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Benjamin J. DeadmanAnalytical & Biological Research Facility (ABCRF)
Dept. of Chemistry & School of Pharmacy
University College Cork
SSPC Masterclass in Synthetic Organic ChemistryUCD, September 4th, 2014
FLOW CHEMISTRY
This lecture is publicly available on figshare.
http://dx.doi.org/10.6084/m9.figshare.1170109
CONTACT INFORMATION
Email: [email protected]
LinkedIn: ie.linkedin.com/pub/ben-deadman/42/862/787/
ResearchGate: www.researchgate.net/profile/Benjamin_Deadman
Benjamin J. DeadmanPDRA (Anita R. Maguire Group)Analytical & Biological Chemistry Research Facility (ABCRF)Department of Chemistry & School of Pharmacy
University College Cork
Benjamin J. Deadman received an MSc from the University of
Waikato (New Zealand) before moving to the University of
Cambridge (UK) as a Commonwealth Scholar in 2009. He
completed his PhD under the supervision of Prof. Steven Ley in
2013 and is currently a postdoctoral research associate of the
Synthesis and Solid State Pharmaceutical Centre working with
Prof. Anita Maguire at University College Cork.
OUTLINE
1. Introduction to Flow Chemistry
2. The Flow Chemists’ Tool Box
3. Case Studies
1. Gleevec
2. Meclinertant
4. Useful Resources
INTRODUCTION TO FLOW CHEMISTRY
Historical Perspective & Recent Trends
Advantages of Continuous Processing
Key Concepts
Current Limitations
Continuous Oil Refining
Shell Martinez refinery
California
Since 1915
Continuous Fermentation
Morton Coutts
Dominion Breweries, NZ
1956
BASF. The Haber-Bosch process and the era of fertilizers http://www.basf.com/group/corporate/en/about-basf/history/1902-1924/index (accessed Aug 27, 2014).Al-Qahtani, K. Y.; Elkamel, A. Planning and Integration of Refinery and Petrochemical Operations; Wiley: Weinheim, Germany, 2010; p. 206.New Zealand Institute of Chemistry. The Continuous Brewing of Beer http://nzic.org.nz/ChemProcesses/food/6A.pdf (accessed Aug 27, 2014).
EARLY HISTORY OF CONTINUOUS CHEMICAL PROCESSING
Bosch Haber Process
Fritz Haber & Carl Bosch
BASF
1909-1913
Continuous processing is common
in petrochemical, bulk chemical
and beverage industries.
FINE CHEMICAL AND PHARMACEUTICAL INDUSTRIES
Typically small volume of high value products
Predominantly batch processing
because:
• Manufacturing plants need to be versatile
• Produce multiple product lines in short runs
• Quick changeover between products (bulk
continuous processes may run non-stop for > 1 year)
• Increased costs offset by high value of product
• Environmental efficiency low priority
GREEN CHEMISTRY PRINCIPLES
Charter for Life as a Synthesis Chemist
1. Prevent waste rather than treat/clean it up later
2. Invoke atom economy
3. Design safer chemicals
4. Use & generate less toxic substances
5. Massively reduce quantities of solvents used
6. Design syntheses for energy efficiency
7. Renewable feedstock for large scale processes
8. Minimise steps in synthesis
9. Use of highly-selective catalytic reagents
10. Design materials that innocuously degrade
11. Real-time monitoring for pollution prevention
12. Minimise potential for accidents
P. T. Anastas, J. C. Warner, Green Chemistry: Theory and Practice, Oxford University Press: New York, 1998, p.30.S. V. Ley, Enabling Technologies in Synthesis, Cambridge Graduate Lecture Series, 2013.
CANNOT IGNORE THE ENVIRONMENTAL IMPACT OF SYNTHESIS
CONTINUOUS FLOW PROCESSING IN PHARMA
Lab scale flow reactors in medicinal chemistry
e.g. Vapourtec, Syrris Africa/Asia, Uniqsis FlowSyn, ThalesNano
H-Cube + others
Custom flow systems in process development
e.g. GSK (Stevenage)
Continuous processing pilot plants
e.g. Pfizer (Cork), Eli Lilly (Kinsale)
It may have taken 100 yrs but, since 2000,
continuous processing is now gaining momentum in pharma.
