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  • The nature of the substituents is critical because they increase or decrease the nucleophilicity of the ring:Electron donating groups increase yields.Electron withdrawing groups decrease yields.
  • T3P – Propane PhosphonicAcid Anhydride

Transcript

  • 1. An Introduction to FlowChemistry and its Benefits:“The Future Of ChemicalSynthesis”
  • 2. Who are we?• ThalesNano is a technology company that gives chemiststools to perform novel, previously inaccessible chemistrysafer, faster, and simpler.• Market leader: Over 700 customer install base on 6continents.• Own chemistry team.• 11 years old-most established flow reactor company.• R&D Top 100 Award Winner.
  • 3. Catalysis reactor: Modular: H-Cube ProH-Cube ProH2 Generation150 C, 100 barHydrogenationSelective C-C couplingGas Module12 Extra gases100 barPhoenix Module450 CNovel heterocyclesAutomated injection& collection.OptimizationMettler Toledo’sFlowIR™Instant results
  • 4. ThalesNano MarketsAgrochemical Food,CosmeticsPetrochemicalPharmaceuticalBiotechCatalysisDiscovery Development Production
  • 5. Why do we neednew synthetictechniques?
  • 6. Any change?Conventional laboratory, 1900IT effectivity ca.10,000,000 xInstrumental ca. 100,000 xConventional lab,2005:effectivity changed cca. 100 x
  • 7. Organic Synthesis – Growing Complexity• 1980’s – 2-3 Steps• 1990’s – 3-4 Steps• Today – 4-8 Steps• Future – 8-50 Steps
  • 8. Industry TrendsNCE
  • 9. What is the issue with chemical space?Region covered in aconventionallaboratoryAt ThalesNanopressure / barTemperature/C100 200 300Unexploitedchemistry space-1000100200300400500
  • 10. Expanding the Range of Reaction Conditions“prepare what you designed andreally want rather than what youcan readily synthesize”To achieve the above goal weneed a chemical technologytoolbox aiming at acceleration ofsynthetic problem solving!Nature Reviews Drug Discovery 11, 355-365 (May 2012)
  • 11. Safety Issues
  • 12. Chemical Production and E-Factors in Industry
  • 13. The push for flow• This has led companies to look at newtechniques to: Cut down on number steps→Lower cost Increase yields→less purification downstream Reduce catalyst screening time Re-examine untouchable chemistries→novel molecules→competitive edge Automate→more efficient• Flow is one of these techniques beinginvestigated.
  • 14. What is flowchemistry andhow does it differto batch?
  • 15. What is flow chemistry?Performing a reaction continuously, typically on small scale,through either a coil or fixed bed reactor.ORPumpReactor Collection
  • 16. Kinetics In Flow Reactors• In a microfluidic device with a constant flow rate, theconcentration of the reactant decays exponentially withdistance along the reactor.• Time in a flask reactor equates with distance in a flowreactorXAdX/dt > 0dA/dt < 0
  • 17. Improving Mixing:Speeding UpProcesses
  • 18. Mixing (batch vs. flow)Flow reactors can achievehomogeneous mixing anduniform heating inmicroseconds (suitable forfast reactions)
  • 19. •Benefits• Safety• No filtration necessary• Enhanced phase mixingFixed Bed Mixing: Catalyst System-CatCart®•Over 100 heterogeneous andImmobilized homogeneous catalysts10% Pd/C, PtO2, Rh, Ru on C, Al2O3Raney Ni, Raney CoPearlmans, Lindlars CatalystWilkinsons RhCl(TPP)3Tetrakis(TPP)palladiumPd(II)EnCat BINAP 30
  • 20. H-Cube Pro Overview• HPLC pumps continuous stream of solvent• Hydrogen generated from water electrolysis• Sample heated and passed through catalyst• Up to 150 C and 100 bar. (1 bar=14.5 psi)NHO2NNHNH2H
  • 21. Reaction times comparison batch vs. flowAldoxim reductionAldehyde reduction051015202530t/minFlowBatchHydrogenation in batch vs. flow systems020040060080010001200t/minAlkylation Suzuki-Miyaura Azide synthesis SonogashirareactionFlowBatchReactions performed in X-Cube™vs. batch modeCover a much bigger parameter space within a very short period of time
  • 22. H-Cube® Reaction ExamplesNOOEtArNHOOEtArAcetic Acid20% Pd(OH)2/C,70 bar, 70oC70% Yield, 5gRuO2, 100 C100 bar, 1 mL/min99% ConversionBatch: 200 C, 200 bar, 48 hoursBatch: 150 C, 80 bar, 3 days
  • 23. Gas Module• Versatile:Compressed Air, O2, CO, C2H4, SynGas,CH4, C2H6, He, N2, N2O, NO, Ar.• Fast:Reactions with other gases complete inless than 10 minutes• Powerful:Up to 100 bar capability.• Robust:All high quality stainless steel parts.• Simple:3 button stand-alone control or via simpletouch screen control on H-Cube Pro™.
