Flow Chemistry: An innovative tool for chemical processing

CSIRO Materials Science and Engineering

Flow Chemistry: An innovative tool for chemical processing

Using the latest in flow chemistry technology, CSIROs Division of Materials Science and Engineering (CMSE) can rapidly address the synthesis and scale-up development of small molecules and polymeric materials. Why flow chemistry?
Emergent global trends around the development of new approaches to sustainable chemical manufacturing are rapidly gaining momentum, and are driven by the unacceptably high inefficiency with the present state-of-theart large scale production of chemicals. By way of example, for every kilogram of fine chemical produced by the pharmaceutical industry, 5100 times that amount of chemical waste is generated. Such low efficiency in organic syntheses presents great challenges in resource conservation, and creates new and ongoing environmental and health concerns related to the treatment of chemical wastes. To address these challenges, innovative solutions to both the way chemical transformations are performed, i.e. innovative synthetic methods, and new paradigms for highly efficient scaled production are urgently needed. Transitioning from inefficient and waste intensive processes to acceptable, resource efficient alternatives requires a significant change in approach and available technologies. In this respect, the use of flow reactors and continuous flow processing technology has emerged as an alternative to traditional batch processing.

Continuous flow processing

Flow reactors for continuous flow processing are typically tubular or microfluidic chip-based systems, with well defined lateral dimensions, in which chemical reactions take place in a continuous stream within in a well defined temporal and spatial environment. Flow reactors offer many advantages over conventional batch reactors, including: Superior inherent safety reduced reactor volumes; containment of hazardous substances Fast and efficient mixing Superior heat and mass transfer control over exothermic reactions Access to greater reaction conditions space Safe processing of dangerous and unstable intermediates Reproducibility better process control resulting in higher reaction yields and product purities Unlimited scalability high reactor throughput by continuous processing; reactor scale-up by numbering-up of reactor units Reduced capital and maintenance costs i.e. low cost-of-entry Reduced energy usage and operating costs Integrated in-line analysis and automation. Through its investment in continuous flow processing technologies, CMSE will focus on providing innovative chemical production and engineering solutions for the chemical industry.

Capability
Using commercial and proprietary flow chemistry equipment CMSE can readily address all areas of the R&D pipeline, including discovery (library generation), and process development and scale-up. Key capabilities include: Corrosive fluids capability (strong acids, strong bases) Organometallic reagents (Grignards, organolithiums) High temperature processing for process intensification (cycloaddition chemistry, thermal rearrangements, pyrolysis chemistries) Continuous flow gas-liquid reactions (hydrogenation, carbonylation and other gas chemistries) Telescoped synthesis (multi-step synthesis of intermediates and products using multiple flow streams) Continuous polymer synthesis using free or controlled radical mechanisms (RAFT polymerisation technology) Continuous flow processing of highly exothermic reactions (ionic liquids) Fast reaction profiling and optimization Use of polymer-supported reagents for heterogeneous reactions (ion exchange, redox chemistry, in-line purification) Laboratory and pilot-scale flow photochemistry Scale-up to kilogram quantities.

Flow processing makes chemical production safer, more reproducible and scalable while offering reduced cost and low environmental impact

purification

analysis

flow reactor

pressure regulator

A
feed tanks

B
product tank
Automated liquid and solid handlers to process multiple batch samples (Chemspeed, Mettler-Toledo) Individually configured reactor set-ups or additions to existing reactor systems comprising HPLC pumps, syringe pumps and standard and specially modified microfluidic tubing and connectors.

The laboratory (facilities and equipment)

CSIROs flow chemistry laboratory is equipped with state-of-the-art synthesis work stations and flow instruments. Both convection and microwave heating units are available, in addition to commercial and proprietary polymer supported reagents, scavengers and catalysts. These instruments are dedicated to highly integrated discovery, process development and scale-up programmes for internal research and external partners. List of flow equipment at CMSE: Vapourtec R-2C/R-4 and R-2+/R-4 fully integrated microreactor systems Uniqsis FlowSyn microreactor systems, with fraction collector Tube-in-tube reactor assembly for gas handling Thalesnano H-cube and H-cube midi Biotage Initiator microwave reactor Laboratory and pilot-scale flow photoreactor

Expertise and track record

Multistep synthesis of bioactive compounds (histrionicotoxin alkaloids, isoxazolidines) Drug API process development Synthesis of ionic liquids Polymer synthesis using RAFT and conventional polymerisation technologies Synthesis of photochromic dyes Synthesis of platform chemicals and biofuels from renewable resources.

Collaborations
Professor Steven Ley and Dr Ian Baxendale, Innovative Technology Centre, University of Cambridge Professor Andrew B. Holmes, University of Melbourne.

> [Above] Schematic diagram of a continuous flow reactor. [Right] CSIROs flow chemistry equipment.

Publications
Brasholz M, Johnson BA, Macdonald JM, Polyzos A, Saubern S, Tsanaktsidis J, Holmes AB, Ryan JH. 2010. Tetrahedron. 66: 6445-6449. Brasholz M, Macdonald JM, Saubern S, Ryan JH, Holmes AB. 2010. Chem. Eur. J. 16: 11471-11480. Brasholz M, von Knel K, Hornung CH, Saubern S, Tsanaktsidis J. 2011. Green Chemistry. 13, in press. Hornung CH, Guerrero-Sanchez C, Brasholz M, Saubern S, Chiefari J, Moad G, Rizzardo E, Thang SH. Org. Proc. Res. Dev., ASAP. Palmieri A, Ley SV, Hammond K, Polyzos A, Baxendale IR. 2009. Tetrahedron Lett. 50:3287-3289. Palmieri A, Ley SV, Polyzos A, Ladlow M, Baxendale IR. 2009. Beilstein J. Org. Chem. 5: No.23, DOI: 10.3762/bjoc.5.23. Polyzos A, OBrien M, Petersen TP, Baxendale IR, Ley SV. 2010. Angew. Chem. Int, Ed. DOI: 10.1002/anie.201006618.

For further information: Technical contact: Dr. John Tsanaktsidis Research Program Leader Functional Small Molecules Phone: 61 3 9545 2487 Fax: 61 3 9545 2446 Email: John.Tsanaktsidis@csiro.au Business contact: Dr. Kirsty Reed Business Development Manager Phone: 61 3 9545 2484 Mobile: 61 4 2105 7428 Fax: 61 3 9545 2446 Email: Kirsty.Reed@csiro.au

Feb 2011