Synthesis of N-Phenethylnorhydromorphone, A
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SYNTHESIS OF N-PHENETHYLNORHYDROMORPHONE, A HYDROMORPHONE ANALOGUE by KAREN LO B.Sc. (Pharm.), University of British Columbia, 1998 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE in THE FACULTY OF GRADUATE STUDIES (Faculty of Pharmaceutical Sciences) We accept this thesis as conforming to the required standard THE UNIVERSITY OF BRITISH COLUMBIA August 2001 © Karen Lo, 2001 In presenting this thesis in partial fulfilment of the requirements for an advanced degree at the University of British Columbia, I agree that the Library shall make it freely available for reference and study. I further agree that permission for extensive copying of this thesis for scholarly purposes may be granted by the head of my department or by his or her representatives. It is understood that copying or publication of this thesis for financial gain shall not be allowed without my written permission. Department The University of British Columbia Vancouver, Canada DE-6 (2/88) ABSTRACT Since its clinical introduction in 1926 11, hydromorphone (7) has been used in the treatment of moderate to severe pain. Hydromorphone (7) is a semi-synthetic congener of morphine (1), and it has a relative analgesic potency of 5 tol compared to its parent compound 1. It has been shown from previous structure-activity relationships on opioid analgesics that when a peripheral group on the molecule is modified, the analgesic activity of the molecule is altered. Specifically, the substitution of a phenethyl moiety for the methyl group on the basic nitrogen of opioid analgesics produces an increase in analgesic activity. For example, fentanyl (27), which is part of the piperidine group of analgesics, is found in rats to be 300 times more potent than morphine (1), the gold standard for comparative effects between opioid analgesics. To date, the A/-phenethyl derivative 20 of hydromorphone has not been synthesized. As such, the purpose of this study was to synthesize N- phenethylnorhydromorphone (20); and ultimately to test the analgesic activity of 20 in the rat model. We hypothesized that the direct alkylation of norhydromorphone (17) with an alkyl halide via an SN2 reaction mechanism would be an effective route for the synthesis of A/-phenethylnorhydromorphone (20). Although the chemical method proved to be effective in producing the desired compound 20, it was not efficient, producing a low yield of 1.3%. The identity of compound 20 was confirmed by high-performance liquid chromatography-tandem mass spectrometry, infrared spectroscopy, and 1H NMR analysis, both one-dimensional and two-dimensional. In conclusion, an alternate approach towards the synthesis of compound 20 will need to be examined in order to improve the productive yield, such that more product will be available for further studies on the analgesic activity of A/-phenethylnorhydromorphone (20). Research Supervisor Keith M. McErlane, Ph.D. TABLE OF CONTENTS ABSTRACT ii TABLE OF CONTENTS iv LIST OF SCHEMES vi LIST OF FIGURES vii LIST OF TABLES viii LIST OF APPENDICES ix LIST OF ABBREVIATIONS x ACKNOWLEDGEMENTS xiii DEDICATION xv CHAPTER 1. INTRODUCTION 1 1.1 Historical Background 4 1.2 Chemistry of Hydromorphone (7) 9 1.3 Pharmacology of Hydromorphone (7) 12 1.3.1 Pain 12 1.3.2 Opioid Receptors 14 1.3.3 Mechanism of Action 18 1.3.4 Clinical Use 20 1.4 Clinical Pharmacokinetics of Hydromorphone (7) 21 1.5 Metabolism of Hydromorphone (7) 25 iv 1.6 Structure-Activity Relationships of Morphine (1) and Related Compounds 30 1.7 Thesis Rationale, Hypotheses and Objectives 34 CHAPTER 2. RESULTS AND DISCUSSION 36 2.1 Synthesis of /V-Phenethylnorhydromorphone (20) 37 2.2 Methiodide Salt Reaction 39 2.3 Synthesis of Norhydromorphone (17) 41 2.4 Direct Alkylation of Norhydromorphone (17) 42 2.4.1 Ether Hydrolysis of A/,3-0-diphenethylnorhydromorphone (31) 47 2.4.2 Protecting Groups 48 2.5 Final Strategy in the Synthesis of A/-Phenethylnorhydromorphone (20) 51 2.6 Compound Characterization 56 2.7 Conclusion 61 CHAPTER 3. EXPERIMENTAL 62 3.1 General 62 3.2 Chemicals 64 3.3 Instrumentation 66 3.4. Chemical Methods 68 References 73 Appendices 82 v LIST OF SCHEMES Scheme 1 /V-substitution of hydromorphone (7) to produce N- phenethylnorhydromorphone (20). 37 Scheme 2 Intermediates 17 and 29 produced for the synthesis of 20. 38 Scheme 3 Synthesis of A/-phenethylnorhydromorphone (20) via the methiodide salt reaction. 39 Scheme 4 Synthesis of norhydromorphone (17). 41 Scheme 5 Synthesis of A/-phenethylnorhydromorphone (20) through direct alkylation of norhydromorphone (17). 42 Scheme 6 Ether hydrolysis of the di-alkylated by-product A/,3-0- diphenethylnorhydromorphone (31). 47 Scheme 7 Phenolic OH group protection with the tetrahydropyran ether in the synthesis of 20. 49 Scheme 8 Phenolic OH group protection with the TMS ether in the synthesis of 20. 