Chiral enantioseparation of racemic drugs

CHIRAL SEPARATION OF RACEMIC DRUGS POON YIN FUN (B.Sc.(Hons.). NUS) A THESIS SUBMITTED FOR THE DEGREE OF DOCTOR OF PHILOSOPHY DEPARTMENT OF CHEMISTY NATIONAL UNIVERSITY OF SINGAPORE 2005 ACKNOWLEDGEMENTS I would like to express my heartfelt gratitude to my supervisor, A/P Ng Siu Choon for his advice, useful discussions and guidance throughout the whole project. I am also grateful to Prof Chan Sze On, Hardy for the follow-up supervision done on my pH.D candidature. My sincere thanks also go to Dr I Wayan Muderawan for his kind advice in organic synthesis and his help in proofreading this thesis. I like to thank Dr Chen Lei for sharing her ideas in the analytical aspects involved in this project and being ever so helpful to clear my doubts on the project. I would like to thank the technical and laboratory staff in the Faculty of Science of the University for the immense help. In particular, I am indebted to Mdm Frances Lim Guek Choo who has been so helpful to clarify my doubts concerning chromatographic separations and the use of the HPLC instrument; Mdm Han Yanhui and Miss Peggy Ler for helping with the Nuclear Magnetic Resonance analyses; Mdm Toh Soh Lian and Miss Serene Lim for providing me with precious knowledge and life-long skills which will be useful for me as a chemist. Lastly, I will also remember all my friends and seniors in the Functional Polymer Laboratory and Collaborative Research Laboratory with whom I have worked and have helped me in one way or another. I am also grateful for the understanding and support rendered by my family and friends throughout my work. i TABLE OF CONTENTS ACKNOWLEDGEMENTS i TABLE OF CONTENT ii SUMMARY vii LIST OF SYMBOLS AND ABBREVIATIONS xi LIST OF PUBLICATIONS xii Chapter 1: INTRODUCTION 1.1. The History of Enantiomeric Resolution 1.2. Chiral Analysis 1.3 Major Racemate Separation Technologies 11 1.4 Liquid Chromatography – Direct and Indirect Methods 13 1.5 Mechanism of Separation 15 1.6 Classification of Chiral Stationary Phases 17 1.6.1 Dinitrobenzoyl phases (Pirkle CSP) 18 1.6.2 Protein bonded phases 20 1.6.3 Chiral phases with inclusion effects 1.6.3.1 Cyclodextrin bonded phases 20 1.6.3.2 Crown-ether phases 24 1.6.4 Polymeric phases 25 1.6.5 Chiral ligand exchange phases (CLEC) 26 1.7 Chiral Simulated Moving-Bed Chromatography (SMB) 28 1.8 Time Frame of Cyclodextrin Discovery 29 1.9 Physical Properties of Cyclodextrins 30 1.10 Application of Cyclodextrins in Chromatography 31 ii 1.11 Work Done by our Research Group 33 1.12 Racemic Drugs and Compounds 36 1.13 Scope of Work 37 Chapter PREPARATION OF CSPs 41 2.1 Synthetic Methodologies 42 2.2 Purpose of Immobilization at C2-OH position 42 2.3 Modifications involving reaction of C6 Primary Hydroxy Group 44 2.4 Modifications involving reaction of C2 Secondary Hydroxy 44 Group 2.5 Selective Tosylation of Cyclodextrin 46 2.6 Differentiation between C2-tosylated-CD and C6-tosylated-CD 48 2.7 Differentiation between C2-tosylated-CD and C3-tosylated-CD 50 2.8 Azidolysis 52 2.9 Carbamoylation and Staudinger Reaction 56 2.10 The Hydrosilylation Route 58 2.11 List of CSPs 61 2.12 Column Efficiency and Surface Coverages 63 Chapter STUDY OF THE EFFECTS OF IMMOBILIZATION POSITION OF CYCLODEXTRIN AND SUBSTITUENTS ON ENANTIOSELECTIVITY 67 3.1 Introduction 68 3.2 Characteristics of CSPs 72 3.3 Basic Concepts for Chromatographic Separation 73 3.4 Chromatographic Properties of Perphenylcarbamoylated CD CSPs 75 iii 3.4.1 Comparisons between CSP-AM-2-PC and CSP-AM-6-PC under Normal Phase and Reversed-Phase 75 3.5 Chromatographic Properties for Peracetylated CD CSPs 90 3.6 Comparison between Phenylcarbamate CD CSPs and Acetyl CD 3.7 CSPs using Flavanone Compounds 94 Permethylated series and Perbenzoylated series 97 3.7.1 Chromatographic Properties of Permethylated CD CSPs 98 3.7.2 Chromatographic Properties of Perbenzoylated CD CSPs 101 3.8 Conclusion 103 Chapter STUDY OF THE EFFECTS OF SUBSTITUENTS ON PHENYL GROUPS OF PHENYLCARBAMOYLATED CD ON ENANTIOSELECTIVTY 107 4.1 Introduction 108 4.2 Characteristic of the CSPs 111 4.3 Discussion on the π-basic columns 112 4.4 Comparison between π-basic and π-acidic phases 117 4.5 Influence of the Substituents present on Phenyl Groups on Carbamate Moiety 121 4.6 Separation and Comparisons using Racemic drugs 122 4.7 Conclusion 124 Chapter COMPARISON BETWEEN TWO IMMOBILIZATION PROCEDURES AND PROPOSAL OF NEW SYNTHETIC METHODOLOGIES 126 5.1 Introduction 127 5.2 Comparisons between Immobilization Procedures using iv Perphenylcarbamoylated CD CSPs 5.3 128 Comparisons between Immobilization Procedures using Permethylated