| Bladder cancer is one of the top ten cancers in global cancer incidence and mortality,which not only seriously threatens human’s body health,increases people’s economical and psychological burden,but also adds the economy bill to the national economy.At present,the main treatment methods of bladder cancer are chemotherapy,immunotherapy and targeted therapy.Among them,chemotherapy is the basic way,and the use of it is earlier than the other two.But immunotherapy and targeted therapy are the hotspot means in recent years and have made great progress in new drug development.Erdafitinib,which is approved by US FDA for market on april 12,2019,is used to cure the fibroblast growth factor receptor(FGFR3/FGFR2)gene variant locally advanced or metastatic bladder cancer,also suitable for patients who have not responded to platinum-containing chemotherapy.Erdafitinib is developed by Janssen Pharmaceutical company,possessing significant meaning because it is the first targeted drug for the treatment of FGFR3/FGFR2 gene variant locally advanced or metastatic bladder cancer.Currently,the research about synthesis of erdafitinib is not complete,all the aspects need to strengthen.Like Gordon research team,they developed a reaction routine to obtain erdafitinib.Using 7-bromoquinoxaline-2-ol as raw material,after substitution,C-N coupling catalyzed by palladium acetate,the erdafitinib was acquired.But the matter is,there are some shortcomings,such as expensive price of catalysts,complex post-processing,and long reaction time.Erdafitinib plays an important role in the treatment of bladder cancer,but the price is so expensive that many people cannot afford it.So it is urgent to develop a routine with lower costs of material,easy operation,friendly post-processing,and higher yield to lower its cost price.This topic regards erdafitinib as the target compound,explores its synthesis ways,and optimizes its synthesis process.The new routine started from 1-methylpyrazole as raw material,after acetylation,bromination,cyclization,C-N coupling,substitution,we got erdafitinib in five steps.After we finished preliminary study,we optimized every reaction step by choosing suitable solvents,temperature,time and raw material molar ratio,finally we got a way with lower costs,easy operation,simple post-processing,and reasonable yield 15.4%.The acquired target compound and all the intermediates are tested by nuclear magnetic resonance spectrometer to determine the structure.Different from existing synthetic routes,our synthetic routine is more economic and easy operation,the more important diference lies in the synthesis of quinoxaline intermediate: the original route is a substitution reaction with palladium acetate as a catalyst,and this topic is based on the ring-forming reaction of o-phenylenediamine and α-bromoketone under the catalysis of triethylenediamine,which a major innovation of this subject.In conclusion,this project has determined an economical and friendly reaction route by researching and optimizing the synthesis process of erdatinib,and the total yield is 15.4%. |