50 Scheme 9 The synthesis of A/-phenethylnorhydromorphone (20) involving acylation, reduction, and oxidation of norhydromorphone (17). 52 Scheme 10 The synthesis of A/-phenethylnorhydromorphone (20) involving acylation, reduction, and oxidation of nordihydroisomorphine (19). 54 vi LIST OF FIGURES Figure 1 The two basic structures recognized amongst the opium alkaloids. 2 Figure 2 Absolute configuration and conformation of morphine (1). 8 Figure 3 Absolute configuration and conformation of hydromorphone (7). 10 Figure 4 Synthesis of hydromorphone (7). 11 Figure 5 Beckett and Casy's representation of the "analgesic receptor surface". 15 Figure 6 The corresponding ligands to the u-, K-, and o-opioid receptors. 16 Figure 7 Mechanism of action of u-opioid receptors. 18 Figure 8 The three common mechanisms of opioid action. 19 Figure 9 The metabolites of hydromorphone (7). 27 Figure 10 TLC taken three hours after the start of the reaction. 45 Figure 11 The chemical structure of /V-phenethylnorhydromorphone (20). 56 Figure 12 A detailed view and the Newman projection of 9-H, 10flC-H, and 100-H. , 559 vii LIST OF TABLES Table 1 The pharmacokinetic parameters of hydromorphone (7) in healthy volunteers. 23 Table 2 Selected structural-activity relationships of morphine (1). 31 Table 3 Reaction conditions of methods 1-6 for the direct alkylation of 17. 43 Table 4 Summary of the chemical shifts for /V-phenethylnorhydromorphone (20). 58 viii LIST OF APPENDICES Appendix 1 LC-MS and LC-MS-MS spectra of hydromorphone (7). 83 Appendix 2 IR spectrum of hydromorphone (7). 84 1 Appendix 3 H NMR spectrum of hydromorphone (7) in d6-DMSO. 85 Appendix 4 1H * 1H NMR spectrum of hydromorphone (7) in de-DMSO. 86 Appendix 5 LC-MS and LC-MS-MS spectra of norhydromorphone (17). 87 Appendix 6 LC-MS and LC-MS-MS spectra of nordihydroisomorphine (19). 88 Appendix 7 LC-MS and LC-MS-MS spectra of W-phenethylnorhydromorphone (20). 89 Appendix 8 IR spectrum of A/-phenethylnorhydromorphone (20). 90 Appendix 9 1H NMR spectrum of W-phenethylnorhydromorphone (20) in de-DMSO. 91 Appendix 10 1H NMR spectrum of /V-phenethylnorhydromorphone (20) in de-DMSO with D20 added. 92 Appendix 11 1H x 1H NMR spectrum of /V-phenethylnorhydromorphone (20) in de-DMSO. 93 Appendix 12 LC-MS and LC-MS-MS spectra of A/-trichlorocarbethoxynorhydromorphone (30). 94 Appendix 13 1H NMR spectrum of W-trichlorocarbethoxynorhydromorphone (30) in de-DMSO. 95 Appendix 14 LC-MS spectrum of /V,3-0-diphenethylnorhydromorphone (31). 96 Appendix 15 LC-MS and LC-MS-MS spectra of /V,3-0-trichlorocarbethoxynorhydromorphone (38). 97 Appendix 16 1H NMR spectrum of A/,3-0-trichlorocarbethoxynorhydromorphone (38) in de-DMSO. 98 ix LIST OF ABBREVIATIONS AUC area under the plasma concentration versus time curve bp boiling point br s broad singlet cAMP cyclic adenosine monophosphate d doublet dd doublet of doublets 5 chemical shift (measured in ppm), delta opioid receptor (COCI)2 oxalyl chloride COSY " correlation spectroscopy (1H X1H NMR) D2O deuterium oxide DHP dihydropyran DMSO dimethyl sulfoxide d6-DMSO deuterated dimethyl sulfoxide Gi inhibitory G-protein 1H NMR proton nuclear magnetic resonance 1H x 1H NMR proton-proton nuclear magnetic resonance HPLC high-performance liquid chromatography hr hour Hz hertz i.v. intravenous IR infrared spectroscopy x J coupling constant (measured in Hz) K kappa opioid receptor Ke elimination rate constant IJAIH4 lithium aluminum hydride LC-MS high-performance liquid chromatography-mass spectrometry LC-MS-MS high-performance liquid chromatography-tandem mass spectrometry u mu opioid receptor m multiplet mp melting point m/z mass-to-charge ratio [M+1]+ protonated molecular ions MRM multiple reaction monitoring MS mass spectrometry NMR nuclear magnetic resonance p.o. oral PCA patient-controlled analgesia ppm parts per million a sigma opioid receptor s singlet tviP elimination half-life TEA triethylamine TLC thin-layer chromatography TMS trimethylsilyl UDP uridine diphosphate xi apparent volume of distribution xii ACKNOWLEDGEMENTS I would like to thank first and foremost my supervisor Dr. Keith McErlane for his faith in me, and for giving me the opportunity to work in his lab, thus allowing me to accomplish something I never thought I would have been capable of. Secondly, I would like to thank Dr. Stelvio Bandiera for taking on the role of my acting supervisor during Dr. Keith McErlane's absence, and to Dr. Wayne Riggs for his encouraging advice and support. In addition I need to thank the other members of my committee, which include Dr. Helen Burt, Dr. John Sinclair, and Dr. Gail Bellward. I am forever indebted to Dr. Michael Pungente, who taught me so much within the past few months, and for his guidance, encouragement and support. To Dr. Robbin Burns, Dr. Virginia Borges, and Dr. Salete Bennetton, my past lab members, who have left and moved on to bigger and better things, thank you for the company and encouraging talks over the past years.