Synthesis And Derivatization Of Key Intermediates Of Biphenylmethylene Piperazine Anticancer Drugs

Apoptosis is an important self-stabilizing mechanism of multicellular organisms,which plays a vital role in the development of normal living organisms and the maintenance of homeostasis.The abnormalities in apoptosis often lead to body lesions including tumors.At present,there are three main apoptotic pathways:mitochondrial pathway,death receptor pathway and endoplasmic reticulum pathway.Among them,the mitochondrial pathway which is also known as intrinsic pathway is the most classic.More than 25 Bcl-2 family proteins have been discovered and these proteins are divided into two subfamilies based on their function,the anti-apoptotic Bcl-2 protein family and the pro-apoptotic Bcl-2 protein family.Family members regulate apoptosis through protein-protein interaction(PPI).Studies have shown that the Bcl-2 protein family is closely related to the process of apoptosis,and it is also an important target for the treatment of tumors.After nearly two decades of efforts,many small-molecule Bcl-2 inhibitors have been discovered,and biphenylmethylene piperazine-based Bcl-2 inhibitors have a significant therapeutic effect on tumors.Venetoclax is the most prominent among the biphenylmethylene piperazine inhibitors of Bcl-2.Venetoclax was approved by the FDA in 2016 for the treatment of 17p-deleted chronic lymphocytic leukemia.Venetoclax is the first small-molecule drug based on protein-protein interaction and has a very high research value.This topic mainly focuses on the synthesis of key intermediates of Venetoclax and related intermediates(1H-pyrrolo[2,3-b]pyridin-5-ol).Through the analysis of the preparation routes reported in the literature,we designed a new synthetic route and made a lot of optimization work to determine the optimal reaction conditions.Compared with the reported method,the new synthesis route simplifies the experimental operation,improves the yield,and reduces the use of certain toxic substances.In this work,benzimidazole-based Bcl-2 inhibitors were designed and synthesized according to the key structures of biphenylmethylene piperazine-based Bcl-2 inhibitors.In this dissertation,15 new compounds,8 intermediates and 7 targets were synthesized.All the compounds were confirmed by 1H NMR and 13C NMR.