The Synthesis And Processing Optimization Of Dibekacin And Arbekacin

Aminoglycoside antibiotics are consisted of aminosugars and aminocyclitols which are connected by oxygen bridge bonds. In a host of aminoglycoside antibiotics, arbekacin shows better antibacterial activity, lowwer resistance, and fewer side effects. In more than 20 years of clinical practice, it has been praised by many patients with severe infection. Kanamycin B is a raw material for the production of dibekacin, and arbekacin was synthesized from dibekacin. However, in the fermentation process of kanamycin A, which is a raw material for the production of amikacin, there will be generating a large number of kanamycin B. The cheap kanamycin B is mostly used for veterinary antibiotics in China, while in foreign countries, especially in Japan, pharmaceutical enterprises transform the kanamycin B to very expensive arbekacin, and they monopolize the synthesis process of arbekacin, which causes the market of arbekacin out of stock. In order to benefit many patients, it's very essential to design synthetic routes of dibekacin and arbekacin, which show more advantages, such as short, environmentally friendly and high yield. Also we must try our best to realiz the industrialized production of arbekacin.The synthesis of arbekacin has two major difficulties:(1) how to selectively remove the 3'-OH and 4'-OH on the ring I with the rest four hydroxyls unchanged; (2) how to selectively add only one AHB at 1-NH2 on the ring ? with the remaining four aminos unchanged. The synthesis methods of epoxy structure principle and Corey-Winter principle show difficult process control, many by-products, harmful to the environment and low yield, so those two synthesis methods are abandoned, eventually we choose the Tipson-Cohen principle to synthesize arbekacin. Firstly, we use 1, 1-dimethoxy cyclohexane to protect 4'-OH and 6'-OH on ring ?, and then use benzylsulfonyl chloride to protect amino and hydroxyl groups, including 3'-OH and 4'-OH on ring ?. Under the condition of zinc powder and sodium iodide, it can transform 3'-OBs and 4'-OBs into double bond on ring ?. After that, we use acetic acid to remove 4" and 6" hydroxyl protection groups on ring ?. Then we utilize liquid ammonia and sodium metal to deprive benzyl sulfonyl, and finally reduce to obtain dibekacin. By inquiring references of the synthesis process of amikacin, we use hexamethyldisilazane protect amino and hydroxyl groups, then under certain conditions utilize the active ester to replace the protection group at ?-NH2 selectively, finally remove the remaining protection groups. After processing optimization, the total yield from kanamycin B to arbekacin can stably reach to about 14%, and the whole route process shows easier to control, more simple operation, less environmental pollution. Furthermore, magnification tests show high yield, feasibility and security, which lays good foundation for the industrialization process of arbekacin.