Sulfuric Acid → 2,6-Difluoro-N-{1-[(5-hydroxy-2-methylphenyl)methyl]-1H-pyrazol-3-yl}benzamide

HRID 1946347Notes

Reaction equation

HRID 1946347 reaction equation
N[C:2]1[CH:3]=[CH:4][C:5]([CH3:25])=[C:6]([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)[CH:7]=1.S(=O)(=O)(O)[OH:27].N([O-])=O.[Na+].NC(N)=O>O.S([O-])([O-])(=O)=O.[Cu+2].C(OCC)(=O)C>[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:6]2[CH:7]=[C:2]([OH:27])[CH:3]=[CH:4][C:5]=2[CH3:25])[N:10]=1)=[O:24]

Participants

8

Reactant 4

HCID 1118Sulfuric AcidHCID 1176UreaHCID 23668193Sodium NitriteHCID 59548012N-{1-[(5-amino-2-methylphenyl)methyl]-1H-pyrazol-3-yl}-2,6-difluorobenzamide

Product 1

HCID 595478422,6-Difluoro-N-{1-[(5-hydroxy-2-methylphenyl)methyl]-1H-pyrazol-3-yl}benzamide

Reagents, catalysts & solvents 3

HCID 24462Copper SulfateCatalystHCID 962WaterSolvent3×HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
2.5 °C

Procedure

To N-{1-[(5-amino-2-methylphenyl)methyl]-1H-pyrazol-3-yl}-2,6-difluorobenzamide (for a preparation see Intermediate 48) (0.312 g, 0.911 mmol) in an ice-water bath was added sulphuric acid specific gravity 1.84 (3 ml, 56.3 mmol). To the stirred suspension was slowly added water (5 ml). To the slight suspension was added a solution of sodium nitrite (0.132 g, 1.91 mmol, Aldrich) in water (1 ml). The solution was maintained at 0-5° C. for 20 min. To the solution was added urea (0.350 g, 5.83 mmol, Aldrich) and then copper (II) sulphate (50 mg, 0.313 mmol, Fluka). The mixture was heated to 90° C. for 30 min. The mixture was allowed to stand at ambient temperature overnight. The mixture was diluted with water (100 ml) and then ethyl acetate (50 ml). The phases were separated and the aqueous phase extracted with ethyl acetate (25 ml). The combined organic extracts were concentrated in vacuo to leave a brown gum (0.3 g). The residue was loaded in dichloromethane and purified on silica 50 g using 0-100% ethyl acetate-cyclohexane. The appropriate fractions were combined and evaporated in vacuo to give the title compound as a yellow foam (206 mg); LCMS (System 4) MH+=344, tRET=2.36 min.

Workup

  1. temperatureThe mixture was heated to 90° C. for 30 min
  2. customThe phases were separated
  3. extractionthe aqueous phase extracted with ethyl acetate (25 ml)
  4. concentrationThe combined organic extracts were concentrated in vacuo

Sources & evidence

ORD record
ord-0e072480a1f74f628f679e1971c95af7
Source dataset
uspto-grants-2013_03
Patent number
US08399436B2

Reaction notes

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