由D-木糖合成克流感及零流感

Abstract

流行性感冒長期以來不斷的危害全球人類與動物及禽類，流感藥物被視為對抗流感大流行的最後一道防線，神經胺酸酶抑制劑克流感(Tamiflu)是近年來非常受歡迎的流感藥物，然而持續突變的流感病毒逐漸出現克流感的抗藥性，因此新一代流感藥物需要繼續的開發。 2007年我們實驗室發表以木醣(D-xylose)為起始物的合成途徑，同時將克流感上的羧酸基換成磷酸基而得到零流感(Tamiphosphor)，其中以胍基衍生物(guanidine derivative)具有更好的抑制效果。然而，在大量化的開發中這套合成方法卻不如預期中的容易，因此本論文著重在改善以D-木醣為起始物的合成途徑。由逆合成分析，我們將合成途徑的中間產物換成一個具有雙保護的胺基化合物，並改變合成順序而成功的得到關鍵中間產物，再利用他們合成克流感與零流感。

Influenza has endangered human for a long time. Anti-influenza drugs are regarded as the last line of defense against influenza pandemics. Tamiflu, one of neuraminidase inhibitors, has been a popular drug for influenza therapy. However, the newly-mutated influenza viruses have strong resistance against Tamiflu. Thus, new drugs are needed for new influenza viruses. Tamiphospor is one of candidates for anti-influenza drugs. In 2007, our group has used D-xylose as a starting material to synthesize Tamiflu, Tamiphosphor (a phosphonate congener), and the guanidine derivative. Both Tamiphosphor and its guanidine derivative are more potent than Tamiflu. However, some problems such as yielding side products were encountered when we tried to synthesize these drugs in a large scale. In this thesis, I focus on how to improve the efficiency of synthesis from D-xylose. By retrosynthetic analysis, I change the sequence of synthesis by using a diprotected amine as the key intermediate, and thus successfully carry out the formal synthesis of both Tamiflu and Tamiphosphor.