By no means am I a flow chemistry expert, but as probably the case for many other chemists, continuous processing has piqued my interest over the past few years. This interest in flow chemistry is thanks to some spectacular advances in discovery chemistry, process research and development, and the manufacturing of drugs and fine chemicals intermediates (see for instance this collection of papers: Organic Process Research & Development 2008, 12, 905-1015).
Also, I have increasingly been involved in flow chemistry projects since METTLER TOLEDO introduced the ReactIR™ DS Micro Flow Cell earlier this year. The ReactIR™ DS Micro Flow Cell allows scientists to monitor continuous processes in situ and in real time. As a result, Adrian Burke and I took advantage of the opportunity to attend the 4th Annual Uniqsis Flow Chemistry Symposium to learn more about the technology, meet with experts on the topic, and show them the ReactIR™ DS Micro Flow Cell. The one-day Symposium was held last week at the British Consulate in Cambridge, MA.
I really enjoyed the conference that gathered about 75 participants, mostly from the life science industry and academia, around surprisingly diverse topics such as microchips, microfluidic, meso and micro-mixed tubular devices used for a not less diverse number of applications:
- combinatorial chemistry
- discovery chemistry
- early and advanced research and development
- academic projects
- preliminary engineering
I also had the privilege to attend the hands-on training session held the day after at Massachusetts Institute of Technology (MIT)’s Chemistry Department. The training session allowed me to practice the use of the Uniqsis FlowSyn and converse with fellow development chemists about the use, benefits, and limitations of such modern synthetic tools.
Trying to cover the conference in a blog would be beyond what people expect from a blog post so let me just highlight briefly what I personally found fascinating, interesting, or surprising:
- Dr. Mark Ladlow, CSO at Uniqsis, started with an introduction to Uniqsis’ approach to flow chemistry. I really like the Auto-LF package that can be used to collect fractions of reaction mixture coming out of the column, making product isolation more straightforward, but also automatically feed the column with a set of diverse reagents in order to prepare a library of compounds. As I realized during the hands-on training session, programming on the touch pad has been made straightforward. I also find the calculators on their website valuable to estimate how much time is saved upon running a reaction at a higher temperature or pressure.
- Dr. Tyler McQuade from Florida State University presented some applications of micro reactors to chemical synthesis. The core of the presentation was actually on the preparation of ibuprofen on a chip using a 3-step Friedel-Craft/Tamura-Favorskii quench sequence.
- Dr. Noel Wilson from Abbott Laboratories gave a fascinating overview of Abbott’s strategy regarding continuous processing. He made a clear difference between micro flow devices like the Syrris FRX, the H-Cube, and the O-Cube on one hand, and mesoflow instruments like the Vapourtec R2/R4. The first category of instruments would be used more for screening and safe and efficient generation of compound libraries whereas the 2nd category would be also suited to process characterization and scalability study. I like the idea that flow chemistry enables the use of underutilized though invaluable chemical reactions and technologies such as ozonolysis and photochemistry. Adrian Burke and I presented a poster resulting from a collaboration with Abbott about the use of the ReactIR™ DS Micro Flow Cell to monitor an ozonolysis process. Noel presented several case studies to illustrate his point including the use of the home-made continuous photochemistry instrument LOPHTOR to construct bicyclic structures using [2+2] cyclizations. The idea is to take advantage of this type of reactions, so far reserved to special labs, to access compounds with a novel or unusual structure early-on in the drug discovery process, and gain a competitive advantage as a result.
- Although I had already attended talks given by Prof. Steven Ley, Cambridge University (UK), I feel like each one of them impresses me more than the previous one. Trying to summarize the depth and the breadth of this one would be impossible. So, let me just say that these instruments are unique in that today they allow to safely and efficiently handle hydrogen, ozone, carbon dioxide, and carbon monoxide in a standard organic synthetic lab environment. Numerous examples showed how to make the best of existing and various flow chemistry devices (HEL FlowCAT, H-Cube, O-Cube, Uniqsis FlowSyn), and ReactIR™ for real time reaction analysis, to almost fully automatically construct complex molecules in multiple steps (Spirangien, Gleevec, Hennoxazole). Working for a company involved in process automation, I was particularly interested in the use of ReactIR™ for automated feed-forward control of reagent flow rate based on real time component concentration. The recipe self adjusts and precisely control the addition of sensitive or unsafe reagents, like hydrazine, resulting in safer and more efficient process conditions. Does it make it more impressive to add that the lab instruments were controlled from a student’s cell phone in his apartment? Although the software interface was locally developed, we are actively working at making this kind of algorithm commercially available. Prof. Ley mentioned he actively collaborates with Joel Hawkins at Pfizer on some of these projects. You can find more details on Prof. Ley use of ReactIR™ in one of his papers (Organic Process Research & Development 2010, 14, 393–404) and The Application of the ReactIR™ Flow Cell to Continuous Processing Technology webinar available on-demand.
