| Overactive bladder(OAB)is a common chronic disease with representative clinical manifestations of frequent urination,urgency,urge incontinenceand nocturia.According to statistics,the incidence rate of OAB is 13% in the world,and it has increasing tendency.Mirabegron is a new drug for the treatment of adults' OAB disease,which is developed by Japan's Anstai Pharmaceutical Company.It was marketed in Japan on September 16,2011 and was approved by the US FDA in June 2012.As the first ?3 adrenergic receptor oral new drugs,mirabegron is favored by doctors and patients due to its significant efficacy and small side effects.At present,the domestic market of mirabegron and its related products mainly rely on imports,while the market for mirabegron's raw materials and intermediates demand is increasing year by year.According to statistics in 2015,the sales of mirabegron have exceeded 680 million US dollars which indicate a very broad market prospects.In this paper,a new synthesis route was designed based on the analysis of the existing synthetic routes.The new route used R-mandelic acid as raw material,which was acylated by mixed anhydride method,amide reduction,catalytic hydrogenation and condenser acylation.And then the whole route was optimized to get the best result.First of all,a mixed anhydride method was used to replace condensation reaction by EDCI and HOBt,which increased the cost and pollution.R-mandelic acid was reacted with pivaloyl chloride to form a mixed anhydride,and the hydroxyl group of mandelic acid was protected at the same time.The mixed anhydride was then reacted with 4-nitro-phenylethylamine amide,and the protection group was hydrolysed producing M-1.It was found that triethylamine hydrochloride could lead to the production of by-products during amidation.In order to remove the triethylamine hydrochloride produced in the first step,water was added to the reaction system.In this process,pivaloyl chloride replaced the costly condensing agent EDCI and HOBt in the original process,which reduced the cost of raw materials and industrial waste in a mild reaction conditionThe yield was increased from 88% to 92%with purity> 99%,ee> 99%.In summary,this route was a green synthetic route which was suitable for industry production.After that,Na BH4-BF3·Et2O system was used to reduce the amide bond,replacing the expensive borane-tetrahydrofuran solution and 1,3-dimethyl imidazolidinone in the original patent.The optimum reaction condition was got after a considerable amount of experiments which reduced the cost.The amide was effectively reduced with the yield of 88%,purity > 99% and ee> 99%.In the third step,the nitro group was reduced to amino group follow the method of catalytic hydrogenation of palladium on carbon in the original process route.Reaction conditions,such as temperature,pressure,time and catalyst specification were optimized.At the same time,the catalyst was recoverd.Finally,M-3 was got with the yield of 92%,product purity > 99%.The final step for the synthesis of mirabegron was the condensation reaction of amino group and carboxylic acid following the original synthesis route,using the selective condensing agent EDCI.The reaction temperature,time,the amount of condensing agent and other conditions were optimized.The yield stabilized at 71%,and the purity was > 99% after recrystallization.In summary,mirabegron was synthesized by the four-step reactions with a total yield of 52.8%.Mirabegron and related intermidiates were confirmed by NMR,MS and HPLC.Mirabegron was produced in this prosess withlow cost,high yield and high quality. |
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