New synthetic technologies in medicinal chemistry

RSC Drug Discovery Edited by Elizabeth Farrant New Synthetic Technologies in Medicinal Chemistry Foreword by Steven V Ley New Synthetic Technologies in Medicinal Chemistry RSC Drug Discovery Series Editor-in-Chief: Professor David Thurston, London School of Pharmacy, UK Series Editors: Dr David Fox, Pfizer Global Research and Development, Sandwich, UK Professor Salvatore Guccione, University of Catania, Italy Professor Ana Martinez, Instituto de Quimica Medica-CSIC, Spain Dr David Rotella, Montclair State University, USA Advisor to the Board: Professor Robin Ganellin, University College London, UK Titles in the Series: 1: Metabolism, Pharmacokinetics and Toxicity of Functional Groups: Impact of Chemical Building Blocks on ADMET 2: Emerging Drugs and Targets for Alzheimer’s Disease; Volume 1: BetaAmyloid, Tau Protein and Glucose Metabolism 3: Emerging Drugs and Targets for Alzheimer’s Disease; Volume 2: Neuronal Plasticity, Neuronal Protection and Other Miscellaneous Strategies 4: Accounts in Drug Discovery: Case Studies in Medicinal Chemistry 5: New Frontiers in Chemical Biology: Enabling Drug Discovery 6: Animal Models for Neurodegenerative Disease 7: Neurodegeneration: Metallostasis and Proteostasis 8: G Protein-Coupled Receptors: From Structure to Function 9: Pharmaceutical Process Development: Current Chemical and Engineering Challenges 10: Extracellular and Intracellular Signaling 11: New Synthetic Technologies in Medicinal Chemistry How to obtain future titles on publication: A standing order plan is available for this series A standing order will bring delivery of each new volume immediately on publication For further information please contact: Book Sales Department, Royal Society of Chemistry, Thomas Graham House, Science Park, Milton Road, Cambridge, CB4 0WF, UK Telephone: +44 (0)1223 420066, Fax: +44 (0)1223 420247, Email: books@rsc.org Visit our website at http://www.rsc.org/Shop/Books/ New Synthetic Technologies in Medicinal Chemistry Edited by Elizabeth Farrant Worldwide Medicinal Chemistry, Pfizer Ltd., Sandwich, Kent, UK RSC Drug Discovery Series No 11 ISBN: 978-1-84973-017-4 ISSN: 2041-3203 A catalogue record for this book is available from the British Library r Royal Society of Chemistry 2012 All rights reserved Apart from fair dealing for the purposes of research for non-commercial purposes or for private study, criticism or review, as permitted under the Copyright, Designs and Patents Act 1988 and the Copyright and Related Rights Regulations 2003, this publication may not be reproduced, stored or transmitted, in any form or by any means, without the prior permission in writing of The Royal Society of Chemistry or the copyright owner, or in the case of reproduction in accordance with the terms of licences issued by the Copyright Licensing Agency in the UK, or in accordance with the terms of the licences issued by the appropriate Reproduction Rights Organization outside the UK Enquiries concerning reproduction outside the terms stated here should be sent to The Royal Society of Chemistry at the address printed on this page The RSC is not responsible for individual opinions expressed in this work Published by The Royal Society of Chemistry, Thomas Graham House, Science Park, Milton Road, Cambridge CB4 0WF, UK Registered Charity Number 207890 For further information see our web site at www.rsc.org Foreword I think everyone recognises the pharmaceutical industry has undergone, and is still undergoing, massive changes in the way drugs are discovered, synthesised and manufactured The medicinal chemist plays a vital role in coordinating the wide-ranging scientific disciplines and driving technological innovations in the quest for these new medicines This enormously complex task must also be responsive to the demands of our modern society, be they for economical reasons, having enhanced safety profiles or leading to environmental issues Similarly, time-lines and the global nature of this highly competitive business add additional burdens to the discovery process For these many reasons the molecular architects who