Recent Advances in Flow Chemistry

1. Recent Advances in Flow Chemistry

2. Asia Unique Modules • Asia FLLEX: The Flow Liquid-Liquid Extraction module • Continuous aqueous work-up • Mixes organic and aqueous streams, allows time for diffusion and then separate phases. • Asia Sampler and Diluter: • Takes a sample, dilutes it before injecting onto an HPLC/LCMS/UPLC. • Dilution factors from 5 to 250. • Compatible with the most popular analytical systems (Agilent, Waters, etc...).

3. Asia Tube Cooler • Reactor temperature: Ambient down to -68°C (dependent upon cooling medium) • Range of fluoropolymer, stainless steel and Hastelloy Asia Tube Reactors can be cooled. • Can either be used in standalone mode or can plug into an Asia Heater to have the reaction temperature monitored and displayed • Visible reactions: Reactions in Fluoropolymer tube reactors remain visible due to a double glazing insulation and nitrogen purge • Easy to use: Removable & easy to fill container for cooling medium • Compact • Launched in March 2014

4. New product launch • Syrris has developed a novel cooling system for ultra cold flow chemistry processes. • The proprietary technology allows extremely cold flow reactions in a very compact unit, powered only by mains power

5. Asia Cryo Controller – Reactions as low as -100°C ! • Ultra cold flow processes: Cools tube reactors to -70°C or microreactors to -100°C. • Mains power only: No dry ice, liquid N2, running water or circulator required for cooling! • Compact: The module is just 16cm (6.3”) wide. • Flexible: The module can cool a wide range of reactors including glass or quartz microreactors (62.5μl or 250μl) and fluoropolymer or stainless steel tube reactors (4ml and 16ml). • Clear reaction view: Clear insulation and a nitrogen purge ensure the reaction can be viewed even at ultra low temperatures. • Easy automation: The Asia Cryo Controller can connect to the Asia Manager PC Software

6. Asia Cryo Controller – As low as -100°C ! Quick and easy swap • Tube reactor temperature control • Fluoropolymer , Stainless Steel or Hastelloy • Ambient to -70°C • Microreactor temperature control • Glass or quartz • Ambient to -100°C

7. What’s next for Flow Chemistry?

8. Why use Electrochemistry? • Electrochemistry enables: • Unique activation of reagents enabling selectivity and transformations not possible by other techniques • A reduction in the quantities of toxic and hazardous oxidising/reducing reagents used. • Ideal for creating reactive intermediates • Ideal for multi-step synthesis • Rapid oxidations and reductions (even up to 6 electron oxidation) • Oxidative synthesis of drug metabolites • Electrochemistry is a surface phenomenon • High surface areas to volume ratios are required • A small gap between the electrodes lowers the requirement for additives/electrolytes • Electrochemistry and Flow Chemistry are a perfect marriage !!

9. Electrochemical Oxidation: Batch vs. Flow Acknowledgement: R. Stalder (Burnham Inst.)

10. Electrochemical Oxidation: Batch vs. Flow Acknowledgement: R. Stalder (Burnham Inst.)

11. Electrochemical Oxidation: Batch vs. Flow Acknowledgement: R. Stalder (Burnham Inst.)

12. Electrochemical Oxidation: Batch vs. Flow Acknowledgement: R. Stalder (Burnham Inst.)

13. FLUX Control Module • Syrris is developing a flow electrochemistry system known as the FLUX module • It will become part of the Asia product family • The FLUX module controls the current or the voltage applied to the electrodes, locates the cell on the front of the module • Can work in constant Voltage or constant Current mode Gasketwithchannels Asia FLUX control module (serpentine flow path) Counter electrode Control module Electrical Temperature control module connector Working electrode Cell and holder

14. Electrochemistry Flow Cell • The flow cell consists of pairs of electrodes separated by a gasket. • Cell can be divided to isolate anode from cathode. • Cell volume 225ml. • Electrode materials include SS, Pt, C, Mg, Cu. Electrodes are located on here

15. TEMPO-mediated electrooxidation of primary and secondary alcohols in a microfluidic electrolytic cell • The University of Southampton oxidised 15 different alcohols to the corresponding aldehyde/ketone • The reaction used a catalyst that could be electrochemically regenerated, allowing greener chemistry • J. T. Hill-Cousins, J. Kuleshova, R. A Green et al, ChemSusChem, 2012, 5, 326-331

16. Benzylic Oxidation of Tolyl Substrates • AbbVie2and Burnham Inst, FL1, US have been investigating a number of different applications in FLUX • Anodic oxidations • Fluorinations, Aryl Couplings, Reductive cyclisations and oxidative metabolite synthesis. • First reaction was oxidation of p-methoxytoluenecompounds • Reaction is well researched on an industrial scale • Achieved both 4e- and 6e- oxidation (6e- oxidation of p-methoxytoluenewas yielded 62%) • Methoxylation of o-Anisole to the four- and six- electron products has never been seen in the electrochemical literature • G. P. Roth1, R. Stalder1, T. R. Long1, D. R. Sauer2, S. W. Djuric2J Flow Chem, 2013 , Vol 3, 2, pp 34-40

