The Research Of Rucaparib Synthesis And Salify Process

Rucaparib is researched by Clovis Oncology originally,which is mainly used in treatment of entity cancer as breast cancer,ovarian cancer,pancreatic cancer as polyadenosine diphosphate ribosome polymerase inhibitor(PARP inhibitor).Rucaparib has been approved by FDA on Dec.19,2016 as three line drug using in BRCA variation later period ovarian cancer.Rucaparib has been approved by FDA on Jun.6,2018 using in recurrent epithelial ovarian cancer and falloplan tube cancer which are rearcting completely or partilly to platinum chemotherapy drugs,Also using in primary peritoneal carcinoma mantainence treatment.FDA qualified Rucaparib as the bleakthrough therapy qualitication on signal using to BRCA1/2+mCRPC who has been treated by anti-anddrogen receptor therapy or pacitaxel chemotherapy on Oct.2,2018.According to the related literatures and patents,two synthetic routes can be found which only can be conducted in Laboratory phase.That's too difficult to scale-up to pilot plant.To study the manufacture procedures,the phosphates compound can be synthesized by the synthetic route which is using benzpyrole as start material,including bromination,plus side chain,reductive amination reaction,hydrochloride,alkalization procedures.This synthetic route has some advantages,as the short steps,uncomplicated operation,the high recovery,the low cost,but also has some technical difficulty.The purpose of this thesis is optimization of reaction conditions,shorten the speed limit step of every synthetic reaction step according to synthetic experiments and selecting the best reaction peocess.In this research,the key to solved the control strategy of the impurity A quanity producted,separatation of the impurity A(?0.1%),separatation and depleting the catalyst Pd(?20ppm)in the reductive amination reaction.The yield of the reaction can be more than 90%.Rucaparib is in the form of phosphate and the dosage canbe to use is injection.For improving bioavailability and drug targeting,clients comfortable capability and facilitate drug delivery,this thesis wants to select other kinds salt-types rucaparib which have the same pesticide effect and in the form of oral.By studying the physical and chemical properties of several kinds of salt-forming compounds,camphor sulfonate rucaparib has been synthesized which is easy to salify,quality stability,qualify the standard of medicinal grade oral drug.