design these exquisite structures and the synthesisers who transform simple building blocks to functional systems are forced to be increasingly creative and innovative by taking their craft to a higher art form The rapid evolution and incorporation of new tools and novel technologies together with advances that arise by challenging the chemical reactivity dogmas of the past provides the engine to drive future successes This book refreshingly brings together diverse concepts, techniques and processes, all of which enhance our ability to assemble functional molecules and provides the reader with a modern skill set and an appreciation of the dynamic character of medicinal chemistry today Indeed, many of the authors remove the constraints and blinkers associated with the traditional labourintensive practices of the past and provide a glimpse of the future The chapters reflect modern thinking in terms of automation and parallel methods of synthesis, particularly focussing on design by making what should be made as opposed to what can be made There is an emphasis on work-up tools using solid-supported reagents and scavengers to eliminate many of the time-consuming unit operations necessary to obtain pure materials during unoptimised synthesis sequences These RSC Drug Discovery Series No 11 New Synthetic Technologies in Medicinal Chemistry Edited by Elizabeth Farrant r Royal Society of Chemistry 2012 Published by the Royal Society of Chemistry, www.rsc.org v vi Foreword concepts lead on naturally to methods of fast serial processing whereby microwave methods of heating are now commonplace in medicinal chemistry laboratories Furthermore, opportunities arise by moving from conventional batch-mode synthesis to dynamic continuous or segmental flow-chemistry methods This concept requires new thinking and apparatus but opens up exciting ways to conduct chemistry either in microfluidic channels or in larger systems which incorporate packed scavenger tubes to facilitate work-up using a machine assisted approach A further chapter focuses on high throughput reaction screening including biological methods No longer is it acceptable to use expensive and talented operators to perform routine tasks; rather these should be relegated to more automated environments Likewise, the use of software packages for reaction optimisation such as ‘‘design of experiment’’ and ‘‘principal component’’ analysis are now widely adopted and proving their worth in synthesis programming The final visionary chapter on emerging technologies paints a seductive picture of the future In particular, it features the importance of knowledge capture and its use in a closed loop, integrated and interactive fashion by bringing together wide-ranging techniques and devices The future is indeed a bright one and will continue to develop based upon the collective genius of its practitioners Steven V Ley Cambridge Preface It is fair to say that, for a synthetic chemist working in drug discovery, the last 15 years have seen sometimes uncomfortable levels of change in the tools and methods applied to the task of designing and synthesising new potential drug molecules The experiments of the late 1990’s with high throughput, almost industrialised, approaches to lead-molecule generation and testing failed to result in an associated increase of new drugs on the market The ethos behind this movement was a response to the promise of advances in genomic technology to provide an enormous wealth of drugable targets for the industry to exploit, all needing tool molecules and lead material to start the process towards a drug Over recent years, estimates of the number of genes that can be considered disease-modifying targets have been refined, resulting in the late Sir James Black’s observation:w ‘‘The techniques have galloped ahead of the concepts We have moved away from studying the complexity of the organism; from processes and organisation to composition.’’ Despite the fact that, with a few exceptions, the enormous libraries of closely related structures of the 1990’s are now no longer being made, the technological ingenuity of this period has had a lasting impact on synthetic chemistry Many of the techniques developed during this time are now being used routinely in medicinal chemistry labs the world over to increase productivity and access new chemical space; this is the true legacy of the ‘‘combichem revolution’’ It is hoped that this book provides a useful background and context for scientists already engaged in drug discovery or entering this fascinating and w The Financial Times, February 1st 2009, interview by Andrew Jack RSC Drug Discovery Series No 11 New Synthetic Technologies in Medicinal Chemistry Edited by Elizabeth Farrant r Royal Society of Chemistry 2012 Published by the Royal Society of Chemistry, www.rsc.org vii viii Preface worthwhile profession, as well as demonstrating the undoubted benefits of the judicious use of synthetic technologies in drug discovery I would like to thank the chaptor authors, all of whom are experts and pioneers in these fields, for their high quality and timely contributions In addition I acknowledge the particular contribution of Dr David Fox at Pfizer Sandwich and Gwen Jones at RSC Publishing for their ‘‘gentle’’ persistence in helping me get this project to completion Special thanks also go to Rachel Osborne who was heroic in her efforts to write the chapter on microwave assisted chemistry in an incredibly short time-frame and late in the evolution of this book Dr Elizabeth Farrant Director, Worldwide Medicinal Chemistry Pfizer WRD Sandwich, Kent, UK Contents Chapter Chapter Introduction Elizabeth Farrant 1.1 Introduction 1.2 The Legacy of Combinatorial Chemistry 1.3 Case Study: Sorafenib 1.4 Conclusion References 1 High Throughput Chemistry in Drug Discovery Andy Merritt 2.1 2.2 2.3 2.4 2.5 2.6 2.7 2.8 Introduction The Potential of High Throughput Chemistry in Drug Discovery The Start of Combichem in Drug Discovery From Peptides to Small Molecules My Library’s Bigger Than Your Library: The ‘Universal’ Library From Combichem to High Throughput Chemistry: Remembering It’s All About Drugs Technology to Make It Happen Illustrative Approaches in Drug Discovery 2.8.1 SAR Development using Parallel Chemistry 2.8.2 Lead Discovery: Split and Mix Examples 2.8.3 Dynamic Combinatorial Chemistry: From Fragments to Libraries RSC Drug Discovery Series No 11 New Synthetic Technologies in Medicinal Chemistry Edited by Elizabeth Farrant r Royal Society of Chemistry 2012 Published by the Royal Society of Chemistry, www.rsc.org ix 11 13 14 17 21 22 26 29 150 Chapter 18 V A Polyakov, M I Nelen, N Nazarpack-Kandlousy, A D Ryabov and A V Eliseev, J Phys Org Chem., 1999, 12, 357 19 S J Rowan and J K M Sanders, J Org Chem., 1998, 63, 1536 20 C Amatore, A Jutand, G Meyer and L Mottier, 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alkenes, hydroformylation 76 alkynes, cycloadditions 76, 132 amides bond formation and cleavage 11, 16, 129–30 chemistry 12, 23, 71, 74, 144 as intermediates 23 libraries 29, 47–8, 75 amidoximes 83, 117 amino acids b-amino acids 80–1 L-tert-leucine 115 anisole 45–6 antibiotics 32 anticancer drugs API (active pharmaceutical ingredient) 42 Argonaut 47 Arrhenius equation 66 2-arylbenzoxazoles 23, 24 2-arylindoles 28 Astex 30 Astra Zeneca 9, 16 asymmetric synthesis 112 atom economy 131 atom efficiency 81, 102 Aurora kinase 31 automated chemistry and screening 144 automated flow switching 98, 120 automated fraction collectors 110 automated sequential batch processing 96 automated stop flow 119 automation in combinatorial chemistry 8, 11, 17–21, 34 in high throughput reaction screening 59–60 in high throughput salt screening 58 information as synthetic output 138, 140, 144 microwave-assisted chemistry 85 Aventis aza-Michael additions 80–1 azides 56–7, 82, 97, 112, 132 aziridines 132 Azixa 79–80 b-ketoesters 114 batch-mode flow chemistry advantages 90–1 microwave-assisted chemistry 70, 85–6 reaction screening and 54, 56 Subject Index batch processing automated sequential 96 converting to flow 110–11 distinguished from flow 56, 70 flow chemistry advantages over 92–8, 101–2, 139 microwave chemistry and 70, 85–6, 118–19 scalability 85–6 Bayer bead-bound libraries 1, 