Recent advances for serial processes of hazardous chemicals in fully integrated microfluidic systems

The development and enlargement of toxic and hazardous chemicals are severely limited by health and safety concerns. We summarize studies on fully integrated micro-chemical systems and total processes to reduce accidental exposure to various regents that are toxic, explosive, or carcinogenic, which significantly improved the safety of work involving risky compounds. This review covers the leak-free continuous-flow processes of hazardous chemicals in fully integrated microfluidic systems, specially denoted as micro-total envelope systems (μ-TESs), that are conducting a serial process of the generation of hazardous reagents, in-situ purification and separation, subsequent reaction, and product isolation with improved efficiencies. These attempts suggest safe and efficient tools and processes of useful but hazardous chemicals for researchers and manufacturing workers in the field of pharmaceutic discovery, natural products, biology as well as materials synthesis.

[1]  T. Fukuyama,et al.  Koch–Haaf reaction of adamantanols in an acid-tolerant hastelloy-made microreactor , 2011, Beilstein journal of organic chemistry.

[2]  C. Kappe,et al.  Continuous flow synthesis of β-amino acids from α-amino acids via Arndt–Eistert homologation , 2014 .

[3]  C. Wiles,et al.  Continuous flow reactors: a perspective , 2012 .

[4]  Andrew R. Bogdan,et al.  Efficient access to new chemical space through flow--construction of druglike macrocycles through copper-surface-catalyzed azide-alkyne cycloaddition reactions. , 2010, Chemistry.

[5]  D. Barnes,et al.  A facile method for the preparation of MOM-protected carbamates. , 2009, Organic Letters.

[6]  M. Bols,et al.  Radical Azidonation of Benzylic Positions with Iodonium Azide. , 2001, Angewandte Chemie.

[7]  Steven V. Ley,et al.  Flow ozonolysis using a semipermeable Teflon AF-2400 membrane to effect gas-liquid contact. , 2010, Organic letters.

[8]  H. Adkins,et al.  Hydroformylation of Unsaturated Compounds with a Cobalt Carbonyl Catalyst , 1949 .

[9]  B. Griedel,et al.  A Simple and Cost Effective Synthesis of Chloromethyl Methyl Ether , 1994 .

[10]  D. Ripin,et al.  Large-scale oxidations in the pharmaceutical industry. , 2006, Chemical reviews.

[11]  D. Roberge,et al.  A two-step continuous-flow synthesis of N-(2-aminoethyl)acylamides through ring-opening/hydrogenation of oxazolines. , 2011, Chemistry.

[12]  C. Kappe,et al.  Click chemistry under non-classical reaction conditions. , 2010, Chemical Society reviews.

[13]  Klavs F. Jensen,et al.  The role of flow in green chemistry and engineering , 2013 .

[14]  N. Oger,et al.  Handling diazonium salts in flow for organic and material chemistry , 2015 .

[15]  S. Ley,et al.  Teflon AF-2400 mediated gas-liquid contact in continuous flow methoxycarbonylations and in-line FTIR measurement of CO concentration. , 2011, Organic & biomolecular chemistry.

[16]  G. Maas.  New syntheses of diazo compounds. , 2009, Angewandte Chemie.

[17]  P. Bailey.  The Reactions Of Ozone With Organic Compounds , 1958 .

[18]  Steven V Ley,et al.  Flow chemistry: intelligent processing of gas-liquid transformations using a tube-in-tube reactor. , 2015, Accounts of chemical research.

[19]  Adam McCluskey,et al.  The expanding utility of continuous flow hydrogenation. , 2015, Organic & biomolecular chemistry.

[20]  Steven V Ley,et al.  Safe and reliable synthesis of diazoketones and quinoxalines in a continuous flow reactor. , 2011, Organic letters.

[21]  Steven V Ley,et al.  [3 + 2] Cycloaddition of acetylenes with azides to give 1,4-disubstituted 1,2,3-triazoles in a modular flow reactor. , 2007, Organic & biomolecular chemistry.

[22]  K. Jensen,et al.  Flow distribution and ozonolysis in gas-liquid multichannel microreactors , 2006 .

[23]  Dominique Roberge,et al.  Synthesis of 5-substituted 1H-tetrazoles from nitriles and hydrazoic acid by using a safe and scalable high-temperature microreactor approach. , 2010, Angewandte Chemie.

[24]  Peter H Seeberger,et al.  Applying flow chemistry: methods, materials, and multistep synthesis. , 2013, The Journal of organic chemistry.

[25]  Stefan Bräse,et al.  Organic azides: an exploding diversity of a unique class of compounds. , 2005, Angewandte Chemie.

[26]  N. Irving Sax,et al.  Dangerous properties of industrial materials , 1957 .

[27]  N. Leadbeater,et al.  Continuous-flow, palladium-catalysed alkoxycarbonylation reactions using a prototype reactor in which it is possible to load gas and heat simultaneously. , 2011, Organic & biomolecular chemistry.

