Flow Chemistry Asia 2019 Agenda

Conference Registration, Materials Pick-Up, Morning Coffee and Tea

Flow and Plasma Chemistry – Disruptive Technologies Transform Industry through Theme-based Approach
Volker Hessel, Professor, School of Chemical Engineering, The University of Adelaide, Australia

At our Faculty at the University of Adelaide, we have developed a unique Theme-based approach which truly leads to an interdisciplinary research outcome (as opposed to multidisciplinary), and this is run as cross-faculty and cross-discipline action. Core is a selection and targeting of industrial windows of opportunity to be translated to an industrial showcases, which is followed by technology development and stakeholder engagement. Outcome is an aim for transformative change of industry by disruptive technologies, breaking with existing approaches, and pharmaceutical industry was changed that way. This offers release of large sustainability gain and leads to entirely new business models.
One feature and benefit of themes is to allow to cluster own research. First attempt was in 2007 with a cluster on Novel Process Windows (NPW). Those regimes systematically utilise unusual and typically harsh process conditions for enhanced activation of chemistries in continuous-flow and connection of multi-step chemistries [Hessel, ChemSusChem 2013]. In this talk, three recent thematic research clusters will be presented, to show how above methodology guides and promotes holistic, transformative research.

Solvent Factory (2017 onward) The FET-Open project ONE-FLOW translates the ‘vertical hierarchy’ of chemical multistep synthesis with its complex machinery into self-organising ‘horizontal hierarchy’ of a compartmentalized flow reactor system (www.one-flow.org). The new concept of a ‘Solvent Factory’ uses multi-phase liquids as integrated reactor-separator; ideally without need of any post-processing and –purification steps. This switch from hardware- to soft matter processing tools is especially beneficial, when approaching multi-step reactions with its many reactors and separators, and replacing them by one.
Fertilizing with Wind (2014 onward) Plasma-enabled chemical nitrogen fixation using air (N2) allows to manufacture NO/NO2 which can be further converted to yield nitric acid by absorption in aqueous solution. In a similar way, nitrogen and hydrogen can be reacted by plasma catalysis to give ammonia. In this way, fertilisers can be made “out of air” and using wind as green energy source. It will be discussed how this can lead to a transformation of agriculture to a precision horticulture. This is currently implemented in Uganda, as much growing AgTech nation, and e-agriculture, based on ICT using mobile phones, is a cross-discipline enabler. With U Warwick, the ERC Synergy research offers a large opportunity for fundamental revisit of plasma catalysis and its symbiosis.

Space manufacturing (2018 onward) Space manufacturing is off-earth manufacturing - the advanced technologies are for dual use: also on earth, in deep sea, in dry lands, and other disruptive scenarios. Space medicine is already now a business case and the next cancer drug might be developed in space. A think tank analysis has been made how to make medicines and nanoformulations stable to cosmic rays. Space mining is at the edge to become a business case. Flow-based extraction of artificial asteroid ores is investigated with coiled micro-flow inverters, posing adjacent metal separation tasks, not known on earth. A topic of similar importance is the continuous-flow based soil-solvent extraction of phosphorus (with and without rare earths); the remote mine might be in Morocco’s Western Sahara or in Moon’s Procellarum KREEP Terrane. Space farming is a mid-term development issue, and plasma based N-fixation can play a key role. Space chemistry research on flow-made quantum dots will be presented, hosted on a satellite, will be reported, to sever as satellite decoy for counterstrike measure. This demands fluid flow without pumps. A stop-flow for three reaction steps comprises solid-liquid mixing under zero gravity, heating and reaction, and ejection of a nanodust cloud in the space.

The Broader Importance of Flow Chemistry to Manufacture of Pharmaceuticals
Andrew Rutter, Senior Director, GlaxoSmithKline, United Kingdom

Flow chemistry’s importance to medicines manufacture goes far beyond enabling different (better) chemistry – it is about providing agility (and compliance) in how we design and build medicines supply chains. I will explore how flow chemistry builds to Continuous Manufacturing processes and how this approach supports agility in the supply of medicines. I will link this approach to advances in modularization and a digital twin of the process. This philosophy is equally applicable in Small and Large Molecule manufacture.

