Study On The Synthesis Of A Non-steroid Anti-inflammatory Drug Loxoprofen Sodium

Loxoprofen sodium,as a non steroidal anti-inflammatory drugs,was discovered for the treatment of scapulohumeral periarthritis,arthritis,pain and other symptoms after surgery in clinic,because of the advantages of strong analgesic effect,little gastrointestinal side effect.Now it is one of the widely used medicines in clinic.A lot of literatures have reported the synthesis of loxoprofen sodium as an API.Preparation from condensation of 2-(4-halogenmethyl phenyl)propionate and 2-oxocyclopentane carboxylic ester is the most traditional and frequently reported synthetic method.The purity of loxoprofen sodium prepared by this method is usually lower than 99%.After tedious recrystallization,more than 99% pure product can be obtained.To overcome this problem,this work employs the process control strategy,based on the E.J.Corey retrosynthetic analysis principle,to design and develop two new synthetic routes of loxoprofen sodium.In route one,4-methyl acetophenone was chosen as the starting material,followed by hydrogenation,chlorination,Grignard reaction,free radical reaction,esterification,Sommelet reaction,Prins reaction,hydrogenation andhydrolysis to prepare the target drug with 9 steps and with a total yield of20%.The product was found as pure as 99% or more.In route two,the product was easily furnished from the same starting material 4-methyl acetophenone.Moreover,only 8 steps were need to produce loxoprofen sodium in a total 18% yield and high purity of more than 99%,followed by hydrogenation,chlorination,Grignard reaction,free radical reaction,esterification,Stork reaction and hydrolysis reaction.The both synthetic routes can be complished by utilizing cheap materials and through simple reaction operations,which shows obvious advantages over previous synthetic metheods.The newly developed processes provide a new way for the synthesis of high purity loxoprofen sodium and can be highly expeted to be applided to pharmaceutical industry.