Research On The Synthetic Route Of Abemaciclib

Cancer is one of the major diseases threatening human life.Studies have demonstrated that cell cycle regulation is closely related to the occurrence and development of cancer.Cell cycle dependent kinase(CDK)inhibitors can selectively inhibit the activity of Cyclin-Cyclin dependent kinase complexes in tumor tissues and further prevent the abnormal proliferation of tumor cells.At present,three CDK inhibitors have been approved by the FDA for the treatment of breast cancer and many of their endpoints in clinical trials have shown satisfactory results.Abemaciclib is a new oral CDK 4/6 inhibitor developed by Eli Lilly.It was approved for marketing in the United States in 2017 and three years later in China.It indicated in combination with Aromatase Inhibitors for the treatment of women with hormone receptor(HR)-positive,human epidermal growth factor receptor 2(HER2)-negative advanced or metastatic breast cancer with disease progression following endocrine therapy.The clinical program of Abemaciclib combined with immunotherapy and endocrine therapy is also under development.Its indications for cervical squamous cell carcinoma,non-small cell lung cancer and other indications are in clinical phase Ⅱ trials.The main work of this thesis is to study and optimize the synthesis route on Abemaciclib.On the basis of a thorough investigation of the literatures,we first analyzed the advantages and disadvantages of the literature reported synthetic route and optimized the process based on synthetic route of Eli Lilly Company.Then we designed and synthesized new route and intermediates according to the retrosynthetic analysis.We also make an exploratory attempt about the N-arylation of aromatic heterocycles in the last step of the route.Compared to the original research route,we first optimized the cyclization reaction with the participation of environmental-friendly solvents,simplified the post-treatment process and increased the yield of this step by nearly 20%.Second,we screened out the optimal combination of the ligand and catalyst of the aryl boronation reaction with the yield of this step increasing by 14%.Meanwhile we also tried an environmental-friendly photocatalytic reaction and increased the yield of this step by 31%.The optimization of last step included the application of Buchwald-Hartwig reaction and the aromatic nucleophilic substitution reaction which laid the foundation for the subsequent exploration of N-arylation of aromatic heterocycles.We designed new synthesis route and intermediates based on retrosynthetic analysis in order to achieve a relatively green and economical route.To the key problem of N-arylation of aromatic heterocycles,the application and optimization of Ullmann reaction in Abemaciclib synthesis were studied based on their mechanism.We designed and synthesized 11 novel ligands and our results showed that oxamides ligands L72 are suitable for carbon-nitrogen coupling of Abemaciclib substrate skeleton.Finally,the yield was equivalent to the original research route.In Summary,we optimized the defecient reactions in the original research route,solved the existing problems in the original research route,and improved the reaction yield,made the material and work-up more green and environmental-friendly.We also designed and synthesized new routes and intermediates,and optimized the route of more green and environmental-friendly.We used three different reaction types to optimize the N-aromatization of heterocyclic in the synthesis of Abemaciclib.Finally,the yield of the reaction was equivalent to that of the original route through the Ullmann coupling reaction catalyzed by copper/oxamide ligands,which shows the potential application for the synthesis of Abemaciclib in industry.