309

Index a Arndt-Eistert transformation of acyl acetonitrile azeotrope 168 chlorides 144 acetophenone 176, 181 aromatic acids 144 acetylenic ketones 29 aromatic aldehydes 187 active pharmaceutical ingredients (API) artemether 267 73 artemisinin 16, 157, 185 active principle ingredient (API) 135 artemisinin-based APIs 267 adamantane analogues 155 arylboronic acids 224 adipic acid 59, 60 AstraZeneca batch process 265 𝛼 adrenergic 1A receptor 149 atom economy 80, 193 affinity chromatography procedure azide salt 109 153 azides and diazoacetates 205 AKS-186 12 1,2-azido alcohol 173 alkenes and alkynes 1-(azidomethyl)-3,5-bistrifluoromethyl) trans-1,2-dichloroethane 143 benzene 205 alkoxycarbonylation 200 alkylanthrahydroquinone 43, 44 b allyltrimethylsilane 236 back pressure regulator (BPR) 29 α,β-unsaturated ketones 177 Baeyer–Villiger oxidation 36 α-dibromoketones 142 batch hydrogenation reactions 195 α-hydroxyphosphonates 170 batch photochemical technology 3 α-ketoamide 201 batch-reactor-based synthesis 25 Amberlite IRA900F (Amb-F) 172 Bayer sandwich microreactor 54 amide bond 140 Becker–Döring–Zeldovich nucleation amide production 64 theory (CNT) 279 aminofuran 231 benzaldehyde 124, 170, 172 3-aminoindolizine 148 benzofuran 2-boronic acid 225 anethole 197 benzoic acid 125, 207 aniline derivatives 152 benzophenone 202 aquivion PFSA-catalyzed synthesis benzotriazoles 145 179 benzyl alcohol, oxidation 124, 126 Armijo conjugate gradient method 124 benzylamine 15

Sustainable Flow Chemistry: Methods and Applications, First Edition. Edited by Luigi Vaccaro. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2017 by Wiley-VCH Verlag GmbH & Co. KGaA. 310 Index

benzyl azide 109, 223 CETP inhibitors 96 benzyl bromide 11 10-channel packed-bed microreactor benzyl ethers 150 45, 46 β-amino acids 175 chemical accidents 85 β-azido ketones 174 chemical efficiency 80 β-hydroxy ester 172 chemical reaction fouling 281 β-nitroacrylates 180 4-chlorobenzotrifluoride 121 β-pinene 65 cholesterylester transfer protein (CETP) biodiesel production 111 96 biodiesel waste-stream processing 113 classical nucleation theory (CNT) 279 biological fouling 281 cleaner bio-derived solvents 268 biologically active 3-alkylmethylene- cleaner chemistry 138 1H-isoindolin-1-one click cyclisation reaction 206 AKS-186 12 coagulation 284 biphenylboronic acid 224 coated microreactors 47–49, 51 Bodroux protocol 141 co-axial dual pipe reactor 296 bovine carbonic anhydrase II (bCAII) coaxial flow-focusing reactor 297 150 co-current laminar flow reactor 298 Box Behnken des,ign (BBD) 111 collision efficiency coefficient 285 breakpoint cluster region Abelson colloidal fouling 283 tyrosine kinase (BCR-Abl) commercial and industrial microwave inhibitors 150 reactors 221 4-bromoanisole 184 compact flow photoreactors 6 bromobenzene 204 ConjureTM Segmented Flow Reactor 4-bromophenol 170 System 137 2-bromopyridine 203 continuous Bodroux reaction 141 Buchwald-Hartwig amination 261 continuous catalyst-recycling system bulk nucleation/self-nucleation 278 140 1-butyl-3-methylimidazolium continuous crystallisation oscillotary tetrafluoroborate 28 baffled reactor system 290 continuous flow chemistry 135 c continuous flow hydrogenation 198 camptothecin derivatives 13 continuous flow reactions Candida antarctica lipase B 55 fluorous solvent 32 carbonylation 200 ionic liquid 26 carbonylative Sonogashira coupling continuous flow reactors 193 reaction 29 colloidal fouling 283 carbonylative Sonogashira reactions green engineering 300 139 insoluble by-products 294 casein kinase I inhibitors 155 nucleation 278 catalytic system, recovery and recycle of soft particles 286 166 solid actives 288 CatCart 197 surface fouling 280 ‘cation flow’ system 236 suspended micro-particles 291 CCR8 147 suspended nanoparticles 292 CdSe quantumdots 116 continuous flow technology 249 CEM monomode reactor 226 continuous processing Index 311

