Presentation on theme: "Rapid Chemical Space Exploration – Applications from Discovery to Manufacturing Neal Sach Senior Principal Scientist 10777 Science Centre Drive La Jolla,"— Presentation transcript:
1 Rapid Chemical Space Exploration – Applications from Discovery to Manufacturing Neal Sach Senior Principal Scientist Science Centre Drive La Jolla, CA 92121, USA ACS Technical Achievements in Organic Chemistry Philadelphia, USA August 22nd 2012The Evolution of Reaction Optimization Technologies
2 Contents An Introduction to Reaction Optimization Workflows Reaction Optimization in Process ChemistryAdapting to Discovery ChemistryCase ExamplesFirst item is short as with the audience its preaching to the choir
3 Solving Chemistry Across the Portfolio Discover Drugable MoleculesSupply Drug SubstanceDevelop Commercial ProcessesTransfer Technology to ProductionHow we do this in less time and at a lower cost?Supply ChainDiscoveryProcessResearchDevelopmentManufacturingCovalent BondsReaction ConditionsWork Up ConditionsVariations
4 Adapting to Industry Pressures Technology must ‘fill the gap’WorkloadResourcesApologies for showing this slide! Nice thing though is that its lasted two decades.199X20XX
5 The First Reaction Optimization Tool In 1998 a Process Research Technology Group was created with the aim of speeding Process DevelopmentThe SK233 was the first tool of its kind, 10 simultaneous reactions with integrated analytics1g per reaction, 10 reactions, 10-50ml volumeOne instrument and an 18 year old just out of school! 3 reactions a day was considered acceptable, how could we improve that? 10 reactions per day was a start plus the integrated analytics provided a large amount of information per reaction. This was a significant improvement on current productivities.Primary amide could be followed and we could see how long the reaction actually was, compared with just leaving it overnight.
6 UK-427,387 – The Tipping PointDespite a few successes, the general adoption of the SK233 and reaction optimization technologies was slow……but that was to change…UK-427,387 was nominated as a follow up PDE5 inhibitor to Sildenafil (Viagra)Culture paradigm shift.Material requirements (10g per run!).Technical failures.
7 UK-427,387 Pyrazole Alkylation 25kg Required for Phase 1Issues (where to start?!)30% overall yield2:1 undesired : desired pyrazole7 days reaction time, complex conditions (4 solids, 2 solvents)5-14% undesired alkylated isolatedParallel Synthesis Robot (PSR)250mg per reaction, 50 reactions, 5-25ml volumeSelectivity the wrong way!Project team had 6-week deadline.Almost forced their hand to work with the technology
8 UK-427,387 Pyrazole Alkylation New ConditionsResults30:1 selectivity achieved12hrs vs. 6 days reaction timeScaled to 32kg, 71% isolated yield of 99% purity25kg Required for Phase 1Screen120 reactions run over 3 weeks12 bases x 10 solventsStrong base requiredLithium count-ion neededMeCN solvent found to be keyBeforeAfter1:2 N1:N230:1 N1:N2120 reactions in 3 weeks doesn’t seem like much now.Note the HPLC run-time! 10 minutes!This chemistry was a game changed and people begun to see the potential for reaction screening technologyQ. Would this obscure hit have been found in the short time frame allowed without reaction screening technology?
