N-methyl-2-pyrrolidone → 5-Cyano-3,4-difluoro-2-(2-fluorophenylamino)-benzoic acid methyl ester

HRID 500576Notes

Reaction equation

HRID 500576 reaction equation
[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8](Br)[C:7]([F:11])=[C:6]([F:12])[C:5]=1[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[F:20].[CH3:22][N:23]1C(=O)CCC1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].[C-]#N.[C-]#N.[Zn+2]>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([C:22]#[N:23])[C:7]([F:11])=[C:6]([F:12])[C:5]=1[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[F:20]

Participants

6

Reactant 2

HCID 13387N-methyl-2-pyrrolidoneHCID 59519391Methyl 5-bromo-2-(2-fluorophenylamino)-3,4-difluorobenzoate

Product 1

HCID 865986425-Cyano-3,4-difluoro-2-(2-fluorophenylamino)-benzoic acid methyl ester

Reagents, catalysts & solvents 3

HCID 11186Zinc cyanide (Zn(CN)2)CatalystHCID 635956Ferrocene-1,1'-bis-(diphenylphosphine)CatalystHCID 9811564Bis(dibenzylideneacetone)palladiumCatalyst

Conditions

Temperature
120 °C

Procedure

A mixture of 5-bromo-3,4-difluoro-2-(2-fluorophenylamino)-benzoic acid methyl ester (1.00 equiv.), dppf (0.02 equiv.), Pd2dba3 (0.01 equiv.), and Zn(CN)2 (0.60 equiv.) in NMP is stirred at 120° C. in a sealed tube. After stirring for 20 hours, the reaction mixture is cooled to room temperature and quenched with a 4:1:4 (volume) mixture solution of saturated aqueous NH4Cl-conc NH4O-water. The mixture is extracted with EtOAc. The organic layer is washed with saturated aqueous NH4Cl/concentrated NH4OH/water, and brine. The organic layer is dried over MgSO4, filtered, and concentrated under reduced pressure to give the crude material that is purified by flash column chromatography to afford the desired product.

Workup

  1. stirringAfter stirring for 20 hours
  2. temperaturethe reaction mixture is cooled to room temperature
  3. customquenched with a 4:1:4 (volume) mixture solution of saturated aqueous NH4Cl-conc NH4O-water
  4. extractionThe mixture is extracted with EtOAc
  5. washThe organic layer is washed with saturated aqueous NH4Cl/concentrated NH4OH/water, and brine
  6. dry with materialThe organic layer is dried over MgSO4
  7. filtrationfiltered
  8. concentrationconcentrated under reduced pressure
  9. customto give the crude material that
  10. customis purified by flash column chromatography

Sources & evidence

ORD record
ord-a7036860263343c48869817e57257f9a
Source dataset
uspto-grants-2010_08
Patent number
US07772234B2

Reaction notes

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