FLOW CHEMISTRY
Benjamin J. Deadman Analytical & Biological Research Facility (ABCRF) Dept. of Chemistry & School of Pharmacy University College Cork SSPC Masterclass in Synthetic Organic Chemistry UCD, September 4th, 2014
This lecture is publicly available on figshare. http://dx.doi.org/10.6084/m9.figshare.1170109 CONTACT INFORMATION
Benjamin J. Deadman PDRA (Anita R. Maguire Group) Analytical & Biological Chemistry Research Facility (ABCRF) Department of Chemistry & School of Pharmacy University College Cork
Email: [email protected]
LinkedIn: ie.linkedin.com/pub/ben-deadman/42/862/787/
ResearchGate: www.researchgate.net/profile/Benjamin_Deadman
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 EARLY HISTORY OF CONTINUOUS CHEMICAL PROCESSING
Continuous Oil Refining Shell Martinez refinery Continuous Fermentation California Morton Coutts Since 1915 Dominion Breweries, NZ 1956 Bosch Haber Process Fritz Haber & Carl Bosch Continuous processing is common BASF in petrochemical, bulk chemical 1909-1913 and beverage industries.
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). 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
CANNOT IGNORE THE ENVIRONMENTAL IMPACT OF SYNTHESIS
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. CONTINUOUS FLOW PROCESSING IN PHARMA
It may have taken 100 yrs but, since 2000, continuous processing is now gaining momentum 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) 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
Reactors Pumps • Reaction stages • Several types • May be heated, cooled etc • Deliver solvents or reagents Microfluidic Chip • Reproducible flow rate critical Small volume with to control stoichiometry excellent mixing • Laboratory pumps For fast reactions • Piston • Syringe • Process pumps Coiled Tube Reactor • Peristaltic Usually 2 to 20 mL • Gear Centrifugal volume Provides residence time for Mixing T-Piece reaction
Packed Column • Mixes two flow streams Contains immobilised/solid • Variety of types reagents, catalysts or scavengers
Injection Loop Back Pressure Regulator
• For introducing small volumes of reagents/substrates • Controls system pressure • Typicall Rheodyne 2-position type • Allows superheated conditions • May be wide bore for flow chemistry • Spring resistor or simple restriction HEAT TRANSFER
Heat Transfer proportional to surface-area/volume ratio
SA/V is significantly higher in tubular geometry
250 mL RB flask 10 mL tube reactor ~0.7 cm2/mL (1 mm o.d.) ~40 cm2/mL
Fast transfer from hot to cold Ambient reaction stages
Heat
Fast heat transfer into reaction Fast heat transfer out of reaction Avoid temperature Can control reaction Cool gradients exotherms without external cooling Ambient N. E. Leadbeater, An Introduction to Flow Chemistry: A Practial Laboratory Course, Vapourtec: Suffolk, UK, 2014. MASS TRANSFER & MIXING Combining flow streams allows rapid and controlled mixing
Flow A 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 Mixed Y-piece mixers Flow
Flow B 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
Bo Bodenstein number 4훽퐷휏 β channel geometry (square = 30, tube = 48) 퐵표 = = 퐹표훽 τ residence time 2 dt tube diameter 푑푡 Fo Fourier number
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.)
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
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. PLUG VS LAMINAR FLOW
Reynolds Number
푖푛푒푟푡푖푎푙 푓표푟푐푒푠 휌v퐷 푅푒 = = 퐻 Laminar Flow 푣푖푠푐표푢푠 푓표푟푐푒푠 휇 [A] 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)
t Re < 2000 laminar flow
Plug Flow Re > 4000 turbulent/plug flow [A] Most laboratory flow reactors actually have laminar flow
• Need to find steady state conditions • Mathematical models for this t • Or use in-line analysis
• Axial dispersion can be prevented by
segmented flow (e.g. with N2 or fluorous spacer) http://www.engineeringtoolbox.com/reynolds-number-d_237.html http://en.wikipedia.org/wiki/Reynolds_number 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.
휋 푡푢푏푒 푣표푙푢푚푒 = × (𝑖푛푛푒푟 푑𝑖푎푚푒푡푒푟 푐푚 )2 × 푙푒푛𝑔푡ℎ (푐푚) 4 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 limits Polymer 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
Immobilised Reagents
Scavenging
Catch & Release
Avoid labour/time intensive work-up & purification procedures: • Reaction quenching • Aqueous washes • Chromatography • Crystallisation • Distillation
S. V. Ley, Enabling Technologies in Synthesis, Cambridge Graduate Lecture Series, 2013. POLYMER SUPPORTED SCAVENGERS Some common scavengers Acidic Basic
Metal Electrophilic Nucleophilic Scavenging
and many others.
