Synthetic Process Development Of Tratinib, A Targeted Drug For Gastric Cancer

Telatinib is a potent inhibitor of VEGFR and PDGFR kinase,which acts on vascular endothelial growth factor(VEGF)and its receptors VEGFR-2 and VEGFR-3.It also acts on human platelet-derived growth factor(PDGF)and its receptor PDGFR-?.Telatinib inhibits tumor growth and induces apoptosis in cancer cells.Telatinib is in the phase II clinical development stage internationally and is used as a targeted anticancer drug in combination with capecitabine and cisplatin for chemotherapy of advanced untreated gastric cancer.So far,Telatinib has accumulated in more than 300 patients and conducted a total of seven Phase I,Phase lb and Phase II clinical studies.Telatinib is a highly selective VEGF inhibitor that is under development and can be used to achieve long-term inhibition of the intended target.In this thesis,we mainly studied the experimental synthetic route of Telatinib.We found out the optimal reaction conditions,developed thedetection methods of intermediates,and scaled up the whole synthetic route gradually in the gram-level to the kilogram-level.We continued to optimize the reaction parameters for each step and post-processing.Finally,the obtained final product Telatinib was structurally characterized.In this thesis,we designed a more reasonable process route by consulting relevant literature and reports,using pyridine-2,4-dicarboxylic acid,furan-2,3-dicarboxylic acid and 4-chloroaniline hydrochloride as starting materials.The Telatinib product is obtained by a nine-step reaction such as esterification reaction,amidation reaction,hydrazine reaction,chlorination reaction,nucleophilic substitution reaction,ester reduction reaction and salt formation reaction.Every step of the various factors was investigated and re-studied,including the equivalence ratio of reactants,the choice of solvent,reaction temperature,reaction time,refining system etc.Finally,a synthetic routewas developed with a simple operation,easy to control parameters,mild condition.After product optimization,the final purity of small batch can reach to 99.5%.In order to achieve the continuous process,we synthesized compound 3,compound 4,compound 5 and compound 7in a continuous process,and control the intermediates of compound 7.The synthesis of compound 9 and compound 10 is also a continuous process,and the intermediate detection control of compound 10 is carried out.The synthesis of compound 11 is the third process,and the intermediate is also inspected.The synthesis of compound 12is the fourth process,and the intermediate is also inspected.The synthesis of Telatinib isthe final step.In the scaled trial production,the parameters of process steps were optimized,and the pharmaceutical intermediate standards were reasonably developed and effectively controlled.Through the accumulation of experimental data during the gram-level to the kilogram-level enlargement experiment,a synthetic route of Telatinib is obtained,which is safe,environmentally friendly,easy to operate,easy to control parameters,and high in product purity.The quality of Telatinib crude product refined by isopropyl alcohol meets the medicinal standards.The purity of the refined product was 99.5%,and the unknown single impurity was below 0.1%.The intermediate product andTelatinib were confirmed by infrared,ultraviolet,high-resolution mass spectrometry,nuclear magnetic resonance spectroscopy and carbon spectroscopy,matched with the reported data.