batch vs. continuous manufacturing d 83 Dalcetrapib 96 chemical efficiency 80 dehydration of ethanol 119 economic sustainability and process 1,4-dehydropryrimidine 198 intensity 85 density functional theory (DFT) 280 environmental sustainability and Derjaguin-Landau-Verwey-Overbeek process intensity 84 (DLVO) theory 284 global warming potential 81 design of experiment (DoE) 106 materials input per service 81 di- and trifluoromethylation of missing metrics 81 acrylamides 242 process intensity 84 acrylates 242 profitable process 77 diazomethane 145, 206, 207 socially sustainable process 79 dibromomethane 143 sustainability 77 dibromopyridines 182 continuous-flow chemistry diclofenac 158 advantages 5 9,10-dicyanoanthracene (DCA) 16 continuous-flow photochemical Diels–Alder reaction 230 technology 6 diethyl 1,4-dihydro-2,6- continuous-flow photochemistry 6 dimethylpyridine-3,5- continuous-flow microreactor 63 dicarboxylate 224 continuous-flow photochemical diethylphosphite 170 technology 6 dihydroartemisinic acid 15 continuous-flow photochemistry 6, 7 dihydroartemisinin 268 continuous-flow three step synthesis of 2,3-dihydrofuran 121 carbamates 186 3,4-dihydropyrimid-2-thione 197 copper [11C]carbonyl complex Dillmann-Meier theory 280 (Cu(Tp*)[11C]CO) 201 2,5-dimethoxy-2,5-dihydrofuran 237 copper catalysed azide-alkyne 205 dimethyl acetylenedicarboxylate 223 corrosion fouling 281 dimmable medium-pressure mercury CpRu(MeCN)3PF6 209 lamp 7 Crabtrees catalyst 196 dipeptidyl peptidase 4 (DPP4) inhibitors cradle-to-gate life cycle inventory (LCI) 150 263 1,3-dipolar cycloadditions 144, 235 cross-linked polymer matrix (K2621) disubstituted pyridines 182 47 disubstitutedpyridines 183 crystallization fouling 281 D-optimal designs 106 Cu(IMes)Cl 243 double carbonylation reaction 30 Cumulative Energy Demand (CED) Dowex 50WX8 57 method 263 drug discovery custom-made quartz microreactors 14 cleaner chemistry 138 Cu tube reactor 206 enhanced synthesis 140 cyanosilylation 176 laboratory equipment 136 cyclobutane 9 reactivity patterns 142 cyclofluidic optimization platform 151 safety 144 2-cyclohexen-1-ol 28 sustainable, see sustainable drug cyclopropanation of alkenes 144 discovery 145 Cytos® 270 Dwell device 7 312 Index

e flexible fluorinated ethylene propylene EcoInvent 257 (FEP) 7 economic sustainability and process flocculation 284 intensity 85 flow chemistry 103, 249 Efactor 80 flow micromixer 25 electrochemical benzylic flow microreactors 183 methoxylation/oxidation 241 flow Mizoroki-Heck reaction 36 electroosmotic microreactor 28 flow photochemical production plant Emrys Optimizer microwave system 14 223 flow process emulsion co-polymerisation 286 collaboration of disciplines 89 energy efficiency 194, 220 continuous processes 88 energy efficient light sources 5 CETP inhibitors 96 environmental performance indicators numbering up 91 260 plant configurations and continuous environmental sustainability and improvement 90 process intensity 84 SGLT2 inhibitors 98 environmental sustainability assessment status of pharmaceutical industry 86 AIChE/IChemE metrics 250 thermal Overman rearrangement 94 chemical industries 252 Vilsmeier reaction 95 gate-to-gate system boundary 251 flow reactions 219 process improvement 257 flowSyn 137 renewable energy sources 252 flowSynth system 222 