FLOW CHEMISTRY - Amazon S3 · FLOW CHEMISTRY This lecture is ... CONTINUOUS FLOW PROCESSING IN PHARMA Lab scale flow reactors in medicinal chemistry ... MAKINGS OF A FLOW REACTOR

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.

mailto:[email protected]

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.

http://www.basf.com/group/corporate/en/about-basf/history/1902-1924/index

http://nzic.org.nz/ChemProcesses

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)

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.

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


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

http://syrris.com/flow-products

SYRRIS ASIA REACTORS

http://syrris.com/flow-products

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


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

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

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

http://www.microsaic.com/products

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


TEMPERATURE DEPENDENCE OF SELECTED IONS


REACTION OPTIMISATION ASSISTED BY ON-LINE ESI-MS

Optimised ConditionsAcetone, 50 οC


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

http://www.uniqsis.com/paProductsDetail.aspx?ID=ACC_GAM_1

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.

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

http://www.uniqsis.com/paProductsDetail.aspx?ID=ACC_POLE

http://www.uniqsis.com/paProductsDetail.aspx?ID=ACC_PBPF

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.

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)



IMATINIB SN2 REACTION



IMATINIB C-N CROSS COUPLING REACTION



IMATINIB AUTOMATED FLOW SYNTHESIS



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



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.


GRIGNARD REACTION

Adamantanone EthynylMgBr

NH4Cl satured

sonicator


RITTER REACTION & CYCLISATION

Temperature-dependent 5-enol-exo-dig cyclisation


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


HYDROLYTIC CLEAVAGE

AMINO ACID FLOW SYNTHESIS


DMAP MONOLITH

C. Battilocchio et al., Chem. Eur. J., 2013, 19, 7917.

METHYLATION & IN-LINE SCAVENGING


IN-LINE SOLVENT SWITCH

B. Deadman et al., Green Chem., 2013, 15, 2050.

CLAISEN CONDENSATION & IN-LINE CRYSTALLISATION


KNORR PYRAZOLE & IN-LINE EXTRACTION



HYDROLYSIS: BATCH VS. FLOW

GENERATION & USE OF PHOSGENE IN FLOW


DEPROTECTION


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.

http://www.mendeley.com/groups/4654251/flow-synthesis/papers/

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

Documents

FLOW CHEMISTRY - Amazon S3 · FLOW CHEMISTRY This lecture is ... CONTINUOUS FLOW PROCESSING IN PHARMA Lab scale flow reactors in medicinal chemistry ... MAKINGS OF A FLOW REACTOR