The HANU-Reactor: Development of a Scalable Continuous-Flow Photoreactor
Hannes Gemoets, R&D Engineer, Creaflow

In the last decade, continuous-flow photochemistry has received much attention from researchers in academia as well as industry. With the groundwork now in place, the focus has been shifted to the realization of scalable photochemistry, and in this context, the HANU-reactor was developed. This pulsating-flow plate reactor contains static mixing elements that induce a split-and-recombine flow path, and is equipped with a large window lid for maximum light exposure. The synergetic use of the reactor geometry with a pulsating flow regime, results in plug flow behavior combined with intense mixing, regardless of its net flow rate. The innovative design allows the user to operate the reactor at both short and very long light exposure times, without compromising the mixing efficiency or the need for flow recirculation. To demonstrate its potential, an intramolecular [2+2]-cycloaddition was performed, producing an impressive 2.3 kg of Cookson’s diketone per day, utilizing a single 15 mL lab-scale HANU-reactor. Thanks to the innovative design, the HANU-reactor can be linearly scaled. Preparative photochemistry is now readily accessible by simply widening its process channel without the need to change any process parameters.[4] In addition, the pulsatile flow expands the window to heterogeneous reaction processing (e.g. heterogeneous photocatalyst). Furthermore, the window lid allows visual inspection as well as application of non-invasive, through-window inline spectroscopic PAT.

Morning Coffee and Tea Break and Networking

Exploiting Segmented Flow Chemistry In Modern Compound Library Synthesis
Andrew Mansfield, Flow Chemistry Leader, Syrris

The pharmaceutical industry continues to go through changes both in its approach to drug discovery and in the way, it uses new enabling technologies. The constant demand to deliver new drugs to market is the driver to adopt new strategies to improve the speed through early discovery to production and to the point of care. One of the major challenges faced today in drug discovery programs is the increasing demand to deliver a continuous supply of active compounds, generally novel and structurally diverse, in increasing numbers and in shorter timelines.  The use of continuous flow technology in the chemical synthesis of libraries allows the exploration of novel reaction windows to deliver a wider chemical space and more compound diversity over traditional methods. The technique enables the rapid optimization of synthetic protocols, access to reactions that were formerly avoided because of scale or safety concerns, telescoped reactions avoiding purification between steps and ready-made scale-up strategies.  This presentation illustrates how flow chemistry technology has enabled the synthesis of a range of structurally diverse compounds across a range of chemistries with the benefits of automation and reaction control.

Networking Lunch, Meet with Exhibitors and View Posters

A Large Capacity Micro Channel Reactor (SMCR®) For Promoting Industrialization of Flow Chemistry
Akira Matsuoka, Researcher, Technical Development Group, Kobe Steel Ltd., Japan

• Concept of a large capacity micro channel reactor (SMCR^®) with simple numbering up method by multi-channel plate stacking
• Several practical applications of SMCR^®

Particle Synthesis Strategies in Microreactors
Simon Kuhn, Professor, Department of Chemical Engineering, KU Leuven Belgium, Belgium

This talk will present approaches for the controlled and continuous formation of particles, either as organic crystals or as inorganic precipitates. Control of the particle size distribution is achieved by either implementing a two-phase flow strategy or using high-frequency ultrasound. Both presented reactor concepts serve as important stepping stones to efficiently handle solids in microreactors.

Afternoon Coffee and Tea Break and Networking

Micro-Packed Bed Reactors for Continuous API Manufacturing
Jisong Zhang, Associate Professor, Tsinghua University , China

The engineering principles of micropacked bed reactors and applications of this reactor on the continuous API manufacturing will be discussed.

