The automated flow synthesis of fluorine containing organic compounds by CHANTAL SCHOLTZ Submitted in partial fulfilment of the requirements for the degree PHILOSOPHAE DOCTOR In the Faculty of Natural & Agricultural Sciences UNIVERSITY OF PRETORIA PRETORIA Supervisor: Dr D.L. Riley February 2019 DECLARATION I, Chantal Scholtz declare that the thesis/dissertation, which I hereby submit for the degree PhD Chemistry at the University of Pretoria, is my own work and has not previously been submitted by me for a degree at this or any other tertiary institution. Signature :.......................................... Date :..................................... ii ACKNOWLEDGEMENTS I would herewith sincerely like to show my gratitude to the following individuals for their help, guidance and assistance throughout the duration of this project: My supervisor, Doctor Darren Riley, for his knowledge and commitment. Thank you for being a fantastic supervisor and allowing me the opportunity to learn so many valuable skills. My husband, Clinton, for all your love, support and patience and for always being there for me. You are the best. My family, for all the encouragement and support you gave me as well as always believing in me. I will always appreciate what you have done for me. Mr Drikus van der Westhuizen and Mr Johan Postma for their assistance at the Pelchem laboratories with product isolation and characterisation. Dr Mamoalosi Selepe for NMR spectroscopy services, Jeanette Strydom for XRF services and Gerda Ehlers at the UP library for her invaluable assistance. All my friends and colleagues for the continuous moral support, numerous helpful discussions and necessary coffee breaks. My colleagues at Chemical Process Technologies for their ongoing support and motivation, especially Dr Hannes Malan and Prof. Mukut Gohain. Pelchem, Ketlaphela, the NRF, the Department of Science and Technology, the University of Pretoria and Chemical Process Technologies for financial assistance throughout this project. Uniqsis for technical support. Finally, I would like to thank God for blessing me with the ability to do this project and for giving me the strength I needed to complete it, without Him it would not have been possible at all. This work was supported by the National Research Foundation of South Africa (grant number 87893), the University of Pretoria (University, Science Faculty Research Councils and Research and Development Program), South Africa and Pelchem Pty Ltd. Opinions expressed in this thesis and the conclusions arrived at, are those of the author, and are not necessarily attributed to the NRF. iii " To a synthetic chemist, the complex molecules of nature are as beautiful as any of her creations. The perception of that beauty depends on the understanding of chemical structures and their transformations, and, as with a treasured work of art, deepens as the subject is studied, perhaps even to a level approaching romance. It is no wonder that the synthetic chemist of today is filled with joy by the discovery of a new naturally occurring structure and the appearance of yet another challenge to synthesise.1" E.J. Corey 1 Corey, E.J. Angew. Chem. Int. Ed. Engl. 1991, 30, 455. iv SUMMARY Organofluorine chemistry has a rich history, spanning as far back as the 16th century to current times where it is frequently used in the pharmaceutical industry. The incorporation of fluorine within a molecule has the ability to modify the pharmacokinetic as well as pharmacodynamic properties of that compound. This means that the presence of fluorine can have a profound impact on the nature and functioning of a drug. As a result of these properties of fluorine it has been incorporated in many successful drugs such as Prozac, Lipitor, celecoxib and numerous anti-cancer agents. However, the incorporation of fluorine is not always straight forward, which has resulted in the development of a number of different fluorinating agents and fluorinating processes. Flow chemistry is the newest addition to this ever-evolving field, allowing for more efficient syntheses with substantially improved safety profiles and yields. Flow chemistry is a novel technology which can be used for the economical manufacture of fine chemicals, and more specifically, active pharmaceutical ingredients (API’s) in an environment where economies of scale are often not realized. Flow chemistry is defined as the “use of continuous plug flow reactors as opposed to conventional batch reactors” for the synthesis of fine chemical intermediates and API’s. As a result of flow chemistry being a relatively new field, its use for fluorination and the synthesis of fluorinated drugs has not yet been extensively explored. This study focusses on the conversion of traditional batch synthesis to