S. V. Ley, Enabling Technologies in Synthesis, Cambridge Graduate Lecture Series, 2013. IN-LINE WORK-UP & MONITORING
• 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. REACTION TELESCOPING SCALE UP SAFETY BENEFITS
Reaction Telescoping Scale Up Run flow reactor longer to obtain more product Make & use hazardous intermediates Can scale out – run multiple reactors in parallel Reduced intermediate stock Manufacturing industry would use larger diameter No need to transport intermediates tubes (e.g. 11.7 mm i.d. in Novartis/MIT system)1
An Example Phoenix 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 VAPOURTEC R & E REACTORS
http://www.vapourtec.co.uk/products/rseriessystem UNIQSIS FLOWSYN REACTORS
http://www.uniqsis.com/ SYRRIS ASIA REACTORS
http://syrris.com/flow-products MICROFLUIDIC CHIP 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. COILED TUBE REACTORS
http://www.vapourtec.co.uk/products/rseriessystem http://www.uniqsis.com/ S. V. Ley, Enabling Technologies in Synthesis, Cambridge Graduate Lecture Series, 2013. MONOLITHIC REACTORS
S. V. Ley, Enabling Technologies in Synthesis, Cambridge Graduate Lecture Series, 2013. 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. ACR PREPARATION OF N-IODOMORPHOLINE SLURRY
• The Coflore ACR is designed to keep solids in suspension, offering potential for the continual No agitation pumping of slurries.
• N-iodomorpholine.HI is a useful reagent for iodinating terminal alkynes. Seconds after • Potential applications of ACR for salt forming turning on reactions in organic solvents. agitation.
AM Technology; www.amtechuk.com. Browne, D. L.; Deadman, B. J.; Baxendale, I. R.; Ley, S. V.; Org. Process Res. Dev., 2011, 15, 693. 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 • Body: Self contained unit enclosing all electronics, high-vacuum and backing ELECTROSPRAY MASS SPECTROMETER 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 ON-LINE ELECTROSPRAY MASS SPECTROMETRY
A pump 1 B pump 2 C mixing tee D reactor coil E 6-port valve F ESI-MS G sampling loop H waste discharge I back pressure regulator J pump 3 K back pressure regulator L pump 4 M µ-mixing tee N 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 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. 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
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 Conditions Acetone, 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. THE FUTURE OF IN-LINE ANALYSIS
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. GAS PERMEABLE TUBING: FLOW OZONOLYSIS
O’Brien, M.; Baxendale, I. R.; Ley, S. V. Org. Lett. 2010, 12, 1596–1598. TUBE-IN-TUBE GAS FLOW REACTOR
Gases used:
CO2 Angew. Chem. Int. Ed. 2011, 50, 1190. Org. Process Res. Dev. 2014, DOI: 10.1021/op500213j
O3 Org. Lett. 2010, 12, 1596.
H2 Chem. Sci. 2011, 2, 1250. Org. Process Res. Dev. 2012, 16, 1064.
O2 Chem. Sus. Chem. 2012, 5, 274. Adv. Synth. Catal. 2013, 355, 1905. CO Org. Biomol. Chem. 2011, 9, 6903. Org. Biomol. Chem. 2011, 9, 6575. GAS Chem. Eur. J. 2014, DOI:10.1002/ejoc.201402804. NH3 Synlett 2012, 23, 1402. Ethylene Synlett 2011, 18, 2643. ChemCatChem 2013, 5, 159. SUBSTRATE Diazomethane Org. Lett. 2013, 15, 5590. • Reactor volume 0.28 – 0.56 mL (1 - 2.0 m AF-2400) J. Org. Chem. 2014, 79, 1555. • Gas pressure up to 35 bar RSC Adv. 2014, 4, 37419. • Small effective volume of gas input (safety!) Syngas • Adaptable to common laboratory heaters/coolers Synlett 2011, 18, 2648. • Flow rates 0.1 – 10 mL/min ChemCatChem 2013, 5, 159. • Easy to reconfigure Formaldehyde Eur. J. Org. Chem. 2013, 4509.