KEY ADVANTAGES OF CONTINUOUS PROCESSING
1. Efficient heat transfer
2. Efficient mass transfer and controlled mixing
3. Reproducibility
4. Simple scale-up
5. Extreme reaction conditions
6. Reaction telescoping
7. In-line work-up and monitoring
8. Automated operation
9. Improved safety
MAKINGS OF A FLOW REACTOR
Pumps
• Deliver solvents or reagents
• Reproducible flow rate critical
to control stoichiometry
• Laboratory pumps
• Piston
• Syringe
• Process pumps
• Peristaltic
• Gear Centrifugal
Injection Loop
• For introducing small volumes of reagents/substrates
• Typicall Rheodyne 2-position type
• May be wide bore for flow chemistry
Mixing T-Piece
• Mixes two flow streams
• Variety of types
Back Pressure
Regulator
• Controls system pressure
• Allows superheated conditions
• Spring resistor or simple restriction
Reactors• Reaction stages• Several types• May be heated, cooled etcMicrofluidic ChipSmall volume with
excellent mixingFor fast reactions
Coiled Tube ReactorUsually 2 to 20 mLvolumeProvides residence time for reaction
Packed ColumnContains immobilised/solidreagents, catalysts or scavengers
HEAT TRANSFER
N. E. Leadbeater, An Introduction to Flow Chemistry: A Practial Laboratory Course, Vapourtec: Suffolk, UK, 2014.
Heat Transfer proportional to surface-area/volume ratio
250 mL RB flask
~0.7 cm2/mL10 mL tube reactor
(1 mm o.d.)
~40 cm2/mL
SA/V is significantly higher in tubular
geometry
Fast heat transfer into reaction Avoid temperaturegradients
Fast heat transfer out of reaction Can control reaction
exotherms without external cooling
Heat
Cool
Ambient
Ambient
Fast transfer from hot to coldreaction stages
MASS TRANSFER & MIXING
Flow A
Flow B
Mixed
Flow
Combining flow streams allows rapid and controlled mixing
Minimal concentration gradients (usually)
=>Reduce by-product formation
Simple T-piece often sufficient (for 1 mm o.d. or less) but
more specialised micro-mixers also available
Simple T or Y-piece mixers
Baffled micro-mixer
Nagy, K. D.; Shen, B.; Jamison, T. F.; Jensen, K. F. Org. Process Res. Dev. 2012, 16, 976-981.Lee, C.-Y.; Chang, C.-L.; Wang, Y.-N.; Fu, L.-M. Int. J. Mol. Sci. 2011, 12, 3263–3287.
MASS TRANSFER & MIXING
Nagy, K. D.; Shen, B.; Jamison, T. F.; Jensen, K. F. Org. Process Res. Dev. 2012, 16, 976-981.Sniady, A.; Bedore, M. W.; Jamison, T. F. Angew. Chem., Int. Ed. 2011, 50, 2155– 2158.
𝐵𝑜 =4𝛽𝐷𝜏
𝑑𝑡2 = 𝐹𝑜𝛽
Bo Bodenstein numberβ channel geometry (square = 30, tube = 48)τ residence timedt tube diameterFo Fourier number
base dt (μm) τ (s) P BP Bo Da Fo
1 500 30 99 0 23 22 0.48
2 500 300 80 6 230 2.2 4.8
3 500 600 87 9 461 1.1 9.6
4 500 1200 88 11 922 0.54 19.2
1 750 30 91 8 10 50 0.21
2 750 300 70 11 102 4.8 2.1
3 750 600 80 17 204 2.4 4.3
4 750 1200 78 13 409 1.2 8.5
Tested on Rapid Glycosylation:By-product formation was suppressed when flow rate is high (i.e. low res. time τ)& tube diameter is small (5 mm i.d.)
PLUG VS LAMINAR FLOW
http://www.engineeringtoolbox.com/reynolds-number-d_237.htmlhttp://en.wikipedia.org/wiki/Reynolds_number
[A]
t
[A]
t
Laminar Flow
Plug Flow
𝑅𝑒 =𝑖𝑛𝑒𝑟𝑡𝑖𝑎𝑙 𝑓𝑜𝑟𝑐𝑒𝑠
𝑣𝑖𝑠𝑐𝑜𝑢𝑠 𝑓𝑜𝑟𝑐𝑒𝑠=
𝜌v𝐷𝐻
𝜇
Reynolds Number
ρ density of fluid (kg/m3)
v mean velocity of fluid (m/s)
DH hydraulic diameter of the tube (m)
μ dynamic viscosity of the fluid (Pa.s)
Re < 2000 laminar flow
Re > 4000 turbulent/plug flow
Most laboratory flow reactors actually have laminar flow
• Need to find steady state conditions• Mathematical models for this• Or use in-line analysis
• Axial dispersion can be prevented by segmented flow (e.g. with N2 or fluorous spacer)
REACTION TIME CONTROL
Residence time = average time substrate molecule spends in reaction stage
(e.g. heated reactor coil)
= volume (mL)
flow rate (mL/min)
• Generally leave reactor volume fixed and adjust flow rates to change
residence time. Decrease flow rate to increase res. Time.
