Process Development For The Synthesis Of Osimertinib

Osimertinib is a third-generation small molecule epidermal growth factor tyrosine kinase inhibitor for the treatment of non-small cell lung cancer.It has the advantages of high selectivity,low drug resistance,long lasting effect,and high safety.The synthesis process of Osimertinib has some problems,such as long steps,low yield,and poor atomic economy.Therefore,it is important to develop a process route with high yield,good atomic economy and safety.In this study,Osimertinib was synthesized from 2,4-difluoro-nitrobenzene through nucleophilic substitution,nitro reduction,nitrification,methylation,Friedel-Crafts alkylation,amidation and other reactions.The key steps in this route were further studied and optimized.In the nucleophilic substitution reaction,solvents of different polarity were used for the reaction,and it was found that the use of non-polar solvents would enhance the stability of the intermediate Meisenheimer complex,so that 4-fluoro-2-nitroanisole could be obtained with higher selectivity.By changing the feeding mode of the reaction to control the concentration of substrate and nucleophile,the disubstituted by-products were reduced.The reaction was carried out with sodium methanol,which reduced the cost and increased the yield to 98%.In the synthesis of 4-fluoro-2-methoxy-5-nitroaniline,the nitrification system with concentrated sulfuric acid as the solvent and potassium nitrate as the nitrification reagent was determined to solve the problems of low nitrification yield.The optimal reaction temperature was 0℃.By a simple method of adjusting the PH,a high purity product was obtained in a yield of 91%,an increase of nearly 14% compared to the 77% reported in the literature.In Fourier reaction,anhydrous aluminum trichloride was used as catalyst to improve the reaction yield.Selecting the appropriate amount of catalyst can reduce the formation of by-products.By choosing the appropriate reaction temperature,the reaction yield was increased from 81% to 91%.In the nitro reduction reaction,the hydrogenation reduction system using Raney nickel as catalyst makes the route greener and the yield higher.In the nucleophilic substitution reaction,the p-toluene sulfonic acid enhances atomic economy and reduces production cost.In the last two steps of the route,a "onepot" method was used to synthesize Osimertinib,which reduced the reaction steps and the production cost.The overall yield of the route is nearly 10% higher than that reported in the literature.In this paper,we design and optimize the synthesis process of Osimertinib.With its high yield,high atomic economy,low production cost,simple process,easy purification,green process,and safety,this method is of great application value and practical importance.