CD CSPs 5.4 132 Chromatographic Properties of the CSP made from a New Procedure 134 5.5 Effect of Phenyl Isocyanate Capping on Enantioselectivity 137 5.6 Conclusion 141 Chapter CHROMATOGRAPHIC PROPERTIES AND CONDITIONS INVESTIGATION FOR A CSP BASED ON C2ALLYLCARBAMIDO-PERMETHYLATED CD 143 6.1 Introduction 144 6.2 Comparison of CSP-2-ME with other CSPs (CD immobilized at primary rim) 6.3 145 Investigation of HPLC separation conditions using Permethylated CD CSP 6.3.1 Influence of pH on Chromatographic Properties 148 149 6.3.2 Influence of Composition of Organic Modifier on Chromatographic Properties 155 6.4 Chiral Amino Acid Separations 157 6.5 Conclusion 160 Chapter EXPERIMENTAL 163 7.1 Reagents and Apparatus 164 7.2 HPLC Conditions 165 7.3 Carbamoylation 166 v 7.4 Methylation 172 7.5 Acetylation 174 7.6 Benzoylation 175 7.7 Preparation of mono-(6A-derivatised)- β-CD 176 7.8 Immobilization Reactions 183 7.9 Preparation of HPLC column 186 Chapter CONCLUSIONS 187 Future Developments 194 REFERENCES 196 vi SUMMARY Enantiomers are molecules which cannot be superimposed on their mirror images. The separation of enantiomers is important in many industries and scientific disciplines. The pharmaceutical industry in particular is concerned with the separation of enantiomers since many of these isomers are known to have different physiological activities. For example, in the case of the β-blocker propranolol, only the l-isomer is beneficial in treating angina pectoris, while d-propranolol mediates the antiarrhythmic and antihypertensive activity of the racemic mixtures. Since Louis Pasteur first discovered the spontaneous resolution of racemic ammonium sodium tartrate (1848), many physical and chemical separative methods have evolved with the fundamental aim to afford drugs safe for consumption. Separation of drug enantiomers through the use of chiral stationary phases (CSPs) via chromatographic means offers a convenient, rapid and reliable technique to separate enantiomers. A search of the literatures concerning separation science reveals that there is an abundance of CSPs on the market that can achieve enantioseparation to racemates. Over the past two decades, there has been a dynamic growth in CSP research; in 1987, a classification system was drawn out for these CSPs according to the type of separating materials (namely cellulose, cyclodextrin, crown ether, proteins, Pirkle-type molecules and metal complexes) with their unique mechanisms. Even though there is an abundance of CSPs in the market, there is, till today, no one single CSP that can universally separate all types of racemates (acids, bases and bulky solutes), and the exact separation mechanism between CSP and solute still remains obscure. vii This thesis reports the application of several CSPs based upon β-cyclodextrin (β-CD) as chiral selector in chromatographic separations of several classes of racemates. β-CD, consisting of an optically active hydrophobic cavity, was chosen due to its excellent selectivity in chiral separations when bonded to silica supports. It is also relatively inexpensive and easily available. It is hoped that this work can help to gain a better understanding of the mechanism behind chiral separation using β-CD chiral stationary phases. Our research group has done several studies on the development of novel CDbased CSPs using different synthetic approaches with successful outcomes. Many enantioseparations have been achieved using these columns and they are feasible for use in the analytical as well as the preparative scale. Drawing on this success, this work seeks to expand the application of the existing CD columns by developing chiral separating phases based on several modified CDs. In this dissertation, fifteen modified CD CSPs, based on a stable single urea linkage to the silica support, were prepared and their chromatographic properties were evaluated using High performance liquid chromatography (HPLC) and compared using a broad range of racemic drugs and compounds. Research in this project focused on several areas, the effects of different CD immobilization position (via C2OH and C6-OH) to the silica support, different substituent groups (phenylcarbamate, acetyl, methyl, benzoyl) on the CD and different immobilization approaches on chromatographic properties. The influence of changing pH of the buffer and mobile phase composition on enantioseparation of several racemic drugs and compounds viii were also examined using a permethylated CD CSP based on the chiral selector, mono-(2A-allylcarbamido-2A-deoxy)-permethylated β-CD. HPLC results have shown that all fifteen modified CD CSPs can