• Simple to work out res. time for tube reactors.
• Axial diffusion (like peak broadening in chromatography) a problem when flowing through packed bed reactor.
𝑡𝑢𝑏𝑒 𝑣𝑜𝑙𝑢𝑚𝑒 =𝜋
4× (𝑖𝑛𝑛𝑒𝑟 𝑑𝑖𝑎𝑚𝑒𝑡𝑒𝑟 𝑐𝑚 )2 × 𝑙𝑒𝑛𝑔𝑡ℎ (𝑐𝑚)
AUTOMATED OPERATION & REPRODUCIBILITY
Lange, H.; Carter, C. F.; Hopkin, M. D.; Burke, A.; Goode, J. G.; Baxendale, I. R.; Ley, S. V., Chem. Sci. 2011, 2, 765-769.
EXTREME REACTION CONDITIONS
Can easily generate back pressure in flow chemistry systems
Access much higher temperatures (<250 oC) with any given solvent by increasing backpressure
Pressure limitsPolymer tubing systems ~14 bar (depends on temp.)Full stainless steel or hastelloy systems <200 bar
http://www.kentchemistry.com/links/Matter/Phasediagram.htm
EXTREME REACTIONS - INDUCTIVE HEATING
Andreas Kirschning Group, Leibniz University of Hannover, http://www.kirschning-group.com/flow-chemistry.html
IN-LINE WORK-UP
S. V. Ley, Enabling Technologies in Synthesis, Cambridge Graduate Lecture Series, 2013.
Avoid labour/time intensive work-up & purification procedures:• Reaction quenching• Aqueous washes• Chromatography• Crystallisation• Distillation
ImmobilisedReagents
Scavenging
Catch &Release
POLYMER SUPPORTED SCAVENGERS
Acidic Basic
Metal Scavenging
Electrophilic Nucleophilic
S. V. Ley, Enabling Technologies in Synthesis, Cambridge Graduate Lecture Series, 2013.
Some common scavengers
and many others.
• Window into a closed reactor system.
• Reactive intermediates
• Hazard monitoring
• Quantitative analysis
• Quality Control
• Safety, Control and Timing
• 3rd stream matching
• Immediate feedback
• Identify problems before they leave the
reactor system
• No interruptions of system for analysis.
IN-LINE WORK-UP & MONITORING
REACTION TELESCOPINGSCALE UP
SAFETY BENEFITS
Reaction TelescopingMake & use hazardous intermediates
Reduced intermediate stock
No need to transport intermediates
Scale UpRun flow reactor longer to obtain more product
Can scale out – run multiple reactors in parallel
Manufacturing industry would use larger diameter tubes (e.g. 11.7 mm i.d. in Novartis/MIT system)1
An ExamplePhoenix Chemicals Ltd. (UK) produced diazomethane in a continuous process.2
Diazomethane will explosively decompose when:
• heated• shocked• exposed to acids
60 metric tonnes/annum!
Operated without incident for 9 years before being shutting down
[1] Jamison, T. F.; Jensen, K. F.; Myerson, A. S.; Trout, B. L. et. al. Angew. Chemie Int. Ed. 2013, 52, 12359.[2] L. D. Proctor and A. J. Warr, Org. Process Res. Dev., 2002, 6, 884–892.
