Study On The Process Of Eltromobopag

As a small molecule thrombopoietin receptor agonists,eltromobopag is for the treatment of thrombocytopenia with unique pharmacological effects and broad market prospects,therefore it attracted the attention of many scholars.At present,the synthetic route of eltromobopag is relatively simple,and it has the problems of high production cost,low yield and waste water.Therefore,it is of great theoretical significance and research value to get a green and eco-synthrtic route.This paper has carried on the research to the synthetic of eltromobopag and has completed the following work:The key steps of the route 2 were optimized and improved.Phenol hydroxymethylation,replacing expensive methyl iodide with cheap dimethyl sulfate not only greatly reduced the cost,but also slightly improved the yield;Suzuki coupling reaction process using heterogeneous catalyst palladium carbon instead of(Triphenylphosphine)palladium,its yield increased from 47% to 98.3%,and the catalyst can be recycled after filtration;in the preparation of 3,4-dimethyl phenylhydrazine hydrochloride,the use of sodium bisulfite instead of stannous chloride as a reducing agent,can avoid a large number of acidic wastewater generation and tin recovery;in the preparation of 1-(3,4-dimethylphenyl)-3-methyl-1H-pyrazole-5(4H)-one,the use of methanol instead of sodium acetate and acetic acid,simplified the operation.The overall yield of the improved route increased by 46.4% over the existing route.Although the improved route has a great improvement in cost and environmental protection,there are still some problems.Therefore,this paper designed a new route of eltromobopag,which used 2-Bromo-6-nitrophenol as raw material,followed by phenolic hydroxyl base protection,Suzuki coupling reaction,de-benzyl and nitro reduction of a pot reaction to synthesis 2’-hydroxy-3’-amino benzene-3-carboxylic acid;in the preparation of 1-(3,4-dimethylphenyl)-3-methyl-1H-pyrazole-5(4H)-one,Ullmann coupling reaction reduced the cost and avoided to produce acid waste water.The new route improved the overall yield of the process by 9%,shortening the synthesis steps,simplifying the operation,and completely solving the problem of producing acidic wastewater.This route is in line with the concept of green chemical development.In summary,this paper successfully designed an eltromobopag synthetic route which has the feature of inexpensive raw materials,intermediates and easy purification and more convenient industrial production.Compared with the original process,its simple process conditions,byproducts easily recycling and lower production costs is much more of synthetic significance.