research projects 258 fluorination and trifluoromethylation Sheldon’s E-factor 250 212 environmentally persistent fluoropolymer membrane 186 pharmaceutical pollutants fluorous/aqueous biphasic flow system (EPPPs) 79 34 epoxide 170 fluorous-organic multi-layered systems epoxidized soybean oil (ESO) 53 32 ethanolamine 123 fluorous solvent 32 ethyl 2-indolecarboxylic ester 221 fluorous tag method 37 ethyl cinnamate 196 fouling factor 282 ethyl diazoacetate 207 Friedel–Crafts reaction 240 European association of research and frontline antimalarial agent artemisinin technology organizations 15 (EARTO) 86 furanone 11 European reference Life Cycle Database furfural 16 257 g f Galden HT135 33 falling film micro reactor 195, 196 γ-amino® alcohols 177 fenchone 203 γ-nitrocarbonyls 171 Fisher indole synthesis 227 Gibbs free energy 279 five-module chemical assembly system glass microreactors 45, 46 157 global warming potential (GWP) 81 flash chemistry 142 glycerol 113 Index 313 glycine ester 207 imidazo[1,2-b]pyridazing 155 green chemistry 187 imidazo[1,2-b]pyridazine analogues green engineering 300 155 greener process 278 imidazole-1-sulfonyl azide green supercritical CO2 117 hydrochloride 110 Grignard-mediated magnesium amide 4.6 (imidazole-1-sulfonyl azide formation 141 hydrochloride benzylamine) 110 h imidazolium-based ionic liquids 32 H-Cube 197 imidazopyridine library 149 H-mordenite (HS-690) 186 immersion well reactor system 3 halogen-lithium exchange methodology inductive heating 230 203 insoluble by-products 294 halogen-lithium exchange reaction Intergovernmental Panel on Climate 203 Change (IPCC) 255 Hantzsch synthesis 224 iodoarenes 211 heterogenous acidic catalysts 178 ionic liquid 26 heterogeneous catalytic systems 169 iridium catalyst 196 heterogeneous photoreactions 14 irinotecan 13 heterogeneous Rh catalysts 199 isoxazole derivates 104 highly efficient self-optimizing Heck reaction 121 j homogeneous catalysis 195 jet flow reactor 298 homogeneous photoreactions 8 human toxicity potential (HTP) 254 k hydrogenation 195 KBr by-product 294 falling film micro reactor 195 Knoevenagel condensation 125 hydrogen peroxide adipic acid 59 l coated microreactors 47–49, 51 laminar co-axial flow reactor 297 domestic and industrial pollution Li exchange and Murahasi coupling treatments 45 reactions 204 epoxides 52–56 life cycle assessment (LCA) organic peroxides 56 artemisinin 266 oxidation reaction 60–66 chemical industries 252 pilot-scale 52 cradle-to-gate system boundary 251 sulfoxides and sulfones 58 environmental factors 250 trickle-bed/packed-bed reactor 45, gate-to-gate system boundary 251 46 microreactors 270 hydrophosphonylation of benzaldehyde organometallic catalysts 261 170 process improvement 257 2-hydroxy cyclohexanone 28 renewable energy sources 252 hydroxyphthalimidine 12 research projects 258 hypervalent iodine reagents 211 Sheldon’s E-factor 250 life cycle impact assessment 252 i life cycle inventory 252 imidazo[1,2-a]pyridines 154 low-nucleophilic amines 142 314 Index

L-pipecolinic acid 209 heating characteristics 220 400L stainless steel batch micro- and home-made flow reactors reactor 128 224 penetration depth 220 m microwave (MW) heating 183 m-anisaldehyde 128 Miniflow 200SS 223 m-bromoanisole 128 mini-trickle bed reactor 52 MagSilica 300, 231 m-iodotoluene 200 maleimide 9 monoarylated product 123 malononitrile 124, 125 monomode microwave flow reactor mass flow controller (MFC) 28 system 227 materials input per service multifunctional reactors 277 (MIPS) 81 multi-microcapillary flow reactor matrix metalloproteinase (MMP) (MμCFR) 10 inhibitor 1, 27 