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研究生:王莉雯
研究生(外文):Li-Wen Wang
論文名稱:外消旋suprofen硫酯之動態動力分割製程開發
論文名稱(外文):Development of the dynamic kinetic resolution process of racemic suprofen 2,2,2 trifluoroethyl thioester
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:62
中文關鍵詞:動態動力分割中空纖維管脂肪分解酵素
外文關鍵詞:lipasedynamic kinetic resolutionhollow fibersuprofen
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因為生產單一光學藥物之重要性日益增加,所以本論文嘗試對非類固醇消炎藥(S)-suprofen之批次及半批次製程進行分析與模擬。
本文先依照前人之經驗擬定外消旋suprofen三氟乙硫酯動態動力分割之反應條件,進而對酵素水解、消旋以及自發性水解之反應參數作詳細探討,以利理論數值之偶合;分別採用固定化酵素Lipase MY以及三辛基胺作為水解及消旋觸媒,並測定產物suprofen於環己烷及不同pH值氫氧化鈉溶液之間的分配係數、於薄膜系統之質傳係數且探討添加三辛基胺對其質量傳送的影響。
結合中空纖維薄膜之優點,於有機相進行動態動力分割反應的同時,採用pH值11之氫氧化鈉溶液進行產物的萃取分離並提供作為反應物水的來源;實驗證明於固定時間內加入高濃度之氫氧化鈉及基質溶液可以開發(S)-suprofen之半批次製程,且與理論值比較獲得互相符合的結果。
As single enantiomer drugs become increasingly important, the purpose of this work is aimed to develop a theoretical model in predicting the production of a non-sterodial anti-inflammatory drug of (S)-suprofen operating in batch and semibatch modes.
A series of experiments were carried out to determine all kinetic parameters for the lipase-catalyzed hydrolysis and trioctylamine-catalyzed racemization. The distribution coefficients of suprofen between cyclohexan with or without adding trioctylamine and the aqueous sodium hydroxide solution of different pH values, and the mass transfer coefficient through a hollow fiber membrane were obtained.
Dynamic kinetic resolution of racemic suprofen 2,2,2-trifluorothioester in a semibatch reactor with in situ extraction of (S)-suprofen into an aqueous sodium hydroxide solution through a hollow fiber membrane was furthermore performed, and compared with the theoretical predictions.
第一章 緒論 1
1.1 對掌性異構型藥物 1
1.1.1 藥理活性 1
1.1.2 政府管理條例及過往案例 2
1.1.3 非類固醇消炎藥 4
1.2 生物觸媒於有機合成之應用 5
1.2.1 微水有機溶劑中之酵素反應 7
1.2.2 脂肪分解酵素 8
1.3 對掌異構物的消旋反應暨動態動力分割 10
1.4 薄膜反應器 11
1.5 研究動機 14
第二章 原理 15
2.1 酵素催化動力分割反應 15
2.2 酵素失活模式 16
2.3 基因遺傳演算法 17
2.4 鹼觸媒催化消旋反應 20
2.5 動態動力分割反應 22
2.6 產物於有機溶劑/鹼水溶液間的分配 23
2.7 薄膜總包質傳係數 23
2.8 動態動力分割配合薄膜進行萃取分離 25
第三章 實驗 29
3.1 實驗藥品暨設備 29
3.1.1 實驗藥品 29
3.1.2 儀器設備 30
3.2 分析方法 30
3.2.1 有機相 30
3.2.2 水溶液相 33
3.3 實驗方法 33
3.3.1 三氟乙硫酯的合成 33
3.3.2 固定化酵素的製備 34
3.3.3 酵素動力參數的擬合 34
3.3.4 消旋反應參數的擬合 34
3.3.5 鹼觸媒對酵素活性的影響 35
3.3.6 鹼觸媒催化基質自發性水解反應 35
3.3.7 分配係數之測定 35
3.3.8 薄膜總包值傳係數之測定 35
3.3.9 動態動力分割配合中空纖維管進行萃取與分離 36
3.3.10 半批次反應器 36
第四章 結果與討論 37
4.1 動力參數擬合 37
4.2 基因演化法擬合失活常數 39
4.3 鹼觸媒催化消旋反應之參數擬合 42
4.4 動態動力分割 42
4.5 鹼觸媒催化基質自我水解反應 44
4.6 分配係數之測定 47
4.7 薄膜總包質傳係數之測定 49
4.8 動態動力分割配合鹼溶液進行萃取分離 50
4.9 半批次反應器 51
第五章 結論暨未來展望 54
第六章 參考文獻 56
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