The Synthesis And Process Optimizing Of Dibekacin And Arbekacin

Heretofore, as the third generation aminoglycoside antibiotics respectively, arbekacin is the best aminoglycoside antibiotics because it is better therapeutic effect and lower toxicity. At present, most methods of synthesizing arbekacin have the problem of lower total yield and much too complicated, what’s more the main synthetic process is occupied by Japanese enterprises, as a result arbekacin’s market supplies are inadequate, and the price is expensive. The worst is that most domestic factories discard kanamycin B which is the fermented byproduct of producing kanamycin A, which caused serious waste and environmental pollution. Therefore, we need to find a new way of synthesizing arbekacin, which should has the advantage of high total yield、less complicated and environments friendly.Dibekacin is the most important intermediate in the process of synthesis arbekacin from kanamycin B, also is the most critical place while the most difficult in the entire synthetic route. For the synthesis of dibekacin from kanamycin B, all the issues focus on how to remove the 3’and 4’hydroxyl group of kanamycin B effectively. Generally speaking, there are four ways to realize this process, including Tipson-Cohen method, Corey-Winter method, the formation of olefin with the assistance of transitional metal Ti and the formation of olefin through epoxy structure. Unfortunately, the reactive conditions of the first method always are too severe and the fourth method need rigorous reactive condition too. So in the dissertation, I pay my attention to the second and the third way. At the same time, I summarizes previous studies of synthetic routes of dibekacin, making optimization of some important steps based on laboratory-amplification and the consideration of industrial production. Finally, the total yield of dibekacin is 28%-30%.At last, I use dibekacin as the material to synthesize arbekacin. The method I applied is using HMDS to protect all the hydroxy and amino groups in dibekacin, and then addict side chain selectively to obtain arbekacin. The reaction mechanism has been speculated and verificated. I also make the impurities analysis of arbekacin. Based on the reaction mechanism and impurities analysis, I make some optimization to this method and make this way practical.