Study On The Process Of Large-scale Production Of Esomeprazole Magnesium And Its Important Intermediates

This thesis mainly focused on the research of the large-scale progress development of esomeprazole magnesium synthesis,used for the treatment of gastroesophageal reflux disease,and the study on the synthesis of important intermediate 2-mercapto-5-methoxy benzimidazole as two major parts.First of all,after comparing the existing processes of esomeprazole magnesium,2-mercapto-5-methoxybenzimidazole and 2-chloromethyl-3,5-dimethyl-4-methoxy Picoline hydrochloride were selected as the starting material,the intermediate Ufiprazole was obtained after the first etherification reaction.And then the chiral oxidation of thioether was conducted to afford esomeprazole sodium,which finally reacted with magnesium chloride to provide esosemethrin as magnesium salt.The overall yield reached more than 45%,with single miscellaneous less than 0.1%and HPLC purity more than 99%.Through the optimization of the reaction conditions for each step and the purification methods development of the final product,one practical process for large-scale production has been obtained,with mild reaction conditions and stable product quality.Secondly,based on the summary to the existing screening process,using Methoxyaniline,one commercial inexpensive compound,as the starting material,underwent amino protection,nitration,hydrolysis,catalytic hydrogenation and condensation of loop reaction,totally 5 step,2-thiol-5-methoxy-lH-benzimidazole ’was obtained finally.In this study,80%hydrazine hydrate was used for catalytic hydrogenation.After the reduction reaction,the 2-mercapto-5-methoxy-lH-benzimidazole was obtained by directly reaction of CS2 and KOH with the reaction liquid of the obtained intermediate,with the yield result more than 70%.Moderate reaction conditions was obtained after optimization of such subject,also with the generation of waste controlled.Optimized work-up treatment process greatly improved the product quality and ensured the overall yield to meet the quality requirement for esomeprazole magnesium production.