Lithium Hexamethyldisilazide → N-(1-{[4-chloro-2-(trifluoromethyl)phenyl]methyl}-1H-pyrazol-3-yl)-2,6-difluorobenzamide

HRID 1946403Notes

Reaction equation

HRID 1946403 reaction equation
[F:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:3]=1[C:4]([NH:6][C:7]1[CH:11]=[CH:10][NH:9][N:8]=1)=[O:5].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=1[C:36]([F:39])([F:38])[F:37]>C1COCC1>[Cl:35][C:32]1[CH:33]=[CH:34][C:29]([CH2:28][N:9]2[CH:10]=[CH:11][C:7]([NH:6][C:4](=[O:5])[C:3]3[C:12]([F:16])=[CH:13][CH:14]=[CH:15][C:2]=3[F:1])=[N:8]2)=[C:30]([C:36]([F:37])([F:38])[F:39])[CH:31]=1

Participants

5

Reactant 3

HCID 2733832Lithium HexamethyldisilazideHCID 34925974-Chloro-2-(trifluoromethyl)benzyl bromideHCID 178522346HCID 178522346, compound2×

Product 1

HCID 46945199N-(1-{[4-chloro-2-(trifluoromethyl)phenyl]methyl}-1H-pyrazol-3-yl)-2,6-difluorobenzamide

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent3×

Procedure

To a solution of 2,6-difluoro-N-1H-pyrazol-3-ylbenzamide (for a preparation see Intermediate 9)(3 g, 13.4 mmol) in THF (30 ml) was added 1.0 M lithium bis(trimethylsilyl)amide in THF (13.5 ml, 13.5 mmol, Aldrich). The resulting orange solution was stirred at ambient temperature under nitrogen for 30 min. To the reaction was added a solution of 1-(bromomethyl)-4-chloro-2-(trifluoromethyl)benzene (3.7 g, 13.5 mmol, Fluorochem) in THF (5 ml). The resulting orange solution was stirred at ambient temperature under nitrogen overnight. The solvent was removed in vacuo and the residue partitioned between ethyl acetate (125 ml) and aqueous sodium bicarbonate (75 ml). The phases were separated and the organic phase washed with aqueous sodium bicarbonate (50 ml). The combined aqueous phases were washed with ethyl acetate (75 ml). The organic phases were combined, dried, filtered and the solvent removed in vacuo. The residue was loaded in dichloromethane and purified on silica 100 g×2 using a 0-50% ethyl acetate-cyclohexane. The appropriate fractions were combined and evaporated in vacuo to give the title compound as a yellow solid (2.83 g); LCMS: (System 4) MH+=416, tRET=3.14 min.

Workup

  1. stirringThe resulting orange solution was stirred at ambient temperature under nitrogen overnight
  2. customThe solvent was removed in vacuo
  3. customthe residue partitioned between ethyl acetate (125 ml) and aqueous sodium bicarbonate (75 ml)
  4. customThe phases were separated
  5. washthe organic phase washed with aqueous sodium bicarbonate (50 ml)
  6. washThe combined aqueous phases were washed with ethyl acetate (75 ml)
  7. customdried
  8. filtrationfiltered
  9. customthe solvent removed in vacuo
  10. custompurified on silica 100 g×2 using a 0-50% ethyl acetate-cyclohexane
  11. customevaporated in vacuo

Sources & evidence

ORD record
ord-9ca072c291284089b0722d53c3fe3ec3
Source dataset
uspto-grants-2013_03
Patent number
US08399436B2

Reaction notes

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