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
Microreactor temperature control
Glass or quartz
Ambient to -100°C
Tube reactor temperature control
Fluoropolymer , Stainless Steel or Hastelloy
Ambient to -70°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
Asia FLUX control module
Control
module
Working
electrode
Counter
Electrical
connector
Gasket with channels
(serpentine flow path)
Temperature control module
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,

16. Benzylic Oxidation of Tolyl Substrates
AbbVie2 and 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-methoxytoluene compounds
Reaction is well researched on an industrial scale
Achieved both 4e- and 6e- oxidation (6e- oxidation of p-methoxytoluene was 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. Djuric2 J 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/ /ml400316p ACS Med. Chem. Lett., Accepted Oct 1st 2013

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/ /ml400316p ACS Med. Chem. Lett., Accepted Oct 1st 2013

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/ /ml400316p ACS Med. Chem. Lett., Accepted Oct 1st 2013

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/ /ml400316p ACS Med. Chem. Lett., Accepted Oct 1st 2013

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 !!
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