Application Of Electroreduction In The Preparation Of Drug Intermediates

Mental illness is a common disease with an increasing incidence.The treatment of mental illness has become a hot topic of contemporary research,and the research and optimization of process of antipsychotic drugs is the top priority.Among them,aromatic amino compounds have a wide range of applications in the fields of medicinal chemistry,organic chemistry,materials,etc.,and are also key drug intermediates in process research of antipsychotic drugs.Aromatic amino compounds are often reduced from aromatic nitro compounds.In this paper,a more environmentally friendly and efficient electrochemical reduction method is selected to reduce aromatic nitro compounds compared to traditional chemical synthesis,which has good application prospects and application value.This article studies the three-step synthesis of important aromatic amino drug intermediates and their analogues of four antipsychotic drugs Aripiprazole and Brexpiprazole,including etherification,N-alkylation,and electroreduction reaction.In this paper,Cyclic voltammetry(CV)and Constant Potential Electrolysis(CPE)are used to optimize the electro-reduction steps of important aromatic nitro drug intermediates and their analogs of Aripiprazole and Brexpiprazole.The optimized process is as follows:(1)Using 3-nitrophenol as substrate,N,N-dimethylformamide as solvent,potassium carbonate as acid binding agent,etherification reaction with three alkylating agents at room temperature,etherification yield 86.7%～93.6%.(2)Using 1-(2,3-dichlorophenyl)piperazine hydrochloride,1-(benzo[b]thienyl)piperazine hydrochlorideassubstrates,1-(3-bromopropoxy)-3-nitrobenzene,1-(4-bromobutoxy)-3-nitrobenzene are alkylating agents,tetrahydrofuran is used as solvent,sodium hydroxide is used as acid binding agent,N-alkylation occurs under reflux In the reaction,the yield of N-alkylation is 81.3%～85.2%.(3)The cathode compartment electrolyte is 0.5 mol/L sulfuric acid,the cathode is red copper,and the working area is 2 cm~2;the anode compartment electrolyte is 0.25 mol/L sulfuric acid,the anode is platinum mesh,and the working area is 2 cm~2.With a substrate concentration of 0.016 mol/L and a constant potential of-2.0 V in a 40℃constant temperature water bath,four amino compounds were synthesized with a yield of93.3%-97.4%.