Flow Chemistry Congress Boston 2013

I had the pleasure of attending the Flow Chemistry Congress Boston 2013 last week. 

Organized by SelectBio and the Flow Chemistry Society, the conference was held at the Revere Hotel on Stuart Street. I discovered that the Revere Hotel is a comfortable setting for such a conference.  Regarding the conference attendees:  there were bout 35 delegates, a fairly stable audience over the years, most were already familiar with the use of continuous flow chemistry, or just starting and trying to learn more. Most participants were from North America with a blend of industry scientists (Pfizer, Rhodes Technologies, GlaxoSmithKline, DSM, Cytec, Sanofi) and academic researchers (MIT, Boston University).Flow Chemistry Congress 2013 Boston

The first keynote address was presented by MIT Professor Klavs Jensen who gave us an overview of investigations published by his team over the past 5 years. I paid particular attention to the solvent switch strategy using fluorinated or non-fluorinate membrane separation. An upcoming Green Chemistry paper (2013) will relate the details. The presentation also included the preparation in flow of diphenylphosphoryl azide and the Fluoxetine project. In conclusion, Professor Jensen mentioned a great need to develop flow distillation and flow solid separation on a micro-scale.

David Ager gave an overview of the DSM approach to continuous processing in the areas of nitration, chlorination, and low temperature, all reactions typically hazardous or difficult to conduct in batch. DSM makes use of the Corning Glass microchip technology. I learned that SiC reactors are now made available by ESK Austria. The enhanced preparation of Naproxen in flow was one of the case studies Dave presented. Other chemistries that could take advantage of this approach include hydrogenation with H2, oxidation with oxygen, and the use of NO. Examples are now available where FDA approved and validated GMP continuous processes.

Dominique Hebrault Mettler ToledoPaul Richardson from Pfizer gave us a discovery chemistry perspective on flow using several examples: a Schotten Baumann reaction, a Pd-catalyzed arylation and click-chemistry.

I enjoyed the talk from Paul Watts who recently moved from Hull University (UK) to become Research Chair in Microfluidic Bio/Chemical Processing, Nelson Mandela Metropolitan University, South Africa. The talk included various aspects of flow chemistry using the Chemtrix-Labtrix technology, high throughput reaction parameter optimization (> 200 experiments / day!) and kinetic investigation in flow. Chemistry examples included a Swern oxidation, a Strecker reaction with an immobilized catalyst, a KF-promoted fluorination (to be published in Lab Chip in 2013), and the synthesis of coumarin. Paul reminded us of the three current industrial applications of continuous processing in the fine chemicals industry: the synthesis of nitroglycerin by Xian Chemicals in China, the manufacturing of an agrochemical intermediate by DSM in Austria, and Naproxen by DSM as well in the Netherlands.

Frank Gupton gave a valuable perspective on the use of continuous processing to bring down the cost of Active Pharmaceutical Ingredients (APIs) manufacture when it moves into generic status. Telmisartan, angiotensin receptor blocker, was taken as an example (market $238 million/year). Frank presented some ligand-free cross-coupling  process enhancement using graphene as a metal solid support. Online analysis using UPLC from Waters was utilized here.

Professor Oliver Kappe gave an overview of case studies conducted in his team relating the use of high temperature/pressure conditions under potentially explosive conditions. I kept in mind the chlorination of alcohols using HCl gas, the oxidation of cyclohexene using hydrogen peroxide to access Nylon, the unusual use of diimide to reduce olefins, the oxidation of alcohol with TEMPO, and finally the use of propylene carbonate as a green solvent. In addition to the benefits typically attributed to flow chemistry, Professor Kappe emphasized the possibility to run in flow chemical reactions difficult or impossible to consider previously.

As always, it was a pleasure to hear Nicholas Leadbeater from University of Connecticut describing with great enthusiasm his recent research development. This time, the presentation was focused on undergraduate teaching and the use of microwave and real time analytical technologies, e.g. Raman and mid-IR, to produce fine chemicals and biofuels. Reactive gases described in the various examples were CO, O2. A Vapourtec flow instrument was used. A more efficient preparation of levulinic acid (food flavoring agent and fuel additive) and  3-acetyl coumarin were used as an examples.

The talk from Tyler McQuade, now back at the University of Florida after a period with Peter Seeberger at the Freie Universität Berlin and Max-Plank Institut in Postdam, was catalysis-oriented. He presented progress in the area of using enzymes on packed-bed microreactors. Proline was used to generate enantioselectivity in the alpha-amination of aldehydes using nitrosobenzene.

MIT Professor Tim Jamison came to present some photochemistry in flow including [3+2] catalyzed cycloaddition and peptide fragment synthesis, as well as more improvement of the Friedel Crafts condensation applied to the preparation of Ibuprofen and the use of molten salts as solvents. I found the mapping approach for the optimization of DIBAL reductions of esters into aldehydes especially interesting. On the side of using flow to run highly energetic reactions, Tim described the synthesis of tetrazoles via azidation and the use of diimide as a clean reducing agent.

Greg Roth from the Sanford Burnham Medical Research Institute went into an area I do not know well but wanted to learn more about: the use of electrochemistry in synthetic chemistry. We learned about the measurement and use of constant current and potential difference between anode and cathode to oxidize ethers into ketones, then carboxylic acids, as well as the electrofluorination with KF, and the preparation of drug metabolite using the FLUX technology.

Continuous Flow ChemistryVisiting the exhibits and talking to vendors is always a great experience to learn and discover new technologies. For instance, Covaris’ use of adaptive focused acoustic was new to me. The technologies has been successfully applied to dissolution, instant mixing, suspension, produce nano-crystals, make nano-emulsion thanks to the high energy delivered. Another use is carbon nanotubes wetting, well known to be challenging. The technology is applicable from sub-mL scale to large scale operations.

Stimulating as well is the creation of Zaiput, a spinoff from MIT focused on commercial development of the flow separation fluorine membrane (see e.g. Angew. Chem. Int. Ed. 2007, 46, 5704 –5708) developed by Professor Jensen and colleagues. Dominique Surinx, CEO and founder of Borit, Belgium, explained how his small company (25 people) that develops metal plate technology for the fuel cell market is trying to expand into the flow chemistry market. The key benefits of the technology he developed are: manufacturing cost at high volume much lower than glass microchip, better heat exchange than glass. The company is still small though to satisfy and support an international market that requires some level of integration with process control and accessories.

Overall, it was an enlightening 2-day conference that allowed me to catch up with the ever-growing local flow chemistry community.