Synthesis Of Tyrosine Kinase Inhibitors

At present,more and more attention has been attracted to the exploration of antitumor drugs.Traditional anti-tumor drugs usually have the disadvantages such as the highly toxic and side effects and prone to multi-drug resistance.Therefore,one of the current hotspots in the field of global medical research is the development of safe,effective and highly targeted anti-tumor drugs.During the investigation on the application of anti-tumor drugs,the researchers found that the cell signal transduction system in tumor cell proliferation is a new target for the role of anti-tumor drugs.Protein tyrosine kinase is a type of protein with tyrosine kinase activity.It can participate in signal transduction and ensure that the processes including cell proliferation,differentiation,migration,apoptosis,and angiogenesis are in order.Once the abnormal activation of protein kinase results in incorrect signals,it may reduce cell apoptosis,leading to a variety of diseases.Therefore,proteins or kinases that play a key role in cell signal transduction pathways have become targets of new targeted drugs.Such drugs have the characteristics of strong effectiveness,low toxicity and side effects,strong specificity,and good tolerability.Therefore,the development of this type of anti-tumor drugs becomes a hotspot in related field of medicinal chemistry.The purpose of this work is to synthesize a powerful small molecule multi-target kinase inhibitor,（7S,13R）-11-fluoro-7,13-dimethyl-6,7,13,14-tetrahydro-1,15-Ethylene-bridged pyrazolo[4,3-f][1,4,8,10]benzooxatriazacyclotridecyn-4（5H）-one.5-Fluoro-2-hydroxyacetophenone was utilized as the starting material.After several multi-step attempts,it was finally determined to use an ammoniation-resolution-coupling-Mitsunobu coupling-saponification-deprotection-cyclization route for the synthesis.The structure of the target product was characterized by ¹H NMR,¹³C NMR and mass spectra.The improved method effectively shortened the length of the synthetic route.The relatively mild conditions and easy operation would make the method more applicable,Moreover,the diastereoselectivity of the target product was also increased.