Study On The Syntheic Method And Synthetic Process Of Ibrutinib

Ibrutinib(trade name Imbruvica)is the first small molecule drug targeting BTK for mantle cell lymphoma(MCL)developed by Johnson &Johnson and Pharmacyclics.At the end of 2013,it was approved by the Food and Drug Administration of the United States(FDA)for marketing.In addition to mantle cell lymphoma(MCL),it has been approved for use in chronic lymphoblastic leukemia(CLL),17p-deficient chronic lymphoblastic leukemia,Waldenstrom’s macroglobulinemia(WM),small lymphocytic lymphoma(SLL),chronic graft-versus-host disease(c GVHD)and gastric cancer.In 2017,the global sales of Ibrutinib exceeded $3 billion,and it is expected to reach $9.5 billion by 2024.Based on the enormous medicinal and market value of Ibrutinib,it is of great significance to study the synthesis method and process optimization of Ibrutinib.At present,the reported main synthesis processes of Ibrutinib have the characteristics of longer route,more side reactions and lower overall yield.Moreover,some of them also use some dangerous and expensive reagents,which is not conducive to industrial scale-up production.On the basis of the original synthetic route,the reaction steps were reduced through continuous reaction.The process optimization of each step was studied carefully and systematically,then the optimum conditions of each step were determined.The optimized process significantly reduced the side reactions and greatly improved the yield of the reactions.The recrystallization method of the intermediate and crude Ibrutinib was developed by the author.It solves the quality problems of intermediate and finished products very well.The synthesis of Ibrutinib using 3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine as starting materials,through Mitsunobu reaction,deprotection and amidation reaction.The overall yield was70% and the purity was 99.8%.Mitsunobu reaction and deprotection two-step reaction were prepared by "one-pot method" to reduce the waste liquor after treatment and obtain higher yield.Crude Ibrutinib obtained by amidation reaction could be recrystallized to obtain target compounds with high purity and yield.In the process of synthesizing Ibrutinib,the process of each step was optimized and the structure of the target compound was confirmed comprehensively.The method can obtain high purity target product by increasing intermediate and crude product crystallization through continuous reaction.The improved process simplifies the post-treatment operation and greatly improves the yield.At the same time,it reduces the production cost,and is more green environmental friendly and is suitable for industrial production.