Cesium carbonate → 5-Chloro-2-[(5-chloro-2-{[3-methyl-1-(1-methylethyl)-1H-pyrazol-5-yl]amino}-4-pyridinyl)amino]benzonitrile

HRID 62534Notes

Reaction equation

HRID 62534 reaction equation
[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:10][C:11]2[C:16]([Cl:17])=[CH:15][N:14]=[C:13](Cl)[CH:12]=2)=[C:6]([CH:9]=1)[C:7]#[N:8].[CH3:19][C:20]1[CH:24]=[C:23]([NH2:25])[N:22]([CH:26]([CH3:28])[CH3:27])[N:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1C=CC(P(C2C(OC3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=CC=3)=CC=CC=2)C2C=CC=CC=2)=CC=1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:10][C:11]2[C:16]([Cl:17])=[CH:15][N:14]=[C:13]([NH:25][C:23]3[N:22]([CH:26]([CH3:28])[CH3:27])[N:21]=[C:20]([CH3:19])[CH:24]=3)[CH:12]=2)=[C:6]([CH:9]=1)[C:7]#[N:8]

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 1210181-Isopropyl-3-methyl-1H-pyrazol-5-amineHCID 4285986Bis[2-(diphenylphosphino)phenyl] etherHCID 575169175-Chloro-2-[(2,5-dichloro-4-pyridinyl)amino]benzonitrile

Product 1

HCID 667692605-Chloro-2-[(5-chloro-2-{[3-methyl-1-(1-methylethyl)-1H-pyrazol-5-yl]amino}-4-pyridinyl)amino]benzonitrileYield 35.1%

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 312751,4-DioxaneSolvent

Procedure

To a solution of 5-chloro-2-[(2,5-dichloro-4-pyridinyl)amino]benzonitrile (1.8 g, 6.03 mmol) and 3-methyl-1-(1-methylethyl)-1H-pyrazol-5-amine (0.839 g, 6.03 mmol) in 1,4-dioxane (40 mL) was added cesium carbonate (5.89 g, 18.09 mmol) and the reaction mixture was degassed. DPEPhos (0.260 g, 0.482 mmol) was added followed by palladium acetate (0.054 g, 0.241 mmol) and the reaction mixture was heated to reflux overnight. The suspension was then filtered. The dioxane was evaporated. Solid was partitioned between 1 M HCl and ethyl acetate. Layers were separated, and organic layer discarded. The HCl-containing layer was neutralized and extracted with 2×50 mL of ethyl acetate. Organic layers were combined, washed with brine, dried over MgSO4, filtered and evaporated. 5-Chloro-2-[(5-chloro-2-{[3-methyl-1-(1-methylethyl)-1H-pyrazol-5-yl]amino}-4-pyridinyl)amino]benzonitrile (850 mg, 2.118 mmol, 35.1% yield) was isolated as a yellow solid. 1H NMR (400 MHz, DMSO-d6) ppm 1.25 (d, J=6.57 Hz, 6H) 2.09 (s, 3 H) 4.35 (quin, J=6.57 Hz, 1 H) 5.89 (s, 1 H) 6.03 (s, 1 H) 7.46 (d, J=8.84 Hz, 1 H) 7.81 (dd, J=8.72, 2.65 Hz, 1 H) 7.96 (s, 1 H) 8.11 (d, J=2.53 Hz, 1 H) 8.42 (s, 1 H) 8.54 (s, 1 H) HPLC Rt=2.60 min, MS (ESI): 400.8, 403.1 [M+H]+.

Workup

  1. customthe reaction mixture was degassed
  2. temperaturethe reaction mixture was heated
  3. temperatureto reflux overnight
  4. filtrationThe suspension was then filtered
  5. customThe dioxane was evaporated
  6. customSolid was partitioned between 1 M HCl and ethyl acetate
  7. customLayers were separated
  8. additionThe HCl-containing layer
  9. extractionextracted with 2×50 mL of ethyl acetate
  10. washwashed with brine
  11. dry with materialdried over MgSO4
  12. filtrationfiltered
  13. customevaporated

Sources & evidence

ORD record
ord-e9b43bbb025c436a8bf4d32622b993f5
Source dataset
uspto-grants-2016_09
Patent number
US09446034B2

Reaction notes

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