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

HRID 1045981Notes

Reaction equation

HRID 1045981 reaction equation
[CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([NH:8][C:9](=O)[CH3:10])[C:4]([CH3:12])=[N:3]1.[H-].[Na+].ClC1C=[C:20]([I:22])[C:19]([C:23]([F:26])([F:25])[F:24])=[CH:18][N:17]=1.O.[OH-].[Li+]>CCOC(C)=O.O>[I:22][C:20]1[C:19]([C:23]([F:26])([F:25])[F:24])=[CH:18][N:17]=[C:9]([NH:8][C:5]2[C:4]([CH3:12])=[N:3][N:2]([CH3:1])[C:6]=2[CH3:7])[CH:10]=1

Participants

7

Reactant 4

HCID 24758Sodium hydrideHCID 168937Lithium hydroxide, monohydrateHCID 27737912-Chloro-4-iodo-5-(trifluoromethyl)pyridineHCID 22335537N-(1,3,5-trimethylpyrazol-4-yl)acetamide

Product 1

HCID 670754954-iodo-5-(trifluoromethyl)-N-(1,3,5-trimethylpyrazol-4-yl)pyridin-2-amineYield 27.2%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
35 °C

Procedure

N-(1,3,5-trimethylpyrazol-4-yl)acetamide (1.142 g, 6.83 mmol) was added to sodium hydride (0.288 g, 6.83 mmol) suspended in nitrogen-degassed DMF (5 mL) under nitrogen. The resulting light suspension was stirred at 35° C. for 30 minutes then 2-chloro-4-iodo-5-(trifluoromethyl)pyridine (1 g, 3.25 mmol) was added. The reaction mixture was allowed to cool to room temperature, stirred for 1 hour and quenched with water (20 mL). Lithium hydroxide hydrate (0.409 g, 9.76 mmol) was added, the mixture was stirred at room temperature for 1.5 hour and then diluted with EtOAc and water. The phases were separated and the organic phase was washed with brine, dried over magnesium sulfate and concentrated. The crude product was purified by flash chromatography on silica gel (40 g) eluting with 0 to 50% EtOAc in DCM to afford 4-iodo-5-(trifluoromethyl)-N-(1,3,5-trimethylpyrazol-4-yl)pyridin-2-amine (350 mg, 27.2%) as an off-white solid.

Workup

  1. customdegassed DMF (5 mL) under nitrogen
  2. temperatureto cool to room temperature
  3. stirringstirred for 1 hour
  4. customquenched with water (20 mL)
  5. stirringthe mixture was stirred at room temperature for 1.5 hour
  6. customThe phases were separated
  7. washthe organic phase was washed with brine
  8. dry with materialdried over magnesium sulfate
  9. concentrationconcentrated
  10. customThe crude product was purified by flash chromatography on silica gel (40 g)
  11. washeluting with 0 to 50% EtOAc in DCM

Sources & evidence

ORD record
ord-e708c6ef353d4e94bf2f6ef4b5c3d9b5
Source dataset
uspto-grants-2013_10
Patent number
US08569298B2

Reaction notes

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