give effective separations. In brief, the perphenylcarbamoylated CD CSP gave separations to all 31 racemates tested in this thesis under normal as well as reversed-phase conditions and was found to be particularly useful in the separations of a diverse range of racemates compared to peracetylated CD CSP, permethylated CD CSP and perbenzoylated CD CSP. A series of CSPs, where CD derivatives were regioselectively bonded at the C2-OH position to the silica gel, were prepared, and when evaluated for chiral separations, showed different separation behaviours as compared to those bonded at the C6-OH position. Results indicated that inclusion complexation to the CD cavity with bulky CD substituents was sterically hindered on the phase where the wider opening (secondary face) of the CD torus was bonded to the silica support. Their synthetic approaches and characterisations were described in chapter 2. Three other phenylcarbamate CD CSPs, i.e. per(p- chloro)phenylcarbamoylated CD CSP, per(3,5-dimethy)phenylcarbamoylated CD CSP and per(p-methoxy)phenylcarbamoylated CD CSP, were also synthesized and compared with the unsubstituted perphenylcarbamoylated CD CSP. Among the four, the unsubstituted perphenylcarbamoylated CD CSP was demonstrated to give the best separations to a range of racemates, and π-π interactions were demonstrated to be important forces in the separation mechanisms. Chromatographic properties can be affected by different CD immobilization procedures and this had been demonstrated by the use of four synthetic methods to generate different types of CD CSPs. HPLC results showed that achiral, non-selective interactions with surface amino and silanol ix In the near future, chiral resolution would still be expected to dominate asymmetric synthesis for industrial scale production and enantioseparation using analytical means will continue to be important. Improvements of the existing technologies (chiral separations and molecular modelling) to meet future demands in terms of speed, performance and low costs can be foreseen. 195 REFERENCES 1. Stinson S.C.; Chem. & Eng. News; 1997, 28 2. Rouhi M.; Chem. & Eng. News; 2004, 47 3. Jamali F., Mehvar R, Pasutto F.M.; J. Pharm. Sci.; 1989, 78, 4. Pasteur L.; Ann. Chim. Phys.; 1848, 24, 442 5. Schenk W.Jr.; Experientia; 1952, 8, 337 6. Kotake M., Sakan T., Nakamura N., Senon S.; J. Am. Chem. Soc.; 1951, 73, 2973 7. Dalgliesh C.E.; J. Chem. Soc.; 1952, 3940 8. Prelog V.; Weiland P.; Helv. Chim. Acta; 1944, 27, 1127 9. Klemn L.H., Reed D.; J. Chromatogr.; 1960, 3, 364 10. Gil-Av E., Feibush B., Charles-Sigler R.; Gas Chromatography; Institute of Petroleum : London, 1966, p227 11. Rogozhin S.V., Davankov V.A.; USP. Khim.; 1968, 37, 1327 12. Hegelson R.C.; Timko J.M.; Morean P.; Peacock S.C.; Mayer J.M.; Cram D.J.; J. Am. Chem. Soc.; 1974, 96, 6762 13. Kritulović A.M.; Chiral Separation by HPLC – Applications to Pharmaceutical Compounds; Ellis Horwood : New York, 1990 14. Allenmark S.G.; Chromatographic Enantioseparation, Methods and Applications; Ellis Horwood : New York, 1991 15. Zief M., Crane L.J.; Chromatographic Separations; Marcel Dekker : New York, 1990, Chp 16. Stevenson D., Wilson I.D.; Recent Advances in Chiral Separations; Plenum Press : New York, 1988, pp 115-120 17. Schreier P., Bernreuther A., Huffer M.; Analysis of Chiral Organic Molecules; Walter de Gruyther : New York, 1995 196 18. Lough W.J., Wainer I.W.; Chirality in Natural and Applied Science; Blackwell Science : Boca Raton, 2002 19. Bijvoet J.M.; Proct. Koninkl. Ned. Wetenschap.; 1949, B52, 313 20. Dorsey J.G., Foley J.P., Cooper W.T., Barford R.A.; Barth H.G.; Anal. Chem.; 1992, 64, 353R-389R 21. König W.A.; Gas Chromatographic Enantiomer Separation with Modified Cyclodextrins; Heidelberg : Hüthig Buch, 1992 22. Wong C.S., Hoekstra P.F., Karlsson H., Backus S.M., Mabury S.A., Muir D.C.G.; Chemosphere; 2002, 49, 10 23. Williams K.L., Sander L.C., Wise S.A.; Chirality; 1996, 8, 325 24. Di L., McConnell O.J., Kerns E.H., Sutherland A.G.; J. Chromatogr. B; 2004, 809, 2, 231 25. Kim T.Y., Kim H.J.; J. Chromatogr. A; 2001, 933, 99 26. Anderson S., Halvorsen T.G., Pedersen-Bjergarrds S.; J. Pharm. Biomed. Anal.; 2003, 33, 2, 263 27. Lee W., La S., Choi Y.M.; Bull. Kor. Chem. Soc.; 2003, 24, 8, 1232 28. Scriba G.K.E.; Electrophoresis; 2003, 24, 22-23, 4063 29. Gel-Moreto N., Streich R., Galesa R.; Electrophoresis; 2003, 24, 15. 