http://www.cambridgereactordesign.com/pdf/Gastropod%20for%20Gas%20Liquid%20Reactions.pdf http://www.uniqsis.com/paProductsDetail.aspx?ID=ACC_GAM_1 http://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. LOW TEMPERATURE REACTORS
Vapourtec Cooling Modules
Reactions at temperatures from Uniqsis/CRD Polar Bear RT to -89 °C Uniqsis/CRD Polar Bear Plus
Uniqsis/Cambridge Reactor Design: Polar Bear, http://www.uniqsis.com/paProductsDetail.aspx?ID=ACC_POLE Uniqsis/Cambridge Reactor Design: Polar Bear Plus, http://www.uniqsis.com/paProductsDetail.aspx?ID=ACC_PBPF Vaourtec, http://www.vapourtec.co.uk/products/reseriessystem/cooledreactor 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. SOLVENT SWITCHER
Volatile Exhaust Desolvation Gas Capillary Sprayer Heated Omnifit Column • 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 Liquid (piston pump not suitable because Withdrawn 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. IN-LINE SOLVENT SWITCH AND CONCENTRATION
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 DISTILLATION
Semi-continuous nitro alkene formation and Michael addition by Soldi et al. 2008
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. CASE STUDY 1 IMATINIB (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 myelogenous leukemia (CML) and gastrointestinal stromal tumors (GISTs)
Approved for several other cancers
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. X-Ray crystal structure binding of imatinib with the kinase domain of Abl. BATCH SYNTHESIS
Insoluble intermediates difficult to process in continuous flow.
Deadman, B. J.; Hopkin, M. D.; Baxendale, I. R.; Ley, S. V. Org. Biomol. Chem. 2013, 11, 1766–1800. 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
“Catch - React – Release”
Avoid precipitation by building pyrimidine core on a monolithic support
Containment of malodorous sulfur containing by-products
Ingham, R. J.; Riva, E.; Nikbin, N.; Baxendale, I. R.; Ley, S. V. Org. Lett. 2012, 14, 3920–3923. CASE STUDY 2 MECLINERTANT (SR48692) MECLINERTANT (SR48692)
SR48692 meclinertant Selective neurotensin receptor 1 antagonist
Neurotensin functions Temperature control Pain sensation Apetite modulation
Significant role in diseases Parkinson’s disease Schizophrenia Many cancers
neurotensin
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. BATCH SYNTHESIS OF SR48692
R. Boigegrain et al., Eur. Pat., 1991, 0477049. BATCH SYNTHESIS OF SR48692
Was not commercially available
Synthesis is not as trivial as literature suggests
Tendency to “capture” inorganic impurities in the cage
R. Boigegrain et al., Eur. Pat., 1991, 0477049. AMINO ACID FLOW SYNTHESIS
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
6.6 g/h of product, equating to over 200 g per day when processing in a continuous fashion. Residence time 15 seconds
Fluid flow Gas flow
C. Battilocchio et al., Org. Process Res. Dev., 2012, 16, 798. HYDROLYTIC CLEAVAGE
C. Battilocchio et al., Org. Process Res. Dev., 2012, 16, 798. 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. HYDROLYSIS: BATCH VS. FLOW
C. Battilocchio et al., Chem. Eur. J., 2013, 19, 7917. 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 Reviews On being green: can flow chemistry help? Ley, S. V. Chem. Rec. 2012, 12, 378–390. Flow chemistry syntheses of natural products Pastre, J. C.; Browne, D. L.; Ley, S. V. Chem. Soc. Rev. 2013, 42, 8849–8869. The integration of flow reactors into synthetic organic chemistry Baxendale, I. R. J. Chem. Technol. Biotechnol. 2013, 88, 519–552. Novel process windows for enabling, accelerating, and uplifting flow chemistry Hessel, V.; Kralisch, D.; Kockmann, N.; Noël, T.; Wang, Q. ChemSusChem 2013, 6, 746–789. Applying flow chemistry: methods, materials, and multistep synthesis McQuade, D. T.; Seeberger, P. H. J. Org. Chem. 2013, 78, 6384–6389. Tools for chemical synthesis in microsystems Jensen, K. F.; Reizman, B. J.; Newman, S. G. Lab Chip 2014, 14, 3206–3212. The role of flow in green chemistry and engineering Newman, S. G.; Jensen, K. F. Green Chem. 2013, 15, 1456-1472. Continuous flow synthesis. A pharma perspective Malet-Sanz, L.; Susanne, F. J. Med. Chem. 2012, 55, 4062–4098. Flow Chemistry - A Key Enabling Technology for (Multistep) Organic Synthesis Wegner, J.; Ceylan, S.; Kirschning, A. Adv. Synth. Catal. 2012, 354, 17–57. Continuous flow multi-step organic synthesis Webb, D.; Jamison, T. F. Chem. Sci. 2010, 1, 675–680. ICONS TEMPLATE FOR CHEMDRAW
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 ACKNOWLEDGEMENTS
University of Cambridge Prof. Steven V. Ley Claudio Battilocchio Richard Ingham Prof. Ian R. Baxendale Duncan Browne Benjamin Bhawal Eric Sliwinski Matthew Kitching The Innovative Technology Centre Nikzad Nikbin & many others Lucie Guetzoyan
University College Cork Prof. Anita R. Maguire Dr. Stuart G. Collins
ABCRF
Financial Support Commonwealth Scholarship Commission Cambridge Commonwealth Trust LB Wood Travelling Scholarship Science Foundation Ireland (SSPC)