Murahashi coupling reaction 204 metal-catalyzed cross-coupling chemistry 138 n metalloproteinase inhibitor product N-benzylbenzamide 201 105 N-Boc-γ-amino alcohols 177, 178 Me-THF solvents 268 Néel relaxation process 230 methoxycarbonylation 200 N-Heterocyclic carbenes (NHCs) 242 4-methoxyphenyllithium 204 Nelder-Mead Simplex (NMS) algorithm methyl 2-acetamidoacrylate 198 122 methyl benzoate 206 (±)-neostenine 9 methyl ethyl ketone peroxide neurolepticum 232 (MEKPO) 61 neurolepticum Olanzapine 231 2-methyl-1,4-naphthoquinone 60 neuropeptide YY5 receptor antagonist methyl pyrrolidinecarboxylate 236 [11C]MK-0233 201, 202 methyl-Z-(𝛼)-acetamidocinnamate 4-nitrobenzyl bromide 238 195 N-methylpyrrole 214 micro- and home-made flow N,N-diethyl-N-methyl-N-(2- reactors 224 methoxyethyl)ammonium microflow plant 13 bis(trifluoromethanesulfonyl) microlitre microwave reactor 229 imide [deme][TFSI] 236 microreactors 270 Novozym 435, 32 microreactor technology nucleation 278 ecological advantages 128 nucleophilic aromatic substitution 223 economical advantages 128 micro- to mesoreactors 5 o microwave-assisted, continuous-flow o-benzoquinone 212 organic synthesis (MACOS) o-Iodonitrobenzene 231 protocol 225 olanzapine 232 microwave-assisted flow chemistry organic electrochemistry 234 commercial and industrial microwave organic peroxides 56 reactors 221 organic solvents 166 ethyl 2-indolecarboxylic ester 221 organometallic catalysts 261 first monomode reactor 221 organometallic reagents 202 Index 315 organozinc halides 139 photo-induced radical C-H bromination oxathiepinone 170 34 photooxygenations 15 p photoreaction modes 2 Paal-Knorr reaction 123 p-iodotoluene 200 packed-bed microstructured reactor plate reactor 54 57 p-methoxybiphenyl 226 palladium-catalysed amination p-methoxytoluene 239 reactions 234 Pollution Prevention Act 165 palladium-catalysed C–N poly-L-leucine (PLL) 54 cross-coupling reactions 233 polymer-micelle incarceration method palladium catalyst bed 225 50 p-anisaldehyde 124, 125 polymer-supported organic bases 169 particulate fouling 281 polystyrene-supported benzenesulfonic Paternó-Büchi reaction 209 acid 59 p-bromobenzonitrile 224, 225 polystyrene-supported phosphazene Pd/BrettPhos/NaOtBu system 261 base exploitation 169 [Pd(IPr*)(cin)Cl] catalysts 264 polystyrene-supported tert-butylimino- 2 Pd(OAc) /BINAP catalyst toluene 264 2-diethylamino-1,3- Pd-SILP-catalyzed Heck reaction 168 dimethylperhydro-1,3,2- 1-pentanol 120 diazaphosphorine (PS-BEMP) peracetic acid 65 169, 170 perfluorosulfonic acid (PFSA) resins polystyrene-supported triethylamine 179 (PS-TEA) 169 pharmaceutical API manufacture 264 polytetrafluoroethylene (PTFE) pharmaceutical development capillary-based reactors 7 clinical development 76 potassium phenylpropanoate 12 continuous improvement 77 potentially explosive azides 108 preclinical development 75 potentially hazardous hydroperoxide process for launch 76 16 second generation process 76 process mass intensity (PMI) 80 pharmaceutically relevant azide 205 product quality 74 Pharmaceuticals in the environment propyl caffeate 32 (PIE) 79 P2X7 biological evaluation 156 phase-vanishing bromination 33 pyrazole 148 phenol methylation 222 pyridine carboxylic acid 198 phenolysis of epoxides 171 pyrimidine synthesis 198 phenylboronic acid 184 pyrrole derivative 123 1-phenylethanol 181 pyrrolidine analogues 147 phenyl formates 140 pyrrolidine scaffold 147 photochemical bromination 182 photochemical water treatment 6 r photochemistry and green chemistry 4 reactive singlet oxygen 15 photochemistry module deep UV 7, 8 “release and catch” phenomenon 167 [5+2]-photocyclization 10 renewable feedstocks 194 [2+2]-photocycloaddition 9 response surface modelling (RSM) 110 [5+2]-photocyloaddition 9 Responsible Care Global Charter 165 316 Index