2716 30. Amina A.; Electrophoresis; 2001, 22, 15, 3107 31. Maier N.M., Franco P., Lindner W.; J. Chromatogr. A; 2001, 906, 32. Kielbasínski P., Rachwalski M., Mikolajczyk M., Moelands M.A.H., Zwanenburg B., Rutjes F.P.J.T.; Tetrahedr.: Asymmetry; 2005, 16, 12, 2157 33. Davankov V.A.; Chromatographia; 1989, 27, 9/10, 475 34. Pirkle W.H, Pochapsky T.C.; Chem. Rev.; 1989, 89, 347 197 35. Ahn S., Ramirez J., Grigorean G., Lebrilla C.B.; J. Am. Soc. Mass Spectrom.; 2001, 12, 3, 278 36. Wainer I.W.; Trends in Anal. Chem.; 1987, 6, 37. Mehta A.C.; J. Chromatogr.; 1988, 426, 38. Dappen R., Hans A., Meyer V.R.; J. Chromatogr.; 1986, 373, 39. Magora A., Abu-Lafi S., Levin S.; J. Chromatogr. A; 2000, 2, 183, 194 40. Guebitz G.; Chromatographia; 1990, 30, 9/10, 555 41. Felix G., Descorps V.; Chromatographia; 1995, 40, 11-12, 680 42. Iredale J., Aubry A.F., Wainer I.; Chromatographia; 1991, 31, 7-8, 329 43. Lee C.K., Kim E.J., Jun J.H.; Bull. Kor. Chem Soc.; 1999, 20, 10, 1153 44. Szejtli J.; Chem. Rev.; 1998, 98, 5, 1743 45. Jozwiakowski M.J., Connors K.A.; Carbohydr. Res.; 1985, 143, 51 46. Bargmann-Leyder N., Truffert J.C., Tambuté A., Caude M.; J. Chromatogr. A; 1994, 66, 27 47. Welch C.; J. Chromatogr. A; 1994, 666, 48. Harata K.; Chem. Rev.; 1998, 98, 1803 49. Harata K.; J. Chem. Soc., Chem. Commun.; 1988, 928 50. Chacko K.K., Saenger W.; J. Am. Chem. Soc; 1981, 103, 1708 51. Harata K.; Bull. Chem. Soc. Jpn.; 1987, 60, 2763 52. Saenger W., Jacob J., Gessler K., Steiner T., Hoffmann D., Sanbe H., Koizumi K., Smith S.M., Takha T.; Chem. Rev.; 1998, 98, 1787 53. Echegoyen L., Kaifer A.E.; Physical Supramolecular Chemistry; Kluwer Academic : London, 1996, p273 54. Connors K.A.; Chem. Rev.; 1997, 97, 1325 55. Shitangkoon A., Vigh G.; J. Chromatogr. A; 1996, 738, 31 198 56. Armstrong D.W.; Stalcup A.M., Hilton M.L., Duncan J.D., Faulkner J.R., Chang S.C.; Anal. Chem.; 1990, 62, 1610 57. Stalcup A.M., Chang S.C, Armstrong D.W.; J. Chromatogr.; 1991, 540, 113 58. Armstrong D.W, Ward T.J, Armstrong R.D., Beesley T.E.; Science; 1986, 232, 1132 59. Nah T.H., Cho E.H., Tang M.D., Lee Y.K., Park J.H.; J. Chromatogr. A; 1996, 722, 41 60. Park J.H., Nah T.H.; J. Chem. Soc., Perkin Trans 2, 1994, 1359 61. Mayer B., Marconi G., Klein C., Kohler G., Wolschann P.; J. Inclusion Phenom. Mol. Recogn. Chem.; 1997, 29, 79 62. Berthod A., Chang S.C., Armstrong D.W.; Anal. Chem.; 1992, 64, 395 63. Dowd M.K., French A.D., Reilly P.J.; Carbohydr. Res.; 1994, 264, 64. Buvári-Barcza A., Barcza L.; Talanta; 1999, 49, 577 65. Lipkowitz K.B., Pearl G., Coner B., Peterson M.A.; J. Am. Chem. Soc.; 1997, 119, 600 66. Lipkowitz K.B., Coner R., Peterson M.A., Morreale A., Shackelford J.; J. Org. Chem.; 1998, 63, 732 67. Lipkowitz K.B., Coner R., Peterson M.A.; J. Am. Chem. Soc.; 1997, 119, 11269 68. Morinder U., Sundholm E.G.; J. Liq. Chromatogr.; 1987, 10, 13, 2825 69. Matsui Y., Okimoto A.; Bull. Chem. Soc. Jpn.; 1978, 51, 10, 3030 70. Kuroda Y., Suzuki Y., He J., Kawabata T., Shibukawa A., Wada H., Fujima H., Go-oh Y., Imai E., Nakagawa T.; J. Chem. Soc., Perkin Trans 2; 1995, 1749 71. Schneider H.J., Hacket F., Rüdiger V.; Chem. Rev.; 1998, 98, 1755 72. Bergeron R.J., Channing M.A., Gibeily G.J., Pillor D.M.; J. Am. Chem. Soc.; 1977, 99, 15 199 73. Gafni A., Cohen Y., Kataky R., Palmer S., Parker D.; J. Chem. Soc., Perkin Trans 2; 1998, 19 74. Armstrong D.W., Nome F., Spino L.A., Golden T.D.; J. Am. Chem. Soc.; 1986, 108, 1418 75. Loukas Y.L.; Anal. Chem.; 1998, 70, 966 76. Clarke R.J., Coates J.H., Lincoln S.F.; Adv. Carbohydr. Chem. Biochem.; 1988, 46, 205 77. Bertrand G.L., Faulkner J.R., Han S.M., Armstrong D.W.; J. Phys. Chem.; 1989, 93, 6863 78. Dhillon R., Easton C.J., Lincoln S.F.; Aust. J. Chem.; 1995, 48, 1117 79. Fujita K., Ueda T., Imoto T., Tabushi I., Toh N., Koga T.; Bioorg. Chem.; 1982, 11, 72 80. Tung C.H., Zhen Z., Xu H.J.; J. Photochem.; 1986, 32, 311 81. Kamiya M., Mitsuhashi S., Makino M., Yoshioka H.; J. Phys. Chem.; 1992, 96, 95 82. Rontoyianni A., Mavridis I.M., Hadjoudis E., Duisenberg A.J.M.; Carbohydr. Res.; 1994, 252, 19 83. Demarco P.V., Thakkar A.L.; Chem. Commun.; 1970, 84. Li S., Purdy W.C; Anal. Chem.; 1992, 64, 1405 85. Szetjli J.; Cyclodextrin Technology; Kluwer : Dordretcht, 1988 86. Anan’eva I.A., Shapovalova E.N, Lopatin S.A, Shpigun O.A., Varlamov V.P., Davankov V.A., Armstrong D.W.; Anal. Chem.; 2002, 57, 4, 331 87. Lee S.H., Berthod A., Armstrong D.W; J. Chromatogr.; 1992, 603, 83 88. Nie M.Y., Zhou L.M., Wang Q.H., Zhu D.Q.; Anal. Sci.; 2001, 17, 1183 89. Merino M., Gonzalez E.B., San-Medel A.; Anal. Chim. Acta; 1990, 234,127 200 90. Li S., Purdy W.C.; J. Chromatogr.; 1991, 543, 105 91. Florance J., Galdes A.; Konteatis Z., Kosarych Z., Langer K., Martucci C.; J. Chromatogr.; 1987, 414, 313 92. Florance J., Konteatis Z.; J. Chromatogr.; 1991, 345, 299 93. Chang A.C., Ji H., Lin G.; Liq. Chromatogr.; 1990, 522, 