Synthesis Of Dovtinib Lactic Acid Salt

With the gradual increase of patients with cancer, various anticancer drugs afteranother, from the previous treatment of electric shock into clinical studies, Dovitinibhas being tested in clinical-Ⅲ studies.Dovitinib is a derivatives of benzimidazole quinolinone，studies have shown thatit had the obvious curative effect on the treatment of advanced liver cancer. There isgreat potential in the treatment of Hepato cellular carcinoma （HCC）, kidney cancer.In this paper，by consulting relevant literature，summarizes the advantagesand disadvantages of synthetic routes of dovitinib lactate. Finally, I have chosen the5-chlorine-2-nitro aniline and N-methyl piperazine reflux reaction, then itcan formation of5-(4-methylpiperazin-1-yl)-2-nitrobenzenamine, Reducing5-(4-methylpiperazin-1-yl)-2-nitrobenzenamine the compound by catalytic hydrogenation, it will obtain the4-(4-methylpiperazin-1-yl)benzene-1,2-diamine,and then with β-ethoxy-β-imino acid ethyl ester hydrochloride was refluxed under acidic conditions, so we can get ethyl2-(5-(4-methylpiperazin-1-yl)-1H-benzo[d]imidazol-2-yl)acetate, and ethyl2-(5-(4-methylpiperazin-1-yl)-1H-benzo[d]imidazol-2-yl)acetate with2-amino-6-Fluorobenzonitrile cyclization was synthesized dovitinib,.At last， dovitinib and lactate on imatinib lactate salt. This method can avoids the shortcomings of which the amino is easy to be oxidation, and simplifies the operation steps.By the optimization of the reaction conditions of every step, we finally choose a5-chloro-2-nitroaniline with N-methylpiperazine in the molar ratio1:3,solvent is not necessary; in ethanol as solvent at75℃with palladium on carbon hydrogenation,2-amino-6-fluobenzonitrile select the preparation temperature of90℃. And finally with lithium diisopropylamide as a base at40℃, we can obtain Dovitinib,the last step use ethanol as a solvent,the yield have beenimproved to some extend. the products can be solved easily. The whole synthetic routes have been accomplished and we had successfully reached the goal.The intermediate for the synthesis of process was analyzed and correlationStructure characterized by the means of melting point, IR, HPLC， NMR. The results show that the products meet the target product,and the performance index andstructure of the synthesized compound correspond with the requirement of target.Itcan be predicted that the route is feasible which is using the5-chloro-2-nitro aniline asinitial material to synthesize dovitinib lactate.