Total Synthesis And Structural Modification Of Ibrutinib

With the development of society,people are plagued by all kinds of diseases,especially cancer,and thousands of people are diagnosed with cancer every day.BTK is a member of the Tec family of kinases which are one of the largest kinase families in mammals.BTK is closely related to a series of signaling pathways of survival,activation,proliferation and differentiation of B lymphocytes,When BTK regulates abnormally,it can cause related diseases such as mantle cell lymphoma,acute lymphoblastic leukemia,non-Hodgkin's lymphoma,etc.Since the discovery of BTK in the 1990 s,various BTK inhibitors have been developed.These inhibitors can be divided into two major groups that are reversible and covalently irreversible.One of the most effective inhibitor was ibrutinib,which was approved by FDA in November 2013 to treat patients who infected with a cell lymphoma.The development of a new generation of BTK inhibitors is imperative because of genetic mutations and drug resistance.In view of the many problems existing in the original synthesis route of ibrutinib,we intend to develop a new synthetic route and reconstruction the ibrutinib,hoping to further increase activity and expand indications.In the second chapter,we synthesized ibrutinib with N-Boc-3-aminoperidine and 4-phenoxybenzoic acid.The Boc protecting group is first used to protect the chiral amino group on the N-Boc-3-aminopiperidine,the nitroso was then introduced on-NH with nitrous tetrafluoroborate,and then the nitroso is restored with Zn/glacial acetic acid to form the amino group.(R)-tert-butyl 3-(1-(tert-butoxycarbonyl)hydrazino)piperidine-1-carboxylate was generated,and removal of the double Boc protecting group with trifluoroacetic acid yielded(R)-3-indole Gipperidine.We made 4-phenoxybenzoyl chloride from 4-phenoxybenzoic acid with thionyl chloride,and this acid chloride reacts with malononitrile to give 2-(hydroxy(4-phenoxyphenyl)methylene)malononitrile,reuses trimethyl orthoformate and 2-(Hydroxy(4-phenoxyphenyl)methylene)malononitrile to form 2-(Methoxy(4-Phenoxyphenyl)))methylene)malononitrile,this compound reacts with(R)-3-mercaptopiperidine,and then protects the piperidine ring with Boc to generate the key intermediate(R)-3-(5-amino-4-cyanide)Tert-butyl 3-(4-phenoxyphenyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate.This key intermediate is reacted with formamide to generate(R)-3-(4-amino-3-(4-phenoxyphenyl)-1H –pyrazolo [3,4-d]pyrimidin-1-yl)Piperidine-1-carbaldehyde,which was deoxygenated with NaOH solution,and it was reacted with acryloyl chloride to produce the target compound ibrutinib.The synthetic route we designed is simple,and the reaction conditions are mild,and the chiral introduction during the reaction is ingenious,which makes the synthetic optical purity of ibrutinib high.In the third chapter,in view of the fact that other literature modifys the structure of the phenanthroline and piperidine ring of ibrutinib,although it has a very active compound after modification,it is not a BTK inhibitor,and the core of the inbrutinib route we designed: synthesis of pyrazole rings and pyrimidine rings.Considering comprehensively,we will modify the pyrimidine ring by using the key intermediate(R)-3-(5-amino-4-cyano-3-(4-phenoxyphenyl)-1H-pyrazole-1-Based on the structural modification of tert-butyl piperidine-1-carboxylate.We make cyanoacetic acid into cyanide acetyl chloride,this acid chloride recombines with(R)-3-(5-amino-4-cyano-3-(4-phenoxyphenyl)-1H-pyrazole-1-Based on the reaction of tert-butyl piperidine-1-carboxylate,after connecting with cyanoacetyl chloride,potassium tert-butoxide is used to shut off the six-membered ring,and after the ring is closed,acryloyl chloride and piperidine ring are reacted to produce the target compound(R).1-(1-Acryl-3-yl)-4-amino-6-oxo-3-(4-phenoxyphenyl)-6,7-dihydro-1H-pyrazolo[3,4-B]pyridine 5-carbonitrile,which was identified by nuclear magnetic resonance spectroscopy and high resolution mass spectrometry.