Microreaction Technologies for Engineering and Functional Materials
Guangsheng Luo, Professor, Tsinghua University, China

Microchemical process technologies have high promising prospects for the development of green and low-carbon chemical industries. The new technologies are also expected to make some great changes in the preparation of engineering and functional polymer materials. The microreaction processes with high viscosity polymer solutions as reactants are very hard to control for the poor mixing, high pressure drop, and complex phase change performances. In our recent work, controllable preparation of polymer materials in microreactors have been carried out. For the preparation of bromobutyl rubber (BIIR), we have developed a PTFE-lined microreactor platform and obtained high quality BIIR based on excellent mixing ability. We developed a highly efficient method for the synthesis of polyvinyl butyral (PVB) in a microchemical system. In this presentation, we will present the details of the development.

Reaction and Particle Engineering in Flow: From Scalable, Intensified Chemistry to Designer Drug Products
Saif Khan, Associate Professor, Chemical and Biomolecular Engineering, National University of Singapore, Singapore

In this talk, I will provide an overview of our research on engineering micro- and milli-fluidic systems to develop advanced manufacturing processes that bridge both primary (drug substance) and secondary (drug product) pharmaceutical manufacturing.

Macrocyclization Processes in Flow
Shawn Collins, Full Professor, Université de Montréal, Canada

Traditional macrocyclization reactions often use batch reactors and/or apparatus for slow addition protocols. However, an emerging alternative exists in performing macrocyclizations in continuous flow. Continuous processing can offer several advantages, including higher yields and shorter reaction times due to improved mass and energy transfer. Continuous flow macrocyclizations involving the olefin metathesis reaction, the Glaser-Hay coupling, CuAAC as well as new photochemical macrocyclizations will be discussed.

Close of Day 1 of the Conference

Morning Coffee, Tea and Networking

Go With the Flow, or Not? The Basic Principles of Flow Chemistry for Synthetic Organic Chemists
Timothy Noël, Professor, University of Amsterdam, Netherlands

Flow chemistry is typically used to enable challenging reactions which are difficult to carry out in conventional batch equipment. Consequently, the use of continuous-flow reactors for applications in organometallic and organic chemistry has witnessed a spectacular increase in interest from the chemistry community in the last decade. However, flow chemistry is more than just pumping reagents through a capillary and the engineering behind the observed phenomena can help to exploit the technology’s full potential. Here, we aim to give a concise overview of the most important engineering aspects associated with flow chemistry, such as mixing, heat transfer, multistep reaction sequences, etc. In addition, we will give suitable chemistry examples where appropriate to demonstrate the impact of flow processing on synthetic organic chemistry.

3D Printed Reactor Inserts For Heterogeneous Catalysis – New Chemical Manufacturing Solutions
Christian Hornung, Research Group Leader, CSIRO, Australia

With a design guided by CFD, 3D-printed from base metals such as stainless steel, and coated with a catalyst using either cold spraying, electroplating or wash coating, catalytic static mixers are used to replace fixed bed columns in continuous flow heterogeneous catalysis. The deposition methods have been optimized in order to minimize catalyst leaching levels, resulting in only ppb levels of catalyst contamination in the product. We have demonstrated the versatility of this technology for gas-liquid hydrogenations in the pharmaceutical, fine chemical and related industries.

Morning Coffee and Tea Break and Networking

Efficient Amide Bond Formation Based on Micro-Flow Technology
Shinichiro Fuse, Professor, Nagoya University, Japan

Efficient amide bond formations were developed based on rapid mixing and precise control of temperature using micro-flow reactors. The developed synthetic methodology was used for low cost, less wasteful, and high yielding synthesis of peptides and amino acid N-carboxy anhydrides.

From Automated Precision Polymer Synthesis to Nanoparticle Morphology Control in Continuous Flow
Tanja Junkers, Professor, School of Chemistry, Polymer Reaction Design group, Monash University, Australia

An overview is given on the continuous flow multistep synthesis of complex macromolecules, the employment of machine learning to achieve unprecedented polymer synthesis accuracy and inline purification of polymers. Further, it will be demonstrated how continuous flow can improve nanoparticle synthesis in polymerization-induced self-assembly, and how kinetic morphology control over size and shape of nanoobjects can be achieved by flow mixing of block copolymers.

