The Synthesis And Preliminary Crystal Form Research Of The New Oral Anticoagulant Dabigatran Etexilate Mesylate

With the change of people's life style.cardiovascular and cerebrovascular diseases have become the highest incidence of diseases in our country and the world.and present the trend of getting younger.Currently,people died from cardiovascular and cerebrovascular diseases account for 51%of the total annual mortality rate in China each year.Thus,the cardiovascular and cerebrovascular diseases have become the number one killer.The occurrence of cardiovascular and cerebrovascular diseases is often related to the formation of thrombosis in the blood vessels.At present,the traditional anticoagulants used clinically often have many disadvantages including slow onset,poor specificity.high risk of bleeding,the clinical monitoring and others Therefore,there is an urgent need to develop new oral anticoagulants to overcome the above mentioned shortcomingsDabigatran etexilate mesylate(Pradaxa).ethyl 3-{2-{{4-{N-[(hexyloxy)carbonyl?carbaminmidoyl}phenyl} amino}methyl}-1-methyl-N-(pyridine-2-yl)-1H-benzo[d]imi dazole-5-carboxamido} developed by I3oehringer Ingelheim is the first oral direct anticoagulant drug since 50 years after warfarin and its trade name is Pradaxa.It not only has a series of virtues such as effective,predictable and consistent anticoagulant effect and good stroke prevention but also has the advantages of lower bleeding risk.no need for routine monitoring and others when compared with the traditional anticoagulants.Dabigatran etexilate was first put on the market in Germany and the UK in April 2008.And then,this drug was approved by the FDA of the United States on October 19th,2010 for preventing the formation of blood clots in the veins in the patients who had compelted total hip or total knee joint arthroplasty and stroke and systemic coagulation in the patients with nonvalvular atrial fibrillation.At present,dabigatran etexilate has been approved in more than 80 countries around the world,which accounts for 11%of the entire anticoagulation market share of sales and ranking third in the top.Thus,dabigatran etexilate has an enormous prospect in the field of anticoagulant therapy.In view of this,the study on its synthetic method has a great significance.On the basis of accessing numerous relevant literatures,four reported synthetic routes were summarized.Through analyzing and comparing their reaction conditions.yields,isolation and purity methods,we confirmed the following synthetic route:Dabigatran was generated using the commercialized and inexpensive intermediate 1.3-[(3-amino-4-methylaminobenzoyl)(pyridin-2-yl)amino]propanoate as the starting materia]via through closed loop reaction after amidation.Pinner reaction and nucleophilic substitution.Finally,dabigatran etexilate mesylate was prepared by reaction of dabigatran with methanesulfonic acid.Firstly,reaction conditions of the small-scale synthetic route was investigated.In the synthesis of intermediate 3,the reaction factors including reaction solvent.reaction temperature.the reaction molar ratio and post-processing were optimized so that the operation procedure was simplified and the yield was significantly improved.In the Pinner reaction.the reaction factors including reaction solvent,reaction time and post-processing were optimized,which greatly reduced the solvent consumption.lowered the cost and reduced the emission of irritant gases.In the nucleophilic substitution with hexyl chloroformate to generate dabigatran etexilate,the reaction factors including reaction solvent,the choice of alkali.the reaction molar ratio and the reaction temperature were optimized so that the formation of impurity was greatly reduced.In addition-in the process of the post-processingc we found optimal recrystallization conditions,which made the purity of dabigatran etexilate meet the requirement of quality standards.In the synthesis of dabigatran etexilate mesylate,we optimized the reaction solvents so that the recovery yield of the product was remarkably improved.Secondly,in the study of the process amplification at 20g-and 50g-scales respectively,the reaction conditions,yields and purity of intermidiates and target product were explored and optimized.so that a stable 50g-scale route of the amplification process was achieved,which provided reliable datas for the following pilot-scale.Finally,in research on the crystal form of dabigatran etexilate mesylate,we applyed contrast phrase microscope,TGA-DSC and XRPD to explore the crystallization process and transformation process of crystal form.On this basis,we prepared medicinal crystal form of dabigatran etexilate mesylate which was consistent with the crystal form made by the original company.We established a new route of the process amplification suitable for the spilot-scale,the characteristics of which were warm reaction conditions.simple operations,high yields and low costs.The total yield of this route was improved to 54.43%from 7.80%reported in literatures and the purity of product prepared by this route was over 99.77%.