New Process For The Synthesis Of2-(4-Bromomethylphenyl)Propionic Acid

Loxoprofen sodium is a new kind of anti-inflammatory drugs, which belongs to arylpropionic acid derivatives, with the advantages of small dosage, high efficiency, low toxicity and side effects.2-(4-bromomethylphenyl) propionic acid is the key intermediate for the synthesis of loxoprofen sodium, but the usual synthesis routes of it with shortcomings of difficult sources of raw materials, complex production process, high content of by-products, low yield, high cost and large amount of waste. Therefore, the study on the new synthesis process has important significance.In this paper, with reference to the relevant data, the synthesis of2-(4-bromo methylphenyl) propionic acid was composed of three parts. Firstly, the synthesis of2-methanesulfonyloxymethyl propionate,the optimum conditions was:n (methyl lactate):n (methanesulfonyl chloride):n (triethylamine)=1:1.6:1.3, reaction temperature being30～35℃, reaction time being3h, the dosage of methylene chloride was m (methylene chloride):m (methyl lactate)=2.9:1. Under this condition, the yield of2-methanesulfonyloxymethyl propionate was95.4%, the purity was98.5%.Then the synthesis of2-phenylpropionic acid by the Friedel-Crafts alkylation reaction of benzene and2-methanesulfonyloxymethyl propionate. The optimum conditions was:n (2-methanesulfonyloxymethyl propionate):n (aluminum trichloride): n (benzene)=1.0:2.0:6, the reaction temperature being40-45℃,reaction time being6h. Under this conditions, the yield of2-phenylpropionic acid was73.8%, the purity was94.2%; Finally, with the bromomethylation of2-phenylpropionic acid gets2-(4-bromomethylphenyl) propionic acid. The optimum reaction conditions were n (2-phenylpropionic acid):n (potassium bromide):n (formaldehyde):n (water):n (sulfuric acid)=1:1.64:1.2:6.0:3.73, the reaction time being20h, and the reaction temperature being70-75℃. Under the above conditions, the yield of2-(4-bromomethylphenyl) propionic acid was54.4%, the purity was91.79%. After three times of recrystallization, the purity of the product reached98.47%.The selectivity of the reaction was improved markedly with concentrated sulfuric acid as reaction medium.This method had some advantages such simple process, mild reaction conditions and better selectivity.