Thionyl Chloride → N-(2,6-Difluoro-3-hydroxy-phenyl)-5-(3-fluorophenyl)-2-methoxy-3-methyl-benzamide

HRID 1771696Notes

Reaction equation

HRID 1771696 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.O=S(Cl)Cl.[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+]>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]=[C:10]([CH3:19])[C:11]=1[O:17][CH3:18]

Participants

6

Reactant 4

HCID 24386Thionyl ChlorideHCID 516892Sodium BicarbonateHCID 227559833-Amino-2,4-difluorophenolHCID 894437175-(3-Fluorophenyl)-2-methoxy-3-methyl-benzoic acid

Product 1

HCID 89443615N-(2,6-Difluoro-3-hydroxy-phenyl)-5-(3-fluorophenyl)-2-methoxy-3-methyl-benzamideYield 19.3%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
70 °C

Procedure

To 5-(3-fluorophenyl)-2-methoxy-3-methyl-benzoic acid (1.09 g, 4.19 mmol, 1.1 eq) was added SOCl2 (10 mL, 12.6 mmol, 3.0 eq). The reaction was heated to 70° C. and stirred for 6 h, then the solvent was removed. The residue obtained was dissolved in THF (10 mL) and added to a mixture of 3-amino-2,4-difluorophenol (intermediate X(a)) (0.405 g, 2.8 mmol, 1.0 eq) and NaHCO3 (1.17 g, 13.9 mmol, 5 eq) in THF (8 mL) at 0° C. The reaction was warmed to room temperature, stirred for 2 h then quenched by addition of water. The aqueous layer was extracted with EtOAc and the combined organic extracts were washed with water and brine dried (Na2SO4) and evaporated in vacuo. The crude residue obtained was purified by column chromatography (petroleum ether:EtOAc 1:0 to 10:1) to give the title compound as a white solid (209 mg, 19%).

Workup

  1. customthe solvent was removed
  2. customThe residue obtained
  3. temperatureThe reaction was warmed to room temperature
  4. stirringstirred for 2 h
  5. customthen quenched by addition of water
  6. extractionThe aqueous layer was extracted with EtOAc
  7. washthe combined organic extracts were washed with water and brine
  8. dry with materialdried (Na2SO4)
  9. customevaporated in vacuo
  10. customThe crude residue obtained
  11. customwas purified by column chromatography (petroleum ether:EtOAc 1:0 to 10:1)

Sources & evidence

ORD record
ord-79c332fe8b074f98962a3e7b771a7bad
Source dataset
uspto-grants-2016_02
Patent number
US09249085B2

Reaction notes

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