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

HRID 919168Notes

Reaction equation

HRID 919168 reaction equation
OS(O)(=O)=O.N([O-])=O.[Na+].[Cl:10][C:11]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[C:14]([F:22])[C:12]=1[NH2:13].OS(O)(=O)=O.[N:28]([O-])=O.[Na+].[C:32]([CH2:34][C:35]([C:38]#[N:39])=CO)#[N:33].C([O-])(=O)C.[Na+]>C(O)(=O)C.O>[NH2:33][C:32]1[N:13]([C:12]2[C:14]([F:22])=[CH:15][C:16]([C:18]([F:21])([F:20])[F:19])=[CH:17][C:11]=2[Cl:10])[N:28]=[C:35]([C:38]#[N:39])[CH:34]=1

Participants

9

Reactant 6

HCID 1118Sulfuric Acid2×HCID 517045Sodium AcetateHCID 199141572-Chloro-6-fluoro-4-(trifluoromethyl)anilineHCID 23668193Sodium NitriteHCID 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
0 °C

Procedure

To a stirred concentrated H2SO4 (473 mL) was added NaNO2 (81.63 g, 1.18 mol, 1.20 eq.) at 0˜5° C. in several portions. Then the mixture was heated to 45˜50° C. and stirred at this temperature for 1 hour. This acid mixture was cooled to 0° C. and reserved to use in the next step. 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. temperatureThen the mixture was heated to 45˜50° C.
  2. temperatureThen the mixture was heated to 50° C
  3. stirringAfter stirring for 1 hour
  4. stirringAfter stirring for 1 hour
  5. extractionextracted with dichloromethane (DCM)
  6. stirringThe organic layers were stirred vigorously with 30% ammonium hydroxide solution overnight
  7. customThe organic phase separated
  8. dry with materialdried over anhydrous Na2SO4
  9. filtrationfiltered
  10. concentrationconcentrated under vacuum
  11. customto give yellow solid
  12. customThe solid was recrystallized from ethyl acetate (EA)

Sources & evidence

ORD record
ord-4ab41ba947d54a08826d384bd1e9397e
Source dataset
uspto-grants-2016_03
Patent number
US09273007B2

Reaction notes

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