[28]  G. Whitesides.  The origins and the future of microfluidics , 2006, Nature.

[29]  Ian R. Baxendale,et al.  The Use of Gases in Flow Synthesis , 2016 .

[30]  Andrew R. Bogdan,et al.  The Use of Copper Flow Reactor Technology for the Continuous Synthesis of 1,4‐Disubstituted 1,2,3‐Triazoles , 2009 .

[31]  Andreas Seidel-Morgenstern,et al.  Continuous synthesis of artemisinin-derived medicines. , 2014, Chemical communications.

[32]  J. A. Barton,et al.  Bretherick's Handbook of Reactive Chemical Hazards , 1990 .

[33]  T. Fukuyama,et al.  Radical carbonylations using a continuous microflow system , 2009, Beilstein journal of organic chemistry.

[34]  D. Roberge,et al.  Safe Generation and Synthetic Utilization of Hydrazoic Acid in a Continuous Flow Reactor , 2012, Journal of Flow Chemistry.

[35]  C. Hayes,et al.  Synthesis of β-keto esters in-flow and rapid access to substituted pyrimidines. , 2010, The Journal of organic chemistry.

[36]  T. Wirth,et al.  Controlling hazardous chemicals in microreactors: Synthesis with iodine azide , 2009, Beilstein journal of organic chemistry.

[37]  Krist V. Gernaey,et al.  Process Intensification Tools in the Small‐Scale Pharmaceutical Manufacturing of Small Molecules , 2015 .

[38]  T. Fukuyama,et al.  Modernized low pressure carbonylation methods in batch and flow employing common acids as a CO source. , 2013, Organic letters.

[39]  C. Oliver Kappe,et al.  Mechanistic Insights into Copper(I)-Catalyzed Azide-Alkyne Cycloadditions using Continuous Flow Conditions , 2010 .

[40]  Timothy F. Jamison,et al.  Continuous flow multi-step organic synthesis , 2010 .

[41]  V. Shahi,et al.  Stable and hydroxide ion conductive membranes for fuel cell applications: Chloromethyaltion and amination of poly(ether ether ketone) , 2013 .

[42]  Volker Hessel,et al.  Copper(I)-catalyzed azide-alkyne cycloadditions in microflow: catalyst activity, high-T operation, and an integrated continuous copper scavenging unit. , 2012, ChemSusChem.

[43]  J. Yoshida,et al.  Flow microreactor synthesis in organo-fluorine chemistry , 2013, Beilstein journal of organic chemistry.

[44]  A. Bogdan,et al.  Synthesis of 5-iodo-1,2,3-triazole-containing macrocycles using copper flow reactor technology. , 2011, Organic letters.

[45]  Ping Zhang,et al.  Continuous Flow Total Synthesis of Rufinamide , 2014 .

[46]  T. Wirth,et al.  Diazo compounds in continuous-flow technology. , 2015, ChemSusChem.

[47]  A. S. Chawla,et al.  Medicinal chemistry of tetrazoles. , 1980, Progress in medicinal chemistry.

[48]  Claudio Battilocchio,et al.  A Flow-Based Synthesis of 2-Aminoadamantane-2-carboxylic Acid , 2012 .

[49]  A. Gee,et al.  Gas-liquid segmented flow microfluidics for screening Pd-catalyzed carbonylation reactions. , 2012, Chemistry.

[50]  C. Kappe,et al.  Continuous flow synthesis of α-halo ketones: essential building blocks of antiretroviral agents. , 2014, The Journal of organic chemistry.

[51]  Asterios Gavriilidis,et al.  Ozonolysis in Flow Using Capillary Reactors , 2011 .

[52]  Albert Folch,et al.  3D-Printed Microfluidics. , 2016, Angewandte Chemie.

[53]  M. Cartwright,et al.  Correlation of Structure and Sensitivity in Inorganic Azides I Effect of Non‐Bonded Nitrogen Nitrogen Distances , 2010 .

[54]  A. Ritzén,et al.  Multistep continuous-flow synthesis in medicinal chemistry: discovery and preliminary structure-activity relationships of CCR8 ligands. , 2013, Chemistry.

[55]  Ferenc Darvas,et al.  High-efficiency aminocarbonylation by introducing CO to a pressurized continuous flow reactor. , 2008, Organic letters.

[56]  Christopher G. Frost,et al.  Heterogeneous catalytic synthesis using microreactor technology , 2010 .

[57]  T. Wirth,et al.  Microreactors in organic synthesis and catalysis , 2008 .

[58]  T. Kang,et al.  Extracellular Microreactor for the Depletion of Phenylalanine Toward Phenylketonuria Treatment , 2015 .

[59]  Timothy M. Braden,et al.  Improved Synthesis of 1-(Azidomethyl)-3,5-bis-(trifluoromethyl)benzene: Development of Batch and Microflow Azide Processes , 2009 .