TECHNOLOGY INTERFACE
LIMITATIONS OF FLOW CHEMISTRY
• Don’t have access to 100 years of flow reactions
• Your chemistry is only as good as your reactor
• Preventative maintenance & technical knowledge essential
• Solid particulates are a challenge still
• There are solutions but still not generally applicable
Review on handling solids in flow
R. L. Hartman, Org. Process Res. Dev., 2012, 16, 870–887.
THE FLOW CHEMISTS’ TOOL BOX
Chip, Coil & Column Reactors
Immobilised Reagents, Catalysts & Scavengers
Agitating Cell Reactors
Tube-in-Tube Membrane Reactors
In-Line Reaction Monitoring
In-Line Work-Up
http://www.vapourtec.co.uk/products/rseriessystem
VAPOURTEC R & E REACTORS
http://www.uniqsis.com/
UNIQSIS FLOWSYN REACTORS
Jensen, K. F.; Reizman, B. J.; Newman, S. G. Lab Chip 2014, 14, 3206–3212.Geyer, K.; Codée, J. D. C.; Seeberger, P. H. Chem. Eur. J. 2006, 12, 8434–8442.Born, S.; O’Neal, E.; Jensen, K. F. In Comprehensive Organic Synthesis; Elsevier, 2014; Vol. 9, pp. 54–93.S. V. Ley, Enabling Technologies in Synthesis, Cambridge Graduate Lecture Series, 2013.
MICROFLUIDIC CHIP REACTORS
http://www.vapourtec.co.uk/products/rseriessystemhttp://www.uniqsis.com/S. V. Ley, Enabling Technologies in Synthesis, Cambridge Graduate Lecture Series, 2013.
COILED TUBE REACTORS
S. V. Ley, Enabling Technologies in Synthesis, Cambridge Graduate Lecture Series, 2013.
MONOLITHIC REACTORS
AGITATING CELL REACTORS
• The ACR comprises several layers creating a series of cells linked by inter-cell channels.
• Each cell can contain an agitator (different agitators for variety of applications).
• The ACR unit is mounted on to an agitating device (an oscillator) whose frequency can be varied.
AM Technology; www.amtechuk.com.
AM Technology; www.amtechuk.com.Browne, D. L.; Deadman, B. J.; Baxendale, I. R.; Ley, S. V.; Org. Process Res. Dev., 2011, 15, 693.
No agitation
Seconds after turning on agitation.
• The Coflore ACR is designed to keep solids in suspension, offering potential for the continual pumping of slurries.
• N-iodomorpholine.HI is a useful reagent for iodinating terminal alkynes.
• Potential applications of ACR for salt forming reactions in organic solvents.
ACR PREPARATION OF N-IODOMORPHOLINE SLURRY
FLOWIR: IN-LINE INFRA RED SPECTROSCOPY
o Body: FlowIRTM, fitted with a Mercury Cadmium Telluride (MCT) detector.
o Small footprint (137 x 241 x 116 mm)
o Flow cell: Attenuated Total Reflectance (ATR) diamond and silicon sensors
o 10 or 50 µL flow cells
o Up to 50 bar and 120 °C
o Full infrared spectral region from 650 to 4000 cm-1 at 4 cm-1 resolution
o iC IR 4.3 software for system operation and data analysis
Carter, C. F.; Lange, H.; Ley, S. V.; Baxendale, I. R.; Wittkamp, B.; Goode, J. G.; Gaunt, N. L., Org. Process Res. Dev. 2010, 14, 393-404.http://uk.mt.com/gb/en/home/products/L1_AutochemProducts/L2_in-situSpectrocopy/flow-ir-chemis.html
MEASUREMENT OF DISSOLVED GAS CONCENTRATION BY IR
Koos, P.; Gross, U.; Polyzos, A.; O’Brien, M.; Baxendale, I.; Ley, S. V. Org. Biomol. Chem. 2011, 9, 6903–6908.
THE THIRD STREAM PROBLEM
Lange, H.; Carter, C. F.; Hopkin, M. D.; Burke, A.; Goode, J. G.; Baxendale, I. R.; Ley, S. V., Chem. Sci. 2011, 2, 765-769.
