Oxalyl chloride → N-(6-chloro-2-fluoro-3-hydroxy-phenyl)-2-fluoro-5-(3-fluorophenyl)benzamide

HRID 1771641Notes

Reaction equation

HRID 1771641 reaction equation
[F:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)=[CH:7][C:3]=1[C:4]([OH:6])=O.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[Cl:31].C([O-])(O)=O.[Na+]>C(Cl)Cl.C1COCC1.CN(C=O)C>[Cl:31][C:30]1[C:25]([NH:24][C:4](=[O:6])[C:3]2[CH:7]=[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=3)[CH:9]=[CH:10][C:2]=2[F:1])=[C:26]([F:33])[C:27]([OH:32])=[CH:28][CH:29]=1

Participants

8

Reactant 4

HCID 65578Oxalyl chlorideHCID 516892Sodium BicarbonateHCID 463123323',4-Difluoro-[1,1'-biphenyl]-3-carboxylic acidHCID 847644353-Amino-4-chloro-2-fluorophenol

Product 1

HCID 89445317N-(6-chloro-2-fluoro-3-hydroxy-phenyl)-2-fluoro-5-(3-fluorophenyl)benzamideYield 26%

Reagents, catalysts & solvents 3

HCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
0 °C

Procedure

To a mixture of 2-fluoro-5-(3-fluorophenyl)benzoic acid (intermediate III(a)) (478 mg, 2.04 mmol, 1.0 eq) and (COCl)2 (777 mg, 6.13 mmol, 3.0 eq) in DCM (20 mL) was added DMF (0.3 mL). The reaction mixture was stirred at 0° C. for 1 h, then the solvent removed in vacuo. The residue obtained was dissolved in THF (20 mL) and added dropwise to a solution of 3-amino-4-chloro-2-fluoro-phenol (intermediate X(d)) (330 mg, 2.04 mmol, 1.0 eq) and NaHCO3 (515 mg, 6.13 mmol, 3.0 eq) in THF (20 mL). After the addition, the reaction mixture was stirred at room temperature for 30 min. The THF was evaporated in vacuo and the aqueous solution adjusted to pH 3 by addition of 1M HCl. The mixture was extracted with EtOAc and the combined organic extracts were dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by column chromatography (EtOAc:petroleum ether, 0:1 to 1:1) to give the title compound as a yellow solid (200 mg, 26%).

Workup

  1. customthe solvent removed in vacuo
  2. customThe residue obtained
  3. additionAfter the addition
  4. stirringthe reaction mixture was stirred at room temperature for 30 min
  5. customThe THF was evaporated in vacuo
  6. additionthe aqueous solution adjusted to pH 3 by addition of 1M HCl
  7. extractionThe mixture was extracted with EtOAc
  8. dry with materialthe combined organic extracts were dried (Na2SO4)
  9. filtrationfiltered
  10. customevaporated in vacuo
  11. customThe residue was purified by column chromatography (EtOAc:petroleum ether, 0:1 to 1:1)

Sources & evidence

ORD record
ord-6f00c1704a3f4d0b9b9c518e8175e4f4
Source dataset
uspto-grants-2016_02
Patent number
US09249085B2

Reaction notes

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