continuous flow processes for 5- fluorocytosine (marketed as the drug Flucytosine), hexafluorobuta-1,3-diene, aryl diazonium tetrafluoroborate salts, aryl hydrazines and celecoxib (marketed as the drug Celebrex) in an effort to develop processes which would be more industrially viable or at the very least, expand the scope of technology available to organofluorine chemists. v LIST OF ABBREVIATIONS ACN - acetonitrile API - active pharmaceutical ingredient ATP - adenosine triphosphate BER - borohydride exchange resin BPR - back pressure regulator COX - cyclooxygenase CTT - 2-chloro-1,1,2-trifluorotriethylamine DAST - diethylaminosulfur trifluoride DFI - 2,2-difluoro-1,3-dimethylimidazolidine DMF - N,N-dimethylformamide DMSO - dimethyl sulfoxide DTBP - di-tert-butyl peroxide 3-EAN - 3-ethoxyacrylonitrile ETFA - ethyl trifluoroacetate EWG - electron withdrawing group 5-FC - 5-fluorocytosine FFM - falling film microreactor h - hours HFBD - hexafluorobuta-1,3-diene HFC-134a - 1,1,1,2-tetrafluoroethane HT PTFE - high temperature polytetrafluoroethylene vi IPA - isopropanol / isopropyl alcohol IPN - isopentyl nitrite LDA - lithium diisopropylamide 4-MAP - 4-methylacetophenone MBC - micro bubble column MFSDA - methyl fluorosulfonyl difluoroacetate NFSI - N-fluorobenzenesulfonimide NMR - nuclear magnetic resonance NSAIDs - non-steroidal anti-inflammatory drugs PET - positron emission tomography PGs - prostaglandins psi - pound-force per square inch, 1 psi = 0.068 atm PTFE - polytetrafluoroethylene Rf - retention factor RT - room temperature SDF - selective direct fluorination TBAF - tetrabutylammonium fluoride TLC - thin layer chromatography THF - tetrahydrofuran TMSCF3 - trifluoromethyltrimethylsilane XRF - X-ray fluorescence vii TABLE OF CONTENTS 1. Chapter 1: Fluorine in Organic Chemistry……........................... 2 1.1. Keywords…………………………………………………………... 2 1.2. Abstract…………………………………………………………….. 2 1.3. The history of fluorine....................................................................... 2 1.4. What makes fluorine special for use in medicinal compounds…….. 4 1.4.1. Mimic effect………………………………………………… 5 1.4.2. Block effect and metabolic stability………………………… 5 1.4.3. Effect on lipophilicity………………………………………. 7 1.4.4. Inductive effects and the influence on pKa…………………. 8 1.4.5. Conformational effects……………………………………… 10 1.4.6. Binding interactions and affinity…………………………… 11 1.5. Fluorinated drugs………………………........................................... 12 1.5.1. Anti-cancer agents………………………………………….. 13 1.5.2. Anti-inflammatories………………………………………… 17 1.5.3. Anaesthetics…………………………………………………. 20 1.5.4. Atherosclerosis……………………………………………… 20 1.5.5. Psychiatric drugs……………………………………………. 22 1.5.6. Antibacterial agents………………………………………… 24 1.5.7. Antifungal agents…………………………………………… 26 1.5.8. Antiparasitic agents…………………………………………. 27 1.5.9. Antiviral agents……………………………………………… 28 1.5.10. Miscellaneous drugs………………………………………… 28 1.5.11. Radiolabelling and positron emission tomography (PET)….. 30 viii 1.6. Fluorination reagents………………………………………………. 31 1.6.1. Sources of nucleophilic fluorine……………………………. 32 1.6.2. Sources of electrophilic fluorine……………………………. 35 1.7. Fluorinations utilising flow chemistry……………………………... 39 1.8. Conclusion…………………………………………………………. 51 1.9. References.......................................................................................... 53 2. Chapter 2: 5-Fluorocytosine................................................................ 58 2.1. Keywords…………………………………………………………… 59 2.2. Abstract............................................................................................... 59 2.3. Introduction…………………………………………………………. 59 2.4. Results and Discussion……………………………………………… 63 2.5. Conclusion………………………………………………………….. 72 2.6. Experimental Section……………………………………………….. 72 2.7. References........................................................................................... 73 3. Chapter 3: Hexafluorobuta-1,3-diene…………………………….. 76 3.1. Keywords…………………………………………………………… 77 3.2. Abstract............................................................................................... 77 3.3. Introduction…………………………………………………………. 77 3.4. Results and Discussion……………………………………………… 80 3.5. Conclusion………………………………………………………….. 87 3.6. Experimental Section……………………………………………….. 87 3.7. References........................................................................................... 90 ix 4. Chapter 4: Aryl Diazonium Tetrafluoroborate Salts…………. 93 4.1. Keywords…………………………………………………………… 94 4.2. Abstract…........................................................................................... 94 4.3. Introduction…………………………………………………….…… 94 4.4. Results and Discussion……………………………………………… 103 4.5. Conclusion………………………………………………………….. 118 4.6. Experimental