MICROSAIC 3500 MID MINIATURE
ELECTROSPRAY MASS SPECTROMETER • Body: Self contained unit enclosing all
electronics, high-vacuum and backing pumps.• Small footprint (35 x 18 x 62 cm)
• Microengineered• Ion source• Vacuum interface• Ion guide• Quadrupole mass filter
• Less nebulisation gas needed• No need for large external rotary
pump• 80-800 m/z mass range• Unit resolution• 8 pg limit of detection in SIM
S. Wright, R. R. A. Syms, R. Moseley, G. Hong, S. O’Prey, W. E. Boxford, N. Dash, and P. Edwards, Journal of Microelectromechanical Systems, 2010, 19, 1430–1443.A. Malcolm, S. Wright, R. R. A. Syms, N. Dash, M.-A. Schwab, and A. Finlay, Anal Chem, 2010, 82, 1751–8.D. L. Browne, S. Wright, B. J. Deadman, S. Dunnage, I. R. Baxendale, R. M. Turner, and S. V. Ley, Rapid Commun. Mass Spectrom., 2012, 26, 1999–2010.http://www.microsaic.com/products
A pump 1B pump 2C mixing teeD reactor coilE 6-port valveF ESI-MSG sampling loopH waste dischargeI back pressure
regulatorJ pump 3K back pressure
regulatorL pump 4M µ-mixing teeN inline filter
D. L. Browne, S. Wright, B. J. Deadman, S. Dunnage, I. R. Baxendale, R. M. Turner, and S. V. Ley, Rapid Commun. Mass Spectrom., 2012, 26, 1999–2010.http://www.microsaic.com/products
ON-LINE ELECTROSPRAY MASS SPECTROMETRY
Browne, D. L.; Wright, S.; Deadman, B. J.; Dunnage, S.; Baxendale, I. R.; Turner, R. M.; Ley, S. V. Rapid Commun. Mass Spectrom. 2012, 26, 1999–2010.L. Friedman and F. M. Logullo, J. Org. Chem., 1969, 34, 3089–3092.F. M. Logullo, A. H. Seitz, and L. Friedman, Organic Syntheses, 1973, 5, 54.
BENZYNE GENERATION IN FLOW
BENZYNE GENERATION IN FLOW
Browne, D. L.; Wright, S.; Deadman, B. J.; Dunnage, S.; Baxendale, I. R.; Turner, R. M.; Ley, S. V. Rapid Commun. Mass Spectrom. 2012, 26, 1999–2010.
ON-LINE ESI-MS: GETTING THE WHOLE PICTURE
Browne, D. L.; Wright, S.; Deadman, B. J.; Dunnage, S.; Baxendale, I. R.; Turner, R. M.; Ley, S. V. Rapid Commun. Mass Spectrom. 2012, 26, 1999–2010.
TEMPERATURE DEPENDENCE OF SELECTED IONS
Browne, D. L.; Wright, S.; Deadman, B. J.; Dunnage, S.; Baxendale, I. R.; Turner, R. M.; Ley, S. V. Rapid Commun. Mass Spectrom. 2012, 26, 1999–2010.
REACTION OPTIMISATION ASSISTED BY ON-LINE ESI-MS
Optimised ConditionsAcetone, 50 οC
Browne, D. L.; Wright, S.; Deadman, B. J.; Dunnage, S.; Baxendale, I. R.; Turner, R. M.; Ley, S. V. Rapid Commun. Mass Spectrom. 2012, 26, 1999–2010.
Goals:• Controlled continuous chromatography• Fourth and fifth streams• Remote monitoring and control• Full In-line analysis of new compounds
Hopkin, M. D.; Baxendale, I. R. and Ley, S. V. Chim. Oggi./Chemistry Today, 2011, 29, 28-32.
THE FUTURE OF IN-LINE ANALYSIS
GAS PERMEABLE TUBING:
FLOW OZONOLYSIS
O’Brien, M.; Baxendale, I. R.; Ley, S. V. Org. Lett. 2010, 12, 1596–1598.
Gases used:
CO2Angew. Chem. Int. Ed. 2011, 50, 1190.Org. Process Res. Dev. 2014, DOI: 10.1021/op500213j
O3Org. Lett. 2010, 12, 1596.
H2Chem. Sci. 2011, 2, 1250.Org. Process Res. Dev. 2012, 16, 1064.
O2Chem. Sus. Chem. 2012, 5, 274.Adv. Synth. Catal. 2013, 355, 1905.
COOrg. Biomol. Chem. 2011, 9, 6903.Org. Biomol. Chem. 2011, 9, 6575.Chem. Eur. J. 2014, DOI:10.1002/ejoc.201402804.
NH3Synlett 2012, 23, 1402.
EthyleneSynlett 2011, 18, 2643.ChemCatChem 2013, 5, 159.
DiazomethaneOrg. Lett. 2013, 15, 5590.J. Org. Chem. 2014, 79, 1555.RSC Adv. 2014, 4, 37419.
SyngasSynlett 2011, 18, 2648.ChemCatChem 2013, 5, 159.
