One-step Synthesis Of Fluorophenylsalicylic Acid By Palladium-catalyzed Suzuki-Miyaura Coupling Reaction

Diflunisal（5-（2,4-difluorophenyl）-2-hydroxy-benzoic acid）is a nonsteroidal anti-inflammatory drugs（NSAIDs）with antipyretic,analgesic and anti-inflammatory activities.Compared with the traditional non-steroidal anti-inflammatory drug aspirin,the chemical structure of diflunisal replaces the acetoxy group with difluorophenyl group.And for the characteristics of less anti-platelet side effects and stronger efficacy during the administration,diflunisal has become a good substitute for aspirin.Recently,diflunisal and its derivatives have attracted the attention of researchers due to diverse biological effects,including anti-cancer activities.Due to the lengthy and complicated synthesis method and the harsh reaction conditions,diflunisal has not been widely produced since its discovery.Therefore,the research for efficient and simple synthesis methods has great market potential.In this paper,we developed one-step synthesis of diflunisal via using three different catalytic systems to select an optimal synthetic route.The metal-organic framework of zeolite imidazolyl ester was modified with ethylenediamine as a functional reagent,and then the palladium was supported on the organic framework of ethylenediamine-modified zeolitic imide ester by impregnation method.The ZIF-8,ED-ZIF-8 and Pd/ED-ZIF-8 were characterized by the means of XRD、SEM、TEM、BET、FT-IR、TG and other characterization methods.The reults showed that the palladium was supported on the metal-organic framework successfully,Then the synthesized catalyst was used to synthesize diflunisal.With the molar ratio of5-bromo salicylic acid:2,4-difluorobenzeneboronic acid 1.5:1 as substrates,potassium carbonate as the base,the palladium loading rate of 8.3%,10 hours of reaction time,the reaction temperature of 80°C,and a mixed solution of ethanol and water（volume ratio1:1）,the optimum reaction yield was 78.3%.Fe₃O₄ nanoparticles were prepared by coprecipitation.The nanoparticles magnetic carrier was prepared by miniemulsion polymerization and being modified with a nitrogen heterocyclic carbene ligand.Finally palladium was supported to prepare a nanomagnetic palladium catalyst.The synthesized nano-magnetic palladium catalysts were characterized by XDR,TEM,BET,FT-IR and VSM.The results show that the palladium was supported on the magnetic carrier successfully,and the magnetic response of the catalyst was good.This catalyst was used to synthesize diflunisal and optimize reaction parameters.When 5-bromosalicylic acid:2,4-difluorobenzeneboronic acid in a molar ratio of 1.5:1 was selected as substrates,potassium carbonate as a base,reaction temperature was set to 70℃for 8 hours and the mixture of ethanol and water（volume ratio of 3:1）was as the solvent,the reaction yield of diflunisal was 84.37%.The reuse performance of the catalyst was studied.Under the condition of five cycles of recycling,the yield did not decrease significantly,indicating that the catalyst has good catalyst reusability.Ultrasonic technology was applied to the synthesis of fluorophenylsalicylic acid.Palladium chloride is used as a ligand-free catalyst,and the best process conditions were obtained by optimizing the parameters of reaction system.The highest reaction yield was obtained 98.37%and the purity was 92.61%when the mixture solvent of DMF and pure water（1:1 by volume）was used as a solvent,potassium carbonate as a base,the molar ratio of the reactants 5-bromosalicylic acid and 2,4-difluorobenzeneboronic acid and the base was 1.5:1:2,ultrasonic power was 175 W,reaction temperature was set to 75°C for 100 minutes.