3-Fluoro-5-(trifluoromethyl)benzonitrile

Synthesis

Traditional methods for synthesizing halogenated benzonitrile include photohalogenation, ammonia oxidation, phase transfer catalytic synthesis, or reaction of carboxylic acid with urea. This paper uses substituted benzaldehyde as the starting material to generate 3-fluoro-5-(trifluoromethyl)benzaldehyde oxime, and then the oxime reacts with hydroxylamine to dehydrate and obtain substituted benzonitrile. Although this route has many steps, the yield of each step is high, and the product is easy to separate and purify, which is a feasible route [1]. The synthesis reaction formula for 3-fluoro-5-(trifluoromethyl)benzonitrile is shown in the figure below:

Figure 1 Synthesis reaction formula for 3-fluoro-5-(trifluoromethyl)benzonitrile

In a three-necked flask equipped with a thermometer, condenser, and electric stirrer, add 3-fluoro-5-(trifluoromethyl)benzaldehyde and hydroxylamine hydrochloride in a certain molar ratio. Heat to 70-75℃ and react for 30 min. Then, slowly add 20% (mass fraction) sodium carbonate aqueous solution while stirring. Bubbles are generated (which can be tested with lime water). When the reaction slows down, adjust the pH to 8-9 and stop adding sodium carbonate aqueous solution. Continue stirring; a pale red precipitate appears. Let stand until the pale red color gradually turns milky white. Filter out the precipitate, wash with water 2-3 times, and air dry to obtain a milky white solid powder, 3-fluoro-5-(trifluoromethyl)benzaldehyde oxime, which is weighed and set aside. Add 3-fluoro-5-(trifluoromethyl)benzaldehyde oxime and acetic anhydride to a three-necked flask in a certain molar ratio, heat to 110-120℃, and react for 3 hours. The reaction solution is a light orange-yellow liquid. Cool and let stand; white crystals appear. Filter to obtain crystals, dissolve in alcohol, remove insoluble matter by hot filtration, and separate the filtrate by water extraction to obtain clean 3-fluoro-5-(trifluoromethyl)benzonitrile.

Chemical Properties

off white crystalline

Uses

3-Fluoro-5-trifluoromethylbenzonitrile is a reagent used in the synthesis of cholesteryl ester transfer protein (CETP) inhibitors in the treatment of high cholesterol. Also used in the preparation of substituted pyrimidines with dithioacetals for antimicrobial activity.