9 Development of High Throughput Experimentation (HTE) Workflows 2002-2005 SolidsDispensingRationalDesignStatisticalMethodsReactionExecutionand AnalysisDataCapture andVisualisationDataAnalysisReactionPlatformReactionPlatformFastConclusionsChemistsLiquidsDispensingDataMiningOver the next 3 years there was a significant investment in new technology, increased resource and the HTE workflow evolved over time.Emphasis on fast conclusions that can be used to make decisions. Particularly useful for alternative routes.5Higginson, Paul D.; Sach, Neal W. High-Throughput Experimentation in Pharmaceutical Process R&D: Developing a New Software Workflow to OvercomeDownstream Data-Analysis Bottlenecks and Improve Productivity. Organic Process Research & Development (2004), (8),
10 2002-2005 Investment in Technology By 2005 the HTE group in Process had expanded to 5 FTE’s with state of the art equipment at their disposal25mg per reaction, 50 reactions, 1-2ml volume2mlReactionVolumeOne 2 Many WeighingiChemExplorer Reaction Platform2-4 minute HPLC cycle-time per sampleExplain past experience with all in one systems Detail each piece of technologyExplain miniaturizationAnalytics are key to high-throughputFast HPLCAnalysis PlatformHigh-throughput analytics and generic methods are critical to HTE Modular WorkflowsGaseous ChemistryMany 2 Many Weighing
11 Application of High Throughput Chemistry Workflows Across the Portfolio DiscoveryProcess DevelopmentSupply ChainApplicationsSolubility ProfilingSolid Form IdentificationReaction ScreeningStartResolution ScreeningExplain four categoriesReaction ScreeningChiral Methods – Resolution Screening, Biotransformation Screening, Asymmetric HydrogenationsSalt Screening – Solid form of intermediates generally to ease isolationSolubility Screening - Understanding of solubility to ease work-upAlso that the technology was applicable across the portfolio, both in discovery and, development and even in supply chain and from flow to batch screening. In this talk we are going to focus on reaction optimization and expanding chemical space in Discovery as
12 Example Workflow - Resolution Screening Scalable access to chiral molecules via diastereoisomeric salt formationResolution Coupling Protocol :96 Chiral Acids or Bases1 Solvent10-20mg per reaction : 2g Total0.5 FTE Days1 Day Start to Finish per SolventExplain resolution process
13 Example Results of Resolution Screens Generally Chiral SFC is always the first port of call for Discovery chemists.However this is now changing especially as molecules move towards FIH.Resolution screening is successful in 80% of casesZhou, Ru; Bi, Chris; He, Mingying; Hoffman, Robert; Jalaie, Mehran; Kath, John; Kupchinsky, Stan; Ling, Tony; Lu, Jihong; Marx, Matthew; Richardson, Paul; Sach, Neal; Tran, Khanh; Barbour, Nicole; Cho-Schultz, Su.Asymmetric synthesis of Pyrrolodino-pyridine based CXCR4. Abstracts of Papers, 240th ACS National Meeting, Boston, MA, United States, August 22-26, (2010)
14 Example Workflow - Solubility Screening Isolating good quality material can be as difficult as forming the covalent bondsProblematic isolations may result in large quantities of organic and aqueous waste streams and loss of productTraditional Reaction SequenceBottom-up approach to Reaction DesignDriven by solubility screeningReactionSolventLow Solubilityof ProductHigh Solubilityof Bi-products1.Design Reaction2.Run Reaction3.Analyse Reaction4.Design Work-up5.Work-up Reaction1.Design Reaction2.Run Reaction3.Analyse Reaction4.Design Work-up5.Work-up Reaction
15 Example Results of Solubility Screens Objective:Map solubility of all synthetic intermediates in range of process solventsHTE Workflow:20 solvents screened as standard chosen by chemistSolution saturated and liquors analysedQuantitative LCTypically applied to entire synthesis250mg-1g per screen in 0.5 DayData enables logical decision on reaction solvent when given choice.This is often the case from HTE experimentation results.
16 2007 - Bringing HTE to Discovery 1 FTE!!…the workflow was not designed for this throughput and was too slow…Process Projects5 FTE’sLJSandwichExplain Reaction Optimization workflow and its evolution over time.M wife was not happy that year.
