Oxalyl chloride → N-(2,6-difluoro-3-hydroxy-phenyl)-3-fluoro-5-(3-fluorophenyl) benzamide

HRID 1771659Notes

Reaction equation

HRID 1771659 reaction equation
[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)[CH:10]=1)[C:5]([OH:7])=O.C(Cl)(=O)C(Cl)=O.[NH2:24][C:25]1[C:26]([F:33])=[C:27]([OH:32])[CH:28]=[CH:29][C:30]=1[F:31].C([O-])(O)=O.[Na+]>C(Cl)Cl.CN(C=O)C.C1COCC1>[F:33][C:26]1[C:27]([OH:32])=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:5](=[O:7])[C:4]1[CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)[CH:10]=[C:2]([F:1])[CH:3]=1

Participants

8

Reactant 4

HCID 65578Oxalyl chlorideHCID 516892Sodium BicarbonateHCID 227559833-Amino-2,4-difluorophenolHCID 463123233-(3-Fluorophenyl)-5-fluorobenzoic acid

Product 1

HCID 89444321N-(2,6-difluoro-3-hydroxy-phenyl)-3-fluoro-5-(3-fluorophenyl) benzamideYield 52.1%

Reagents, catalysts & solvents 3

HCID 6228DimethylformamideCatalystHCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolvent

Procedure

To a stirred solution of 3-fluoro-5-(3-fluorophenyl)benzoic acid (533 mg, 2.3 mmol, 1.1 eq) in DCM (10 mL) and DMF (3 drops) at 0° C. was added oxalylchloride (866 mg, 6.8 mmol, 3.3 eq) dropwise. The reaction was warmed to room temperature and stirred for 2 h, and then the solvent removed. The residue that remained was dissolved in THF (6 mL) and added to a solution of 3-amino-2,4-difluoro-phenol (intermediate X(a)) (300 mg, 2.07 mmol, 1.0 eq) and NaHCO3 (868 mg, 10.34 mmol, 5.0 eq) in THF (6 mL) at 0° C. The reaction was warmed to room temperature and stirred for 1 h then quenched by addition of water. The aqueous layer was extracted with EtOAc and the combined organic extracts were washed with 5% Na2CO3, water and brine, dried (Na2SO4), filtered and evaporated in vacuo. The crude residue was recrystallised from DCM: petroleum ether (1:3) and collected by filtration to give the title compound as a solid (390 mg, 52%).

Workup

  1. customthe solvent removed
  2. dissolutionThe residue that remained was dissolved in THF (6 mL)
  3. temperatureThe reaction was warmed to room temperature
  4. stirringstirred for 1 h
  5. customthen quenched by addition of water
  6. extractionThe aqueous layer was extracted with EtOAc
  7. washthe combined organic extracts were washed with 5% Na2CO3, water and brine
  8. dry with materialdried (Na2SO4)
  9. filtrationfiltered
  10. customevaporated in vacuo
  11. customThe crude residue was recrystallised from DCM: petroleum ether (1:3)
  12. filtrationcollected by filtration

Sources & evidence

ORD record
ord-0f0aabab6b1d4a4295582332a03dbafa
Source dataset
uspto-grants-2016_02
Patent number
US09249085B2

Reaction notes

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