2,4-Dichloroaniline → 5-Cyclopropyl-6-(2,4-dichloro-phenylamino)-pyridine-2-carboxylic acid methyl ester

HRID 927337Notes

Reaction equation

HRID 927337 reaction equation
C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1.[CH3:26][O:27][C:28]([C:30]1[CH:35]=[CH:34][C:33]([CH:36]2[CH2:38][CH2:37]2)=[C:32](Cl)[N:31]=1)=[O:29].[Cl:40][C:41]1[CH:47]=[C:46]([Cl:48])[CH:45]=[CH:44][C:42]=1[NH2:43].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:26][O:27][C:28]([C:30]1[CH:35]=[CH:34][C:33]([CH:36]2[CH2:38][CH2:37]2)=[C:32]([NH:43][C:42]2[CH:44]=[CH:45][C:46]([Cl:48])=[CH:47][C:41]=2[Cl:40])[N:31]=1)=[O:29]

Participants

7

Reactant 4

HCID 111232,4-DichloroanilineHCID 11430Potassium CarbonateHCID 27342162-(Dicyclohexylphosphino)biphenylHCID 866747356-Chloro-5-cyclopropyl-pyridine-2-carboxylic acid methyl ester

Product 1

HCID 710873965-Cyclopropyl-6-(2,4-dichloro-phenylamino)-pyridine-2-carboxylic acid methyl esterYield 39%

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 312751,4-DioxaneSolvent2×

Procedure

A solution of palladium(II)acetate (4.24 mg, 18.9 μmol) and 2-(dicyclohexylphosphino) biphenyl (13.2 mg, 37.8 μmol) in dioxane (1.9 ml) under an argon atmosphere was stirred for 10 min at ambient temperature and subsequently added to a suspension of 6-chloro-5-cyclopropyl-pyridine-2-carboxylic acid methyl ester (100 mg, 472 μmol), 2,4-dichloroaniline (76.6 mg, 472 μmol) and potassium carbonate (1.31 g, 9.45 mmol) in dioxane (3.24 ml) under an argon atmosphere. The yellow suspension was heated to reflux and stirred for 20 h. The reaction mixture was poured into 20 mL ice/brine and extracted with i-PrOAc (2×50 mL). The combined organic layers were washed with ice/brine (1×50 mL), dried over sodium sulfate and concentrated in vacuo to give a brown oil. The crude product was purified by flash chromatography (silica gel, 4 g, 0% to 10% heptane/iPrOAc) to give the title compound (62 mg, 39%) as light brown liquid, MS (EI): m/e=337.2 [M+H]+.

Workup

  1. temperatureThe yellow suspension was heated
  2. temperatureto reflux
  3. extractionextracted with i-PrOAc (2×50 mL)
  4. washThe combined organic layers were washed with ice/brine (1×50 mL)
  5. dry with materialdried over sodium sulfate
  6. concentrationconcentrated in vacuo
  7. customto give a brown oil
  8. customThe crude product was purified by flash chromatography (silica gel, 4 g, 0% to 10% heptane/iPrOAc)

Sources & evidence

ORD record
ord-8af34e6b5ff84bb28b0e056ce7af62f8
Source dataset
uspto-grants-2016_03
Patent number
US09290451B2

Reaction notes

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