Process Optimization Research Of The Key Intermedia Of Anti-liver Cancer New Drug Tetrazanbigen

Tetrazanbigen?TNBG?is a new non-cytotoxic anti-hepatocarcinoma compound and independently designed by our group.The synthesis is obtained by cyclization of the key intermediate 2,3-dichloroquinoxaline?DCQX?and 1-aminomethyl-1,2,3,4-tetrahydroisoquinoline?ATIQ?.It was found that DCQX reported more synthetic methods,usually with hydrochloric acid as a catalyst,condensation of o-phenylenediamine with oxalic acid or diethyl oxalate,and then using POCl₃ and DMF for two steps of chlorination.However,in the synthesis process,a large amount of strong corrosive reagent such as concentrated hydrochloric acid or phosphorus oxychloride is required,and there are disadvantages such as long synthesis steps and cumbersome operation.Another synthetic method for the synthesis of ATIQ is also reported,but there are also deficiencies in the reaction conditions,the use of toxic reagents such as pyridine,chloroform,etc.,and the disadvantages of industrial scale-up production.Therefore,optimizing the synthesis process of DCQX and ATIQ,seeking high-yield,environmentally friendly,and economical industrial production routes,plays an important role in promoting the preclinical pharmaceutical research work of TNBG and its derivatives.In addition,according to reports in the literature,DCQX and ATIQ intermediates and their derivatives have a wide range of biological activities:such as DCQX has anti-psychotic,antibacterial and anti-tumor effects;ATIQ has anti-tumor,anti-platelet aggregation,analgesia,anti-depression,anti-histamine,choline agonism and antagonism.Therefore,the synthesis of these two types of intermediates has important practical value for other studies.Based on the previous research results of the research group and related literatures,this paper intends to synthesize ATIQ by acylation,alkylation,cyclization,reduction and deuteration with phenethylamine as the starting material,and optimize the process in each step.Simultaneously,using o-phenylenediamine and its derivatives and oxalic acid as starting materials,a new method of synthesizing DCQX and its corresponding derivatives was explored.The research work of this paper is summarized as follows:1.The"one-pot cooking"method was used to improve and optimize the synthesis method of DCQX.Starting from o-phenylenediamine and oxalic acid,a synthetic method for synthesizing 2,3-dihydroxyquinoxaline with green,low-cost silica gel as a catalyst was found.The cyclization and chlorination two-step reaction of the literature was changed to"one-pot boiling"method,and DCQX and its derivatives were obtained in one step,and the synthesis conditions were optimized and amplified.2.Optimize and amplify verification of ATIQ's synthesis process.Removal of toxic reagents such as pyridine,chloroform,etc.;use POCl₃which is favorable for stirring instead of P₂O₅ as a dehydrating agent and add Lewis acid as a catalyst to catalyze the reaction,reducing the amount of POCl₃;and sodium borohydride to replace sodium borohydride to reduce imine,Avoid the production of by-products.Through the above improvements,the total yield of ATIQ has been increased from 26%to 58%in the literature.In summary,this paper uses phenethylamine and o-phenylenediamine as starting materials to optimize the process of two key intermediates of TNGB,and verifies the process in the pilot?100g?scale.The test results show that the new process synthetic route has high yield,low cost and is suitable for scale-up production,which lays a solid foundation for the pre-clinical research of TNBG and its derivatives.