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title page

Abstract

Contents

I. Introduction 15

I.1. Chirality 15

I.2. β-block 18

I.3. Pharmaceutical Trends 19

I.4. Background and Literature Review 23

I.5. Chromatographic separation Methods 29

II. Experimental 33

II.1. Chemicals and Instruments 33

II.1.1. Chemicals 33

II.1.2. Instruments 34

II.2. Resolution of the enantiomers of racemic bevantolol 35

II.2.1. Selection of a Resolving agent 35

II.2.2. Derivatization of racemic bevantolol with chiral resolving agent 37

II.2.3. Fractionation of (rac)-bevantolol-MCF diastereomer by Semi-prep.HPLC 39

II.2.4. Hydrolysis of the bevantolol-MCF diastereomer 41

II.3. Optimization of the chromatographic conditions 45

II.3.1. Optimization of mobile phase composition 45

II.3.2. Detection wavelength 46

II.4. Characterization of NMR spectroscopy 47

II.5. Characterization of IR spectroscopy 47

II.6. Characterization of UV spectroscopy 48

II.7. Characterization of MASS spectroscopy 48

III. Results and discussion 49

III.1. Effect of mobile phase composition on separation of diastereomers 49

III.1.1/III.1.2. Effect of methanol contents 51

IV. Interpretation of the ¹H-NMR and ¹³C-NMR spectrum 55

V. MASS spectrum of each compound 74

VI. UV spectrum of each compound 82

VII/VI. IR spectrum of each compound 86

VIII. Effect of hydrolysis reaction on the chiral inversion. 92

IX. Hydrolysis of the diastereomers 95

X. Conclusion 97

XI. REFERENCE CITED 98

국문초록 105

감사의 글 106

List of Tables

Table 1. Some single enantiomeric from drugs that have been used clinically for many years 18

Table 2. Worldwide chiral drug sales. 21

Table 3. Candidates for Racemic switches 22

Table 4. Effect of methanol content on the separation of (±)-bevantolol-(-)-MCF diastereomers 52

Table 5. ¹H-NMR chemical shift values of (±)-bevantolol-MCF, S-(-)-bevantolol-(-)-MCF and R-(+)-bevantolol-(-)-MCF. 56

Table 6. ¹H-NMR chemical shift values of racemic-bevantolol, S-(-)-bevantolol and R-(+)-bevantolol. 57

Table 7. ¹³C-NMR chemical shift values of (±)-bevantolol-MCF, S-(-)-bevantolol-(-)-MCF and R-(+)-bevantolol-(-)-MCF. 65

Table 8. ¹³C-NMR chemical chemical shift values of racemic-bevantolol, S-(-)bevantolol and R-(+)-bevantolol. 66

Table 9. Yield and chromatographic purity over preparative enantiomeric resolution of racemic bevantolol 96

List of Figures

Figure 1. Stereochemical structure of thalidomide. 16

Figure 2. Structures of β-blockers. 24

Figure 3. Structure of bevantolol (*, Chiral center) 28

Figure 4. Chromatogram of bevantolol diastereomer 40

Figure 5. Chromatogram of racemic 42

Figure 6. Chromatogram describing collect each diastereomers of rac.bevantolol-(-)-MCF mixture, I : S-(-)-bevantolol-(-)-MCF, II : R-(+)-bevantolol-(-)-MCF, Collected area a and b. 50

Figure 7. Infuence of methanol content upon the separation of bevantolol diastereomers. 53

Figure 8. Effect of methanol content upon the retention time of bevantolol diastereomers. 54

