Sulfuric Acid → 2,6-Difluoro-N-{1-[(4-iodo-2-methylphenyl)methyl]-1H-pyrazol-3-yl}benzamide

HRID 1946397Notes

Reaction equation

HRID 1946397 reaction equation
N[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:24])[C:16]3[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=3[F:23])=[N:10]2)=[C:4]([CH3:25])[CH:3]=1.S(=O)(=O)(O)O.N([O-])=O.[Na+].[I-:35].[K+]>O>[F:23][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]([F:22])[C:16]=1[C:15]([NH:14][C:11]1[CH:12]=[CH:13][N:9]([CH2:8][C:5]2[CH:6]=[CH:7][C:2]([I:35])=[CH:3][C:4]=2[CH3:25])[N:10]=1)=[O:24]

Participants

6

Reactant 4

HCID 1118Sulfuric AcidHCID 4875Potassium IodideHCID 23668193Sodium NitriteHCID 59547916N-{1-[(4-amino-2-methylphenyl)methyl]-1H-pyrazol-3-yl}-2,6-difluorobenzamide

Product 1

HCID 469447822,6-Difluoro-N-{1-[(4-iodo-2-methylphenyl)methyl]-1H-pyrazol-3-yl}benzamide

Reagents, catalysts & solvents 1

HCID 962WaterSolvent

Procedure

To a suspension of N-{1-[(4-amino-2-methylphenyl)methyl]-1H-pyrazol-3-yl}-2,6-difluorobenzamide (for a preparation see Intermediate 33)(400 mg, 1.17 mmol) in water (1.7 ml) in an ice-water bath (internal temperature 5° C.) was added concentrated sulphuric acid specific gravity 1.84 (165 μl, 3.10 mmol) and then a solution of sodium nitrite, super free flowing (90 mg, 1.305 mmol, Aldrich) in ice-cold water (0.5 ml) dropwise. The resulting yellow solution was stirred in an ice-water bath for 30 min. To the mixture was added a solution of potassium iodide, extra pure briquettes (291 mg, 1.75 mmol, Acros) in ice cold ˜1 M sulphuric acid (3 ml). The mixture was allowed to warm to ambient temperature and then heated to 80° C. for 1 h. The mixture was allowed to cool to room temperature for 1 h and was then partitioned between ethyl acetate (50 ml) and water (50 ml). The phases were separated and the organic phase washed with water (20 ml), brine (20 ml), dried (MgSO4), filtered and the solvent removed in vacuo to leave a dark red/brown oil (515 mg). The sample was loaded in dichloromethane and purified on silica 50 g using 0-50% ethyl acetate-cyclohexane. The appropriate fractions were combined and evaporated in vacuo to give the title compound as a yellow oil (223 mg); LCMS: (System 4) MH+=454, tRET=3.14 min.

Workup

  1. custom(internal temperature 5° C.)
  2. temperatureheated to 80° C. for 1 h
  3. temperatureto cool to room temperature for 1 h
  4. customwas then partitioned between ethyl acetate (50 ml) and water (50 ml)
  5. customThe phases were separated
  6. washthe organic phase washed with water (20 ml), brine (20 ml)
  7. dry with materialdried (MgSO4)
  8. filtrationfiltered
  9. customthe solvent removed in vacuo

Sources & evidence

ORD record
ord-85430bc78d7349f18dbbad35c94b3605
Source dataset
uspto-grants-2013_03
Patent number
US08399436B2

Reaction notes

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