  • 24. Problems with Oxidation
  • 25. Alcohol oxidation: Optimization100 • Area% of desired product in GC-MS / (100 – Area% of reactant in GC-MS)General conditions: H-Cube Pro with Gas Module,50 mL/min oxygen gas, 1 mL/min liquid flow rate(0.05M in acetone, 20 mL sample volume), CatCart:70mm., 1 % Au/TiO2 (cartridge: 70mm, THS01639),Batch ref.: Oxygen; perruthenate modifiedmesoporous silicate MCM-41 in tolueneT=80 C; 24 h; Bleloch, Andrew; et al. ChemicalCommunications, 1999 , 8,1907 - 1908Very fast addition of alcohol to gold surface.Alkoxide formation.
  • 26. ImprovedTemperatureControl
  • 27. Miniaturization: Enhanced temperature controlLarge surface/volume rate• Volume is equal to the length cubed, while surface area is equal to lengthsquared.• When the length is shortened, surface-to-volume ratio increases.• Microreactors have surface-to-volume ratio than macroreactors, heattransfer occurs rapidly in a flow microreactor, enabling precise temperaturecontrol.Yoshida, Green and Sustainable Chemical Synthesis Using FlowMicroreactors, ChemSusChem, 2010
  • 28. Heating ControlBatch Flow- Lower reaction volume.- Closer and uniform temperature controlOutcome:- Safer chemistry.- Lower possibility of exotherm.- Larger solvent volume.- Lower temperature control.Outcome:-More difficult reaction control.- Possibility of exotherm.
  • 29. Heat In:Enabling NewChemistries
  • 30. Heat inQ amount of heat transferredt time takenk conductivity of the materialS surface aread distance between the two endsT1 higher temperature endT2 lower temperature endFlow reactorMicrowaveOil BathHeat transfer of Microwave, Flow reactor, Oil Bath (Flask)0 100 200 300 400 500 600 700050100150200250300350400T/°Ct / secHeat transfer works two waysallowing rapid and safe control of reactions
  • 31. Phoenix Flow Reactor: High TemperatureStainless steel coil(1000 m i.d.)Razzaq, T.; Glasnov, T. N.; Kappe, C. O. Eur. J. Org. Chem. 2009, doi:10.1002/ejoc.200900077Temperature: RT- 450 CH-Cube ProPhoenix
  • 32. Phoenix reactor possibilitiesLoop Materials - sizes Stainless steel (1 – 32 ml) – up to450oC and 100bar PTFE coil (4 – 16 ml) – up to150oC and 20bar Hastelloy (4 – 16 ml) – up to 450oCand 100barCartridge Reactor types• CatCart (30, 70 mm) – up to300 C and 100bar• MidiCart – up to 150 C and100bar• Special high temperaturecartridge – up to 450 C and100bar
  • 33. Heterocyclic rings of the future, J. Med. Chem., 2009, 52 (9), pp 2952–2963.• 3000 potential bicyclic systems unmade• Many potential drug like scaffoldsWhy?• Chemists lack the tools to expand into new chemistry spaceto access these new compounds.• Time• KnowledgeThe quest for novel heterocycles
  • 34. Gould-Jacobs Cyclization• Standard benzannulation reaction• Good source of:• Quinolines• Pyridopyrimidones• Naphthyridines• Important structural drug motifsDisadvantages:• Harsh conditions• High b.p. solvents• Selectivity• SolubilityCondensationCyclizationSaponification Decarboxylationmethylenemalonic esterW. A. Jacobs, J. Am. Chem. Soc.; 1939; 61(10); 2890-2895
