Studies On The Synthesis Of Aminomethylbenzoic Acid And Valganciclovir Hydrochloride

This paper is divided into two parts.The first part is the study on the synthesis process of aminomethylbenzoic acid,an important intermediate of antifibrinolytic drugs;the second part is the study on the synthesis process of the key intermediate of valganciclovir hydrochloride,an anti cytomegalovirus drug.Aminomethylbenzoic acid is a commonly used hemostatic drug in the clinic.It has the advantages of a remarkable hemostatic effect and slight side effects.At the same time,aminobenzoic acid is also the key intermediate for the preparation of clotting acid,and the market demand is huge.In this paper,based on the published synthetic route of aminomethylbenzoic acid,a simple,mild,economic and environmental protection synthetic route of aminomethylbenzoic acid with p-chloromethylbenzoic acid as the starting material has been determined through comprehensive analysis,and the important intermediate(?)for the synthesis of aminomethylbenzoic acid has been prepared.The intermediate was characterized by Nuclear Magnetic Resonance Spectroscopy.In this study,the preparation of the key intermediate(?)was realized by the traditional method concentrated sulfuric acid catalysis and the phosphoric acid catalysis newly developed in our laboratory,and the two reaction conditions were systematically optimized,and the step-by-step amplification process was further studied.Through comprehensive comparison,the newly developed p-chloromethylbenzoic acid esterification method based on medium strong acid phosphoric acid catalysis developed by our research group has the following advantages: 1)mild reaction conditions and easy operation by personnel;2)economic and environmental protection of reagents and raw materials used;3)low corrosiveness to equipment and workshop,low requirements;4)easy post-treatment,no toxic waste;5)high yield,good purity,etc Many advantages.This method is obviously superior to the traditional concentrated sulfuric acid esterification method.In this study,not only a new and better esterification method of p-chloromethylbenzoic acid was found,which provided a new process for the synthesis of aminomethylbenzoic acid,but also a new method for the earlier esterification reaction with more research,which provided a useful reference for the synthesis and preparation of more important esters.Valganciclovir Hydrochloride was first introduced by Roche company in Switzerland.It is the L-valine ester prodrug of ganciclovir.It is mainly used in the treatment of cytomegalovirus retinitis in AIDS patients,and it is also used in the treatment of cytomegalovirus infection in patients after a single organ or multiple organ transplantation.In this paper,by analyzing and summarizing the existing synthesis routes,a reaction route for the synthesis of valganciclovir hydrochloride from ganciclovir was determined.In this study,the synthesis process of the important intermediate(?)was explored,and the structure of the intermediate was determined by Nuclear Magnetic Resonance Spectroscopy.At the same time,the reaction conditions of acetylation synthesis were optimized systematically,and the pilot scale-up of the intermediate process was studied.This study provides a useful reference for the subsequent synthesis and industrial scale-up of Valganciclovir Hydrochloride.