143 94. Kawaguchi Y., Tanaka M., Nakae M., Funazo K., Shono T.; Anal. Chem.; 1983, 55, 1852 95. Crini G., Lekchiri Y., Janus L., Morcellet M., Morin N.; Chromatographia; 1999, 50, 11/12, 661 96. Crini G, Lekchiri Y., Martel B., Janus L., Morcellet M.; Chromatographia; 1995, 41, 7/8, 424 97. Pietta G., Mauri P.L., Manera E., Ceva P.L., Rava A.; Chromatographia; 1989, 27, 9/10, 509 98. Krause M., Galensa R.; J. Chromatogr.; 1991, 588, 41-45 99. Haslem E., Lilley T.H., Cai Y., Martin R., Magnolato D.; Planta Medica; 1989, 55, 100. Paleologou M., Li S., Purdy W.C.; J. Chromatogr. Sci.; 1990, 28, 319 101. Paleologou M., Li S., Purdy W.C.; J. Chromatogr. Sci.; 1990, 28, 311 102. Krupcik J., Benicka E., Majek P., Shacani I., Sandra P.; J. Chromatogr. A; 1994, 665, 175 103. Chang C.A., Wu Q.H., Armstrong D.W.; J. Chromatogr.; 1986, 354, 454 104. Armstrong D.W., Chen S., Chang C., Chang S.; J. Liq. Chromatogr.; 1992, 15, 3, 545 105. Sztruhar I., Ladanyi L., Simonyi I., Furdyga E.; Chromatographia; 1989, 27, 7/8, 364 201 106. Stalcup A.M., Gahm K.H.; Balduoza M.; Anal. Chem.; 1996, 68, 2248 107. Stammel W., Woesle B., Thomas H.; Chirality; 1995, 7, 10 108. Armstrong D.W., Demond W., Alak A., Hinze L.W., Riehl T.E., Bui K.H.; Anal. Chem.; 1985, 57, 234 109. Vigh G., Quintero G., Farkas G.; J .Chromatogr.; 1989, 484, 237 110. Packham A.J., Fielden P.R.; J. Chromatogr.; 1991, 552, 575 111. Fujimoto C., Maekawa A., Murao Y., Jinno K., Takeichi T.; Anal. Sci.; 2002, 18, 65 112. Easton C.J., Lincoln S.F.; Modified Cyclodextrins: Scaffolds and Templates For Supramolecular Chemistry; Imperial College Press : River Edge, N.J., 1999, Chp 1, 113. Shiraishi S., Komiyama M., Hirai H.; Bull. Chem. Soc. Jpn.; 1986, 59, 507 114. Froemming K.H., Szejtli J.; Cyclodextrin Pharmacy; Kluwer : Dordretcht, 1988 115. Szejtli J.; Pure Appl. Chem.; 2004, 76, 10, 1825 116. Tahashi K.; Chem. Rev.; 1998, 98, 2013 117. Li S.; Purdy W.G.; Chem. Rev.; 1992, 92, 1457 118. Hedges A.R.; Chem. Rev.; 1998, 98, 2035 119. Wilson T.D.; J. Chromatogr. ; 1988, 448, 1, 31 120. Ho-Hyun M., Sung-Jin J., Lee W.; J. Chromtogr. A; 1998, 822, 155 121. Aboul-Enein H.Y., Serignese V.; Biomed. Chromatogr.; 1997, 11, 1, 122. Rizzi A.M. ; J. Chromatogr.; 1989, 478, 1, 87 123. Rizzi A.M.; J. Chromatogr.; 1989,478, 1, 101 124. Takahashi H., Kanno S., Ogata H., Kashiwada K., Ohira M., Someya K.; J. Pharm. Sci.; 1988, 77, 11, 993 202 125. Blaschke G.; J. Liq. Chromatogr.; 1986, 9, 341 126. Blaschke G., Fraenkel W., Bröker W.; Angew. Chem.; 1986, 98, 808 127. Vanoverbeke A., Baeyens W., Vandenbossche W., Dewaele C.; J. Pharm. Biomed. Anal.; 1994, 12, 7, 911 128. Aboul-Enein H.Y.; Anal. Lett.; 1993, 26, 2, 271 129. Rustichelli C., Ferioli V., Gamberini G., Stancanelli R.; Chromatographia; 2001, 54, 11-12, 731 130. Okamoto Y., Kawashima M., Aburatani R., Hatada K., Nishiyama T., Masuda M.; Chem. Lett.; 1986, 1237 131. Okamoto Y., Hatada K.; J. Liq. Chromatogr.; 1986, 9, 369 132. Davankov V.A., Rogozhin S.V.; J. Chromatogr.; 1971, 60, 280 133. Kuganov A.; J. Chromatogr. A; 2001, 906, 51 134. Ahuja S.; Chiral Separations by Chromatography; Oxford University Press : New York, 2000, p109 135. Ching C.B., Lim B.G., Lee E.J.D., Ng S.C.; J. Chromatogr.; 1993, 634, 215 136. Francotte E., Richert P., Mazzotti M., Morbidelli M.; J. Chromatogr. A; 1998, 796, 239 137. Sommer B.M., Nielsen O., Petersen H., Ahmadian H., Pedersen H., Brosen P., Geiser F., Lee J., Cox G., Dapremont O., Suteu C., Assenza S.P., Hariharan S., Nair U., PCT Int. Appl. WO 2003006449; 2003, 33 pp 138. Dapremont O., Geiser F., Zhang T., Guhan S.S., Guinn R.M., Quallich G.J.; PCT Int. Appl. WO 9957089; 1999, 16 pp. 139. Villiers, A.; Compt. Rend.; 1891, 112, 536 140. Schardinger F.; Zentralbl. Bateriol. Parasitenk. Abt. 2; 1905, 14, 772 141. Schardinger F.; Zentralbl, Bateriol Parasitenk. Abt 2; 1911, 29, 188 203 142. Pringsheim H.; Chemistry of the Saccharides; McGraw-Hill : New York, 1932, p280 143. Pringsheim H.; A Comprehensive Survey of Starch Chemistry; Walton R.P, Ed, Chemical Catalogue Co. : New York, 1928, p35 144. Freudenberg K., Blomguist G., Ewald L., Soff K.; Ber. Dtsch. Chem. Ges.; 1936, 69, 1258 145. Freudenberg K., Meyes-Delius M.; Ber. Dtsch. Chem. Ges.; 1938, 71, 1596 146. Freudenberg K., Cramer F.Z.; Naturforsch.; 1948, 3b, 464 147. French D.; Adv. Carbohydr. Chem.; 1957, 12, 189 148. Cramer F.; Einschlussverbin dungen (Inclusion Compounds); Springer-Verlog : Berlin, 1954 149. Thomas J.A., Stewart L.; Starch, Chemistry and Technology I.; Whistler, R.L., Paschall, E.F., Eds., Academic Press : New York, 1965, p 209 150. Szetjtli J.; Cyclodextrin and Their Inclusion