Oxalyl chloride → N-(2,6-Difluoro-3-hydroxy-phenyl)-3-(3-fluorophenyl)benzamide

HRID 1771606Notes

Reaction equation

HRID 1771606 reaction equation
[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=2)[C:11]([OH:13])=O)[CH:5]=[CH:6][CH:7]=1.C(Cl)(C(Cl)=O)=O.[NH2:23][C:24]1[C:25]([F:32])=[C:26]([OH:31])[CH:27]=[CH:28][C:29]=1[F:30].C([O-])(O)=O.[Na+]>C(Cl)Cl.C1COCC1.CN(C=O)C>[F:32][C:25]1[C:26]([OH:31])=[CH:27][CH:28]=[C:29]([F:30])[C:24]=1[NH:23][C:11](=[O:13])[C:10]1[CH:14]=[CH:15][CH:16]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[CH:9]=1

Participants

8

Reactant 4

HCID 65578Oxalyl chlorideHCID 516892Sodium BicarbonateHCID 27826853'-Fluoro[1,1'-biphenyl]-3-carboxylic acidHCID 227559833-Amino-2,4-difluorophenol

Product 1

HCID 89443548N-(2,6-Difluoro-3-hydroxy-phenyl)-3-(3-fluorophenyl)benzamideYield 50%

Reagents, catalysts & solvents 3

HCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolvent

Procedure

To a stirred solution of 3-(3-fluorophenyl)benzoic acid (430 mg, 1.99 mmol, 1.1 eq), in CH2Cl2 (10 mL) and DMF (0.15 mL) at 0° C. was added (COCl)2 (760 mg, 5.97 mmol, 3.3 eq) dropwise. The reaction was stirred for 2 h, then the solvent removed. The residue dissolved in THF (6 mL) and added to a mixture of 3-amino-2,4-difluoro-phenol (intermediate X(a)) (262.5 mg, 1.81 mmol, 1.0 eq) and NaHCO3 (760 mg, 9.05 mmol, 5 eq) in THF (6 mL) at 0° C. The reaction was stirred for 3 h then quenched by addition of water. The aqueous layer was extracted with EtOAc and the combined organic extracts were washed with Na2CO3, water and brine, dried (Na2SO4), filtered and evaporated in vacuo. The crude residue was crystallised from petroleum ether:EtOAc 3:1 to give the title compound (310 mg, 50%). Evaporation of the filtrate provided a further 180 mg of impure material.

Workup

  1. customthe solvent removed
  2. dissolutionThe residue dissolved in THF (6 mL)
  3. stirringThe reaction was stirred for 3 h
  4. customthen quenched by addition of water
  5. extractionThe aqueous layer was extracted with EtOAc
  6. washthe combined organic extracts were washed with Na2CO3, water and brine
  7. dry with materialdried (Na2SO4)
  8. filtrationfiltered
  9. customevaporated in vacuo
  10. customThe crude residue was crystallised from petroleum ether:EtOAc 3:1

Sources & evidence

ORD record
ord-cb7daa19ad6a4ec6b8d14059f481b9fd
Source dataset
uspto-grants-2016_02
Patent number
US09249085B2

Reaction notes

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