Study On The Synthetic Process Of Metoprolol Succinate And The Synthesis Of The Related Substances

Metoprolol succinate is a?-selective adrenoceptor antagonist used for the treatment of hypertension,angina,myocardial infarction and hypertrophic cardiomyopathy.It has become one of the first-line drugs at the present.Metoprolol succinate extended-release tables overcome the pharmacokinetic deficiencies of the regular-relaease formulations.A stable plasma concentration and uniform?-receptor blocking effect could be maintained if get it once a day.And it has a significant effect for sharp rise in morning blood pressure control and reduce cardiovascular events.At the present,all metoprolol succinate in Chinese market were imported from abroad,because there is no legal source of active pharmaceutical ingredient in China.To break the foreign monopoly,it is very important to study on the synthetic process of metoprolol succinate.In this paper,a synthetic route of metoprolol succinate was chosen from all the reported processes,firstly 4-(2-methoxyethyl)phenol is directly reacted with epichlorohydrin to give the corresponding epoxide,sencondly the resulting epoxide is then reacted with isopropylamine to yield metoprolol,finally metoprolol is reacted with succinate to yield metoprolol succinate.After the optimization of reaction conditions,the regular product which purity was higher than 99.5%was obtained and the total yield was up to 60%.After the optimization of the experimental conditions,the better reaction conditions of each step of the synthesis was obtained.The potimum conditions of the preparetion of 2-((4-(2-methoxyethyl)phenoxy)methyl)oxirane were as follows:the molar ratio of 4-(2-methoxyethyl)phenol,epichlorohydrin and NaOH was 1:1.3:1.0,with water as solvent,the reaction temperature was 40?,and the reaction time was 20 h.The potimum conditions of the preparetion of metroprolol were as follows:with methanol as solvent,the reaction temperature was 50?,and the reaction time was 1.5 h.The optimum conditions of the preparetion of metroprolol succinate was as follows:the molar ratio of metroprolol and succinate was 2:1,with alcohol as solvent,the reaction temperature was 95?,and the reaction time was 2 h,then stir for 3 h at room temperature,and cooled to 0-4?for 6 h.The total yield of the process was 60%,the purity of final product was higher than99.5%,and the content of single impurity was less than 0.1%.The synthetic route had the characterisitic of simple operation,mild conditions,high yield,and good purity.And it had significant developing value and feasibility for industrial application.Based on the structures of 13 imprities which were reported in the usp32 and BP,the sources of their generations were analyzed.Then the synthetic routes were designed and tried,finally 6 impurities of them were obtained and the chemical structures were comfirmed by IR,~1H-NMR and MS.During the process preparation of metoprolol succinate,an unreported new impurity(named Dimer)was found and isolated from the final product.The chemical structure of the Dimer was elucidated,and the source of its generation was analyzed.