Figure 9. ¹H-NMR spectrum of racemic of bevantolol. CDCl₃, 400MHZ 58

Figure 10. ¹H-NMR spectrum of MCF, CDCl₃, 400MHZ 59

Figure 11. ¹H-NMR spectrum of (±)-bevantolol-(-)-MCF, CDCl₃, 400MHZ 60

Figure 12. ¹H-NMR spectrum of S-(-)-bevantolol-(-)-MCF, CDCl₃, 400MHZ 61

Figure 13. ¹H-NMR spectrum of R-(+)-bevantolol-(-)-MCF, CDCl₃, 400MHZ 62

Figure 14. ¹H-NMR spectrum of S-(-)-bevantolol, CDCl₃, 400MHZ 63

Figure 15. ¹H-NMR spectrum of R-(+)-bevantolol, CDCl₃, 400MHZ 64

Figure 16. ¹³C-NMR spectrum of racemic of bevantolol. CDCl₃, 400MHZ 67

Figure 17. ¹³C-NMR spectrum of MCF, CDCl₃, 400MHZ 68

Figure 18. ¹³C-NMR spectrum of (±)-bevantolol-(-)-MCF, CDCl₃, 400MHZ 69

Figure 19. ¹³C-NMR spectrum of S-(-)-bevantolol-(-)-MCF, CDCl₃, 400MHZ 70

Figure 20. ¹³C-NMR spectrum of R-(+)-bevantolol-(-)-MCF, CDCl₃, 400MHZ 71

Figure 21. ¹³C-NMR spectrum of S-(-)-bevantolol, CDCl₃, 400MHZ 72

Figure 22. ¹³C-NMR spectrum of R-(+)-bevantolol, CDCl₃, 400MHZ 73

Figure 23. MASS spectrum of racemic of bevantolol(70ev, EI-MASS) 75

Figure 24. MASS spectrum of MCF(70ev, EI-MASS) 76

Figure 25. MASS spectrum of (±)-bevantolol-(-)-MCF (70ev, EI-MASS) 77

Figure 26. MASS spectrum of S-(-)-bevantolol-(-)-MCF (70ev, EI-MASS) 78

Figure 27. MASS spectrum of R-(+)-bevantolol-(-)-MCF (70ev, EI-MASS) 79

Figure 28. MASS spectrum of S-(-)-bevantolol (70ev, EI-MASS) 80

Figure 29. MASS spectrum of R-(+)-bevantolol (70ev, EI-MASS) 81

Figure 30. UV Spectrum of racemic-bevantolol 83

Figure 31. UV Spectrum of MCF 83

Figure 32. UV Spectrum of diastereomers mixture 84

Figure 33. UV Spectrum of S-bevantolol-MCF 84

Figure 34. UV Spectrum of R-bevantolol-MCF 85

Figure 35. IR Spectrum of racemic-bevantolol (KBr) 87

Figure 36. IR Spectrum of MCF (KBr) 88

Figure 37. IR Spectrum of diastereomers mixture (KBr) 89

Figure 38. IR Spectrum of S-bevantolol-MCF (KBr) 90

Figure 39. IR Spectrum of R-bevantolol-MCF (KBr) 91

Figure 40. Effect of hydrolysis time to S-diastereomers at 50, 70, 90℃. 93

Figure 41. Effect of hydrolysis time to R-diastereomers at 50, 70, 90℃. 93

Figure 42. Effect of hydrolysis time to S-enantiomer at 50, 70, 90℃. 94

Figure 43. Effect of hydrolysis time to R-enantiomer at 50, 70, 90℃. 94

List of Schemes

Scheme 1. Derivatization reaction of bevantolol using Menthyl chlorofomate 38

Scheme 2. Hydrolysis of the diastereomer of bevantolol 43

Scheme 3/III. The overall enantiomeric resolution process of racemic bevantolol 44

초록보기

베반톨롤 라세미체를 키랄유도체화시약인 에스-(-)-멘틸클로로포메이트와 반응시켜 각각의 디아스테레오머를 합성하였다.

역상 분취용 액체크로마토그래피를 이용하여 알-(+)-베반톨롤-(-)엠씨에프 디아스테레오머와 에스-(-)-베반톨롤-(-)_엠씨에프 디아스테레오머를 분취하였다. 역상 분취용 액체크로마토그래피에서 각각의 디아스테오머들의 분리능과 선택계수는 각각 1.82와 1.72로 매우 양호하였으며 59%의 수득율을 나타내었다. 각각의 디아스테레오머는 각종 분광학적방법으로 동정하였다.

각각의 디아스테레오머는 5% 리치움히드록시드 용액에서 가수분해하고 용매로 추출 정제하여 알-(+)-베반톨롤 이난티오머는 99.98% 광학순도와 41.91%의 수득율로 얻었고, 에스-(-)-베반톨롤 이난티오머는 99.97%광학순도와 47.59%의 수득율로 얻었다.

본 베반톨롤의 광학분할법은 베반톨롤 이난티오머 표준품의 확보에 이용될 수 있으며, 더 나아가 키랄스위칭에 의한 베반톨롤 키랄의약품 개발에 활용될 수 있을 것으로 사료된다.

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