  • 35. The nature of the substituents is critical because they increase or decrease the nucleophilicity of the ring:Electron donating groups increase yields, Electron withdrawing groups decrease yields.35Process explorationMeldrum’s acidic route to pyridopyrimidones and tohydroxyquinolinesMeldrum-savCH(OEt)33a-eBatch Flow1a-e 2a-ea: R=H, R=H, X=Nb: R=H, R=H, X=N,c: R=F, R=H, X=C(CH3)d: R=H, R=CN, X=CHe: R=H, R=OCH3, X=CHin THF3d (43%) 3e (60%)3a (89%) 3b (60%) 3c (62%)Cyclization conditions:a: 300 C, 160 bar, 0.6 minb: 300 C, 100 bar, 0.6 minc: 360 C, 100 bar, 1 mind: 350 C, 130 bar, 4 mine: 300 C, 100 bar, 1.5 minLengyel L., Nagy T. Zs., Sipos G., Jones R., Dormán Gy., Ürge L., Darvas F., Tetrahedron Lett., 2012; 53; 738-743No THF polymerization !
  • 36. NOOOAAAAFVPl ketomalonate NOOOOAAANHNH2AAAAFVPDiethyl ketomalonateNHNOOOOAAAA NHNOOOAAAAFVPDiethyl ketomalonateNOOOOAAAAOOONAAAANew Scaffold GenerationPhoenixAAAANHOFVPOAANHAAFVPOOOAAAAAO5 novel bicyclic scaffolds generated-fully characterized.Many more to follow
  • 37. Ring closure on aryl NH : key step• Mitsunobu reaction or traditional heating with T3P did notfurnish the bicyclic heterocycle.• Reaction proceeded smoothly in Phoenix reactor at 300oC with65% yield despite requirement for the cis amide conformer intransition state.Flow offers options to dead ends.
  • 38. Heat Out:Improving SafetyOf High EnergyProcesses
  • 39. Heat Out=Exothermic Chem:in situ generation of reactive intermediates• In batch the reaction can be controlled by low temperature(it slows down the reaction)• In flow it can be at room temperature applyingshort residence time
  • 40. Heat OutLithium Bromide ExchangeBatchFlow• Batch experiment shows temperature increase of 40 C.• Flow shows little increase in temperature.Ref: Thomas Schwalbe and Gregor Wille, CPC Systems
  • 41. Setup of the Ice CubeOzone Module generate O3 from O2100 mL/min, 15 % O3Cooled Reactor Module – teflon tube orglass chip; -50 C.Pump Module – Peristaltic or GearPumpOptional: 1 or 2
  • 42. Selective Ozonolysis Of EugenolReaction parameters:Reagent flow rate 0.7 mL/minQuench flow rate 1.4 mL/minO3 flow rate 17.5 mL/min (~2 eq.)T -5 CcEugenol 0.05 McNaBH40.05 MSolvent EtOHResults:Conversion 100 %misolated 326.2 mgmmax. yield 504 mgIsolated yield 65 %Purity of isolated product 98 %ThalesNano lab basedchemistry-unpublished
  • 43. Nitration in flowOHHO OHOHNO2NO2OHOHO2NMolecular Weight: 261,10Molecular Weight: 126,11PhloroglucinolPump A Pump B Temperature(oC)Loop size(ml)Conversion(%)Selectivity (%)SolutionFlow rate(ml/min) SolutionFlow rate(ml/min)ccHNO3 0.41g PG/15mlccH2SO4 0.4 5 - 10 7 1000 (differentproducts)1.48g NH4NO3/15mlccH2SO4 0.71g PG/15mlccH2SO4 0.5 5 - 10 13 100 1001.48g NH4NO3/15mlccH2SO4 0.51g PG/15mlccH2SO4 0.5 5 - 10 13 50 80 (20% dinitro)70% ccH2SO4 30%ccHNO3 0.61g PG/15mlccH2SO4 0.5 5 - 10 13 (3 bar) 100 10070% ccH2SO4 30%ccHNO3 0.61g PG/15mlccH2SO4 0.5 5 - 10 13 (1 bar) 8070 (30% dinitroand nitro)Batch reference: 30ml ccH2SO4, 1g PG, 1.48g NH4NO3, 5-10oC 10 min, Conversion: 91%
  • 44. ImprovingSelectivity
