Study On The Synthesis Technology Of Furosemide And Related Substances

Furosemide is a fast-acting,potent and efficient circulatory drug for the treatment of edema,peripheral edema and cerebral edema caused by cardiac,cerebral and renal disorders,as well as other related diseases.It has been widely used clinically and has a huge market demand since it was introduced to China in 1969.According to previous literature,the synthesis route and process of furosemide has the shortcomings of expensive raw materials,complicated operation,high equipment requirements,low yield and purity,etc.Some steps also use toxic gas,generating a large amount of organic waste liquid and lack of environmental awareness.In large-scale production,the cost is high and the pollution is heavy.Therefore,based on the designed synthesis route of furosemide,process optimization and process scale-up were carried out in this study.In the subsequent work,the main process impurities were studied,analyzed and synthesized,and the structure of furosemide and impurities was confirmed.Firstly,according to relevant literature,2,4-dichlorobenzoic acid was used as the starting material,and 2,4-dichloro-5-(chlorosulphonyl)benzoic acid(Intermediate I)was obtained by chlorosulfonation with chlorosulfonic acid.Then it was subjected to amination reaction with ammonia water to obtain 2,4-dichloro-5-sulfamoylbenzoic acid(Intermediate II).Finally,the preparation of furosemide is carried out by the substitution reaction with furfuryl amine,and a novel purification method was adopted in the post-treatment.After optimizing the key process parameters for each synthesis step,the experiments were scaled up on a small trial basis and three batches of kilogram grades were prepared.The product yield of this process ranged from 35.96 ～36.68% and the purity ranged from 99.965 ～ 99.980%.Secondly,using impurities A ～ F(EP)as reference substance,the impurities in the product obtained by this process were used HPLC to identify.The results show that the small trial sample contains impurity C,impurity D and unknown impurity,while the amplified sample only contains unknown impurity.Then based on the main source process of the impurities,the route design was carried out and the product with high purity was synthesized in high yield.Finally,in this study,the structure of the synthesized furosemide and impurities A ～ F were characterized by HPLC,MS,NMR and thermal analysis,and the structure was confirmed.In summary,the process for the preparation of furosemide in this study avoids the excessive use of raw materials and solvents,has the advantages of simplicity of operation,low cost and environmental friendliness.Process scale-up has also shown its good reproducibility.At the same time,the purification process provided by this study is easy to implement,and the purity of API can be improved obviously under the premise of increasing yield.The research on related substances is also the basis of process quality control and large-scale synthesis of impurities.There are 62 figures,48 tables and 77 references in this thesis.