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研究生：	布逹拉 Elmaamoun Ahmed
論文名稱：	Recycling High Valued (S)-(+)-Ibuprofen from the Unused Racemic (R,S)-(±)-Ibuprofen Tablets by Green Chemistry
指導教授：	李度 Tu Lee
口試委員:
學位類別：	碩士 Master
系所名稱：	工學院 - 應用材料科學國際研究生碩士學位學程 International Master Degree Program in Applied Materials Science
論文出版年：	2020
畢業學年度：	108
語文別：	英文
論文頁數：	112
中文關鍵詞：	布洛芬、手性分離、非對映體鹽、綠色化學、回收、除消、解析度
外文關鍵詞：	Ibuprofen, Chiral separation, Diastereomeric salt, Green Chemistry, Recycle, deracemization, Resolution
相關次數：	點閱：20 下載：0
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本篇研究目的為利用拆分技術將未使用的藥物「外消旋布洛芬(R,S)-(±)-ibuprofen」回收分離得到價值更高的「右旋布洛芬[(S)-(+)-Ibuprofen]」，應用綠色化學方法作為循環經濟的一部分；拆分技術已應用於非鏡像異構鹽類的分離，如：甲基苄胺[(S)-(-)-α-methylbenzylamine]作為拆分溶劑。在本研究中，透過兩個步驟以達成拆分，首先，將回收的外消旋布洛芬與甲基苄胺的反應，形成右旋布洛芬-甲基苄胺鹽類[(S)-(+)-Ibuprofen-(S)-(-)-α-methylbenzylamine salt]及左旋布洛芬-甲基苄胺鹽類[(R)-(-)-Ibuprofen-(S)-(-)-α-methylbenzylamine salt]，其中，右旋布洛芬-甲基苄胺鹽類則會沉澱析出；第二步，利用添加硫酸與析出的右旋布洛芬-甲基苄胺鹽類反應而得到右旋布洛芬。根據HPLC的純度含量分析得知，回收得到的右旋布洛芬產率為67%，對映體純度為93.2%；右旋布洛芬-甲基苄胺鹽類及右旋布洛芬兩個分子結構成功透過傅里葉轉換紅外光譜(FTIR)、核磁共振氫譜(1H NMR)、光學顯微鏡(OM)及差示掃描量熱法(DSC)分析鑑定；此外，右旋布洛芬的晶體學數據亦透過粉末X-射線繞射(PXRD)分析鑑定。最後，比較本方法與不對稱合成方法(Asymmetric synthesis)，本方法則有較高的產率、較少的步驟、較有利的操作條件及使用較少化學品等的優點。

The aim of this study is to increase the value of recycled (R,S)-(±)-ibuprofen from the unused commercial tablets by resolution, to produce higher valued (S)-(+)-ibuprofen as a part of a circular economy project by applying green chemistry method. The resolution was done by the diastereomeric salt separation method using (S)-(-)-α-methylbenzylamine as a resolving agent. In this work, two steps were performed: (1) reaction of recycled (R,S)-(±)-ibuprofen with (S)-(-)-α-methylbenzylamine to form (S)-(+)-ibuprofen-(S)-(-)-α-methylbenzylamine salt and (R)-(-)-ibuprofen-(S)-(-)-α-methylbenzylamine salt, in which (S)-(+)-ibuprofen-(S)-(-)-α-methylbenzylamine salt was selectively precipitated, followed by (2) recovery of (S)-(+)-ibuprofen by introducing H2SO4 to (S)-(+)-ibuprofen-(S)-(-)-α-methylbenzylamine salt. (S)-(+)-ibuprofen was obtained with 67% overall yield and 93.2% enantiopurity based on HPLC assay. The structures of both (S)-(+)-ibuprofen-(S)-(-)-α-methylbenzylamine salt and (S)-(+)-ibuprofen were successfully verified using FTIR, 1H NMR, OM, and DSC. In addition, the crystallographic data of (S)-(+)-ibuprofen was successfully verified using PXRD. And lastly, by comparing this method with asymmetric synthesis, this method gave better yield, a fewer number of steps, more favorable operating conditions, and fewer chemicals involved.

摘要    v
Abstract    vi
Acknowledgement    vii
List of Figures    xiii
List of Tables    xviii
Chapter 1    Introduction    1
1    Stereochemistry    1
2    History    4
3    The Importance of Chirality    5
4    Diastereomers    6
5    Categories of Racemic Mixtures    9
6    Most Used Techniques    11
7    Diastereomeric Salt of Ibuprofen    15
8    References    17
Chapter 2    Experimental Materials and Methods    25
1    Materials    25
1.1    Chemicals    25
1.2    Solvents    27
2    Experimental Procedures    29
2.1    Solubility Measurement    29
2.2    General Overview of the Process    32
2.2.1    Recycle of (R,S)-(±)-ibuprofen    33
2.2.2    Formation of Diastereomeric Salts    36
2.2.3    Recovery of (S)-(+)-ibuprofen    36
2.2.4    Recovery of (R)-(-)-ibuprofen    37
3    Analytical Measurements    38
3.1    Spectroscopic Method    38
3.1.1    Fourier Transform Infrared Spectroscopy (FTIR)    38
3.1.2    Nuclear Magnetic Resonance Spectroscopy (NMR)    41
3.2    Microscopic Method    43
3.2.1    Optical Microscopy (OM)    43
3.3    Thermal Analysis Methods    45
3.3.1    Differential Scanning Calorimetry (DSC)    45
3.4    Crystallographic Analysis Methods    48
3.4.1    Powder X-ray Diffraction (PXRD)    48
3.5    Separation Method    51
3.5.1    High-Performance Liquid Chromatography (HPLC)    51
4    References    55
Chapter 3    Results and Discussion    59
1    Form Space Determination    59
2    Resolution of the Recycled Racemic (R,S)-() Ibuprofen    65
3    Characterization of (S)-Ibuprofen-(S)-(-)-α-Methylbenzylamine Salt and (S)-(+)-Ibuprofen    68
3.1    FTIR    68
3.2    1H NMR    71
3.3    OM & DSC    75
3.4    PXRD    76
3.5    HPLC    78
4    Novelty of the Resolution Method    81
5    Comparison between the Synthesis of (S)-(+)-Ibuprofen by Asymmetric Synthesis and Diastereomeric Salt    82
6    Green Chemistry in Our Work    86
7    References    88
Chapter 4    Conclusions and Future Works    91
1    Conclusions    91
2    Future Works    91


                                

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