Catalytic Synthesis Of Diflunisal By Ultrasonic Method

Diflunisal is a very good non-steroidal anti-inflammatory.It has good effects and long half-life drug side effects.In recent years,Diflunisal has also been found to have therapeutic effects on hereditary transthyretin amyloid lesions.At present,Diflunisal has been included in the Pharmacopoeia in China,the United States,and the United Kingdom.Diflunisal is a perfect replacement for aspirin.But its lengthy and harsh production process has limited its promotion.Therefore,an efficient and simple production line of Diflunisal has great potential markets and economic benefits.Considering the cost of raw material and process,the synthesis route of 2,4-difluorobromobenzene was selected from the four Diflunisal synthesis routes,and the synthesis reaction in the route was studied..The synthesis reaction of 2,4-difluorophenylboronic acid was studied.By changing the feeding method of the ultrasonic method,2,4-difluorobromobenzene was added dropwise to increase the main reaction rate and increase the 2,4-difluorobenzene.The yield of boric acid,and the influence of the reaction conditions were investigated;the optimum condition was 2,4-difluorobromobenzene:magnesium swarf:triisopropyl borate molar ratio with 1.5:3:1,using 20 ml of tetrahydrofuran as a solvent,The reaction temperature was 40 ?;The ultrasonic power was 175 W;The reaction time was 100 min;The dropping time was 30 min and the highest separation yield was 73.01%.The improved ultrasonic method has fewer by-products,high yield,and reaction at a room temperature.The product can be directly applied to the subsequent synthesis of fluorobenzene salicylic acid by reverse extraction and purification.The experiment of ligand-catalyzed palladium-catalyzed synthesis of Diflunisal was studied.By comparing the yield of Diflunisal under conventional and ultrasonic conditions for different palladium catalysts,the catalytic synthesis of fluorine with palladium chloride under ultrasonic conditions was selected.Benzosalicylic acid and the reaction conditions were optimized to obtain the best reaction conditions:2,4-difluorophenyl boronic acid:5-bromosalicylic acid molar ratio of 1.5:1,2 equivalents of potassium carbonate,1 Mol%palladium chloride,24 ml 50%N,N-dimethylformamide,75 ? reaction temperature,175 W ultrasonic power,and 100 min reaction time.The highest separation yield of Diflunisal is 98.37%.This method is insensitive to air,water vapor,etc.It can react in the air and is of great significance for industrialization.The synthesis of Diflunisal catalyzed by ultrasound-assisted in-situ preparation of PEG nano palladium material was studied.Less than 5 nm polyethylene glycol nanopalladium was prepared.The synthesis reaction was optimized and the optimal reaction conditions were obtained.Conditions are as follows:2,4-Difluorophenylboronic acid:molar ratio of 5-bromosalicylic acid with 1.5:1,2 equivalents of potassium carbonate,10 mmol of polyethylene glycol,1.5 mol%of palladium acetylacetonate,16 ml of 50%ethanol,75 ? reaction Temperature?125 W ultrasonic power,100 min reaction time.The reaction is simple and efficient,without complicated preparation or loading process,and has a high yield,which has certain reference significance for the industrial production of Diflunisal.