17. Benzylic Oxidation of Tolyl Substrates: Batch vs. Flow • Compared flow results with the same reaction in batch • The problem with over-oxidation seen in the batch process is overcome as new starting materials are constantly flowing over the electrodes. • Avoids oxidising already reacted substrates • Very high degree of reproducibility, <3% variation in product formation and an ability to vary product ratios (dependant upon electron equivalents)

18. Preparative Microfluidic Electrosynthesis of Drug Metabolites • The Sanford-Burnham Medical Research Institute, Florida have researched the use of flow electrochemistry to synthesise drug metabolites • Electrochemistry can been used to simulate CYP450 oxidation • However, this has been almost exclusively confined to the analytical scale • In this paper, metabolites of several commercial drugs were synthesised at rates of up to 100mg/hr using flow electrochemistry • R. Stalder and G. P. Roth, dx.doi.org/10.1021/ml400316p ACS Med. Chem. Lett., Accepted Oct 1st2013

19. Preparative Microfluidic Electrosynthesis of Drug Metabolites • The research aimed to synthesise oxidation products of the following drugs using flow electrochemistry (using the Asia Flux Module): • Diclofenac (DCF) • Tolbutamide (TBM) • Primidone (PMD) • Albendazole (ABZ) • Chlorpromazine (CPZ) • A broad range of oxidative chemistry was targeted: aliphatic oxidation, aromatic hydroxylation, S-oxidation, N-oxidation, or dehydrogenation. • R. Stalder and G. P. Roth, dx.doi.org/10.1021/ml400316p ACS Med. Chem. Lett., Accepted Oct 1st2013

20. Preparative Microfluidic Electrosynthesis of Diclofenac Metabolites • Initially, Diclofenac (DCF, an anti-inflammatory) was selected as the substrate • Electrosynthesis of Phase I Metabolite of Diclofenac (DCF-5-OH) was synthesised in 46% yield (vs 25% batch process • Sodium bisulfite used as electrolyte • The 4 and 6 Glutathione Phase II Adducts (DCF-GS) were also both successfully synthesised in a 2 step continuous flow process via the Quinone Imine (DCF-5-QI) glutathione

21. Preparative Microfluidic Electrosynthesis of Drug Metabolites • After the success of Diclofenac, metabolites of four other commercial drugs were synthesised using flow electrochemistry: • Tolbutamide (TBM) (20%) • Primidone (PMD) • Albendazole (ABZ) • Chlorpromazine (CPZ)

22. Preparative Microfluidic Electrosynthesis of Drug Metabolites – Conclusion • Simulation of the in vivo metabolism of drugs have been demonstrated using a continuous-flow electrochemical cell. • Aromatic hydroxylation, alkyl oxidation, sulfoxidation, quinone imine formation, and glutathione conjugation were achieved on a 10 to 100 mg scale of pure isolated metabolites per hour • For any specific compound, the product selectivity of electrochemical oxidation is controlled by the most redox-active sites on the molecule. • R. Stalder and G. P. Roth, dx.doi.org/10.1021/ml400316p ACS Med. Chem. Lett., Accepted Oct 1st2013

23. Preparative Microfluidic Electrosynthesis of Drug Metabolites • Electrosynthesis is not intended to replace analytical biosynthetic techniques • CYP450 Oxidation mechanism very different to Electrochemical mechanism • However, flow electrosynthesis can: • Achieve a reaction output higher than that of typical electroanalytical techniques by several orders of magnitude • Enable complete structural elucidation by NMR • Considerably reduces route development time and synthesis time to metabolites • Enables further bioassays and study of the toxicity of potential drug candidates • Rapid synthesis of new potential drug candidates and analogues • R. Stalder and G. P. Roth, dx.doi.org/10.1021/ml400316p ACS Med. Chem. Lett., Accepted Oct 1st2013

24. Conclusions Flow chemistry is an exciting and growing area of research, coupling with other techniques. Flow electrochemistry shows key benefits Syrris are developing an ‘out-of-the-box’ solution for enabling laboratory scale electrochemistry to be carried out. FLUX module to be launched in 2014 Syrris are currently working with a number of academics across the globe to further the knowledge and use of flow electrochemical strategies.

25. Conclusion • Many more exciting modules and systems to come soon  • Dedicated continuous nanoparticle systems • Dedicated droplet nanoparticle/reactor systems • Including Telos scale up system • Up 300,000 droplets per second !! • For all latest news, visit www.syrris.com • Please visit www.syrris.com/applications to see more chemistry from our customers