Study On The Synthesis Of Dabigatran Etexilate

Dabigatran etexilate is a novel oral anticoagulant drug,which is a prodrug of dabigatran belong to a non-peptide thrombin inhibitor,mainly used for the treatment and prevention of stroke and systemicity in patients with non-valvular atrial fibrillation embolism.Dabigatran etexilate was firstly produced by Boehringer Ingelheim Pharmaceuticals in Germany.In 2008,it went on sale firstly in Germany and the UK.Dabigatran etexilate has many advantages,such as a predictable,stable anticoagulant effect,minimal drug interactions,no drug-food interactions,and no need for routine coagulation testing.This dissertation reviews the current status of thrombotic diseases,the mechanism of thrombosis formation and the latest research progress of anticoagulant drugs.At the same time,the pharmacological effects,adverse reactions and market prospects of dabigatran etexilate were also described,together with the detailed synthetic route of dabigatran etexilate.Based on the related literatures at home and abroad,this dissertation summarizes the advantages and disadvantages of each process route,and improves and optimizes the process.A reasonable route is designed as follows:3-amino-4-（methylamino）benzoic acid is used as a raw material.After cyclization,condensation,and hydrazine,the obtained important intermediate then acylation with n-hexyl chloroformate to obtain dabigatran etexilate.Furthermore,the reaction conditions（such as solvent,reaction temperature,material ratio,etc.）were studied and optimized.In the laboratory test,a yield of 97.0%,a purity of 99.5%of dabigatran etexilate bulk drug was obtained,which met the medicinal quality requirements.In the step-by-step amplification of the laboratory and the pilot process in the workshop,the factors that may affect the industrial production（such as reaction temperature,solvent,etc.）in each step of the reaction process are verified and optimized through multiple experiments,and finally an easy operation is obtained.The synthesis process of dabigatran etexilate with high yield,high purity and low cost provides sufficient experimental data and technical support for the subsequent industrial production.The structures of the obtained intermediates were confirmed by ¹H NMR,¹³C NMR and high resolution.The purity of the final product was determined by HPLC with the purity of 99.9%.