Oxalyl chloride → N-(6-Fluoro-3-hydroxy-2-methyl-phenyl)-3-(3-fluorophenyl)-5-methy-benzamide

HRID 1771753Notes

Reaction equation

HRID 1771753 reaction equation
[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([CH:14]=[C:15]([CH3:17])[CH:16]=2)[C:11]([OH:13])=O)[CH:5]=[CH:6][CH:7]=1.C(Cl)(C(Cl)=O)=O.[NH2:24][C:25]1[C:26]([CH3:33])=[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>[F:31][C:30]1[C:25]([NH:24][C:11](=[O:13])[C:10]2[CH:14]=[C:15]([CH3:17])[CH:16]=[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)[CH:9]=2)=[C:26]([CH3:33])[C:27]([OH:32])=[CH:28][CH:29]=1

Participants

9

Reactant 4

HCID 65578Oxalyl chlorideHCID 516892Sodium BicarbonateHCID 177757273-Amino-4-fluoro-2-methylphenolHCID 463145783-(3-Fluorophenyl)-5-methyl-benzoic acid

Product 1

HCID 89443698N-(6-Fluoro-3-hydroxy-2-methyl-phenyl)-3-(3-fluorophenyl)-5-methy-benzamideYield 63.3%

Reagents, catalysts & solvents 4

HCID 6228DimethylformamideCatalystHCID 962WaterSolventHCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolvent2×

Procedure

To a solution of 3-(3-fluorophenyl)-5-methyl-benzoic acid (448 mg, 1.95 mmol, 1.1 eq) in CH2Cl2 (10 mL) was added (COCl)2 (742 mg, 5.85 mmol, 3.3 eq) and DMF (3 drops) at 0° C. The reaction mixture was stirred at room temperature for 1.5 h. The resulting mixture was concentrated in vacuo to remove the solvent and excess reagent. The solid obtained was dissolved in THF (10 mL) and added dropwise to a mixture of 3-amino-4-fluoro-2-methylphenol (intermediate X(e)) (250 mg, 1.77 mmol, 1.0 eq) and NaHCO3 (744 mg, 8.86 mmol, 5.0 eq) in THF (15 mL) at 0° C. The reaction was allowed to warm to room temperature and stirred for 1 h. Water was added and the aqueous layer extracted with EtOAc. The organic extract was washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue obtained was purified by column chromatography (CH2Cl2:MeOH, 500:1 to 300:1) to give the title compound as a white solid (396 mg, 63%).

Workup

  1. concentrationThe resulting mixture was concentrated in vacuo
  2. customto remove the solvent and excess reagent
  3. customThe solid obtained
  4. temperatureto warm to room temperature
  5. stirringstirred for 1 h
  6. extractionthe aqueous layer extracted 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 obtained
  13. customwas purified by column chromatography (CH2Cl2:MeOH, 500:1 to 300:1)

Sources & evidence

ORD record
ord-1e82f819d961405684b634b618224aee
Source dataset
uspto-grants-2016_02
Patent number
US09249085B2

Reaction notes

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