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

HRID 1771596Notes

Reaction equation

HRID 1771596 reaction equation
[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11]([CH3:17])=[C:12]([CH:16]=2)[C:13]([OH:15])=O)[CH:5]=[CH:6][CH:7]=1.C(Cl)(C(Cl)=O)=O.[NH2:24][C:25]1[C:26]([F: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>[F:33][C:26]1[C:27]([OH:32])=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:13](=[O:15])[C:12]1[CH:16]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[CH:9]=[CH:10][C:11]=1[CH3:17]

Participants

8

Reactant 4

HCID 65578Oxalyl chlorideHCID 516892Sodium BicarbonateHCID 227559833-Amino-2,4-difluorophenolHCID 463145835-(3-Fluorophenyl)-2-methylbenzoic acid

Product 1

HCID 89443775N-(2,6-Difluoro-3-hydroxy-phenyl)-5-(3-fluorophenyl)-2-methyl-benzamideYield 48%

Reagents, catalysts & solvents 3

HCID 6228DimethylformamideCatalystHCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
0 °C

Procedure

To a solution of 5-(3-fluorophenyl)-2-methyl-benzoic acid (310 mg, 2.07 mmol, 1.0 eq) in CH2Cl2 (30 mL) at 0° C. was added (COCl)2 (0.52 mL, 6.0 mmol, 3.0 eq) and DMF (2-3 drops). The reaction was stirred at 0° C. for 2 h, and then the solvent was removed in vacuo. The residue was taken up in THF (30 mL) and added to a suspension of 3-amino-2,4-difluoro-phenol (intermediate X(a)) (195.4 mg, 2.07 mmol, 1.0 eq) and NaHCO3 (339.1 mg, 6.2 mmol, 3.0 eq) in THF (70 mL) at 0° C. The reaction was stirred for 3 h at 0° C. then quenched by addition of water and the aqueous layer extracted with EtOAc. The combined organic extracts were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The crude residue was purified by chromatography (DCM:MeOH, 1:0 to 20:1) to give the title compound as a solid (230 mg, 48%).

Workup

  1. customthe solvent was removed in vacuo
  2. stirringThe reaction was stirred for 3 h at 0° C.
  3. customthen quenched by addition of water
  4. extractionthe aqueous layer extracted with EtOAc
  5. washThe combined organic extracts were washed with brine
  6. dry with materialdried (Na2SO4)
  7. filtrationfiltered
  8. customevaporated in vacuo
  9. customThe crude residue was purified by chromatography (DCM:MeOH, 1:0 to 20:1)

Sources & evidence

ORD record
ord-d69c2e9a9c504c49b0954d7b5f1d0de5
Source dataset
uspto-grants-2016_02
Patent number
US09249085B2

Reaction notes

Loading…