FormaldehydeEur. J. Org. Chem. 2013, 4509.
TUBE-IN-TUBE GAS FLOW REACTOR
GAS
SUBSTRATE
• Reactor volume 0.28 – 0.56 mL (1 - 2.0 m AF-2400)
• Gas pressure up to 35 bar
• Small effective volume of gas input (safety!)
• Adaptable to common laboratory heaters/coolers
• Flow rates 0.1 – 10 mL/min
• Easy to reconfigure
http://www.cambridgereactordesign.com/pdf/Gastropod%20for%20Gas%20Liquid%20Reactions.pdfhttp://www.uniqsis.com/paProductsDetail.aspx?ID=ACC_GAM_1http://www.vapourtec.co.uk/products/reactors/gas
TUBE-IN-TUBE GAS FLOW REACTOR:
HYDROGENATION
O’Brien, M.; Taylor, N.; Polyzos, A.; Baxendale, I. R.; Ley, S. V. Chem. Sci. 2011, 2, 1250.
Uniqsis/Cambridge Reactor Design: Polar Bear, http://www.uniqsis.com/paProductsDetail.aspx?ID=ACC_POLEUniqsis/Cambridge Reactor Design: Polar Bear Plus, http://www.uniqsis.com/paProductsDetail.aspx?ID=ACC_PBPFVaourtec, http://www.vapourtec.co.uk/products/reseriessystem/cooledreactor
LOW TEMPERATURE REACTORS
Vapourtec Cooling Modules
Uniqsis/CRD Polar Bear Plus
Uniqsis/CRD Polar Bear
Reactions at temperatures from
RT to -89 °C
LOW TEMPERATURE REACTORS:
LITHIUM HALOGEN EXCHANGE
Browne, D. L.; Baumann, M.; Harji, B. H.; Baxendale, I. R.; Ley, S. V. Org. Lett. 2011, 13, 3312–3315.
Heated
Omnifit
Column
Capillary
Sprayer
Desolvation
Gas
Volatile
Exhaust
Liquid
Withdrawn
SOLVENT SWITCHER
• Concentric flow of high speed gas assists with forming a fine spray and rapidly evaporates solvent.
• Peristaltic pump draws out concentrated liquid from the bottom (piston pump not suitable because some air is drawn).
• Gas outlet at top of chamber directs solvent vapour and carrier gas to a condenser.
• Heated Vapourtec column jacket gives fine control of evaporation temperature.
B. J. Deadman, C. Battilocchio, E. Sliwinski, and S. V. Ley, Green Chem., 2013, 15, 2050–2055.
Substance Before After
DCM 45.3% 16.1%
EtOH 53.5% 81.7%
Acetaminophen 1.2% 2.2%
Determined by 1H NMR Spectroscopy
Recovered 74% of acetaminophen
IN-LINE SOLVENT SWITCH AND CONCENTRATION
IN-LINE DISTILLATION
L. Soldi, W. Ferstl, S. Loebbecke, R. Maggi, C. Malmassari, G. Sartori, S. Yada, Journal of Catalysis 2008, 258, 289–295.B. J. Deadman, C. Battilocchio, E. Sliwinski, and S. V. Ley, Green Chem., 2013, 15, 2050–2055.
Semi-continuous nitro alkene
formation and Michael
addition by Soldi et al. 2008
CASE STUDY 1IMATINIB (GLEEVEC)
IMATINIB (GLEEVEC)
Launched by Novartis in 2001 under the trade name Gleevec (or Glivec).
Bcr-Abl tyrosine kinase inhibitor
First of the ‘tinib’ drug family
Primarily used to treat chronic myelogenousleukemia (CML) and gastrointestinal stromal tumors (GISTs)
Approved for several other cancers
X-Ray crystal structure binding of imatinib with the
kinase domain of Abl.
Hopkin, M. D.; Baxendale, I. R.; Ley, S. V. Chem. Commun. 2010, 46, 2450–
2452.
Ingham, R. J.; Riva, E.; Nikbin, N.; Baxendale, I. R.; Ley, S. V. Org. Lett. 2012,
14, 3920–3923.
Deadman, B. J.; Hopkin, M. D.; Baxendale, I. R.; Ley, S. V. Org. Biomol.
Chem. 2013, 11, 1766–1800.
Hopkin, M. D.; Baxendale, I. R.; Ley, S. V. Org. Biomol. Chem. 2013, 11,
1822–1839.