  • 45. Flow rate vs. residence time• Increasing the flow rate decreases the residencetime - a tool for selectivity
  • 46. ReactantsProductsBy-productsTraditional Batch MethodGas inletReactantsProductsBy-productsBatch vs. FlowBetter surface interactionControlled residence timeElimination of the productsFlow MethodH-Cube Pro™
  • 47. 0,4 0,6 0,8 1,0 1,2 1,4 1,6 1,8 2,0 2,2859095100105110ConversionSelectivity%Flow rate / mLmin-11% Pt/C (V) catalyst at 0,02 concentration of 4-bromo-nitrobenzeneConditions: 70 bar, EtOH, 25 CSelectivity through residence time controlIncrease and decrease ofresidence time on the catalystcannot be performed in batch.CatalystFlow ratemL/minResidencetime / secConc.mol/dm3Conv.%Sel.%IrO2 2 9 0,2 52 69Re2O7 2 9 0,2 53 73(10%Rh 1% Pd)/C 2 9 0,2 79 60RuO2 (activated)2 9 0,2 100 1001 18 0,2 100 990,5 36 0,2 100 98Ru black 2 9 0,2 100 831% Pt/C dopedwith Vanadium2 9 0,2 100 961 18 0,2 100 930,5 36 0,2 100 84
  • 48. Selective dehydrochlorinationArFFCl ArFFH ArFHH ArHHHA B C DFlowrate(mL/min)Pressure(bar)Temperature (oC)Bubdet Catalyst AmountA (%)AmountB (%)AmountC (%)AmountD (%)1 20 (∆p:5 bar) 110 50 10% Pd/C 26.7% 61.5% - 7%1 20 (∆p:3 bar) 110 50 1% Pd/C 61,90% 29,40% - 2,50%1 20 (∆p:13bar)110 50 5% Rh/C 78.9% 5.1% - 9.2%1 20 (∆p:10bar)110 50 5% Pd/C 26.7% 60.9% - 6.7%1 20 (∆p:5 bar) 110 50 5% Pd/C(S) 25% 63.4% - 6.6%Objective: Match similar selectivity of 60% but without additives ofCsF, S, K2CO3 and PPh3
  • 49. Selective Suzuki coupling (Cl, Cl)The conditions were:1 equivalent of 2,6-dichloroquinoxaline with1.2 equivalent of o-Tolylboronic acidConcentration set to 0.02MSolvent: MethanolBase: NaOHAnalytics: GC-MSNN ClClBHO OHNN ClFlow rate(ml/min)Pressure TemperatureCatalyst BaseResult(bar) (oC) LC-MS, 220nm0.8 20 100Fibrecat 1007(70mm)3 ekvConversion: 82%Selectivity: 48%0.3 20 100Fibrecat 1007(70mm)3 ekvConversion: 99%Selectivity: 48%0.8 20 100Fibrecat 10352.5 ekvConversion: 16%(30mm) Selectivity: 100%0.8 20 100Fibrecat 1029(30mm)2.5 ekvConversion: 18%Selectivity: 100%0.8 20 100Fibrecat 1048(30mm)2.5 ekvConversion: 40%Selectivity: 100%0.8 20 10010% Pd/C2.5 ekvConversion: 89%(30mm) Selectivity: 14%0.5 20 50Fibrecat 10482.5 ekvConversion:17%(30mm) Selectivity: ~100%0.5 20 100Fibrecat 10482.5 ekvConversion: 35%(30mm) Selectivity: ~100%0.2 20 100Fibrecat 10072.5 ekvConversion: 93%(70mm) Selectivity: 73%0.2 20 100Fibrecat 10072.5 ekvConversion: 93%(70mm) Selectivity: 80%0.2 20 100Fibrecat 10292.5 ekvConversion: 12%(30mm) Selectivity: 100%
  • 50. FasterOptimizationAnd Analysis
  • 51. Enabling faster optimization• Batch reactions gave 1 results after 4 hours!H2 / cat.+diphenyl-acetylenecis-stilbenetrans-stilbene1,2-diphenylethaneH2 / cat.H. H., Horváth; G, Papp; Cs., Csajági; F., Joó; Catalysis Communications; 8; 3; 2007; 442-446
  • 52. 30 40 50 60 70 80020406080diphenylethanecis-stilbenetrans-stilbeneconversion%T (0C)Hydrogenation of diphenylacetylene, one day optimization, %f(T)• [RuCl2(mTPPMS)2]/Molselect DEAE• p(H2) = 30 bar, [S] = 0.1 M• Solvent: toluene/ethanol 1/1• 24 experiments in 2 hours.H. H., Horváth; G, Papp; Cs., Csajági; F., Joó; Catalysis Communications; 8; 3; 2007; 442-446
