Enantiomeric Resolution of Racemic Ibuprofen by Diastereomeric Crystallization  through Solvent Selection

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洪英倫(Ying-Lun Hung) 查詢紙本館藏

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化學工程與材料工程學系

論文名稱

(Enantiomeric Resolution of Racemic Ibuprofen by Diastereomeric Crystallization through Solvent Selection)

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摘要(中)

手性在製藥產業中尤其重要，特別在設計活性藥物分子時。當中心碳原子（手性中心）連接到四個不同的基團時，此分子中將存在手性。其中，鏡像異構體間有著相同的物理化學性質，卻在生物體中表達出不同的生物活性與光學性。若忽視對掌性，將會帶給我們無法挽回的悲劇，例如: 沙利度胺悲劇，此悲劇導致數百名新生兒罹患先天性殘缺。現今，許多的手性拆分技術已發展成熟，例如: 通過使用拆分劑形成非鏡像異構鹽類。消旋布洛芬((R/S)-(±)-ibuprofen, (R/S)- (±)-IBU)，是一種的非類固醇抗發炎藥(NASID)，其中，右旋布洛芬((S)-(+)-ibuprofen, (S)-IBU) 是用於緩解疼痛的主要活性成分。因此，在本研究中，右旋布洛芬從消旋布洛芬中拆分回收。此外，本研究選擇左旋甲基苯胺((S)-α-MBA)作為拆分劑，來形成(S)-(+)-ibuprofen-(S)-(-)-α-MBA ((S)-IBU-(S)-α-MBA))，和 (R)-(-)- ibuprofen-(S)-(-)-α-MBA ((R)-IBU-(S) -α-MBA))之非鏡像異構鹽類。 (S)-IBU-(S)-α-MBA之非鏡像異構鹽，會在此部分選擇性沉澱，稱為第一次純化的(S)-IBU-(S)-α-MBA非鏡像異構鹽。結果表明，當此三者的摩爾比 (R/S)-IBU: (S)-α-MBA: KOH 為 2:1:1 時，形成的非鏡像異構鹽會產生最高的回收率(Re%)為21%。也就是說，在此莫爾比下合成，第一次純化的(S)-IBU-(S)-α-MBA非鏡像異構鹽含有最大量的(S)-IBU。 (2) 根據初始溶劑篩选，選擇7個溶劑: 丙酮、甲醇、乙醇、異丙醇、乙酸乙脂、1-丁醇、苯甲醇來對第一步驟得到的鹽類進行再結晶純化，隨後，選擇乙酸乙酯做為再結晶溶劑是因為它從 70°C 冷卻至 25°C 之後會得到最大量的(S)-IBU-(S)-α-MBA非鏡像異構鹽，並且此溶劑可以重複使用。經此次在結晶純化後此鹽類稱為第二次純化的(S)-IBU-(S)-α-MBA非鏡像異構鹽。(3)將第二次純化的(S)-IBU-(S)-α-MBA非鏡像異構鹽溶解在甲醇中，加入硫酸來還原拆分後的右旋布洛芬。 (4) 優化反溶劑添加法的參數來回收且達到高產率的右旋布洛芬。最後，將回收製程成功擴大到18 g以檢視其再現性，並回收使用乙酸乙酯。結果顯示，提純且回收後的右旋布洛芬的總產率為60-69%，對應純度為74-79 %ee 的(S)-IBU。此研究也成功針對兩種布洛芬非鏡像異構鹽類進行傅立葉轉換紅外光譜(FTIR)與X光繞射分析(XRD)，進行熱微差掃描分析儀(DSC)等固態鑑定。最後，與其他使用非鏡像鹽類結晶法的文獻來進行比較，我們的方法具有更高的純度和產率以及製程可放大性等優勢。

摘要(英)

Chirality is an important subject issue in the pharmaceutical industry when designing the small molecules of active pharmaceutical ingredients. Chirality would exist in the molecule when a central carbon atom (chiral center) is attached to four different groups. Among them, enantiomers have identical physico-chemical properties but different in bioactivity and optical property. Ignoring the issue of drug chirality will cause an irreversible tragedy, for example, thalidomide tragedy, caused hundreds of newborn babies with inborn errors. Nowadays, several enantiomeric (chiral) resolution techniques have been developed, for example, diastereomeric salt formation by using an optically resolving agent. (R/S)-(±)-ibuprofen ((R/S)-IBU) is a nonsteroidal anti-inflammatory drug (NASID), in which (S)-(+)-ibuprofen ((S)-IBU) is the main active ingredient for pain relief instead of (R)-(-)-ibuprofen ((R)-IBU). Thus, (S)-IBU would be recovered from (R/S)-IBU in this study. Furthermore, (S)-(-)-α-Methylbenzylamine ((S)-α-MBA) was chosen as the resolving agent to form (S)-(+)-ibuprofen-(S)-(-)-α-MBA ((S)-IBU-(S)-α-MBA)),and (R)-(-)-ibuprofen-(S)-(-)-α-MBA ((R)-IBU-(S)-α-MBA)) diastereomeric salts. The aim of this research is to performed the chiral resolution by diastereomeric crystallization through solvent selection which was divided into four parts: (1) different reaction stoichiometry ratios of the resolving agent ((S)-(-)-α-MBA) and optically inactive base (potassium hydroxide, KOH(aq)) were investigated in the first part to form diastereomeric salts of (S)-IBU-(S)-α-MBA and (R)-IBU-(S)-α-MBA. The diastereomeric salt of (S)-IBU-(S)-α-MBA would selectively precipitated in the first part, called the first enriched diastereomeric salt in (S)-IBU-(S)-α-MBA. The results showed that the diastereomeric salt formation of (R/S)-IBU with a molar ratio of (R/S)-IBU: (S)-α-MBA: KOH of 2:1:1 would give the highest recovery percentage (Re%) of 21%. That is to say, the first enriched diastereomeric salts with above molar ratio would produce the largest amount of (S)-IBU. (2) Cooling recrystallization of diastereomeric salts based on initial solvent screening and solvent selection in seven solvents, including, acetone (ACE), methanol (MeOH), ethanol (EtOH), isopropyl alcohol (IPA), ethyl acetate (EA), n-butyl alcohol, and benzyl alcohol. Subsequently, ethyl acetate was selected because it gave the largest amount of enriched (S)-IBU-(S)-α-MBA after cooling from 70°C to 25°C and the solvent could be reused. The solids harvested from cooling recrystallization were called the second enriched diastereomeric salts in (S)-IBU-(S)-α-MBA. (3) the second enriched diastereomeric salts were dissolved in methanol and cracked by sulfuric acid. (4) optimization of the operating parameters for antisolvent crystallization to recover the enriched (S)-IBU was conducted. Finally, the recovery process was successfully scaled up to 18 g to exam the reproducibility, and recycle of the ethyl acetate, and the process resulted in 69-60% overall yield and 79-74%ee of the enriched (S)-IBU. All solids were analyzed by HPLC to determine the diastereomeric excess and the enantiomeric excess, and all solids were characterized by Fourier transform infrared spectrometer (FTIR) and powder X-ray diffractometer (PXRD) and differential scanning calorimetry (DSC). Our results were also compared with the ones of others groups doing diastereomeric crystallization. Our method offers the advantages of higher purity and yield, and process scalability.