BATCH SYNTHESIS
Deadman, B. J.; Hopkin, M. D.; Baxendale, I. R.; Ley, S. V. Org. Biomol. Chem. 2013, 11, 1766–1800.
Insoluble intermediates difficult to process in continuous flow.
PROPOSED ROUTE FOR FLOW SYNTHESIS
Hopkin, M. D.; Baxendale, I. R.; Ley, S. V. Chem. Commun. 2010, 46, 2450–2452.
Hopkin, M. D.; Baxendale, I. R.; Ley, S. V. Org. Biomol. Chem. 2013, 11, 1822–1839.
IMATINIB AMIDE FORMATION
Release of product from PS-DMAP followed by UV (340 nm)
Hopkin, M. D.; Baxendale, I. R.; Ley, S. V. Chem. Commun. 2010, 46, 2450–2452.
Hopkin, M. D.; Baxendale, I. R.; Ley, S. V. Org. Biomol. Chem. 2013, 11, 1822–1839.
IMATINIB SN2 REACTION
Hopkin, M. D.; Baxendale, I. R.; Ley, S. V. Chem. Commun. 2010, 46, 2450–2452.
Hopkin, M. D.; Baxendale, I. R.; Ley, S. V. Org. Biomol. Chem. 2013, 11, 1822–1839.
IMATINIB C-N CROSS COUPLING REACTION
Hopkin, M. D.; Baxendale, I. R.; Ley, S. V. Chem. Commun. 2010, 46, 2450–2452.
Hopkin, M. D.; Baxendale, I. R.; Ley, S. V. Org. Biomol. Chem. 2013, 11, 1822–1839.
IMATINIB AUTOMATED FLOW SYNTHESIS
Hopkin, M. D.; Baxendale, I. R.; Ley, S. V. Chem. Commun. 2010, 46, 2450–2452.
Hopkin, M. D.; Baxendale, I. R.; Ley, S. V. Org. Biomol. Chem. 2013, 11, 1822–1839.
AUTOMATED ANALOGUE FLOW SYNTHESIS
10 Analogues prepared in 24-35% yield
Single automated flow process for
each analogue
Minimal manual intervention required
One analogue per 6 hours
Single chromatographic purification at
end of flow process
Provided small quantities for activity
testing
Hopkin, M. D.; Baxendale, I. R.; Ley, S. V. Chem. Commun. 2010, 46, 2450–2452.
Hopkin, M. D.; Baxendale, I. R.; Ley, S. V. Org. Biomol. Chem. 2013, 11, 1822–1839.
CATCH – REACT – RELEASE SYNTHESIS OF IMATINIB
Ingham, R. J.; Riva, E.; Nikbin, N.; Baxendale, I. R.; Ley, S. V. Org. Lett. 2012, 14, 3920–3923.
“Catch - React – Release”
Avoid precipitation by building pyrimidine core on a monolithic support
Containment of malodorous sulfurcontaining by-products
CASE STUDY 2MECLINERTANT (SR48692)
MECLINERTANT (SR48692)
D. Gully et al., Proc. Natl. Acad. Sci. U.S.A., 1993, 90, 65.
J. -P. Maffrand et al., Actual. Chim. Ther., 1994, 21, 171.
R. M. Myers et al., ACS Chem. Biol., 2009, 4, 503.
Selective neurotensin receptor 1 antagonist
Neurotensin functions
Temperature control
Pain sensation
Apetite modulation
Significant role in diseases
Parkinson’s disease
Schizophrenia
Many cancers
SR48692
meclinertant
neurotensin
BATCH SYNTHESIS OF SR48692
R. Boigegrain et al., Eur. Pat., 1991, 0477049.
BATCH SYNTHESIS OF SR48692
R. Boigegrain et al., Eur. Pat., 1991, 0477049.
Was not commercially available
Synthesis is not as trivial as literature suggests
Tendency to “capture” inorganic impurities in the cage
AMINO ACID FLOW SYNTHESIS
C. Battilocchio et al., Org. Process Res. Dev., 2012, 16, 798.
C. Battilocchio et al., Org. Process Res. Dev., 2012, 16, 798.
GRIGNARD REACTION
Adamantanone EthynylMgBr
NH4Cl satured
sonicator
C. Battilocchio et al., Org. Process Res. Dev., 2012, 16, 798.
RITTER REACTION & CYCLISATION
Temperature-dependent 5-enol-exo-dig cyclisation
C. Battilocchio et al., Org. Process Res. Dev., 2012, 16, 798.
OZONOLYSIS
Fluid flow
Gas flow
Fluid flow
Gas flow
6.6 g/h of product, equating to over 200 g per day when processing in a continuous fashion.