128 beads packed bean reactors 111–12 polymer-supported reagents 10–11, 27–8, 32, 83 benzodiazepines 11, 12 benzoxazinones 76 benzoxazoles, 2-aryl- 23, 24 Biginelli chemistry 19, 85 binding conformations 4, 143 biological membranes 8, 16–17 biological screening closed loop systems 140, 142 continuous flow 121–2 distribution and fate 141 lead pharmacophore updating 142 target-guided synthesis 132 biomolecules as therapeutics 33 biotin 146 biotransformation screening 2, 54–5 biphenyls 48 blockages in flow chemistry 99–100 BMS (Bristol-Myers Squibb) 23 BOC (tert-butoxycarbonyl) group 78 boronates (Suzuki–Miyaura reaction) 48, 71–3 Bourne reaction 93 bubbles, segmented flow 120 burimamide 149 buspirone, 6-hydroxy- 118 cancer therapy carbamates 24–5, 26, 115 carbonylation 75–6 155 catalysis C–H activation 144–5 catalyst deactivation 67 catalyst screening 51–3 chiral catalysts 112 copper-catalysed reactions 56–7, 82, 86, 132 flow chemistry and 97, 112 metal-catalysed reactions 71–4, 76, 86, 119, 145 pre-catalysts 48, 50 TEMPO 113–14 cationic lipids 33 CCF (central composite face) experiment design 46 CDK2 (cyclin dependent kinase) 30 Celsentri (maraviroc) 42 CETP (cholesterol ester transfer protein) inhibitors 23, 24 C–H activation 144–5 chemical space drug-like 127, 129 novel 2, 4, 118, 136 number of potential drugs 15, 127 chemically intelligent fragmentation 17 chip-based reactors 108–9, 139 chromatography see liquid chromatography cimetidine 149 citalopram 86 cleavable linkers 146 ‘click chemistry’ 25, 27, 144 microwave-assisted 81–3 template guided systems 127, 131–3 closed loop systems drug discovery 121–2 miniaturised flow assays 140, 142 combinatorial chemistry (combichem) see also high throughput antibiotics 32 biomolecules as therapeutics 33 click chemistry and 25 DNA directed assembly and 147 dynamic combinatorial chemistry 29–31, 128–31, 136 156 combinatorial chemistry (continued) history and status of 6–7, 8–11, 14–17 legacy of 1–3, 111 protease inhibitors 32–3 small molecule libraries 11–14 technological advances 17–21 unfulfilled promise of 14–15 compound libraries mergers and small molecule libraries 11–13 universal libraries 7, 13–14 computational docking approaches 25 containers high throughput reaction screening 59–60 microwave vials 68–70, 75–8, 84–5 continuous annular chromatography (CAC) 121 continuous flow biological screening 121–2 continuous-flow (CF) reactor technology 56, 86 see also flow chemistry integration with others 118–19 residence times 105 continuous simulated moving bed chromatography (CSMBC) 120 cooling see also temperature control flow chemistry 117 microwave equipment 68 Peltier cooling units 92 copper-catalysed reactions 56–7, 82, 86, 132 counter-ion selection 58 cross-coupling reactions high throughput reaction screening 46, 48–50 microwave assisted 19, 71–4 Suzuki–Miyaura reaction 48–50 cross-metathesis reactions 80–1 crystallisation flow chemistry 98, 99, 121 high throughput screening 57–8, 85 Subject Index Curtius rearrangements 112 cycle times see reaction times cyclic b-amino acids 80–1 cyclic peptide antibiotics 32 cyclisations 32, 56, 79, 83–4, 117 cycloadditions 56–7, 82–3, 118, 147 Diels–Alder cycloadditions 112, 132 Huisgen cycloadditions 82, 118, 132, 147 Sharpless cycloadditions 132 cyclocarbonylation 76 de-racemisation decarboxylations 55, 78 deconvolution approaches 2, 11, 27, 29, 128 dehydration 11, 79, 117 dehydrogenation 145 diazo species 97, 113, 115 Diels–Alder cycloadditions 112, 132 dihydropyrimidones 19 Dimroth rearrangement 79–80 diols from diketones 77 dipolar polarisation 65 ‘direct-drop’ processes 59 disulfide bonds 31, 129 ‘diversomer’ approach 11 DNA directed assembly 145–7 DoE approach 46–8, 50, 53, 56 dopamine D4 selective ligands 26 drug delivery biomolecules as therapeutics 33 siRNA approaches 134 drug development high throughput reaction screening and 42, 49, 57 salt formation 57 drug discovery see also lead identification; lead optimization closed loop 121–2 combinatorial chemistry and 6–7, 8–11, 34 emerging technologies 126–7 expenditure and productivity 126 157 Subject Index high throughput medicinal