The Research On The Synthesis Process Of Apatinib

This paper briefly introduces the research overview of protein tyrosine kinase（PTKs）,as well as the development of vascular endothelial growth factor receptor-2（VEGFR-2）inhibitors,and elaborates on the mechanism of action,pharmacokinetics,clinical evaluation and safety of apatinib,a VEGFR-2 inhibitor,focusing on the synthetic process of apatinib.Apatinib,a small molecule tyrosine kinase inhibitor,is the world’s first anti-angiogenic targeted drug for the treatment of terminal gastric cancer,as well as currently the only oral agent targeted to terminal gastric cancer.Clinical studies have shown that the drug is relatively safe and adverse reactions are controllable.Researchers have also found that the drug has a good therapeutic effect in breast cancer and other cancers.In this paper,the synthetic routes of apatinib reported in the literature are introduced in detail.Based on the summary and analysis of these methods,a novel synthetic route which is relatively simple and highly efficient and suitable for industrial scale has been designed and established.With p-nitrophenylacetonitrile as a starting material,apatinib was obtained via four steps including di-alkylation,reduction,acylation and re-alkylation.The total yield was increased from 38%to 69.5%（calculated as p-nitrophenylacetonitrile）.Highlight of the process was an optimization of route for preparing key intermediate 4 by the di-alkylation from p-nitrophenylacetonitrile into five-membered ring with potassium tert-butoxide.The reaction conditions of each step were optimized and a route with convenient operation,mild conditions and cheap raw materials was obtained..Through the separation and purification of important intermediates and final product,the obtained important intermediates and target product have been confirmed by m.p.,MS,¹H-NMR and ¹³C-NMR.