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研究生:林瀚淵
研究生(外文):Han-Yuan Lin
論文名稱:微水有機溶劑中利用脂肪分解酵素進行外消旋naproxen三氟乙酯之水解動態動力分割
論文名稱(外文):Lipase-catalyzed dynamic kinetic resolution of (R,S)-naproxen ester in isooctane
指導教授:蔡少偉蔡少偉引用關係
指導教授(外文):Shau-Wei Tsai
學位類別:碩士
校院名稱:國立成功大學
系所名稱:化學工程學系碩博士班
學門:工程學門
學類:化學工程學類
論文種類:學術論文
論文出版年:2002
畢業學年度:90
語文別:中文
論文頁數:67
中文關鍵詞:脂肪分解酵素水解動態動力分割
外文關鍵詞:lipasehydrolysisdynamic kinetic resolutionnaproxen
相關次數:
  • 被引用被引用:1
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  • 下載下載:15
  • 收藏至我的研究室書目清單書目收藏:0
過去研究指出利用Lipase MY進行naproxen三氟乙酯之水解動力分割可獲得相當優異的選擇性及反應性;此外,利用Lipase MY配合三辛基胺為鹼消旋觸媒,進行naproxen三氟乙硫酯之動態動力分割亦有相當好的成效。本論文將探討以外消旋naproxen三氟乙酯為反應物之動態動力分割製程,首先尋找可使之消旋之強鹼觸媒,以便配合Lipase MY進行水解動態動力分割。
本論文中尋得數種可將naproxen三氟乙酯消旋的有機鹼觸媒,且獲得消旋常數與鹼觸媒濃度具有線性關係。此外並發現當鹼觸媒消旋能力愈強,伴隨的無選擇性鹼催化水解亦愈嚴重。由於發現可溶性鹼觸媒會使酵素失活,因此改用固定化鹼觸媒配合Lipase MY進行水解動態動力分割,結果可成功克服傳統動力分割目標產物最高50 %轉化率之限制。最後,以Michaelis-Menten酵素反應機構配合一階消旋反應及酵素失活、酵素抑制作用之動態動力分割模式,可成功獲得與實驗值相當一致的理論結果。
Lipase MY has been successfully employed as the biocatalyst with excellent enantioselectivity and activity in the kinetic resolution of racemic naproxen trifluoroethyl ester via hydrolysis. Besides, a dynamic kinetic resolution process for the lipase-catalyzed hydrolysis of racemic naproxen trifluoroethyl thioester has also been developed by using Lipase MY and trioctylamine as the biocatalyst and racemization catalyst, respectively. Therefore, the purpose of this research is aimed to develop a dynamic kinetic resolution process with (R,S)-naproxen trifluoroethyl ester as the substrate. Stronger organic bases were firstly screened to effectively racemize the substrate. A linear relationship between the interconversion constant and the base concentration was found. However, the stronger was the base in racemization, the higher of hydrolysis of the base was observed. Since the base might deactivate the enzyme, a polymer-supported base was replaced as the racemization catalyst in the dynamic kinetic resolution process. The maximum 50% yield of the desired optical product in the standard kinetic resolution process was overcome. Agreements between the experimental data and theoretical results were found in which an enzymatic Michaelis-Menten kinetics, lipase deactivation and inhibition and a first-order reversible racemization kinetics were employed in the theoretical modelling.
第一章 緒論
1-1 酵素 1
1-2 脂肪酵素 2
1-3 酵素於有機溶劑之行為 5
1-4 對掌性藥物 9
1-5 Naproxen 11
1-6 動態動力分割 14
1-7 研究動機 16

第二章 原理
2-1 鹼觸媒消旋 17
2-2 酵素催化水解動力分割 20
2-3 酵素催化水解動態動力分割 22

第三章 實驗方法
3-1 藥品與材料 24
3-2 實驗設備 25
3-3 分析方法 26
3-4 實驗步驟 28
3-4-1 合成naproxen三氟乙酯 28
3-4-2 酵素固定化 29
3-4-3 鹼觸媒消旋反應 29
3-4-4 不同基質濃度之水解反應初速率測定 29
3-4-5 不同抑制物濃度之抑制作用 30
3-4-6 不同鹼觸媒對動態動力分割外消旋naproxen三氟乙酯之影響 30

第四章 結果與討論
4-1 鹼觸媒消旋能力 31
4-2 酵素催化水解動力分割參數偶合 39
4-3 酵素的抑制作用與失活現象 43
4-4 以DBU為鹼觸媒之酵素催化水解動態動力分割 49
4-5 p-TBD之消旋能力 49
4-6 以p-TBD為鹼觸媒之酵素催化水解動態動力分割 52

第五章 結論與後續研究 61

參考文獻 63
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