Residence time 15 seconds
C. Battilocchio et al., Org. Process Res. Dev., 2012, 16, 798.
HYDROLYTIC CLEAVAGE
AMINO ACID FLOW SYNTHESIS
C. Battilocchio et al., Org. Process Res. Dev., 2012, 16, 798.
DMAP MONOLITH
C. Battilocchio et al., Chem. Eur. J., 2013, 19, 7917.
METHYLATION & IN-LINE SCAVENGING
C. Battilocchio et al., Chem. Eur. J., 2013, 19, 7917.
IN-LINE SOLVENT SWITCH
B. Deadman et al., Green Chem., 2013, 15, 2050.
CLAISEN CONDENSATION & IN-LINE CRYSTALLISATION
C. Battilocchio et al., Chem. Eur. J., 2013, 19, 7917.
KNORR PYRAZOLE & IN-LINE EXTRACTION
C. Battilocchio et al., Chem. Eur. J., 2013, 19, 7917.
C. Battilocchio et al., Chem. Eur. J., 2013, 19, 7917.
HYDROLYSIS: BATCH VS. FLOW
GENERATION & USE OF PHOSGENE IN FLOW
C. Battilocchio et al., Chem. Eur. J., 2013, 19, 7917.
DEPROTECTION
C. Battilocchio et al., Chem. Eur. J., 2013, 19, 7917.
USEFUL RESOURCES
FURTHER READING
Mendeley Reference List (>500 papers)http://www.mendeley.com/groups/4654251/flow-synthesis/papers/
General Flow Chemistry ReviewsOn being green: can flow chemistry help?Ley, S. V. Chem. Rec. 2012, 12, 378–390.
Flow chemistry syntheses of natural productsPastre, J. C.; Browne, D. L.; Ley, S. V. Chem. Soc. Rev. 2013, 42, 8849–8869.
The integration of flow reactors into synthetic organic chemistryBaxendale, I. R. J. Chem. Technol. Biotechnol. 2013, 88, 519–552.
Novel process windows for enabling, accelerating, and uplifting flow chemistryHessel, V.; Kralisch, D.; Kockmann, N.; Noël, T.; Wang, Q. ChemSusChem 2013, 6, 746–789.
Applying flow chemistry: methods, materials, and multistep synthesisMcQuade, D. T.; Seeberger, P. H. J. Org. Chem. 2013, 78, 6384–6389.
Tools for chemical synthesis in microsystemsJensen, K. F.; Reizman, B. J.; Newman, S. G. Lab Chip 2014, 14, 3206–3212.
The role of flow in green chemistry and engineeringNewman, S. G.; Jensen, K. F. Green Chem. 2013, 15, 1456-1472.
Continuous flow synthesis. A pharma perspectiveMalet-Sanz, L.; Susanne, F. J. Med. Chem. 2012, 55, 4062–4098.
Flow Chemistry - A Key Enabling Technology for (Multistep) Organic SynthesisWegner, J.; Ceylan, S.; Kirschning, A. Adv. Synth. Catal. 2012, 354, 17–57.
Continuous flow multi-step organic synthesisWebb, D.; Jamison, T. F. Chem. Sci. 2010, 1, 675–680.
Based on the flow chemistry icons used by
the Steven V. Ley Group at the University of
Cambridge.
The .ctp ChemDraw template file for these
icons is publicly available on figshare at
dx.doi.org/10.6084/m9.figshare.1170073
ICONS TEMPLATE FOR CHEMDRAW
University of CambridgeProf. Steven V. LeyProf. Ian R. Baxendale
The Innovative Technology Centre
University College CorkProf. Anita R. MaguireDr. Stuart G. Collins
ABCRF
ACKNOWLEDGEMENTS
Claudio BattilocchioDuncan BrowneEric Sliwinski
Nikzad NikbinLucie Guetzoyan
Financial SupportCommonwealth Scholarship CommissionCambridge Commonwealth TrustLB Wood Travelling ScholarshipScience Foundation Ireland (SSPC)
Richard InghamBenjamin BhawalMatthew Kitching& many others