Sodium hydride → N-(1,3-dimethylpyrazol-5-yl)-4-iodo-5-(trifluoromethyl)pyridin-2-amine

HRID 1045974Notes

Reaction equation

HRID 1045974 reaction equation
[H-].[Na+].[CH3:3][N:4]1[C:8]([NH:9][C:10](=O)[CH3:11])=[CH:7][C:6]([CH3:13])=[N:5]1.ClC1C=[C:19]([I:21])[C:18]([C:22]([F:25])([F:24])[F:23])=[CH:17][N:16]=1.O.[OH-].[Li+]>C1COCC1.CCOC(C)=O.O.CN(C=O)C>[CH3:3][N:4]1[C:8]([NH:9][C:10]2[CH:11]=[C:19]([I:21])[C:18]([C:22]([F:25])([F:24])[F:23])=[CH:17][N:16]=2)=[CH:7][C:6]([CH3:13])=[N:5]1

Participants

9

Reactant 4

HCID 24758Sodium hydrideHCID 168937Lithium hydroxide, monohydrateHCID 574162N-(2,5-dimethylpyrazol-3-yl)acetamideHCID 27737912-Chloro-4-iodo-5-(trifluoromethyl)pyridine

Product 1

HCID 67075489N-(1,3-dimethylpyrazol-5-yl)-4-iodo-5-(trifluoromethyl)pyridin-2-amineYield 54.1%

Reagents, catalysts & solvents 4

HCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
35 °C

Procedure

A suspension of 2,5-dimethylpyrazol-3-amine (1 g, 9.00 mmol), potassium acetate (0.971 g, 9.90 mmol) and acetic anhydride (1.002 mL, 9.00 mmol) in EtOAc (25 mL) was stirred at 25° C. overnight. Silica gel was added and the mixture was concentrated. The crude product was purified by flash chromatography on silica gel eluting with 0 to 5% MeOH in DCM. The solvent was evaporated to dryness to afford N-(2,5-dimethylpyrazol-3-yl)acetamide (1.400 g, 102%) as a pale yellow oil. Mass spectrum: MH+ 154 Sodium hydride (0.385 g, 9.14 mmol) was added to N-(2,5-dimethylpyrazol-3-yl)acetamide (1.4 g, 9.14 mmol) dissolved in THF (20 mL) under nitrogen. The resulting light suspension was stirred at 35° C. for 30 minutes then 2-chloro-4-iodo-5-(trifluoromethyl)pyridine (1.338 g, 4.35 mmol) was added. DMF (2 mL) was added and the mixture was stirred at 80° C. for 18 hours. The reaction mixture was cooled to room temperature, quenched with water (20 mL). Lithium hydroxide hydrate (0.548 g, 13.06 mmol) was added and the mixture was stirred at room temperature for 1.5 hours. The mixture was diluted with EtOAc and water, the phases were separated and the organic phase washed with brine, dried over magnesium sulfate and concentrated. The residue was purified by flash chromatography on silica gel (40 g) eluting with 0 to 50% EtOAc in DCM. After collection of the fractions and evaporation of the solvents, the resulting solid was triturated in petroleum ether, collected by filtration, washed with petroleum ether and dried to a constant weight to afford N-(2,5-dimethylpyrazol-3-yl)-4-iodo-5-(trifluoromethyl)pyridin-2-amine (900 mg, 54.1%) as an off-white solid.

Workup

  1. stirringthe mixture was stirred at 80° C. for 18 hours
  2. temperatureThe reaction mixture was cooled to room temperature
  3. customquenched with water (20 mL)
  4. stirringthe mixture was stirred at room temperature for 1.5 hours
  5. customthe phases were separated
  6. washthe organic phase washed with brine
  7. dry with materialdried over magnesium sulfate
  8. concentrationconcentrated
  9. customThe residue was purified by flash chromatography on silica gel (40 g)
  10. washeluting with 0 to 50% EtOAc in DCM
  11. customAfter collection of the fractions and evaporation of the solvents
  12. customthe resulting solid was triturated in petroleum ether
  13. filtrationcollected by filtration
  14. washwashed with petroleum ether
  15. customdried to a constant weight

Sources & evidence

ORD record
ord-5a3816f61d8546c593643fcd1f3afdac
Source dataset
uspto-grants-2013_10
Patent number
US08569298B2

Reaction notes

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