Syntheses Of Sorafenib And Regorafenib Synthesis Of Analogue Of Sorafenib For Positron Emission Tomography (PET)

Sorafenib and Regorafenib which were developed by Bayer and Onyx are twomulti-kinase inhibitors used as anticancer drugs. Sorafenib is mainly used for thetreatment of advanced renal cell carcinoma and unresectable hepatocellular carcinoma.Regorafenib is mainly used for the treatment of metastatic colorectal cancer andadvanced gastrointestinal stromal tumors. The purpose of our research was to find akind of low cost, simple operation and high yield synthetic method which is suitablefor industrialized production of Sorafenib and Regorafenib. From the similarstructures and the synthetic routes reported of sorafenib and regorafenib, we can usethe similar synthetic methods to prepare them. In our research, we used two syntheticroutes to prepare Sorafenib and Regorafenib, studied and determined the most sutiableconditions of every reaction of the two methods in detail, ultimately confirmed themost suitable synthetic methods to prepare them. The confirmed synthetic processwas:2-picolinic acid went through chlorination, alcoholysis, amidation, nucleophilicsubstitution to obtain the key intermediate，which was subjected to condensation with4-chloro-3-(trifluoromethy1)phenylisocyanate to prepare Sorafenib or Regorafenib．Positron emission tomography is a kind of non-invasive imaging technique usedfor the detection of radioactive material distribution present in organisms, which hasbeen widely used in the diagnosis and therapeutic monition of tumor, cardiovasculardisease and brain diseases in recent years. The main content of this paper was todesign the18F-labaled analogue of Sorafenib for PET to diagnose and prevent tumor.Our research work is to synthesize precursor17and standard compound27of thetarget compounds (16). The Synthetic method was:2-picolinic acid went throughchlorination, amidation and nucleophilic substitution to obtain the key intermediate19,which was subjected to condensation with4-chloro-3-(trifluoromethy1) phenyliso-cyanate to prepare the compound23．Finally, compound23either reacted with1,2-di(p-toluene-sulfonyloxy)ethane (24) to get the precursor17or with1-(4-methyl-phenylsulfonyloxy)-2-fluoroethane (29) to get the standard compound27.