17 Reaction Optimization in Process Experimental Set-UpProject Team Problemx2x1X nExperiment DesignReaction AnalysisAnswerWorkflow no different to normal chemistry problem but automation enables numbering.Results InterpretationCycle 2 = 4 daysCycle 3 = 6 daysCycle 1 = 2 days
18 2007 - The Discovery Experience Discovery chemists want answers……faster and using less material compared with process development…and they have no product markers!ESD – ExploratoryScreen DevelopmentSDS – Screening/ DesignedSynthesisLD – LeadDevelopmentCS – CandidateSeekingEarlyDevelopmentDiscoverySpeed █Diversity █Yield █Isolation █Scalable █Process DevelopmentScalable █Yield █Isolation █Speed █Diversity █
19 Speeding the WorkflowChallenge over the past three years has been to speed the workflow by removing the bottle necksWhere is the time spent?These steps needed addressingReactionDesignReactionExecutionSemi-Automatedand fast20%AnalysisandVisualisationSemi-automatedand slow30%Manualand slow50%Scouring the literature and designing a custom set of reactions is rewarding but very time consuming. Digging through the literature much of which is poor quality
20 Designing a Reaction Screen in Process Intelligent ReactionDesignChemistsandCeNStatisticalMethodsGreenChemistryPrincipalsLiteratureSurveillanceLiterature surveillance involves a group monitoring transformation and creating a network of surveillance so that new literature does not fall through the net
21 Screening Chemical Space …searching the literature on a per screen basis helps us move into the “correct” chemical space but if the chemistry doesn’t work in this initial screen we spend a lot of time searching or settling at local maxima……what if we moved to a more generic one-size fits all type template… that would save time but…the chemical space covered increases dramatically……besides...was we ever really comfortable excluding this space?will you ever find something new?Large Reaction TemplateUncharteredterritoryCycle 2 = 4 daysCycle 3 = 6 daysCycle 1 = 2 daysBaseLiterature SaysStart HereSolventCatalyst
22 Literature Misdirection Sonogashira ReactionProject team report poor yields using standard conditionsLiterature Search161/161 references utilize Pd(Ph)4)3 or Pd(P(Ph)3)Cl2What have we really learnt?Precedent (we knew that)%Area UV50%50˚C ˚CApologies for the R group. Explain spotfire plot, first instance.This catalyst combination is unprecedented for Sonogashira reactions but likely because it was quite recently invented.Explain Spotfire161 literatureconditionsMass IonCountUn-precendented
23 Increasing Chemical Screening Space vs. Material Demands …discovery project teams cant afford >500mg of material for each screen, in-fact they would like to reduce the amount required…WE NEED TO MINATURIZE (but without diluting)20 Reactions=100mg 200 Reactions=100mg1.2mlReactionVolume120uLReactionVolume2007to2011This magnitude reduction has resulted in less material being required and a much larger reaction space being examined
24 Reducing Scale – Air/Moisture Sensitivity With just 0.04mg of catalyst present the workflow had to be moved into a glove box with a controlled O2 (<10ppm) and H2O atmosphere (<20ppm)Scale (400MW)7.5mg, 0.02mmol0.75mg, 0.002mmolCatalyst (400MW, 10mol%)0.4mg, 0.002mmol0.04mg, mmol12x32mm1.2ml8x30mm120uLThis magnitude reduction has resulted in less material being required and a much larger reaction space being examined
25 Projects by Reaction Type Templated :Suzuki CouplingsBuchwald CouplingsAmide CouplingsHeck CouplingsCarbonylationsClassical Resol.AlkylationsHydrogenationSonogashiraUllman CouplingsHalogenationsetc...
26 Speeding the WorkflowFor templated chemistry (60%) the workflow is significantly faster….…but analytical samples have increased by a magnitude…ReactionDesignReactionExecutionSemi-Automatedand fast30%Analysis andVisualisationSemi-Automatedbut slow60%TemplatedChemistry10%Reaction design consists of check the literature that the expanded screen covers the reported conditions (almost always does)
27 Data Analysis, Capture and Visualisation Capturing data, identifying products, analysing trends and reaching quick conclusionsiChemExplorer Data CaptureRapid Resolution 1200 LC/MSDPer sample cycle-timedropped from 4 to 0.8minsdata points per reaction screen. 100 reactions take 1.5hrsreport and then capture in CeN as well as in-house reaction screening databaseMention the lack of marker in DiscoverySpotfire Visualization with Data DisplayData to knowledge in 1 hour6Mathews, B. T.; Higginson, P. D.; Lyons, R.; Mitchell, J. C.; Sach, N. W.; Snowden, M. J.; Taylor, M. R.; Wright, A. G. Improving quantitative measurements for the evaporative light scattering detector.Chromatographia (2004), 60(11/12),
28 Discovery Orientated Screening Workflow …combining reaction templates with miniaturization and glove box technologies has enabled a reduction in material demands and reduced screen cycle times leading to an increased applicability to Discovery ChemistryDays per ScreenExplain Reaction Optimization workflow and its evolution over timeA templated reaction screen of >100 conditions is now turned around in 24hrs
29 Examples Amide Bond Formations Carboamidation Technology C-N Couplings Explain Reaction Optimization workflow and its evolution over time
30 Amide Bond Formation – A Discovery Problem 25% of all reactions in discovery involve amide couplingsLarge numbers of coupling agents are commercially availableWhich one?