Complexes; Akademai, Kiado : Budapest, 1982, p 296 151. Joshua B., Corcoran R.J., Lehn J.M.; Helv. Chim. Acta.; 1978, 61, 6, 2190 152. Fujimura K., Ueda T., Ando T.; Anal. Chem.; 1983, 55, 446 153. Armstrong D.W., DeMond W.; J. Chromatogr. Sci.; 1984, 22, 411 154. Armstrong D.W., Han Y.I., Han S.M.; Anal. Chim. Acta; 1988, 208, 275 155. Hinze L.W., Riehl T.E., Armstrong D.W.; Demond W., Alak A., Ward T.; Anal. Chem.; 1985, 57, 237 156. Krause M., Galensa R.; J. Chromatogr. A; 1990, 514, 147 157. Chang S.C., Reid III G.L., Chen S., Chang C.D., Armstrong D.W.; Trends in Anal. Chem.; 1993, 12, 158. Ward T.J., Armstrong D.W.; J. Liq. Chromatogr.; 1986, 9, 2, 407 204 159. Pirkle W.H., McCune J.E.; J. Chromatogr.; 1989, 469, 67 160. Kano K.; J. Phys. Org. Chem. ; 1997, 10, 286 161. Lipkowitz K.B., Raghothama S., Yang J.A.; J. Am. Chem. Soc.; 1992, 114, 1554 162. Sakurai M., Kitagawa M., Hoshi H., Inoue Y., Chujo R.; Chem. Lett.; 1988, 895 163. Peyrin E., Guillaume Y.C., Ravel A.; Anal. Chem.; 2000, 72, 1263 164. Ng S.C., Zhang L.F., Ching C.B.; United States Patent 6,017,458, 2000 165. Zhang L.F., Wong Y.C., Ching C.B., Ng S.C.; Tetrahedr. Lett.; 1999, 40, 1815 166. Chen L., Zhang L.F., Ching C.B., Ng S.C.; J. Chromatogr. A; 2002, 950, 65 167. Zhang L.F., Chen L., Lee T.C., Ng S.C.; Tetrahedr. Asym.; 1999, 10, 4107 168. Lai X.H., Ng S.C.; Tetrahedr. Lett.; 2003, 44, 2657 169. Lai X.H., Ng S.C.; J. Chromatogr. A ; 2004, 1031, 135 170. Bai Z.W., Ching C.B., Ng S.C.; Chromatographia; 2003, 58, / 2, 43 171. Ng S.C., Ong T.T., Fu P., Ching C.B.; J. Chromatogr. A; 2002, 968, 31 172. Lai X.H., Ng S.C.; J. Chromatogr. A; 2004, 1059, 53 173. Ng S.C., Chen L., Zhang L.F., Ching C.B.; Tetrahedr. Lett.; 2002, 43, 677 174. Bai Z.W., Lai X.H., Chen L., Ching C.B., Ng S.C.; Tetrahedr. Lett.; 2004, 45, 7323 175. Lai X.H., Bai Z.W., Ng S.C., Ching C.B.; Chirality; 2004, 16, 592 176. http://www.tradewithfrance.org/catalog/pdf/chirosep_cyclose_new.pdf 177. Murakami T., Hanaka K., Morimoto S.; Tetrahedr. Lett.; 1987, 28, 3, 321 178. Melton L.D., Slessor K.N.; Carbohydr. Res.; 1971, 18, 29 179. Byun H.S., Zhong N., Bittman R.; Org. Synth.; 2000, 77, 225 205 180. Zhong N., Byun H.S., Bittman R.; Tetrahedr. Lett.; 1998, 39, 2919 181. Fujita K., Yamamura H., Matsunaga A., Imoto T., Mihashi K., Fujioka T.; J. Am. Chem. Soc.; 1986, 108, 4509 182. Atsumi M., Izumida M., Yuan D.Q., Fujita K.; Tetrahedr. Lett.; 2000, 41, 8117 183. Cimecioglu A.L., Ball D.H., Huang S.H., Kaplan D.L.; Macromolec.; 1997, 30, 155 184. Tabushi I., Shimizu N., Sugiomo T., Shiozuka M., Yamano K.; J. Am. Chem. Soc.; 1977, 99, 21, 7100 185. Khan A.R., Forgo P., Stine K.J., D’Souza V.T.; Chem. Rev.; 1998, 98, 5, 1977 186. Ding R., D’Souza V.T.; Tetrahedr. Lett.; 1990, 31, 30, 4275 187. Ohta K., Fujita K., Shimada H., Ikegami Y., Nogami Y., Koga T.; Chem. Pharm. Bull.; 1997, 45, 4, 631 188. Ueno A., Breslow R.; Tetrahedr. Lett.; 1982, 23, 34, 3451 189. Takahashi K., Hattori K., Toda F.; Tetrahedr. Lett.; 1984, 25, 31, 3331 190. Fujita K., Nagamura S., Imoto T.; Tetrahedr. Lett; 1984, 25, 49, 5673 191. Fujita K., Ishizu T., Oshiro K., Obe K.I.; Bull. Chem. Soc. Jpn.; 1989, 62, 2960 192. Coleman A.W., Zhang P., Parrot-Lopez H., Ling C.C., Miocque M., Mascrier L.; Tetrahedr. Lett.; 1991, 32, 32, 3997 193. Teranishi K., Watanabe K., Hisamatsu M., Yamada T.; J. Carbohydr. Chem.; 1998, 17, 3, 489 194. Teranishi K.; Tetrahedr.; 2003, 59, 2519 195. Breslow R., Czarnik A.W., Lauer M., Leppkes R., Winkler J., Zimmerman S.; J. Am. Chem. Soc.; 1986, 108, 1969 206 196. Breslow R., Czarnik A.W.; J. Am. Chem. Soc.; 1983, 105, 1390 197. Fujita K., Tahara T., Imoto T., Koga T.; J. Am. Chem. Soc.; 1986, 108, 2030 198. Hoffmann B., Bernet B., Vasella A.; Helv. Chim. Acta.; 2002, 85, 265 199. Yano H., Hirayama F., Arima H., Uekama K.; J. Pharm. Sci.; 2001, 90, 200. Garcia-Barrientos A., Garcia-Lopez J.J., Isac-Garcia J., Ortega-Cabellero F., Uriel C., Vargas-Berenguel A., Santoyo-Gonzalez F.; Synth.; 2001, 7, 1057 201. Dienst E., Snellink B.H.M., Piekartz I., Gansey G., Venema F., Feiters M.C., Nolte R.J.M., Engbersen J.F.J., Reinhoudt D.N.; J. Org. Chem.; 1995, 60, 6537 202. Hao A Y, Tong L H, Zhang S F, Gao X M; Carbohydr. Res.; 1995, 277, 333 203. Tian S.P., Zhu H., Forgo P., D’Souza V.T.; J. Org. Chem. ; 2000, 65, 2624 204. Tian S.P., D’Soza V.T.; Tetrahedr. Lett.; 1994, 35, 50, 9339 205. Jiang T., Sukumaran D.K., Soni S.D., Lawrence D.S.; J. Org. Chem.; 1994, 59, 5149 206. Chiu S.H., Myles D.C., Garrell R.L., Stoddart J.F.; J. Org. Chem.; 2000, 65, 2792 207. Ishimaru Y., Masuda T., Iida T.; Tetrahedr. Lett.; 1997, 38, 21, 3743 208. Teranishi