Using Cross Dehydrogenation Coupling To Construct Indanones And The Synthesis Of Brexpiprazole

The cross dehydrogenation coupling reaction directly forms the C-C bond through the cleavage of the C?H bond of the two-molecule reaction substrate under oxidizing conditions becoming the basic strategy for the construction of C-C bonds in synthetic organic chemistry.The cross dehydrogenation coupling reaction has the substrate without pre-functionalization,steps and atom economy,good selectivity,environmental friendly,can be directly used for later functional group modification.The first part is using cross-dehydrocoupling reaction to construct indones.Firstly,we summarize the application of coumarin and indanone,the synthetic method and application of indeno[2,1-c]chromene-6,7-dione.Then we reviewe the reaction of carbonyl-direct dehydrogenation coupling.We employ biologically attractive 3-benzoylcoumarins as substrates through C(sp~2)?H dehydrogenation coupling to synthsize indeno[2,1-c]chromene-6,7-diones.A series of experiments are carried out under different conditions to obtain the optimal condition.Twenty five indeno[2,1-c]chromene-6,7-dione compounds are synthesized,the highest yield is 93%,and ten products with halogen atoms can be further derivatized to produce diverse structure compounds.Comparing with traditional methods,this method has the advantages of fewer reaction steps,simple operation,non pre-functionlization and high atomic economy.Brexpiprazole is a new multi-target drug for the treatment of mental disorders.In the second chapter,we use Ullmann coupling instead of Buchwald-Hartwig coupling to complete the improvement of the process route of brexpiprazole.Firstly,we systematically review the synthesis of antidepressant drug brexpiprazole.A better synthetic route is chosen:4-bromobenzothiophene is used as the starting material through Ullmann coupling react with piperazine to synthesize 1-(Benzo[b]thiophen-4-yl)piperazine(80%yield).1-(Benzo[b]thiophen-4-yl)piperazine is condensed with 7-(4-chlorobutoxy)-1H-quinolin-2-one to obtain the brexpiprazole(80%yield).In this route,we replace the traditional Buchwald-Hartwig coupling with Ullmann coupling to synthesize 1-(benzo[B]thiophen-4-yl)piperazine.We also investigate the reaction factors,such as catalysts,ligands,bases,solvents and temperature.The reaction route has the advantages of short route,low cost,high yields,good purity,and the potential for industrial production of brexpiprazole.