Cesium carbonate → 4-(2-fluoro-4-methylphenylamino)-1,3,8-trimethyl-1H,6H-pyrido[2,3-d]pyridazine-2,5-dione

HRID 1971206Notes

Reaction equation

HRID 1971206 reaction equation
[F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH2:9].C1(P(C2C=CC=CC=2)C2(P(C3C=CC=CC=3)C3C=CC=CC=3)CC=C3C(C=CC=C3)=C2C2C3C(=CC=CC=3)C=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:63]1[C:72]2[C:71](=[O:73])[NH:70][N:69]=[C:68]([CH3:74])[C:67]=2[N:66]([CH3:75])[C:65](=[O:76])[C:64]=1[CH3:77]>C1(C)C=CC=CC=1.CCOC(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:63]1[C:72]2[C:71](=[O:73])[NH:70][N:69]=[C:68]([CH3:74])[C:67]=2[N:66]([CH3:75])[C:65](=[O:76])[C:64]=1[CH3:77]

Participants

8

Reactant 4

HCID 10796Cesium carbonateHCID 679842-Fluoro-4-methylanilineHCID 666733724-chloro-1,3,8-trimethyl-1H,6H-pyrido[2,3-d]pyridazine-2,5-dioneHCID 86595863(+/-)-2,2-Bis(diphenylphosphino)-1,1-binaphthyl

Product 1

HCID 576369294-(2-fluoro-4-methylphenylamino)-1,3,8-trimethyl-1H,6H-pyrido[2,3-d]pyridazine-2,5-dione

Reagents, catalysts & solvents 3

HCID 167845palladium(II) acetateCatalystHCID 1140TolueneSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
80 °C

Procedure

2-Fluoro-4-methylphenylamine (1.10 equivalents), palladium (II) acetate (0.10 equivalents), rac-2,2-bis(diphenylphosphino)-1,1′-binaphthyl (0.15 equivalents), and cesium carbonate (1.50 equivalents) are added to a solution of 4-chloro-1,3,8-trimethyl-1H,6H-pyrido[2,3-d]pyridazine-2,5-dione (1.00 equivalent) in toluene in a sealed vial. After stirring 10 minutes, the mixture is heated to 80° C. After 24 hours, the reaction mixture is cooled to room temperature and diluted with EtOAc. The resulting precipitate is filtered and washed with EtOAc. The filtrate is diluted with EtOAc and washed with water. The aqueous layer is reextracted with EtOAc. The combined organic layers are washed with brine, dried (Na2SO4) and concentrated. Purification by flash column chromatography gives the desired product.

Workup

  1. waitAfter 24 hours
  2. temperaturethe reaction mixture is cooled to room temperature
  3. filtrationThe resulting precipitate is filtered
  4. washwashed with EtOAc
  5. additionThe filtrate is diluted with EtOAc
  6. washwashed with water
  7. washThe combined organic layers are washed with brine
  8. dry with materialdried (Na2SO4)
  9. concentrationconcentrated
  10. customPurification by flash column chromatography

Sources & evidence

ORD record
ord-a5f95e8f96cc494398ba3465163daef6
Source dataset
uspto-grants-2013_04
Patent number
US08431574B2

Reaction notes

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