關鍵字(中)

★ 手性拆分
★ 消旋布洛芬
★ 非對映結晶
★ 溶劑

關鍵字(英)

★ Enantiomeric Resolution
★ Racemic Ibuprofen
★ Diastereomeric Crystallization
★ Solvent

論文目次

摘要 i
Abstract iii
Acknowledgement v
Table of Contents vi
List of Figures ix
List of Tables xiv
Chapter 1 Introduction 1
1.1 Isomers 1
1.2 Chirality 4
1.2.1 Brief Introduction of Chirality 4
1.2.2 The Importance of Chirality 4
1.2.3 Categories of a Racemic Mixture 5
1.2.4 (R/S)-ibuprofen 8
1.3 Asymmetric Synthesis 10
1.4 Chiral Resolution 10
1.4.1 Chromatographic Resolution 10
1.4.2 Kinetic Resolution 11
1.4.3 Preferential Crystallization 11
1.4.4 Diastereomeric Crystallization 11
1.4.5 Other Chiral Resolution Methods 12
1.5 Chiral Resolution of (R/S)-IBU 13
1.6 Conceptual Framework 14
Chapter 2 Experimental Materials and Methods 16
2.1 Materials 16
2.1.1 Chemicals 16
2.1.2 Solvents 17
2.2 Experimental Framework 19
2.2.1 Experimental Design 19
2.3 Diastereomeric Crystallization 22
2.3.1 Reaction Stoichiometry Determination 22
2.4 Solvent Screening and Selection for Cooling Recrystallization of Diastereomeric Salt 24
2.4.1 Initial Solvent Screening 24
2.4.2 Solubility Curves of (R/S)-IBU, the First Enriched Diastereomeric Salts in (S)-IBU-(S)-α-MBA and the Pure (S)-IBU-(S)-α-MBA 26
2.4.3 Cooling Recrystallization of Diastereomeric Salts 28
2.5 Recovery of (S)-Ibuprofen by Anti-Solvent Addition 30
2.5.1 Effect of Solvent Ratio 30
2.5.2 Effect of Aging Time 31
2.6 Recovery Process Scale Up 32
2.6.1 Effect of Antisolvent Addition Rate 32
2.6.2 Scale-up of the Recovery of Enriched (S)-IBU 33
2.7 Analytical Instruments 36
2.7.1 Fourier Transform Infrared Spectrometer (FTIR) 36
2.7.2 Differential Scanning Calorimeter (DSC) 38
2.7.3 Powder X-ray Diffractometer (PXRD) 39
2.7.4 High Performance Liquid Chromatographic analyzer (HPLC) 41
Chapter 3 Results and Discussion 43
3.1 Introduction 43
3.1.1 Use Test of (R/S)-(±)-Ibuprofen, (R/S)-IBU 43
3.1.1.1 FTIR Spectrum and PXRD Pattern 43
3.1.1.2 DSC Scan 44
3.1.2 The Establishment of HPLC Calibration Line 45
3.2 Diastereomeric Crystallization 49
3.2.1 Stoichiometry Determination of Diastereomeric Crystallization 49
3.3 Recrystallization of Diastereomeric Salts by Cooling 56
3.3.1 Solubility Test 56
3.3.1.1 Solubility Test by Gravimetric Method 56
3.3.2 Effects of Solvent and Cooling Temperature Range 61
3.4 Recovery of Enriched (S)-IBU Diastereomeric Salt 66
3.4.1 Effect of Solvent Ratio 66
3.4.2 Effect of Aging Time 69
3.5 Recovery Process Scale Up 71
3.5.1 Effect of Antisolvent Addition Rate 71
3.5.2 Recovery Scale-up of Enriched (S)-IBU 73
3.5.3 Comparison of Diastereomeric Crystallization Performance of (R/S)-IBU in Literature 80
Chapter 4 Conclusions and Future Works 81
4.1 Conclusions 81
4.2 Future Works 81
References 82

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指導教授

李度(Tu Lee)

審核日期

2022-7-26

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