K.; Tetrahedr. Lett.; 2001, 42, 5477 209. Fujita K., Nagamura S., Imoto T., Thara T., Koga T.; J Am. Chem. Soc.; 1985, 107, 3233 210. Ikeda H., Nagano Y., Du Y.Q., Ikeda T., Toda F.; Tetrahedr. Lett.; 1990, 31, 35, 5045 211. Pregel M.J., Buncel E.; Can. J. Chem. ; 1991, 69, 130 212. Khan A.R., Barton L., D’Souza V.T.; J. Org. Chem.; 1996, 61, 8301 213. Sofian A.S.M., Lee C.K., Linden A.; Carbohydr. Res.; 2002, 337, 2377 207 214. Suzuki I., Sakurai Y., Obata K., Osa T., Anzai J.I.; Heterocycles; 1998, 49, 469 215. Rao K.R., Srinivasan T.N., Bhanumathi N., Sattur P.B.; J. Chem. Soc., Chem. Commun.; 1990, 2362, 10 216. Kovács J., Pintér I., Messmer A.; Carbohydr. Res.; 1985, 141, 1, 57 217. Pintér I., Kovács J., Tóth G.; Carbohydr. Res.; 1995, 273, 99 218. Gololobov Y.G., Zhmurova N.I., Kasakhin F.; Tetrahedr.; 1981, 37, 437 219. Gololobov Y.G., Kasukhin L.F.; Tetrahedr.; 1992, 48, 8, 1353 220. Kovacs J., Pintér I., Messer A.; Carbohydr. Res.; 1987, 166, 101 221. Lange G.L., Gottardo C.; Synth. Commun.; 1990, 20, 10, 1473 222. Griebenow K., Laureano Y.D., Santos A.M., Clemente I.M., Rodriguez L., Vidal M.W., Barletta G.; J. Am. Chem. Soc.; 1999, 121, 8157 223. Berthod A.; Chang C.D.; Armstrong, D.W.; Talanta; 1993, 40, 1367 224. Bidlingmeyer B.A.; Warren F.V.; Anal. Chem.; 1984, 56, 14, 1583A 225. Hargitai T., Okamoto Y.; J. Liq. Chromatogr.; 1993, 16, 4, 843 226. Hargitai T., Kaido Y., Okamoto Y.; J. Chromatogr.; 1992, 628, 11 227. Ciucanu I., König W.A.; J. Chromatogr. A; 1994, 685, 166 228. Ciucanu I.; J. Chromatogr. A; 1996, 727, 195 229. Chankvetadze B., Yashima E., Okamoto Y.; Chirality; 1996, 8, 402 230. Tanaka M., Shono T., Zhu D.Q., Kawaguchi Y.; J. Chromatogr.; 1989, 469, 429 231. Stalcup A.M., Chang S.C., Armstrong D.W.; J. Chromatogr.; 1990, 513, 181 232. Armstrong D.W., Li W.Y., Chang C.D., Pitha J.; Anal. Chem.; 1990, 62, 914 233. Armstrong D.W., Hilton M., Coffin L.; LC-GC; 1991, 9, 9, 646 234. Armstrong D.W., Chang C.D., Lee S.H.; J. Chromatogr.; 1991, 539, 83 208 235. Watt A.P., Rathbone D.; J. Liq. Chromatogr.; 1993, 16, 16, 3423 236. Stalcup A.M., Gahm K.H.; Anal. Chem.; 1996, 68, 1369 237. Chen X.M., Yang L., Zou H.F., Zhang Q., Ni J.Y.; Chinese J. Anal. Chem.; 2000, 28, 9, 1074 238. Alvira E., Garcia J. I., Mayoral J. A.; Recent Res. Develop. Chem. Phys.; 2000, 1, 89 239. Christoff M., Okano L.T., Bohne C.; J. Photochem. Photobio. A: Chem.; 2002, 44, 225 240. Duval R., Leveque H., Prigent Y., Aboul-Enein H.Y.; Biomed. Chromatogr.; 2001, 15, 202 241. Han X., Zhong Q., Yue D., Della N., Larock R.C., Armstrong D.W.; Chromatographia; 2005, 61, 5-6, 205 242. Han X.X., Yao T.L., Liu Y., Larock R.C., Armstrong D.W.; J. Chromatogr. A; 2005, 1063, 1-2, 111 243. Heck R., Jicsinszky L., Marsura A.; Tetrahedr. Lett.; 2003, 44, 5411 244. Kaneda T., Fujimoto T., Goto J., Asano K., Yasufuku Y., Jung J.H., Hosono C., Sakata Y.; Chem. Lett.; 2002, 514 245. Lai X.H.; Development of Chiral Stationary Phases for HPLC based on Selectively Modified Cyclodextrin; pH.D thesis, National University of Singapore, 2004 246. Felix G., Zhang T.; J. Chromatogr.; 1993, 639, 141 247. Felix G., Cachau C., Thienpont A., Soulard M.H.; Chromatographia; 1996, 42, 248. Okamoto Y., Kaida Y.; J. Chromatogr. A; 1994, 666, 403 249. Cachau C., Thienpont A., Soulard M.H., Felix G.; Chromatographia; 1997, 209 44, 250. Yamamoto C., Hayashi T., Okamoto Y., Kobayashi S.; Chem. Lett.; 2000, 1, 12 251. Okamoto Y., Noguchi J., Yashima E.; React. Funct. Polym.; 1998, 37, 1-3, 183 252. Zhu Q.H., Ma G.D., Deng Q.Y., Zeng L.M.; Chinese J. Anal. Chem.; 2000, 28, 3, 349 253. Araki T., Tsunoi S., Tanaka M.; Anal. Chim. Acta; 2000, 410, 37 254. Ng S.C., Sun T., Chan H.S.O.; Macromolec. Symp.; 2003, 192, 171 255. Schurig V., Nowotny H.P.; J. Chromatogr.; 1988, 441, 155 256. Roizel B., Baltaze J.P., Sinay P.; Tetrahedr. Lett.; 2002, 43, 2371 257. Tanaka M., Okazaki J., Ikeda H., Shono T.; J. Chromatogr.; 1986, 370, 293 258. Armstrong D.W.; Wang L., Chang L.W.; Ibrahim H., Reid G.R., Beesley T.E.; J Liq. Chromatogr. Rel. Technol.; 1997, 20, 20, 3297 259. Armstrong D.W., Chang L.W., Chang S.C., Wang X., Ibrahim H., Reid G.R., Beesley T.E.; J Liq. Chromatogr. Rel. Technol.; 1997, 20, 20, 3279 260. Fronza G., Fuganti C., Genesio E., Mele A.; J. Inclusion Phenom. Macrocyclic Chem.; 2002, 44, 225 261. Armstrong D.W., Bertrand G.L., Ward K.D., Ward T.J., Secor H.V., Seeman J.I.; Anal. Chem.; 1990, 62, 332 262. Zief M., Crane L.J; Chromatographic Separations; Marcel Dekker : New York, 1990, Chp 263. Ruiz-Angel M.J., Torres-Lapasio J.R., Garcia-Alvarez-Coque M.C.; J. Chromatogr. A; 2004, 1022, 51 210 [...]