Study On The Synthesis Of Flurbiprofen

Flurbiprofen is a new kind of non-steroidal anti-inflammatory (NSAID) agentswhich is widely used because it has merits, for example, high efficiency,low toxicity,and low side effects. However, its synthetic routes reported have many deficienciessuch as the raw materials sources of difficulties, the complex process, moreby-products, lower yield, higher cost and large amount of wastes.So it is of greatimportance to developing an economical and effective synthetic process ofFlurbiprofen.In this paper, Flurbiprofen was synthesized by selective bromination,diazotization, coupling reaction, Grignard reaction, coupling reaction, hydrolysisreaction using4-bromo-2-fluoro-aniline as the start material. The result showed thatthe selectivity of the bromination reaction of2-fluoro-aniline with bromine can beimproved by using the inhibitors for polybromination, and when n(2-fluorine aniline)：n(bromine)：n(inhibitor for polybromination)=1：1.065：0.135, reaction temperatureof10℃, reaction time of3hours, the yield and selectivity were up to85%and85.4%respectively, and the yield and selectivity were increased by approximately30%and10%; in the “one pot method” of diazotization and coupling reaction, the cost of acidicreagent was reduced as much as95%by using composite acid instead oftrichloroacetic acid, the optimum reaction conditions are as follows：n(4-bromo-2-fluoro-aniline bromate)：n(sodium nitrite)：n(the acid)：n(cuprous chloride): n(trimethyl-orthoformate)：n(benzene)=1：1.18：1.36：0.059：0.32：14.27, reaction temperaturebeing40℃, and reaction time being16h，the yield was up to65.5%；The optimumreaction conditions for Grignard reaction and coupling reaction are as follows:n (4-bromo-2-fluoro biphenyl)：n (Mg)：n (2-bromo propionate ethyl)=1：1.1：1.1,andunder the above conditions, the yield and the purity were up to55%and more than99.9%.This process has merits with simple technique, mild conditions, lower syntheticcost and the less waste emissions.