Visible-Light-Driven Fine Chemical Synthesis Using Inexpensive Natural Gases as Feedstocks in Micro-Tubing Reactors
Wu Jie, Assistant Professor, Chemistry Department, National University of Singapore, Singapore

Natural gases such as CO2, ethylene, acetylene, methane, ethane are inexpensive and available in virtually unlimited amounts, making them appealing candidates as C1 and C2 feedstocks for sustainable chemical synthesis. However, any attempt at using natural gases as raw materials in synthetic endeavors has to cope with serious challenges, including the inert reactivity and difficulty of operation. Photocatalysis has witnessed dramatic developments over the past decade which provides enormous opportunities for new catalytic synthetic methodology development using natural gases. In conventional batch reactors, scalability of photo-reactions is hampered due to the attenuation effect of photon transport, which prevents the use of a dimension-enlarging strategy for scale-up. The use of continuous-flow micro-tubing reactors for photochemical applications allows these issues to be overcome, by ensuring uniform irradiation of the entire reaction mixture and scaling-up of photochemical reactions via scaling-out or numbering-up strategies. In this context, my research group at NUS has invented a “stop-flow” micro-tubing (SFMT) reactor platform, which represents an ideal laboratory bench model for reaction discover applications. Assisted by SFMT reactors, we developed methodologies to convert acetylene, CO2, ethylene, and ethane into fine chemicals. Gram-scale synthesis can be easily achieved by the SFMT reactors, and the reaction can be further scale-up by using continuous-flow technology.

Networking Lunch, Meet with Exhibitors and View Posters

Time- and Molecular Structure Resolved Reaction Monitoring in Flow: The Potentials of Ion Mobility- and Mass Spectrometry Approaches
Maarten Honing, Professor, Maastricht University, M4I Institute Maastricht MultiModal Molecular Imaging, Netherlands

In this presentation, recent results on the application of novel ionization technologies, and Ion Mobility Spectrometry combined with MS or MS/MS methodologies will be presented. Its potentials will be discussed using different “stereo-selective” chemical conversions in flow, and attention will be given to the detection of low abundant “synthesis byproducts” lacking chromophores hampering spectroscopic detection.

Kinetic study of TBD Catalyzed d-Valerolactone Polymerization Via a Gas-Driven Droplet Flow Reactor
Kai Wang, Associate Professor, Department of Chemical Engineering, Tsinghua University, China

The kinetic model and reaction mechanism of ring opening polymerization of d-valerolactone catalyzed by TBD were established by gas-driven droplet flow technology.

Afternoon Coffee and Tea Break

Multigram-Scale Flow Synthesis of the Chiral Key Intermediate of (–)-Paroxetine Enabled by Solvent-Free Heterogeneous Organocatalysis
Sándor B. Ötvös, Researcher, Institute of Chemistry, University of Graz, Austria

(–)-Paroxetine is a selective serotonin reuptake inhibitor which is broadly used for the treatment of depression, anxiety and panic disorder. It is currently manufactured by batch processes of 10?15 reaction steps which typically apply classical resolution methods, chiral auxiliaries, enzymatic asymmetrizations or naturally occurring homochiral starting materials as sources for asymmetry. Catalytic enantioselective transformations have also been harnessed for the synthesis of (–)-paroxetine. These methods require less synthetic steps and provide more direct access to the target API, but their applicability for manufacturing is limited by the low productivity of the catalytic asymmetric key step. Motivated by these limitations, we developed a flow process for the synthesis of the chiral phenylpiperidine key intermediate of (–)-paroxetine. The critical step to introduce asymmetry was a solvent-free enantioselective conjugate addition in the presence of a highly robust heterogeneous organocatalyst. The chiral adduct was processed further via a telescoped reductive amination?lactamization?amide/ester reduction sequence which took advantage of a heterogeneous catalytic hydrogenation approach and the application of neat BH₃·dimethylsulfide complex as an efficient reducing agent unprecedented in earlier flow syntheses. The solvent-free or highly concentrated conditions in combination with the remarkably robust catalysts enabled multigram per hour scale production of the chiral target. In addition, the process generated minimal amounts of waste as demonstrated by a cumulative E-factor of 6.

Close of Conference