Cesium carbonate → 4-chloro-6-(1,3-dimethyl-1H-pyrazol-4-ylamino)nicotinonitrile

HRID 1045908Notes

Reaction equation

HRID 1045908 reaction equation
[Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[CH:4][C:3]=1[C:9]#[N:10].[CH3:11][N:12]1[CH:16]=[C:15]([NH:17]C(=O)C)[C:14]([CH3:21])=[N:13]1.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].O.[OH-].[Li+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1>[Cl:1][C:2]1[CH:7]=[C:6]([NH:17][C:15]2[C:14]([CH3:21])=[N:13][N:12]([CH3:11])[CH:16]=2)[N:5]=[CH:4][C:3]=1[C:9]#[N:10]

Participants

8

Reactant 5

HCID 10796Cesium carbonateHCID 168937Lithium hydroxide, monohydrateHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 19346285N-(1,3-dimethylpyrazol-4-yl)acetamideHCID 455880804,6-Dichloropyridine-3-carbonitrile

Product 1

HCID 670759654-chloro-6-(1,3-dimethyl-1H-pyrazol-4-ylamino)nicotinonitrileYield 43.7%

Reagents, catalysts & solvents 2

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

Conditions

Temperature
90 °C

Procedure

4,6-Dichloropyridine-3-carbonitrile (9.60 g, 55.49 mmol), N-(1,3-dimethylpyrazol-4-yl)acetamide (8.5 g, 55.49 mmol, see Example 2.02), palladium(II) acetate (0.374 g, 1.66 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (1.926 g, 3.33 mmol) and cesium carbonate (27.1 g, 83.23 mmol) were weighed out in a flask. Dioxane (110 mL) was added and argon was bubbled through the reaction mixture for 5 minutes at room temperature. The resulting suspension was stirred at 90° C. for 2 hours. The reaction mixture was allowed to cool to room temperature with stirring, water (275 mL) was added followed by the portionwise addition of lithium hydroxide hydrate (6.99 g, 166.47 mmol). The solution was left to stir at room temperature for 30 minutes. The resulting precipitate was collected by filtration, washed with water and dried. The crude product was purified by flash chromatography on silica gel eluting with 0 to 5% MeOH in EtOAc/DCM (1:1). The solvent was evaporated to dryness. The residue was triturated in Et2O, and the resulting precipitate was collected by filtration, washed with Et2O and dried to a constant weight to afford 4-chloro-6-(1,3-dimethylpyrazol-4-ylamino)pyridine-3-carbonitrile (6 g, 43.7%) as a pale yellow solid. 1H NMR spectrum (500 MHz, CDCl3): δ 2.15 (s, 3H), 2.88 (s, 3H), 6.43 (s, 1H), 6.45 (s, 1H), 7.44 (s, 1H), 8.36 (s, 1H); Mass spectrum: m/z (ESI+) (M+H)+=248.

Workup

  1. customargon was bubbled through the reaction mixture for 5 minutes at room temperature
  2. temperatureto cool to room temperature
  3. stirringwith stirring
  4. additionwater (275 mL) was added
  5. waitThe solution was left
  6. stirringto stir at room temperature for 30 minutes
  7. filtrationThe resulting precipitate was collected by filtration
  8. washwashed with water
  9. customdried
  10. customThe crude product was purified by flash chromatography on silica gel eluting with 0 to 5% MeOH in EtOAc/DCM (1:1)
  11. customThe solvent was evaporated to dryness
  12. customThe residue was triturated in Et2O
  13. filtrationthe resulting precipitate was collected by filtration
  14. washwashed with Et2O
  15. customdried to a constant weight

Sources & evidence

ORD record
ord-c3cfb5490cce4427a5491bf500a0178a
Source dataset
uspto-grants-2013_10
Patent number
US08569298B2

Reaction notes

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