口奎諾酮抗菌劑之合成研究.docVIP

口奎 諾酮抗菌劑之合成研究 The Synthesis of Quinolones Antimicrobics 許清雲 Ching-Yun Hsu 正修技術學院化學工程系 Department of Chemical Engineering Cheng-Shiu Institute of Technology 摘 要 本文主要探討 口奎 諾酮 系列抗菌劑的合成研究，由於口奎 諾酮架構中氮原子上的取代基團差異會直接影響抗菌劑活性大小，因此需視抗菌劑結構，於反應過程中各階段適時引入，而建立口奎 諾酮雙六圓環架構時，通常須在高溫下進行環化反應，因此環化反應之前驅物苯胺衍生物的穩定性好壞，常常是合成途徑選擇的主要關鍵，之前本實驗室利用一系列氮-乙基苯胺衍生物和乙氧亞甲基丙二酸二乙酯 (EEMM) 進行Michael加成反應和環化反應，以簡短操作步驟完成口奎 諾酮雙六圓環基礎架構，而且也相繼完成了Flumequine、Oxolinic acid及Nalidixic acid等口奎 諾酮抗菌劑的合成，但是當以氮-環丙基苯胺衍生物系列和EEMM進行反應時，由於環丙基本身穩定性無法承受高溫環化反應，所以無法順利完成口奎 諾酮雙六圓環架構，因此須利用其他合成途徑來建立口奎 諾酮架構部分，此部份抗菌劑如Ciprofloxasin、Enrofloxacin等含氟原子抗菌劑，目前正研究開發中。 關鍵詞： 口奎 諾酮 ，抗菌劑，環化反應，Michael加成反應 ABSTRACT This study focuses on the synthesis of a quinolone series of antimicrobics. The substituted groups on the nitrogen atom of the quinolone skeleton directly affect the antimicrobic activity of quinolones. Therefore, proper introduction of substituted groups during various reaction steps depends on the structure of antimicrobics. On the construction of the bicyclic six-membered ring framework of quinolones, the cyclization is usually proceeded under high temperature. Thus the stability of the precursor for cyclization, aniline derivatives, is usually the key for the choice of synthetic pathway. Previously our laboratory had used a series of N-ethylaniline derivatives and diethyl ethoxy methylene manolate (EEMM) undergoing Michael addition and cyclization to shorten the steps for the construction of the bicyclic six-membered ring framework of quinolones. Moreover we hence had completed the synthesis of quinolone antimicrobics such as flumequine, oxolinic acid and nalidixic acid. However, for the reaction of N-cyclopropyl aniline derivatives and EEMM, the stability of N-cyclopropyl aniline derivatives could not stand the high temperature condition of cyclization. As a result the bicyclic six-membered ring framework of quinolones could not be constructed in this way. Other synthetic pathway is thus needed to build the framework of q