Synthesis Of Novel Vascular Endothelial Growth Factor Receptor-2Tyrosine Kinase Inhibitor

Angiogenesis refers to the process of sprouting from existing blood vessels to generate new blood vessels. Tumor growth, invasion and metastasis depend on angiogenesis. Inhibition of tumor-mediated angiogenesis, blocking cancer cell nutrient pathway, can inhibit cancer cell proliferation.Vascular endothelial growth factor (VEGF), as a vascular endothelial cell-specific heparin-binding growth factor, is a critical angiogenic growth factors in tumor angiogenesis, and it can induce new vascular formation in vivo. Has now been accepted, VEGF plays an important role in endothelial cell differentiation and proliferation, mediated by vascular endothelial growth factor receptor-2(VEGFR-2). Therefore, in the development of anticancer drugs, the tyrosine kinase against VEGFR-2is a key target of drugs, VEGFR-2tyrosine kinase inhibitor has become an important direction for anticancer drugs.The purpose of this study was to synthesize a variety of new indole-benzimidazole derivatives, to obtain a compound with a certain activity and independent intellectual property rights by screening for further activity study. Achievements of this research were as follows:1The new structure, no reports of novel VEGFR-2tyrosine kinase inhibitor had been designed for retrosynthetic analysis. Considering of the reaction feasibility, route complexity and operational safety, etc., designed reasonable synthetic route for every compound.2According to the designed synthetic route, Every compound had been synthesized. By different reaction routes, indole-3-carboxylic acid, indole-3-acetic acid, indole-3-propionic acid, indolin-2-one-3-propionic acid,2-methyl-indole-3-acetic acid and5-methoxy-2-methyl-indole-3-acetic acid were synthesized.3These synthesized indole acids reacted with o-phenylenediamine,4-methyl-o-phenylenediamine and3,4-diamino-benzoic acid ethyl ester respectively, by dehydration cyclization reaction in polyphosphoric acid catalyzed, to produce9kinds of desired indol-benzimidazole derivatives.4(R)-3-quinuclidinyl acetate was respectively synthesized by transesterification with (R)-3-quinuclidinol and ethyl acetate, and by acetic anhydride method with (R)-3-quinuclidinol and acetic anhydride. Compare the two reactions, acetic anhydride method is easier and higher yield.