chemistry and 7–8, 21–34 knowledge based iterative systems 136–47 number of potential drug molecules 15, 127 predicting unforeseen structures 141–3 sorafenib case study 3–4 stages of template guided systems 127–35 dynamic combinatorial chemistry 29–31 casting and moulding 129–30 knowledge based systems and 136 template guided systems 128–31 economics of flow processing 95 electroosmotic systems 105–6, 139 electrostatic field effects 142–3 enantioselectivity 54–5, 57 Encoded Synthetic Library (ESL) 17 energy efficiency 67 enzyme screening kits 54 enzymes biotransformation reaction screening 31, 54–5 target-guided synthesis and 23–4, 132 epibatidine 20 epoxides 131 equipment and automation high throughput reaction screening 59–60 microwave-assisted chemistry 67–70 esterifications 118, 129 exothermic reactions (flow chemistry) 113–17 benefits 92, 97 scale-up 101 set-up 107, 111 experiment design CCF (central composite face) 46 flow chemistry 106–10 heat sources 63–4 statistical design of experiments (DoE) 46–8, 50, 53 explosion risk 74, 77–8 extended electron distribution (XED) model 143 flash heating 72 flow assay devices 139–40 flow chemistry advantages 90–8 batch conversion to 110–11 experimental setup 106–10 high throughput reaction screening 56–7 kinetics and 93–4, 96–7 limitations and technology hurdles 99–102 microwave-assisted 70, 85–6, 95–6, 118–19 miniaturisation 138–41, 144 mixing 92–3, 101, 103–4, 107–8 multistep processes 97–8, 117–19 packed bed reactors 111–12 post-synthetic processes 119–22 published examples 113–18 temperature control in 91–2 theory of 102–6 fluid dynamics 102–6, 139 see also microfluidics fluorination 114, 144 follicle stimulating hormone (FSH) receptor agonists 27–8 fragment-based screening 29–30 FRET (fluorescence resonance energy transfer) detection 51, 60 gaseous reagents flow chemistry 97, 111, 114 microwave-assisted chemistry 75–7 gaseous side products 78, 102 Gemini surfactants 134 gene silencing 133–4 genomics DNA directed assembly 145–7 unfulfilled promise of 1, 158 ghrelin receptor agonists 24, 25 GlaxoSmithKline (GSK) 24, 34, 57, 127 GlaxoWellcome 9, 17 gold 119 GPCR (G protein coupled receptors) see 7-transmembrane receptors at seven Grignard reagents 71, 73, 74, 101 guanidines, acyl- 23 hardware, integrated 137, 140–1, 148 hazardous intermediates 111 hazardous reagents 56–7, 97, 113–14 see also safety heat sources 63–4, 119 Heck reaction 51–2, 112, 147 heterocycles synthesis of aromatic 11, 74, 78–80, 84 synthesis of saturated 80–1 high throughput medicinal chemistry drug discovery and 7–8, 10, 16, 21–34 introduced sorafenib case study 3–4 high throughput reaction screening analytical techniques 60 biotransformation 54–5 catalyst screening 51–3 discrete and continuous variables 44–5, 53 equipment and automation 59–60 Heck reaction 51–2 hydrogenation of nitro compounds 52–3 introduced 42–4 pregabalin biotransformation 54–5 route screening 144 statistical design of experiments (DoE) 46–8, 50, 53, 56 Suzuki–Miyaura reaction 48–51 using flow chemistry 56–7 Williamson ether synthesis 45–6 Subject Index high throughput screening (HTS) 8–9, 13–17, 22–4 miniaturisation 138–41 salt screening 57–8 serendipity in 126 solubility screening 58–9 ‘zero cycle’ screening 137 histamine H2-receptor agonists 149 HIV integrase inhibitors 86 HOF-CH3CN complex 144 HPLC (high performance liquid chromatography) 60, 122, 132 Huisgen cycloadditions 82, 132, 147 hydrazides 79, 84 hydrazones 30, 129–30 hydroformylation 76 hydrogenations catalytic 52–3, 97 C–H activation and 144 with gaseous hydrogen 77–8, 111 imidazoles 118 imines 129, 130 indoles, 2-aryl- 28 information, as an assay product 138, 140, 144 intellectual property (IP) 9, 34 ionic conduction 65 IRORI system 17 iterative deconvolution 11 iterative lead discovery 126–7, 136–8, 140–1, 144, 147–8 kinase inhibitors 3–4, 31, 135 kinetic resolution 54 kinetics and flow chemistry 93–4, 96–7 knowledge based iterative systems DNA directed assembly 145–7 high speed iterative chemistry 144–5 iterative working tools 137–8 overview 136–7 predicting structures 141–3 process rescaling 138–41 Kumada reaction 71, 73 