  • 53. O-Cube™ – H-Cube® - ReactIR™ozonolysis of deceneOzonolysis Quenching withH-Cube®T = -30 ºCCSM = 0.02 M (in EtOAc)O3 excess = 30 %T = -30 ºC to r.t.p = 1 barCat: 10 % Pd/CMettlerFlow IR™O-Cube and ReactIR are trademarks of ThalesNano Inc. and Mettler Toledo InternationalInc., respectively, H-Cube is registered trademark of ThalesNano Inc.ThalesNano lab basedchemistry-unpublishedOzonide eluted into cool vial under N2
  • 54. O-Cube ™ -H-Cube ™ -ReactIR ™ reference IRspectraSpecific absorption:Decene: monosubstituted alkene: 917 cm-1, 999 cm-1 (917 cm-1 selected)Nonanal: carbonyl: 1711 cm-1decenenonanal
  • 55. O-Cube™ -H-Cube® -ReactIR™ monitoringResults:Full Conversion(GCMS)Purity 97% (NMR), no work up neededYield: 85%Reaction of SMIncrease in ProductFR reductionIncrease in ProductFR increase
  • 56. Oxidation followed by inline FlowIRSMT= 50°CT= 65°CT= 80°CT= 95°C T= 110°C T= 125°Cvflow= 0.5vflow= 0.75vflow= 1vflow= 1.5vflow= 2p (bar) T (°C) Vflow (ml/min)33 50 0.533 65 0.533 80 0.533 95 0.533 110 0.533 125 0.533 125 0.7533 125 133 125 1.533 125 2OCH3OH Au-TiO2acetone / O2OCH3HO
  • 57. OHOFFClOHOFFHFirst results: reaction was carried out in batch reaction was followed by Picospin 1H NMR product was identified in the crude reaction mixture purified product was also identified Picospin was tuned to 19FCOOH F2HC-Hydrodehalogenation followed by PicospinSolvent H2-source T (°C) t (h) Productwater Zn/HCl 100 5 100%
  • 58. AutomatingMore Processes
  • 59. H-Cube Autosampler™Gilson 271 Liquid Handler 402 single Syringe pump (10 mL) Direct GX injector (Valco) Low-mount fraction collection (Bio-Chem) Septum-piercing needle Static drain wash station Tubes, connectors, fittingsOpen vial collectionCollection through probe (into closed vial)
  • 60. Step 1: OptimizationStep 2: Library ProductionLibrary Deprotection
  • 61. NH2NH53718060696381Yield (%) IodobenzoicacidAmine305588892580Yield (%)AmineIodobenzoicacid53718060696381Yield (%) IodobenzoicacidAmine305588892580Yield (%)AmineIodobenzoicacidNH2Automated test library synthesisCarbonylationIOHONHNH2NH2IOHONHNH2IOHONHNHNH2NH2NH2IOHOCONHOHONO++X-CUBE
  • 62. MultistepSynthesis
  • 63. Reaction at 0 C instead of -70 CMultistep synthesesX = O, SYoshida, ChemSusChem 2012,5, 339 – 350Residence time = 3.4 s
  • 64. MeOMeO(±)-oxomaritidineNHOBrHONMe3N3N3HOMeCN:THF (1:1), 70 oCOMeOOMe(1)(2)catch, react, releaseMeOOMeNHOrt to 55 oCPh(nBu)2PH2OH2 (g)electrolysisFlow hydrogenation10% Pd/C, THFMeOOMeNHHOOF3C OOCF3MeOOMeNHOCF3O80 oCNMe3RuO4OHMeOOMePhI(O2CX3)2rtNMeOMeOCF3OOMeOH / H2O (4:1)NMe3OH35 oCI.R. Baxendale, J. Deeley, C.M. Griffith-Jones, S.V. Ley, S. Saaby, G. Tranmer, J. Chem. Soc., Chem. Commun., 2006, 2566.Flow Synthesis of Oxomaritidine
  • 65. Faster and SaferScale up