- The next speaker was Dr. Nicholas Leadbeater (University of Connecticut) who I had met earlier this year at the International Conference on Organic Process Research & Development in San Diego and had a great pleasure to meet once again. Nicholas has become known for his work on microwave applications in organic synthesis. He successfully used ReactIR™ to monitor microwave-assisted reactions (Chem. Commun., 2010, 46, 6693–6695). Over the past few months, Nicholas has dedicated himself to the application of flow chemistry to organic and inorganic synthesis: preparation of cisplatin, chromium carbonyl complexes, Diels-Alder cycloaddition, Suzuki coupling, carbonylation reactions.
- Dr. Teresa Makowski works at Pfizer with Joel Hawkins. She offered some captivating insights into the use of the HEL FlowCAT and the development and testing of a tricklebed hydrogenation flow reactor in collaboration with HEL. Joel Hawkins had presented on the topic at the National American Chemical Society (ACS) Meeting held last August in Boston. Unlike the H-Cube, great for discovery chemistry and reaction screening but limited by hydrogen availability, the trickle bed flow reactor affords experimental conditions closer to scale-up and the preparation of up to 40g/h material. Case studies on the hydrogenation of a piperidine derivative and 3-aminobenzoic acid illustrated the benefit of the technology in terms of lower catalyst loading, higher conversion and diastereoselectivity.
- I was sitting next to the following speaker, Anne O’ Kearny McMullan from Astra Zeneca (Macclesfield, UK), at the previous night’s dinner, and as such had the privilege to get a heads-up on her research projects. She presented some of AstraZeneca’s strategy in flow chemistry and the various technologies and developments conducted on some of their site: Södertälje (Alfa-Laval, Grignard chemistry), Mölndal (Vapourtec), Reims (home-made system), Alderley (Uniqsis FlowSyn), Macclesfield (CSTR, Uniqsis FlowSyn). Case studies included nitration, chlorination, SNAr, Li halogen exchange, Heck coupling. Like many other speakers, she concluded that flow chemistry is one tool among others that present strengths (better temperature control, safer operation) as well as limitations (work-up challenges, difficulties with handling slurries).
- Gary Tarver from Merck Sharp & Dohme (Newhouse, Scotland) was last to speak. He belongs to a team of five chemists involved in parallel synthesis for discovery and the preparation of initial samples up to 50g. As such, they are constantly looking for safer and more efficient ways to conduct their projects, microreactors and flow systems, like the Uniqsis FlowSyn and H-Cube, are part of the arsenal of enabling technologies. Gary presented an impressive list of applications, some of them already published (Moffat-Swern Oxidation: Organic Process Research & Development 2008, 14, 911–920). Other examples were: Solid phase Suzuki coupling, nitrile hydrolysis, phosphonate synthesis, Diels-Alder cycloaddition, metathesis, SNAr, nitro group reduction, oxidation with manganese oxide.
In summary, I retain that flow chemistry allows to run reactions faster by taking advantage of higher temperature and pressure conditions and better mixing conditions, and safer by avoiding the accumulation of hazardous reagent or intermediates and providing better heat transfer properties. They also conveniently make available to standard organic synthesis laboratories gaseous reagents (ozone, carbon monoxide, hydrogen, oxygen, carbon dioxide) and unusual reactions conditions (photochemistry) typically reserved to special labs. Examples in organic synthesis now abound, for instance: Roberge, Angew. Chem. Int. Ed., 2010; Org. Proc. Res. & Dev. 2004, 455 and 2009, 698 and Hilberink, 2008 (Swern oxidation); Synthesis, 2003 (Pfizer, Sildenafil); Chem. Comm., 2008, 1100 (Rimonabant); J. Org. Chem., 2005, 7558 (photo-induced [2+2] cycloaddition); Pr. S. Ley, Org. Biomol. Chem. 2010. Limitations associated with column plugging when handling slurries is real but can be mitigated by using solvent combination to improve compound solubility (like DCM + MeOH or dioxane + MeOH instead of NMP or DMF).
Overall, I found the Uniqsis conference well organized with ample breaks and well attended dinners providing plenty of opportunities to discuss with other participants. This was the first Uniqsis Symposium organized in the US. Let’s hope this will be another soon to which I would recommend anyone interested in synthetic chemistry and technology to attend. I’ll be there for sure as well!
Thanks for reading.