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

HRID 1771665Notes

Reaction equation

HRID 1771665 reaction equation
[F:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)=[CH:7][C:3]=1[C:4]([OH:6])=O.C(Cl)(C(Cl)=O)=O.[NH2:24][C:25]1[C:26]([Cl: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.O>[Cl:33][C:26]1[C:27]([OH:32])=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)[CH:9]=[CH:10][C:2]=1[F:1]

Participants

9

Reactant 4

HCID 65578Oxalyl chlorideHCID 516892Sodium BicarbonateHCID 216600263-Amino-2-chloro-4-fluorophenolHCID 463123323',4-Difluoro-[1,1'-biphenyl]-3-carboxylic acid

Product 1

HCID 89443695N-(2-chloro-6-fluoro-3-hydroxy-phenyl)-2-fluoro-5-(3-fluorophenyl)benzamideYield 26%

Reagents, catalysts & solvents 4

HCID 6228DimethylformamideCatalystHCID 962WaterSolventHCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolvent2×

Procedure

To a solution of 2-fluoro-5-(3-fluorophenyl)benzoic acid (intermediate III(a)) (478 mg, 2.04 mmol, 1.1 eq) in DCM (9 mL) and DMF (3 drops) at 0° C. was added (COCl)2 (779 mg, 6.14 mmol, 3.3 eq) dropwise. The reaction mixture was stirred at room temperature for 1.5 h, then the solvent removed in vacuo. The residue obtained was dissolved in THF (7 mL) and added dropwise to a mixture of 3-amino-2-chloro-4-fluoro-phenol (intermediate X(f)) (300 mg, 1.86 mmol, 1.0 eq) and NaHCO3 (781 mg, 9.3 mmol, 5.0 eq) in THF (7 mL) at 0° C. After addition was completed, the reaction mixture was warmed to room temperature and stirred overnight. Water was added and the aqueous mixture was extracted with EtOAc. The organic extract was washed with 5% Na2CO3, water and brine, dried (Na2SO4), filtered, evaporated in vacuo and purified by column chromatography (EtOAc:petroleum ether, 3:20 to 1:4) to give the title as a yellow solid compound (180 mg, 26%).

Workup

  1. customthe solvent removed in vacuo
  2. customThe residue obtained
  3. additionAfter addition
  4. temperaturethe reaction mixture was warmed to room temperature
  5. stirringstirred overnight
  6. extractionthe aqueous mixture was extracted with EtOAc
  7. extractionThe organic extract
  8. washwas washed with 5% Na2CO3, water and brine
  9. dry with materialdried (Na2SO4)
  10. filtrationfiltered
  11. customevaporated in vacuo
  12. custompurified by column chromatography (EtOAc:petroleum ether, 3:20 to 1:4)

Sources & evidence

ORD record
ord-d1d783cf3af84ec08b621292584869a7
Source dataset
uspto-grants-2016_02
Patent number
US09249085B2

Reaction notes

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