159 Subject Index ‘lab on a chip’ concept 109, 121, 132 lactams 9, 80–1 laminar diffusion 93 laminar flow 103, 108, 119 LC-MS 1–2, 19, 31, 60, 139 lead discovery dynamic combinatorial chemistry 129 human input 129, 141–2, 144, 148 knowledge based iterative systems and 136–8, 141 miniaturisation in 138–40, 144, 148 predicting unforeseen structures 141–3 software 137–9, 141, 144, 148 split and mix examples 26–9 traditional iterative approaches 126–7, 137–8 lead diversification systems 141 lead identification 8, 15 lead optimization as drug discovery stage 8, 144 examples 21 molecular weight and lipophilicity 16 parallel lead optimization 7–8, 26, 27, 34 lead pharmacophores 142 libraries see compound libraries ligands (2-MeO-Ph)3P 50 Heck reaction 51 in knowledge-based systems 136, 142 steric and electrostatic effects 49–50, 143 Suzuki–Miyaura reaction 49, 71 in template guided systems 127, 129 lipases 54 Lipinski’s rule (rule of 5) 16, 31 lipophilicity 16, 135 liquid chromatography 19–21, 60, 120–1 high performance (HPLC) 60, 122, 132 LC-MS 1–2, 19, 31, 60, 139 miniaturisation 139 thin layer 60 liquid-liquid extraction 119–20 lithium anions 115 log D solubility studies 120 loss tangent, tan d 65, 66, 77 Lyrich (pregabalin) 54–5 M1 (muscarinic receptor) antagonists 84 magnesium compounds 73–4, 101 magnetic stirring 68–9, 92 maleimides 147 MAOS (microwave-assisted organic synthesis) see microwave-assisted chemistry maraviroc 42–3 melanin concentrating hormone (MCH-1) antagonists 26–7, 28, 78 Merck 48, 86 mergers mesofluidic reactors metal-catalysed reactions 71–4, 76, 118–19, 145 see also palladium; Suzuki copper-catalysed reactions 56–7, 82, 86 metal coated reactors 118–19 metathesis reactions cross-metathesis 80 olefin metathesis 129, 145 ring-closing metathesis 118 methane monooxygenase 145 microfluidics 2, 105, 108, 139 microtitre assays 8, 18 microwave-assisted chemistry aromatic heterocycles 78–80 ‘click chemistry’ 81–3 commercial reactors 67–70 as first resort 71 and flow chemistry 56–7, 95–6, 118–19 gaseous reagents 75–7 introduced 63–4 metal-catalysed reactions 71–4, 118–19 160 microwave-assisted chemistry (continued) non-thermal effects 64–5 nucleophilic substitutions 74–5 parallel synthesis 83–5 polymer-supported reagents 83 reaction rate effects 66–7 saturated heterocycles 80–1 scaling up 70–1, 85–6 theory overview 64–7 transfer hydrogenations 77–8 microwave heating 2, 19–21, 65–7 miniaturisation in lead discovery 8, 43, 138–40, 144, 148 ‘mix and split’ synthesis 128 see also ‘split and mix’ synthesis mixing (flow chemistry) 92–3, 101, 103–4, 107–8 Mo(CO)6 75 modular systems flow chemistry 99, 106, 139 molecular assembly 131 mono-mode microwave 68 reaction screening 60 molecular weight 16 mono-mode (single-mode) microwave equipment 68, 96 morpholine, N-methyl- 24 multi-mode microwave equipment 68, 84 multistep processes click chemistry 131 flow chemistry 97–8 knowledge based systems 136 muscarinic receptor (M1) antagonists 84 nanoparticles 121, 134 1,6-naphthyridines 48–9, 87 natural products screening synthesis 18, 34 Negishi reaction 71, 73 neuraminidase inhibitors 31 Nexavars (sorafenib) 3–4 nitration, selective 116 Subject Index nitro-aldol and nitro-Michael reactions 147 4-nitroacetophenone 52–3 NMO–TPAP (N-methylmorpholineN-oxide-tetrapropylammonium perruthenate) 101 NMP (N-methylpyrrolidinone) 66, 78 Novartis NPY-5 (neuropeptide Y) receptor antagonists 22, 29 nucleophilic substitutions 74–5, 118, 131, 147 ‘ohmic heating’ 119 olefin metathesis 129, 130, 145 organometallic reagents 71–4 Grignard reagents 71, 73, 74, 101 organolithium 115–16 orthogonal library chemistries 129, 138 orthogonal pooling strategies 11 orthogonal protection strategies 27 1,2,4-oxadiazoles 83, 117 oxazolidines 147 oximes 129, 130 ozone 97, 111, 144 packed bed reactors 111–12 palladium catalysts see also Heck; Suzuki C–H activation 145 cyanation 86 hydrazide formation 79 hydrogenation 53 parabolic flow 104–5 parallel lead optimization 7–8, 26, 27, 34 parallel synthesis combinatorial chemistry and 11–12, 18 high throughput reaction screening and 43, 48 lead optimisation example 23 