... examples of drugs that can cause different effects due to the contribution by two different isomers In 2002, the sales of chiral compounds as drugs (individual isomers as well as racemic mixtures) had reached $159 billion, of which approximately 30% of all drug sales were single enantiomers Global sales of single-enantiomer compounds are expected to grow annually by 11.4%.2 This increasing demand of chiral. .. well-established technique before LC is nonetheless still widely used The chiral selector in gas chromatography can be 6 Table 1.1 Features for non-separation methods for chiral analyses17 Methods Features Polarimetry Makes use of the unique property of a chiral compound to rotate the plane of polarization of plane-polarised light The asymmetry of the chiral carbon atom, with its four dissimilar substituent groups,... enantiomerically pure chiral substances into the gas mixture with regular, achiral sweep gas such as helium However, most chiral gas chromatography today incorporates the chiral selector in the stationary phase Cyclodextrin CSPs are now very popular in chiral GC, and with the benefits of the high efficiency and resolving power of capillary GC it is possible to resolve large numbers of components of complex mixtures... Separation-based methods for chiral analysis can be classified according to four main methods, chiral liquid chromatography (LC), chiral gas chromatography 5 (GC), supercritical fluid chiral chromatography (SFC) and chiral capillary electrophoresis (CE) Table 1.2 compares the brief features of these techniques The general principle of any chromatography is based on the partitioning of a substance between... pharmaceutical industry has also stimulated the development of new and specialized companies in asymmetric synthesis giving enantiomerically pure substances.1-3 2 Figure 1.1 Examples of chiral drugs 1.1 The History of Enantiomeric Resolution The resolution of enantiomers can be said to be started by Pasteur4 who first discovered the spontaneous resolution of racemic ammonium sodium tartrate, which yielded two... involving a chiral- bonded ligand, led to chiral resolution Cram and his group12 discovered a different kind of inclusion complex in crown ether, which was later chemically bonded to silica gel to resolve the enantiomers by the HPLC technique Since then, an increased number of chiral phases are available for separating various classes of racemates.13-16 1.2 Chiral Analysis The analysis of enantiomers... instead of CSPs, chiral mobile phase additives (CMA) such as camphonic acid or quinine can also be used Disadvantages: - Many additives are costly - Many additives are not commercially available - Their mode of operation is complex - Removal of chiral additives from the enantiomeric solute is necessary for preparative application 1.5 Mechanism of Separation From a thermodynamic point of view, chiral. .. for the D- and L- amino acid enantiomers.84 Table 1.4 shows the preferred structures of solutes for binding into the cavity of three types of CD which have different internal diameters due to different number of glucose units Table 1.4 The type of molecules associated with the cavity of the three types of CD85 Type of CD Internal Diameter Appropriate structure for complexing the CD α-CD 4.5-6.0 Å Five-... it Two types of crystallisation technology have been used: preferential and diastereoisomer a Preferential crystallisation Involves seeding a supersaturated solution of racemate with pure crystals of one of the enantiomers; this seeding causes only one isomer to crystallise out of solution b Diastereomeric crystallisation A chiral precipitating agent (or resolving agent) is added to a racemic solution... isomers of the racemate, but because of solubility differences, one of the isomer complexes crystallises out more readily than the other 2 Solvent extraction Involves prudent choice of system and solvent because the two isomers often have very similar properties, including their solubility in common solvents Thus, innovative techniques are required in chiral solvent extraction For instance, a chiral . CHIRAL SEPARATION OF RACEMIC DRUGS POON YIN FUN (B.Sc.(Hons.). NUS) A THESIS SUBMITTED FOR THE DEGREE OF DOCTOR OF PHILOSOPHY DEPARTMENT OF CHEMISTY NATIONAL. influence of changing pH of the buffer and mobile phase composition on enantioseparation of several racemic drugs and compounds ix were also examined using a permethylated CD CSP based on the chiral. examples of drugs that can cause different effects due to the contribution by two different isomers. In 2002, the sales of chiral compounds as drugs (individual isomers as well as racemic