Recycling High Valued (S)-(+)-Ibuprofen from the Unused Racemic (R,S)-(±)-Ibuprofen Tablets by Green Chemistry

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布逹拉(Elmaamoun Ahmed) 查詢紙本館藏

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應用材料科學國際研究生碩士學位學程

論文名稱

(Recycling High Valued (S)-(+)-Ibuprofen from the Unused Racemic (R,S)-(±)-Ibuprofen Tablets by Green Chemistry)

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摘要(中)

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。

摘要(英)

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.

關鍵字(中)

★ 布洛芬
★ 手性分離
★ 非對映體鹽
★ 綠色化學
★ 回收
★ 除消
★ 解析度

關鍵字(英)

★ Ibuprofen
★ Chiral separation
★ Diastereomeric salt
★ Green Chemistry
★ Recycle
★ deracemization
★ Resolution

論文目次

摘要 v
Abstract vi
Acknowledgement vii
List of Figures xiii
List of Tables xviii
Chapter 1 Introduction 1
1.1 Stereochemistry 1
1.2 History 4
1.3 The Importance of Chirality 5
1.4 Diastereomers 6
1.5 Categories of Racemic Mixtures 9
1.6 Most Used Techniques 11
1.7 Diastereomeric Salt of Ibuprofen 15
1.8 References 17
Chapter 2 Experimental Materials and Methods 25
2.1 Materials 25
2.1.1 Chemicals 25
2.1.2 Solvents 27
2.2 Experimental Procedures 29
2.2.1 Solubility Measurement 29
2.2.2 General Overview of the Process 32
2.2.2.1 Recycle of (R,S)-(±)-ibuprofen 33
2.2.2.2 Formation of Diastereomeric Salts 36
2.2.2.3 Recovery of (S)-(+)-ibuprofen 36
2.2.2.4 Recovery of (R)-(-)-ibuprofen 37
2.3 Analytical Measurements 38
2.3.1 Spectroscopic Method 38
2.3.1.1 Fourier Transform Infrared Spectroscopy (FTIR) 38
2.3.1.2 Nuclear Magnetic Resonance Spectroscopy (NMR) 41
2.3.2 Microscopic Method 43
2.3.2.1 Optical Microscopy (OM) 43
2.3.3 Thermal Analysis Methods 45
2.3.3.1 Differential Scanning Calorimetry (DSC) 45
2.3.4 Crystallographic Analysis Methods 48
2.3.4.1 Powder X-ray Diffraction (PXRD) 48
2.3.5 Separation Method 51
2.3.5.1 High-Performance Liquid Chromatography (HPLC) 51
2.4 References 55
Chapter 3 Results and Discussion 59
3.1 Form Space Determination 59
3.2 Resolution of the Recycled Racemic (R,S)-() Ibuprofen 65
3.3 Characterization of (S)-Ibuprofen-(S)-(-)-α-Methylbenzylamine Salt and (S)-(+)-Ibuprofen 68
3.3.1 FTIR 68
3.3.2 1H NMR 71
3.3.3 OM & DSC 75
3.3.4 PXRD 76
3.3.5 HPLC 78
3.4 Novelty of the Resolution Method 81
3.5 Comparison between the Synthesis of (S)-(+)-Ibuprofen by Asymmetric Synthesis and Diastereomeric Salt 82
3.6 Green Chemistry in Our Work 86
3.7 References 88
Chapter 4 Conclusions and Future Works 91
4.1 Conclusions 91
4.2 Future Works 91

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指導教授

李度(Tu Lee)

審核日期

2020-1-9

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