[60]  J. V. van Hest,et al.  Continuous flow azide formation: Optimization and scale-up , 2011 .

[61]  M. B. Talawar,et al.  Primary explosives: electrostatic discharge initiation, additive effect and its relation to thermal and explosive characteristics. , 2006, Journal of hazardous materials.

[62]  R. Luque,et al.  Liquid phase oxidation chemistry in continuous-flow microreactors. , 2016, Chemical Society reviews.

[63]  Jan Passchier,et al.  Rapid multiphase carbonylation reactions by using a microtube reactor: applications in positron emission tomography 11C-radiolabeling. , 2007, Angewandte Chemie.

[64]  C. Kappe,et al.  Continuous flow ozonolysis in a laboratory scale reactor. , 2011, Organic letters.

[65]  Dong-Pyo Kim,et al.  Continuous in situ generation, separation, and reaction of diazomethane in a dual-channel microreactor. , 2011, Angewandte Chemie.

[66]  Nicholas E. Leadbeater,et al.  A Continuous-Flow Approach to Palladium-Catalyzed Alkoxycarbonylation Reactions , 2011 .

[67]  R. J. Herr,et al.  5-Substituted-1H-tetrazoles as carboxylic acid isosteres: medicinal chemistry and synthetic methods. , 2002, Bioorganic & medicinal chemistry.

[68]  Norbert Kockmann,et al.  Harsh Reaction Conditions in Continuous‐Flow Microreactors for Pharmaceutical Production , 2009 .

[69]  K. Jensen,et al.  Multistep continuous-flow microchemical synthesis involving multiple reactions and separations. , 2007, Angewandte Chemie.

[70]  Klavs F Jensen,et al.  Accelerating reactions with microreactors at elevated temperatures and pressures: profiling aminocarbonylation reactions. , 2007, Angewandte Chemie.

[71]  Dong-Pyo Kim,et al.  Continuous flow synthesis of toxic ethyl diazoacetate for utilization in an integrated microfluidic system , 2014 .

[72]  Claudio Battilocchio,et al.  Enabling Technologies for the Future of Chemical Synthesis , 2016, ACS central science.

[73]  Riccardo Porta,et al.  Flow Chemistry: Recent Developments in the Synthesis of Pharmaceutical Products , 2016 .

[74]  A. Gavriilidis,et al.  Ozonolysis of some complex organic substrates in flow , 2013 .

[75]  M. Maggini,et al.  Scalable in Situ Diazomethane Generation in Continuous-Flow Reactors , 2012 .

[76]  A. deMello,et al.  A Microfluidic Approach to the Rapid Screening of Palladium-Catalysed Aminocarbonylation Reactions , 2009 .

[77]  L. Flippin.  Directed metalation and new synthetic transformations of 5-aryltetrazoles , 1991 .

[78]  Ian R Baxendale,et al.  Establishing a flow process to coumarin-8-carbaldehydes as important synthetic scaffolds. , 2012, Chemistry.

[79]  David Cantillo,et al.  Continuous-flow technology—a tool for the safe manufacturing of active pharmaceutical ingredients. , 2015, Angewandte Chemie.

[80]  Brahim Benyahia,et al.  Development of a Multi-Step Synthesis and Workup Sequence for an Integrated, Continuous Manufacturing Process of a Pharmaceutical , 2014 .

[81]  M. Bols,et al.  Radical substitution with azide: TMSN3-PhI(OAc)2 as a substitute of IN3. , 2005, Organic & biomolecular chemistry.

[82]  Philip J. Kitson,et al.  Integrated 3D-printed reactionware for chemical synthesis and analysis. , 2012, Nature chemistry.

[83]  A. Maguire,et al.  Taming hazardous chemistry in flow: the continuous processing of diazo and diazonium compounds. , 2015, Chemistry.

[84]  C. Oliver Kappe,et al.  Continuous flow generation and reactions of anhydrous diazomethane using a Teflon AF-2400 tube-in-tube reactor. , 2013, Organic letters.

[85]  K. Jensen,et al.  Synthesis of micro and nanostructures in microfluidic systems. , 2010, Chemical Society reviews.

[86]  M. Berliner,et al.  Simple, rapid procedure for the synthesis of chloromethyl methyl ether and other chloro alkyl ethers. , 2005, The Journal of organic chemistry.

[87]  Steven V Ley,et al.  Multistep synthesis using modular flow reactors: Bestmann-Ohira reagent for the formation of alkynes and triazoles. , 2009, Angewandte Chemie.

[88]  James M. B. Evans,et al.  End-to-end continuous manufacturing of pharmaceuticals: integrated synthesis, purification, and final dosage formation. , 2013, Angewandte Chemie.

[89]  Lukas Küpper,et al.  An Ozonolysis−Reduction Sequence for the Synthesis of Pharmaceutical Intermediates in Microstructured Devices , 2009 .