCID 894435072-Fluoro-3-(3-fluorophenyl)-5-methyl-benzoic acid

Product 1

HCID 894453522-Fluoro-N-(6-fluoro-3-hydroxy-2-methyl-phenyl)-3-(3-fluorophenyl)-5-methyl-benzamideYield 25.6%

Reagents, catalysts & solvents 4

HCID 6228DimethylformamideCatalystHCID 962WaterSolventHCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolvent

Procedure

To a solution of 2-fluoro-3-(3-fluorophenyl)-5-methyl-benzoic acid (intermediate III(e)) (580 mg, 2.3 mmol, 1.1 eq) in CH2Cl2 (10 mL) at 0° C., was added oxalyl chloride (812 mg, 6.4 mmol, 3 eq) dropwise. DMF (10 drops) was added and the mixture was stirred at room temperature for 3 h. The organic solvent and excess reagent were removed under reduced pressure. The residue that remained was dissolved in THF (10 mL) and added dropwise to a mixture of 3-amino-4-fluoro-2-methylphenol (intermediate X(e)) (300 mg, 2.1 mmol, 1 eq) and K2CO3 (1.47 g, 10.6 mmol, 5 eq) in THF (20 mL) at 0° C. After addition was completed, the reaction was allowed to warm to room temperature and stirred for 3 h. The resulting mixture was poured into water and extracted with EtOAc. The combined organic extracts were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue obtained was purified by column chromatography (petroleum ether:EtOAc, 100:1 to 10:1) to give the title compound as a white solid (200 mg, 25%).

Workup

  1. customThe organic solvent and excess reagent were removed under reduced pressure
  2. dissolutionThe residue that remained was dissolved in THF (10 mL)
  3. additionAfter addition
  4. temperatureto warm to room temperature
  5. stirringstirred for 3 h
  6. extractionextracted with EtOAc
  7. washThe combined organic extracts were washed with brine
  8. dry with materialdried (Na2SO4)
  9. filtrationfiltered
  10. customevaporated in vacuo
  11. customThe residue obtained
  12. customwas purified by column chromatography (petroleum ether:EtOAc, 100:1 to 10:1)

Sources & evidence

ORD record
ord-c959bd30dc79407aa60b8419b590d9d0
Source dataset
uspto-grants-2016_02
Patent number
US09249085B2

Reaction notes

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