Study On Synthesis Of 2-(4-Bromomethyl) Phenylpropionic Acid

Loxoprofen, an important non-steroidal anti-inflammatory drug, has significant analgesic, anti-inflammatory and antipyretic effect.2-(4-bromomethyl) phenylpropionic acid is the key intermediate for the synthesis of loxoprofen. The main problems in the synthesis of 2-(4-bromomethyl)phenylpropionic acid for the current domestic manufacturers are that it involved many reaction steps, large amount of emissions of waste, the yield of rearrangement reaction and bromination reaction was not higher enough. A new green technology was studied in this paper, using toluene as raw materials,2-(4-bromomethyl)phenylpropionic acid was prepared through four reaction steps, which included friedelcrafts acylation, hydrogenation, hydrogen carboxylic and bromination. The total yield of 2-(4-bromomethyl)phenylpropionic acid could reach 58.0%.4-Methylacetophenone was prepared from toluene on aluminium trichloride catalyst through friedel-crafts acylation with acetyl chloride as acylating agent. Research results showed that the conversion of toluene and yield of 4-methylacetophenone reached 100% and 99.5% respectively, while the purity of products was 99.2% under the following conditions:dichloromethane as solvent, n(AlCl3):n(toluene):n(acetyl chloride)=1.1:1:1.1, reaction time 1 h, reaction temperature 0℃.4-Methylacetophenone can be reduced to 1-(4-methylphenyl)ethanol with NaBH4 as a reducing agent, the conversion of 4-methylacetophenone and yield of 1-(4-methylphenyl)ethanol approached 99.9% and 99.5% respectively, while the purity of products was 99.2% under the condition of reaction temperature below 10℃, reaction time 5 h, n(4-methylacetophenone):n(NaBH4)=1:1.3.4-methylacetophenone was hydrogenated to 1-(4-methylphenyl)ethanol on CuO-NiO-MnO2/SiO2 catalyst in a fixed bed, the conversion of 4-methylacetophenone and yield of 1-(4-methylphenyl)ethanol approached 100% and 97.6% respectively under the condition of H2 pressure 2.0 MPa, reaction temperature 100℃, n(H2):n (4-methylacetophenone)=30:1, liquid hourly space velocity 0.30 h-1.Taking PdCl2/PPh3/CuCl3 as the catalytic system,2-(4-methylphenyl) propanoic acid was synthized by 1-(4-methylphenyl)ethanol through hydrogen carboxylic reaction. Results showed that, using hydrochloric acid as acidic medium, butanone as solvent, the conversion of 1-(4-m ethyl phenyl)ethanol and the yield of 2-(4-methylphenyl)propanoic acid reached 100% and 71.8% respectively under the condition of reaction temperature 80℃, CO pressure 4.5 MPa, reaction time 24 h. Using bromine as reagent for bromide,2-(4-bromomethyl)phenylpropionic acid was formed by 2-(4-methylphenyl)propanoic acid through bromination reaction, the yield was 83.2%.