Research On The Synthesis Of Tavaborole And Aryl Boronic Acids

Boronic acid are a kind of important organoboron compounds.Since the Suzuki reaction was reported in 1980s,boronic acid compounds have attracted widely attentions.Boronic acid compounds are broadly used in synthetic chemistry,biological sciences and material sciences.For example,boronic acid can be used as building blocks for organic synthesis,small molecular probes for sugars,target screening tools,new material self-assembly blocks.Bortezomib,the first drug with boron atom,was approved by FDA in 2003,therewith the pharmaceutical chemists began to pay close attention to boronic acid compounds.The study of these compounds is no longer limited to target identification,but also used as drug delivery carriers or directly used as therapeutic agents for tumor,viral and bacterial infections.Tavaborole,a broad-spectrum antifungal benzoxaboroles drug approved by the United States FDA in 2014,is used in the treatment of onychomycosis.In the synthetic route of tavaborole reported in the literature,owing to utility of variety of organometallic reagents,great potential safety problems in production emerged.Besides,expensive metal catalysts are still needed in the preparation process.Therefore,it is eagerly needed and highly applicable to develop a green synthetic route of tavaborole for industrial manufacture.In this paper,a new synthesis route was developed by using the method of borylation based on diazonium salts to construct aryl boric acid,which is the key problem in the synthesis of tavaborole.In this route,the 2-amino-5-fluorobenzoic acid was reduced to alcohol,then the alcohol was subsequently reacted with NaNO2 to form diazonium salt.The diazonium salt was used directly for the next step of borylation forming Tavaborole.The new route has short steps,no complicated protection and deprotection operation,and avoids the use of organometallic reagents and transition metal catalysts,but the yield of borylation is low.To solve this problem,we have developed a new visible light induced aryl borylation reaction.As a good substrate,arylazo sulfones with various functional groups are amenable.Significantly,the reaction system is operationally simple without any photocatalyst or additive.In this reaction,arylazo sulfones were used as substrate,B2pin2 as borylating reagent,acetonitrile and water as mixed solvent,and with the irradiation of blue visible light under the condition of nitrogen protection,the arylboronates were obtained at room temperature.In addition,B2(OH)4 can also be used as a borylating reagent to directly obtain aryl boronic acid.We have also proposed a possible reaction mechanism through free radical capture experiments and boron spectrum data.However,this method has not been applied to the synthesis of tavaborole.In this paper,intermediates and target compounds were identified by melting points,1H NMR and 13C NMR.