31 Difficult Amide Bond Formations - Discovery 70%1. T3P2. 1Cl2MPyI60%1. Cyanuric Fluoride2. 2C-DMI-TFBStericallyhinderedSelectivityAmide Coupling Protocol :36 Coupling Agents2 Solvents, 2 Temperatures, 1 Additive150 reactions = 90mg total (300MW)0.5 FTE Days2 Days Start to Finish50%1. (COCl)22. CDMT3. iBuCOCl4. HATU60%1. TPTU2. TDBTU3. TOTTPoint to note here is that different coupling agents offer advantages and that HATU is not always the best answer.Fix’s identified in Discovery are inherited by process.Resource spent must be low though.This also enables more accurate complexity scoring and allocation of resources.ElectronpooramineSelectivity
32 The Amide Bond – Expanding Monomer Space The amide bond remains a popular connection in drug discovery to explorer SAR….…but there are other way of making an amide bond and a monomer analysis reveals the advantages…ArCOOH6441ArCl, Br, I, OTf14136Traditional CouplingOverlap 725 (3.5%)Carboamidation Coupling
33 Carboamidation – Accessing New Chemical Space Carbonylation ScreenDetailsMethod required for primary, secondary and non-nucleophilic amines78 Conditions (0.005mmol, 1mg per reaction)12 catalyst/ligand (combinations (all monomers)56 catalyst/ligand combinations (one monomer)DMAc (0.03M), DIPEA (5eq.), 100C, 8Bar COTechnology
34 Carbonylation Library Validation ConclusionsLigand system works across all demonstration monomersLibrary 1 = 88 designed products82 / 88 achieved = 93% success 0.05mmol scale. How would acid compare?500 products have since been prepared using these conditions (2 weeks)Carbonylation ScreenDetailsTake top eight ligands from initial screen and run under actual library conditions78 Conditions (0.05mmol=10mg per reaction)8 catalyst/ligand combinations3 monomers (3eq.)DMAc (0.1M), DIPEA (5eq.), 100C, 4Bar COCommentsSM is not soluble at this concentration at 25C. Solids weighing robot is used to weigh 80 x 10mg$73/g$640/g
36 Suzuki Optimization %Area UV 80% Issue Screen Design Results Mass Ion MeOH / CsF(aq.) /Pd-132 // 80C / 18hrsIssueTeam tried DME / H2O / Pd(dppf)2Cl2 / 80°C but gave only 50% conversion after 2 daysScreen Design96 conditions (0.003mmol, 1.13mg)110mg for screen6 catalyst/ligand combinations4 bases and 4 solvents80C, 18hrs, glove boxResults1/96 conditions gave >80% in-situ yieldMeOH, CsF and Pd-132 are critical. Three factor interactions are hard to find. One factor at a time optimizations wont work here.Request to Results Cycle Time = 1dayScaled to 200mg, 90% isolated yieldRequest to Registration Time = 2daysOriginalConditionsMass IonCountProductDes Bromo
37 Conclusions KNOWLEDGE PER GRAM PER UNIT TIME Maximize information per reactionMinimize material consumptionMinimize time to explore any given chemical spaceUsing HTE Workflows, optima within a given parameter space can be quickly identified to focus resource at any stage across the portfolio1g/rxnX 10100mg/rxnX 5010mg/rxnX 1001mg/rxnX 2000.05mg/rxn.X 100019982001200420072012
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