Sulfuric Acid → 5-amino-1-(2-chloro-6-fluoro-4-(trifluoromethyl)-phenyl)-1H-pyrazole-3-carbonitrile

HRID 1428999Notes

Reaction equation

HRID 1428999 reaction equation
[Cl:1][C:2]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[C:5]([F:13])[C:3]=1[NH2:4].OS(O)(=O)=O.OS(O)(=O)=O.[N:24]([O-])=O.[Na+].[C:28]([CH2:30][C:31]([C:34]#[N:35])=CO)#[N:29].C([O-])(=O)C.[Na+]>C(O)(=O)C.O>[NH2:29][C:28]1[N:4]([C:3]2[C:5]([F:13])=[CH:6][C:7]([C:9]([F:12])([F:11])[F:10])=[CH:8][C:2]=2[Cl:1])[N:24]=[C:31]([C:34]#[N:35])[CH:30]=1

Participants

8

Reactant 5

HCID 1118Sulfuric AcidHCID 517045Sodium AcetateHCID 199141572-Chloro-6-fluoro-4-(trifluoromethyl)anilineHCID 23693711H2SO4 NaNO2HCID 727412321,2-Dicyano-3-hydroxyprop-2-ene

Product 1

HCID 684093715-amino-1-(2-chloro-6-fluoro-4-(trifluoromethyl)-phenyl)-1H-pyrazole-3-carbonitrileYield 73%

Reagents, catalysts & solvents 2

HCID 176Acetic AcidSolventHCID 962WaterSolvent2×

Conditions

Temperature
50 °C

Procedure

To a solution of 2-chloro-6-fluoro-4-trifluoromethylaniline (210 g, 985.9 mmol) in acetic acid (1.05 L) was added concentrated H2SO4 (44.45 mL) at rt. Then the solution was added dropwise to the above H2SO4—NaNO2 mixture at 0° C. Then the mixture was heated to 50° C. After stirring for 1 hour, this reaction mixture was added to a suspension of 1,2-dicyano-3-hydroxyprop-2-ene (224 g, 1.48 mol, 1.5 eq.) and anhydrous sodium acetate (1.68 kg, 20.4 mol, 13.78 eq.) in H2O (1.05 L) at 5-10° C. After stirring for 1 hour, this reaction mixture was diluted with water and extracted with dichloromethane (DCM). The organic layers were stirred vigorously with 30% ammonium hydroxide solution overnight. The organic phase separated, dried over anhydrous Na2SO4, filtered and concentrated under vacuum to give yellow solid. The solid was recrystallized from ethyl acetate (EA) to afford 5-amino-1-(2-chloro-6-fluoro-4-(trifluoromethyl)-phenyl)-1H-pyrazole-3-carbonitrile as yellow solid (220 g, 73%).

Workup

  1. stirringAfter stirring for 1 hour
  2. extractionextracted with dichloromethane (DCM)
  3. stirringThe organic layers were stirred vigorously with 30% ammonium hydroxide solution overnight
  4. customThe organic phase separated
  5. dry with materialdried over anhydrous Na2SO4
  6. filtrationfiltered
  7. concentrationconcentrated under vacuum
  8. customto give yellow solid
  9. customThe solid was recrystallized from ethyl acetate (EA)

Sources & evidence

ORD record
ord-ac762a846c754048961b1a85dfc9da2f
Source dataset
uspto-grants-2015_01
Patent number
US08937185B2

Reaction notes

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