microwave-assisted 83–5 multi-mode microwave equipment 68 161 Subject Index particle size 112, 121 paxillin/a4 inhibitors 29, 30 Peltier cooling units 92 pentafluorophenyl magnesium bromide 101 peptides combinatorial chemistry and 6, 10–11, 129 cyclic peptide antibiotics 32 protease inhibitors 32–3 solid-phase chemistry and 112 ‘split and mix’ synthesis 11 PET (positron emission tomography) imaging 26, 141 Pfizer 22, 43, 54, 58 phosphines (2-MeO-Ph)3P 50 ferrocenyl- and adamantylsubstituted 51–2 PS-PPh3 83 phosphorylated aryl alkoxides 25 photolysis 119 physicochemical properties 16 piperazines 94 piperidinones 81 plug-flow (PF) reactor technology 56–7, 101, 104, 107, 109–10 polymer-supported reagents see also solid-phase chemistry disadvantages 112 high throughput chemistry 18, 20, 24–5 microwave-assisted chemistry 83–4 polyphosphoric acid (PPA) 79 positional scanning 11, 29 pregabalin 54–5 process optimisation biotransformations 54–5 ‘closed loop’ 122 differential solubility and 59 direct sampling of reactions 60, 95 discrete and continuous variables 44–5, 53 DoE approach 47, 50 flow rates and 106–7 plug- and continuous-flow reactors 56 scaling-up 57, 70 serial approach 45 using high throughput reaction screening 43–5 process synthesisers 70 process times see residence times product degradation 71–2, 92 product solubility 99–100 protease inhibitors 32–3 protecting groups avoiding using 94 high throughput screening 14, 27, 32–4 thermal stability 78 pumps flow chemistry 102, 106–9, 112 miniaturisation and 138 superheated solvents 96 purification flow chemistry 98, 109, 119–20 high throughput screening 43–4, 57–8 microwave-assisted chemistry 74–5 pyrazole-5-carboxylic acid 116 pyridazinones, chloro- 71 pyrido[3,4-d]pyrimidin-4-ylamines 74 pyrimidines, diamino- 22 pyrimidones, dihydro- 19 pyrrolidines 80–1 quinazolines 79 racemic resolution 54–5, 120 radiofrequency (rf) tags 12, 17, 26 radioisotopes 141 Raf kinase inhibitors 3–4 reaction rates flow chemistry and 112–13 microwave-assisted chemistry 66–7, 74 reaction sampling, direct 60, 70, 95 reaction screening see high throughput 162 ‘reaction space’ 45–7 reaction times see also residence times microwave-assisted chemistry 71, 82, 84–5 miniaturisation and 139–41 reagent choice high throughput reaction screening 42–4, 50, 56 solubility, in flow chemistry 99 reagent degradation 91–2 reagents see also polymer-supported reagents direct microwave heating 64 organometallics 71 reductive amination 22, 27, 31, 147 regioselectivity 50, 132 renin inhibitors 22 residence times (flow chemistry) 101–2, 105, 110, 113–18, 122 resin capture and release 18 response surfaces (DoE) 47 Reynolds number 102–3, 139 ring-closing metathesis 118 ring expansion reactions 113 siRNA approaches 127, 133–5 RNA-induced silencing complex (RISC) 133, 135 RNAi therapeutics 33 Roche 22 route screening see high throughput reaction screening ‘rule of 5’ (Lipinski) 16, 31 safety flow chemistry and 94–7, 99, 111, 113, 117 hazardous intermediates 111 hazardous reagents 56–7, 97, 113–14 microwave heating and 74, 77, 83, 85 safety catch linkers 28–9 salicylic acid 116 Subject Index salt screening 57–8 sampling process optimisation by direct 60, 70, 95, 122 sample collection 109–10, 122 sample loops 107, 108 scaffold hopping 22 scalability (flow chemistry) 90–1 miniaturisation 8, 43, 138–40, 144, 148 scaling out 100 scaling-up continuous flow chemistry 100–2, 115 microwave chemistry 70–1, 85–6 plug-flow processes 57 solid-supported chemistry 112 scavengers by-product scavenging 18 in high throughput screening 24, 26 solid-supported 12, 26, 98, 111, 120 Schering Plough 24 secondary reactions see side product formation b-secretase activity 23, 25 g-secretase inhibitors 25 segmented flow 119–20 selective serotonin reuptake inhibitors 86 selectivity, in flow chemistry 94, 111, 116 Selsentry (maraviroc) 42–3 sequential reactions (flow chemistry) 68, 84, 97–8, 119 sequestration 18–19, 24–5 serotonin receptors 29, 86 sertraline 58 7-transmembrane (7-TM) receptors 17, 28 Sharpless cycloadditions 132 side product formation by-product scavenging 18 flow chemistry 91–2, 94, 98–9, 110, 114 