Responsible Care program 165 styrene 202 reusable heterogeneous® catalyst styrene-based dienophiles 211 172 5-substituted 1H-tetrazoles 206 rhodium catalyst 197 sulfoxides and sulfones synthesis 58 rosuvastatin precursor 182 sulphated zirconia (SZ) 47 sulphonamides 150 s sulphur pentafluoride synthesis 213 safer solvents and auxiliaries 194 Super-Modified Simplex Method Sanofi-Genzyme’s continuous process (SMSIM) software 119 249 supported ionic liquid phases (SILPs) selective α-(1 → 2)-mannose 168 glycosylation reactions 104 surface fouling 280 semi-automated optimization suspended micro-particles 291 BBD 111 suspended nanoparticles 292 high-throughput screening 105 sustainable drug discovery potentially explosive azides 108 integrated platforms 149 Swern-Moffat oxidation 107 lead optimization 154 self-optimizing microreactor systems library synthesis 146 benzyl alcohol oxidation 126 stages 146 CdSe quantumdots 116 technologies 157 green supercritical CO2 117 toxicity evaluation 146 highly efficient self-optimizing Heck sustainable etherification 117 reaction 121 Suzuki and Negishi reactions 139 Knoevenagel condensation 125 Suzuki coupling 168 Paal-Knorr reaction 123 Swern-Moffat oxidation 107 SGLT2 inhibitors 98 SYNFLOW 259

silylated nuleophiles, activation 172 synthesis of H2O2 44 ‘smart-scale’ flow reactor 286 synthetic organic photochemistry 1 sodium-glucose transport proteins (SGLT2) 98 t soft particles 286 Taylor flow reaction systems 292 solid actives 288 Taylor-slurry reactor 292 solid polymer electrolyte (SPE) tetrazoles 206 electrolyzer 47 T315I gatekeeper mutant 152 solketal formation 115 thermal Overman rearrangement 94 solketal yield 113 thermomorphous double emulsion solvent-free conditions (SolFC) 169 system 35, 36 sonochemistry 233 thiazole 148 Sonogashira reaction 25 three level four factorial Box-Behnken soybean oil 112 Design 112 Stable Noisy Optimization by Branch time/cost/energy saving and Fit (SNOBFIT) algorithm energy and cost efficiency 183 117 minimization of reaction time 185 stage-gating process 259 process intensification and easy Strategic Approach to International scale-up 181 Chemicals Management titanium silicaite-1 (TS-1) zeolite 52 (SAICM) 79 toluene 11, 12 Index 317 toluene-2,4-diisocyanate 208 unstable organometallic intermediates toluene recycling 265 203 topotecan 13 US Environmental Protection Agency (rac)-Tramadol 204 (US EPA) 165 trans-butyl cinnamate 27 triazole 205 v 1,2,3-triazoles 234 Vapourtec AF-2400 tube-in-tube triazolopyridazines 154 gas-liquid react 200 trickle-bed/packed-bed reactor 45, 46 Vapourtec E-Series 137 Vapourtec tube-in-tube reactor 197 triflic anhydride, (Tf2O) 186 trifluoroacetic acid 12 Vapourtec UV-150 photochemical trifluoroacetic anhydride (TFAA) 107 reactor 8 trifluoromethanesulfonic acid (TfOH) Vildagliptin 95 65, 236 Vilsmeier reaction 95 3,4,5-trimethyloxazole 104 VOYAGER system 222 trimethylsilyl azide (TMSN3) 173 trimethylsilyl cyanide (TMSCN) 175 w triphenylphosphine supported on waste minimization, cross-coupling polystyrene (PS-TPP) 175 reaction 167 tube-in-tube reactors 141, 145, 196 waste-minimized, cyclic-flow protocol 168 u WaveCraft 223 uniqsis flowSyn reactor 184 Wilkinson’s catalyst 197 uniqsis tube-in-tube reactor 200 World Business Council for Sustainable unstable intermediates Development 255 electrochemistry 210 World Commission on Environment photochemistry 207 and Development (WCED) 77