  • 66. Continuous Process Advantages Speed• 50 + times faster reactions Better Process Yields• The continuous process ensuresgreater reproducibility• less out of spec and by-products. Safety• Dangerous reactions, toxicintermediates• High pressure• High temperature• Supercritical reactions Environmental impact,green chemistry• Greener solvents (SCCO2)• Less hazardous waste:• Lower energy consumption Cost Benefits• Lower Cost Production• Lower Material costs• Greater material yields areachieved• Considerable savings inutility costs.• Space requirements aresignificantly lower• Less waste managementand disposal costs• Shorter Development &Scale-up Time Regulatory aspects• Fits into the FDA PATinitiatives
  • 67. H-Cube Midi™ reactor for scale-upKilo Scale
  • 68. ● Genzyme needed 1.2 kg of Zavesca for an internal study, which waspriced at 47K USD per 100 g.Saved~ 500K as opposed to purchasing it. It assayed with higher puritythan previous commercial lots. Kilo scale.Genzyme Chemistry
  • 69. Number up or Scale Out?Advantages for both, but scale out too much and lose flow advantages!
  • 70. Survey ConductedSmall scale: Making processes safer Accessing new chemistry Speed in synthesis andanalysis AutomationLarge scale: Making processes safer Reproducibility-less batchto batch variation SelectivityWhy move to flow?
  • 71. Survey ConductedWhat chemistries?Difficult to perform chemistries• Low temperature exothermic reactions• Reactions with gases• Very slow reactions or unaccessible chemistry• Reactions with selectivity issuesApprox. 30% of reactions!
  • 72. Survey ConductedWhat are the major blockers?• Where do I start?• Literature: Flow chemistry Society• Quick Start Guides• Solubility issues• Test solvents.
  • 73. What sets us apart?ThalesNano focuses on designing reactors around specific chemistrysolutions and where flow can be applied best. We don’t try to applyflow chemistry to everything like our competitors!Exothermic Reactions• Safety• New chemistry• SpeedEndothermic Reactions• Speed• GreenReactions with gases• Safety• Simplicity• Speed• GreenScale up• Safety• Selectivity• Reproducibility• Speed
  • 74. Flow University• Practical Lab Manual• Presentation tutorial• Background notes• Educational Videos In English In Mandarin Chinese Subtitled
  • 75. Chemistry Services Clients"ThalesNano delivered to KosteBiochemicals catalyst screening andreaction optimization services of anuncompromising quality with full analyticsperformed in record-breaking time. A greatteam to work with !“-Charles Carey, Co-founder KosteBiochemicals
  • 76. ComInnex Chemistry Services – Our Sister Company• Our sister drug discovery service provider.• A leader in chemistry, library and medicinal chemistry services• Track record collaborations with >250 customers in US, EU, and Asia.• >800 focused libraries in past 12 years.• European IP standards• Excellent reputation for customer service.• Advantages:• Located in heart of Europe, Budapest.• European standards and expertise at competitive prices on your doorstep.• CADD, Biology, and ADMET support possible.• Access to ThalesNano’s full equipment inventory.• Novel heterocycles platform based on innovative proprietary technologies.
  • 77. AcknowledgementsThank you for your attention!Any questions?Booth 821Some slides reproduced with thepermission of the Flow ChemistrySociety.