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

HRID 1771800Notes

Reaction equation

HRID 1771800 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)(C(Cl)=O)=O.[NH2:25][C:26]1[C:27]([CH3:34])=[C:28]([OH:33])[CH:29]=[CH:30][C:31]=1[CH3:32].C([O-])(O)=O.[Na+]>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]([CH3:32])=[CH:30][CH:29]=[C:28]([OH:33])[C:27]=1[CH3:34])=[O:6]

Participants

9

Reactant 4

HCID 65578Oxalyl chlorideHCID 516892Sodium BicarbonateHCID 141306083-Amino-2,4-dimethylphenolHCID 894435072-Fluoro-3-(3-fluorophenyl)-5-methyl-benzoic acid

Product 1

HCID 894438592-Fluoro-3-(3-fluorophenyl)-N-(3-hydroxy-2,6-dimethyl-phenyl)-5-methyl-benzamideYield 73%

Reagents, catalysts & solvents 4

HCID 6228DimethylformamideCatalystHCID 962WaterSolventHCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolvent2×

Procedure

To a solution of 2-fluoro-3-(3-fluorophenyl)-5-methyl-benzoic acid (intermediate III(e)) (597 mg, 2.4 mmol, 1.1 eq) in CH2Cl2 (15 mL) was added (COCl)2 (916 mg, 7.2 mmol, 3.3 eq) and DMF (5 drops). The reaction mixture was stirred at room temperature for 2 h, then the solvent and excess reagent were removed under reduced pressure. The residue obtained was dissolved in THF (20 mL) and added dropwise to a mixture of 3-amino-2,4-dimethylphenol (intermediate X(c)) (300 mg, 2.2 mmol, 1.0 eq) and NaHCO3 (920 mg, 10.9 mmol, 5.0 eq) in THF (20 mL) at 0° C. After the addition was completed, the reaction was allowed to warm to room temperature and stirred for a further 1 h. The reaction was then poured into water and extracted with EtOAc. The combined organic layers were 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 (588 mg, 73%).

Workup

  1. customthe solvent and excess reagent were removed under reduced pressure
  2. customThe residue obtained
  3. additionAfter the addition
  4. temperatureto warm to room temperature
  5. stirringstirred for a further 1 h
  6. extractionextracted with EtOAc
  7. washThe combined organic layers were washed with water and brine
  8. dry with materialdried (Na2SO4)
  9. filtrationfiltered
  10. customevaporated in vacuo
  11. customThe residue obtained
  12. customwas purified by column chromatography (CH2Cl2:MeOH, 500:1 to 300:1)

Sources & evidence

ORD record
ord-ee0a96283b1649d1868bea47dbd72221
Source dataset
uspto-grants-2016_02
Patent number
US09249085B2

Reaction notes

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