Subject Index fluid dynamics and 105 gaseous side products 78, 102 sildenafil 117 silica, monolithic 112 single-mode (mono-mode) microwave equipment 68, 96 siRNA approaches 127, 133–5 Smithkline Beecham SNAr reactions see nucleophilic substitutions software DoE software 47–8 lead discovery 137–9, 141, 144, 148 reaction optimisation 122 solid-phase chemistry 10–12, 15, 17–18, 24–7, 32 see also polymer-supported amidation 47–8 packed bed reactors 111–12 solid-supported scavengers 98, 111, 120 solvent choice high throughput reaction screening 42–4, 50 high throughput solubility screening 58–9 reaction rates and 74 Suzuki–Miyaura reaction 71 solvents co-solvents 65, 121 inert spacing 12, 57, 104, 107–10 log D solubility studies 120 microwave-assisted chemistry 64, 65–6, 77 superheated 95, 96, 118 sorafenib 3–4 ‘split and mix’ synthesis in combinatorial chemistry 10–12, 13, 15, 17, 21 dynamic combinatorial chemistry 128 in lead discovery 12, 26–9 statistical design of experiments (DoE) 46–8, 50, 53, 56 stereoselectivity 50, 80–1, 145 steric effects 49–50, 143 163 steroids 121 Stille reaction 71 stoichiometric control 94, 102, 107 ‘stop-flow’ reactors 57, 119 structure-activity relationships (SAR) DNA directed assembly 147 lead optimisation examples 21, 23–6, 129, 135–7 parallel approaches 8, 34, 83–5 predicting unforeseen structures 141–3 sorafenib case study 3–4 structure-based modelling systems 141 sulfonamides 24 superheated solvents 95, 96, 118 supported reagents see solidsupported surface-to-volume ratio 92, 120 Suzuki coupling reactions 18, 118 Suzuki–Miyaura reaction 48–51, 71 synthetic automation see automation synthetic routes continuous flow chemistry 98, 100, 110 to heterocycles 74–5, 118 high throughput reaction screening 42–4 Huisgen cycloadditions in 82 including biotransformations 54–5 new technologies 129, 136–8, 141, 144 protecting groups and 78 retrosynthetic programs 144 solid-phase 25 ‘synthetic services’ 144 tan d (loss tangent) 65, 66, 77 target-guided approach 130, 132 see also template guided systems target protein amplification 31 tea bag concept 11–12 technologies combinatorial chemistry 6–7, 17–21 continuous-flow reactors 56, 58, 99–102 164 technologies (continued) emerging, in drug discovery 126–7 plug-flow reactors 56–7, 101, 104, 107, 109–10 in synthetic chemistry 1–2, 129, 136–8, 141, 144 temperature control flow chemistry 91–2, 100, 117 microwave heating 65–6 sub-zero temperatures 115–16 temperature effects high throughput reaction screening 46, 49 reaction rates 66–7 temperature gradients 92–3, 104, 118, 121 template guided systems click chemistry 127, 131–3 dynamic combinatorial chemistry 128–31 introduced 127–8 siRNA approaches 127, 133–5 TEMPO 113–14 tetrazoles 82–3 thermal control see temperature control 1,3-thiazines 18 thiazoles 22–3, 118 thiazolidinones 27 thiazolo[3,2-a]pyrimidines 79 Subject Index thin layer chromatography (TLC) 60 toxicity 75, 134–5, 144 transfection 134 transfer hydrogenations 77–8 triage processes 21, 27, 127, 137 triazoles 118 1,2,3-triazoles 56, 82, 132 [1,2,4]triazolo[4,3-a]pyridines 18, 79 [1,2,4]triazolo[4,3-b]pyridazines 84 trifluoromethylation 101 tube-based reactors 109, 118 turbulent flow 103–4, 108 Tyrocidine A 32 Ugi 3-component reaction 82 ultrasound 99, 119, 121 universal libraries 7, 13–14 unstable intermediates 115–16 ureas 27, 131 Williamson ether synthesis 45–6 Wittig reactions 105, 118, 147 X-ray crystallography 22–3 yield (in HTS) 44–5, 53 ‘zero cycle’ screening 137 zincates 71–3 Zoloft (sertraline) 58 ... Chemical and Engineering Challenges 10: Extracellular and Intracellular Signaling 11: New Synthetic Technologies in Medicinal Chemistry How to obtain future titles on publication: A standing order... in drug discovery or entering this fascinating and w The Financial Times, February 1st 2009, interview by Andrew Jack RSC Drug Discovery Series No 11 New Synthetic Technologies in Medicinal Chemistry. .. manufactured The medicinal chemist plays a vital role in coordinating the wide-ranging scientific disciplines and driving technological innovations in the quest for these new medicines This enormously