4-(Trifluoromethyl)aniline → Leflunomide

HRID 2086374Notes

Reaction equation

HRID 2086374 reaction equation
[F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.[CH3:12][C:13]1[O:17][N:16]=[CH:15][C:14]=1[C:18](Cl)=[O:19]>C([O-])(O)=O.[Na+].CN(C)C(=O)C.C1(C)C=CC=CC=1>[CH3:12][C:13]1[O:17][N:16]=[CH:15][C:14]=1[C:18]([NH:7][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:10])([F:11])[F:1])=[CH:9][CH:8]=1)=[O:19]

Participants

6

Reactant 2

HCID 99644-(Trifluoromethyl)anilineHCID 27599175-Methyl-1,2-oxazole-4-carbonyl chloride

Product 1

HCID 3899LeflunomideYield 86.2%

Reagents, catalysts & solvents 3

HCID 1140TolueneSolventHCID 31374DimethylacetamideSolventHCID 516892Sodium BicarbonateSolvent

Conditions

Temperature
40 °C

Procedure

4-Trifluoromethylaniline (5.75 g, 35.7 mm) was dissolved in a mixture of NaHCO3 (3.16 g, 37.6 mm), N,N-dimethylacetamide (0.7 ml, 7.5 mm) and toluene (70 ml). The mixture was warmed to 40° C. and 5-methylisoxazole-4-carboxylic acid chloride (5 g, 34.4 mm) was added dropwise over 20 min. The mixture was stirred at this temperature for another 3 h. and then it was heated to reflux temperature. The hot mixture was washed with water (3×10 ml). The organic phase was allowed to cool to ambient temperature, which induced leflunomide to precipitate as a white powder. The powder was isolated by filtration and then dried at 60° C. to give leflunomide (8.0 g, 86%) in 99.5% purity.

Workup

  1. temperatureit was heated
  2. temperatureto reflux temperature
  3. washThe hot mixture was washed with water (3×10 ml)
  4. temperatureto cool to ambient temperature
  5. customto precipitate as a white powder
  6. customThe powder was isolated by filtration
  7. customdried at 60° C.

Sources & evidence

ORD record
ord-cb0f6b5efcf3449cbd3b1a8808f4caef
Source dataset
uspto-grants-2004_04
Patent number
US06723855B2

Reaction notes

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