Background and overview[1][2]
4-Fluoro-3-methylbenzoic acid is an important fluorine-containing medicine, pesticide, and dye intermediate, such as used in the synthesis of anti-inflammatory and antibacterial drugs, local anesthetics for surgery, organofluorine pesticides, Herbicides, plant growth regulators, etc. 4-Fluoro-3-methylbenzoic acid was synthesized in two steps using isobutyllithium, p-fluorobenzoic acid, and methyl iodide at -78°C. This method has strict temperature requirements, poor reaction selectivity, and difficult separation of isomers. Yield is low. Using m-xylene as raw material, 4-nitro-m-xylene is synthesized by nitration with mixed acid, and then reduced to synthesize 4-amino-m-xylene, which is then diazofluorinated to synthesize 4-fluoro-m-xylene, and finally used 4-fluoro-3-methylbenzoic acid was synthesized by selective oxidation of dilute nitric acid in an autoclave.
Preparation[1]
Step 1: Preparation of 4-nitro-m-xylene
In a 1L three-neck flask, install a mechanical stirrer, a low-temperature thermometer, and a constant-pressure dropping funnel. Add 150g of m-xylene, cool to -10°C under stirring, and slowly add 300g of concentrated sulfuric acid and 150g of concentrated sulfuric acid dropwise. Mix acid solution composed of concentrated nitric acid, keep the system temperature at -5°C, complete the dropwise addition, continue the reaction for 4 hours, pour the product into ice water, separate the layers, extract the lower layer three times with 100 mL of CH3C13, combine the organic layers, and use hydrogen carbonate Wash twice with sodium solution, then wash with water until neutral, dry, and distill under reduced pressure. Collect the 115~130℃/15mm fraction. The collected fraction is then rectified with a 1m packed column to collect 98~99 ℃/Zmm fraction, 152.1 g of product was obtained, with a yield of 71.2%
Step 2: Preparation of 4-amino-m-xylene
Add 152.1g 4-nitro-m-xylene, 4gPd/C, 300mL isopropyl alcohol and 250g80 hydrazine hydrate in sequence to a 1L three-neck flask equipped with a mechanical stirrer, thermometer and reflux condenser, heat to reflux, and use osmosis Check whether the reaction is complete by loop experiment. After the reaction is completed, filter with suction. Use a rotary evaporator to spin out the isopropyl alcohol from the filtrate, then wash off excess hydrazine hydrate with water, dry, and distill under reduced pressure. Collect the 108-110°C fraction to obtain a colorless liquid. 104.3g, yield 8.6%
Step 3: Preparation of 4-fluoro-m-xylene
Place 258 mL of concentrated hydrochloric acid, 200 mL of water, and 104.3 g of 4-amino-m-xylene in a 1L three-necked flask equipped with a mechanical stirrer, thermometer and reflux condenser, heat to dissolve, cool slightly, and set to low temperature for reaction In the tank, stir continuously to form a paste, and lower the solution temperature to below -5°C. Then add a solution of 66.3g sodium nitrite dissolved in 180mL water from the dropping funnel under stirring, and control the temperature to always be around -5°C. , after the reaction is completed, quickly add the borofluoric acid solution that has been cooled to 0°C to the prepared diazonium salt solution, stir for 10 minutes, filter, and immediately rinse with ice water, ethanol, and diethyl ether in sequence, and collect the solid in a vacuum drying box Dry at room temperature overnight. Add the dry white solid and a small amount of copper powder into a 250mL round-bottomed flask equipped with a distillation device. Heat and decompose it with an alcohol lamp. Steam the product by steam distillation. Extract the water layer twice with dichloromethane and combine the organic matter. The layer was dried with acid overnight, and the methylene chloride was removed with a rotary evaporator. Distilled under normal pressure, the fractions at 142-143°C were collected to obtain 48.7g of colorless liquid with a yield of 45.6%.
Step 4: Preparation of 4-fluoro-3-methylbenzoic acid
Add 9.0g (0.08mol) 4-fluoro-m-xylene and 50mL 30% HNO3 (0.28mol) into a 100mL autoclave with a NO2 absorption device, slowly heat, control the pressure to 1.0MPa, and set the temperature at 110 React at ℃ for 2 hours, stop the reaction, cool to normal temperature and discharge the material, dilute with water, suction filter, dissolve the solid with sodium bicarbonate solution, suction filter, extract the filtrate twice with 30mL ether, boil the water layer, and adjust to pH 3.0 with HC1 After suction filtration and drying, 3.99 g of white body was obtained, with a yield of 56.23% and a melting point of 165 to 166°C (literature value of 164 to 165°C).
Main reference materials
[1] Selective nitric acid oxidation to synthesize 4-fluoro-3-methylbenzoic acid
