2-cyano-N-[4-(trifluoromethyl)phenyl]acetamide Chemical Properties

Melting point:

145-147℃

Boiling point:

386.3±42.0 °C(Predicted)

Density 

1.375±0.06 g/cm3(Predicted)

storage temp. 

Sealed in dry,Room Temperature

solubility 

DMSO (Slightly), Methanol (Slightly)

form 

Solid

pka

4.63±0.10(Predicted)

color 

White to Off-White

Stability:

Hygroscopic

Safety Information

HS Code 

2924297099

2-cyano-N-[4-(trifluoromethyl)phenyl]acetamide Usage And Synthesis

Uses

2-Cyano-N-[4-(trifluoromethyl)phenyl]acetamide (Leflunomide EP Impurity H) is used to prepare aminothiophene carboxylates and carboxamides as adenosine A1 receptor allosteric enhancers. It is also used to synthesize (1,2,3-triazol-4-yl)benzenamines as inhibitors against VEGF receptors 1 and 2.

Synthesis

In 700 L of tetrahydrofuran, 63.4 kg of cyanoacetic acid was dissolved and stirred at room temperature and under nitrogen protection. The resulting solution was cooled to 0 to 10°C, followed by slow dropwise addition of N-methylmorpholine at the same temperature over about 1 hour. Next, 100.0 kg of 4-trifluoromethylaniline was added dropwise. Continuing at the same temperature, 91.3 kg of isopropyl chlorocarbonate was slowly added dropwise to the reaction mixture over about 1 hour. After the dropwise addition was completed, the reaction was continued with stirring for 1 to 2 hours. After completion of the reaction, 200 L of water was added to the reaction mixture, stirred and left to stratify. The organic layer (upper layer) was washed with 16.7% brine, followed by the addition of 400 L of isopropanol and concentrated under reduced pressure until the volume of liquid was reduced to 400 L. 400 L of isopropanol was added again, and the concentration was repeated under reduced pressure until the volume of liquid was 400 L. 100 L of isopropanol was added to the concentrated solution at 20 to 30 °C followed by a slow dropwise addition of 500 L of water at about 20 °C. The reaction was completed with the addition of 500 L of water. After completion of the dropwise addition, stirring was continued for 1 hour at the same temperature. The mixture was cooled to 0 to 10°C and stirred at that temperature for 1 hour. The precipitated crystals were collected by filtration and dried to give 134.5 kg of 2-cyano-N-(4-(trifluoromethyl)phenyl)acetamide (IV) in 95.0% yield.

References

[1] Patent: EP1609778, 2005, A1. Location in patent: Page/Page column 5; 8-9
[2] Patent: WO2017/103942, 2017, A1. Location in patent: Page/Page column 5; 7
[3] Journal of Medicinal Chemistry, 1996, vol. 39, # 23, p. 4608 - 4621
[4] Journal of Medicinal Chemistry, 2017, vol. 60, # 11, p. 4626 - 4635
[5] Journal of Medicinal Chemistry, 1991, vol. 34, # 11, p. 3295 - 3301

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