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

HRID 1771757Notes

Reaction equation

HRID 1771757 reaction equation
[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([CH3:19])[C:11]([O:17][CH3:18])=[C:12]([CH:16]=2)[C:13]([OH:15])=O)[CH:5]=[CH:6][CH:7]=1.C(Cl)(C(Cl)=O)=O.[NH2:26][C:27]1[C:28]([CH3:35])=[C:29]([OH:34])[CH:30]=[CH:31][C:32]=1[F:33].C([O-])(O)=O.[Na+]>C(Cl)Cl.C1COCC1.O>[F:33][C:32]1[C:27]([NH:26][C:13](=[O:15])[C:12]2[CH:16]=[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)[CH:9]=[C:10]([CH3:19])[C:11]=2[O:17][CH3:18])=[C:28]([CH3:35])[C:29]([OH:34])=[CH:30][CH:31]=1

Participants

8

Reactant 4

HCID 65578Oxalyl chlorideHCID 516892Sodium BicarbonateHCID 177757273-Amino-4-fluoro-2-methylphenolHCID 894437175-(3-Fluorophenyl)-2-methoxy-3-methyl-benzoic acid

Product 1

HCID 89444099N-(6-Fluoro-3-hydroxy-2-methyl-phenyl)-5-(3-fluorophenyl)-2-methoxy-3-methyl-benzamideYield 80.5%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolvent

Procedure

To a solution of 5-(3-fluorophenyl)-2-methoxy-3-methyl-benzoic acid (intermediate III(k)) (500 mg, 1.92 mmol, 1.1 eq) in CH2Cl2 (10 mL) was added (COCl)2 (731.6 mg, 5.76 mmol, 3.3 eq) at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 1 h. The resulting mixture was concentrated under reduced pressure and the residue that remained dissolved in THF (6 mL) and added to a mixture of 3-amino-4-fluoro-2-methylphenol (intermediate X(e)) (246.5 mg, 1.75 mmol, 1.0 eq) and NaHCO3 (733.5 mg, 8.73 mmol, 5.0 eq) in THF (8 mL). After the addition, the reaction mixture was stirred for a further 2 h. Water was added and the aqueous layer extracted with EtOAc. The organic extract was washed with 5% Na2CO3, dried (Na2SO4), filtered and evaporated in vacuo. The residue obtained was purified by column chromatography (petroleum ether: EtOAc, 10:1 to 5:1 then CH2Cl2:MeOH, 20:1) to give the title compound as a white solid (540 mg, 80%).

Workup

  1. concentrationThe resulting mixture was concentrated under reduced pressure
  2. dissolutionthe residue that remained dissolved in THF (6 mL)
  3. additionAfter the addition
  4. stirringthe reaction mixture was stirred for a further 2 h
  5. extractionthe aqueous layer extracted with EtOAc
  6. extractionThe organic extract
  7. washwas washed with 5% Na2CO3
  8. dry with materialdried (Na2SO4)
  9. filtrationfiltered
  10. customevaporated in vacuo
  11. customThe residue obtained
  12. customwas purified by column chromatography (petroleum ether

Sources & evidence

ORD record
ord-c31da60c14954afea8898f9f04bb427b
Source dataset
uspto-grants-2016_02
Patent number
US09249085B2

Reaction notes

Loading…