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Rapid Chemical Space Exploration – Applications from Discovery to Manufacturing Neal Sach Senior Principal Scientist 10777 Science Centre Drive La Jolla,

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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 2012 The Evolution of Reaction Optimization Technologies

2 Contents An Introduction to Reaction Optimization Workflows
Reaction Optimization in Process Chemistry Adapting to Discovery Chemistry Case Examples First item is short as with the audience its preaching to the choir

3 Solving Chemistry Across the Portfolio
Discover Drugable Molecules Supply Drug Substance Develop Commercial Processes Transfer Technology to Production How we do this in less time and at a lower cost? Supply Chain Discovery Process Research Development Manufacturing Covalent Bonds Reaction Conditions Work Up Conditions Variations

4 Adapting to Industry Pressures
Technology must ‘fill the gap’ Workload Resources Apologies for showing this slide! Nice thing though is that its lasted two decades. 199X 20XX

5 The First Reaction Optimization Tool
In 1998 a Process Research Technology Group was created with the aim of speeding Process Development The SK233 was the first tool of its kind, 10 simultaneous reactions with integrated analytics 1g per reaction, 10 reactions, 10-50ml volume One 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 Point Despite 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 1 Issues (where to start?!) 30% overall yield 2:1 undesired : desired pyrazole 7 days reaction time, complex conditions (4 solids, 2 solvents) 5-14% undesired alkylated isolated Parallel Synthesis Robot (PSR) 250mg per reaction, 50 reactions, 5-25ml volume Selectivity 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 Conditions Results 30:1 selectivity achieved 12hrs vs. 6 days reaction time Scaled to 32kg, 71% isolated yield of 99% purity 25kg Required for Phase 1 Screen 120 reactions run over 3 weeks 12 bases x 10 solvents Strong base required Lithium count-ion needed MeCN solvent found to be key Before After 1:2 N1:N2 30:1 N1:N2 120 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 technology Q. 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
Solids Dispensing Rational Design Statistical Methods Reaction Execution and Analysis Data Capture and Visualisation Data Analysis Reaction Platform Reaction Platform Fast Conclusions Chemists Liquids Dispensing Data Mining Over 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 Overcome Downstream 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 disposal 25mg per reaction, 50 reactions, 1-2ml volume 2ml Reaction Volume One 2 Many Weighing iChemExplorer Reaction Platform 2-4 minute HPLC cycle-time per sample Explain past experience with all in one systems Detail each piece of technology Explain miniaturization Analytics are key to high-throughput Fast HPLC Analysis Platform High-throughput analytics and generic methods are critical to HTE Modular Workflows Gaseous Chemistry Many 2 Many Weighing

11 Application of High Throughput Chemistry Workflows Across the Portfolio
Discovery Process Development Supply Chain Applications Solubility Profiling Solid Form Identification Reaction Screening Start Resolution Screening Explain four categories Reaction Screening Chiral Methods – Resolution Screening, Biotransformation Screening, Asymmetric Hydrogenations Salt Screening – Solid form of intermediates generally to ease isolation Solubility Screening - Understanding of solubility to ease work-up Also 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 formation Resolution Coupling Protocol : 96 Chiral Acids or Bases 1 Solvent 10-20mg per reaction : 2g Total 0.5 FTE Days 1 Day Start to Finish per Solvent Explain 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 cases Zhou, 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 bonds Problematic isolations may result in large quantities of organic and aqueous waste streams and loss of product Traditional Reaction Sequence Bottom-up approach to Reaction Design Driven by solubility screening Reaction Solvent Low Solubility of Product High Solubility of Bi-products 1. Design Reaction 2. Run Reaction 3. Analyse Reaction 4. Design Work-up 5. Work-up Reaction 1. Design Reaction 2. Run Reaction 3. Analyse Reaction 4. Design Work-up 5. Work-up Reaction

15 Example Results of Solubility Screens
Objective: Map solubility of all synthetic intermediates in range of process solvents HTE Workflow: 20 solvents screened as standard chosen by chemist Solution saturated and liquors analysed Quantitative LC Typically applied to entire synthesis 250mg-1g per screen in 0.5 Day Data 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 Projects 5 FTE’s LJ Sandwich Explain Reaction Optimization workflow and its evolution over time. M wife was not happy that year.

17 Reaction Optimization in Process
Experimental Set-Up Project Team Problem x2 x1 X n Experiment Design Reaction Analysis Answer Workflow no different to normal chemistry problem but automation enables numbering. Results Interpretation Cycle 2 = 4 days Cycle 3 = 6 days Cycle 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 – Exploratory Screen Development SDS – Screening / Designed Synthesis LD – Lead Development CS – Candidate Seeking Early Development Discovery Speed █ Diversity █ Yield █ Isolation █ Scalable █ Process Development Scalable █ Yield █ Isolation █ Speed █ Diversity █

19 Speeding the Workflow Challenge over the past three years has been to speed the workflow by removing the bottle necks Where is the time spent? These steps needed addressing Reaction Design Reaction Execution Semi- Automated and fast 20% Analysis and Visualisation Semi- automated and slow 30% Manual and slow 50% 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 Reaction Design Chemists and CeN Statistical Methods Green Chemistry Principals Literature Surveillance Literature 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 Template Unchartered territory Cycle 2 = 4 days Cycle 3 = 6 days Cycle 1 = 2 days Base Literature Says Start Here Solvent Catalyst

22 Literature Misdirection
Sonogashira Reaction Project team report poor yields using standard conditions Literature Search 161/161 references utilize Pd(Ph)4)3 or Pd(P(Ph)3)Cl2 What have we really learnt? Precedent (we knew that) %Area UV 50% 50˚C ˚C Apologies 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 Spotfire 161 literature conditions Mass Ion Count Un-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=100mg 1.2ml Reaction Volume 120uL Reaction Volume 2007 to 2011 This 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, 0.02mmol 0.75mg, 0.002mmol Catalyst (400MW, 10mol%) 0.4mg, 0.002mmol 0.04mg, mmol 12x32mm 1.2ml 8x30mm 120uL This magnitude reduction has resulted in less material being required and a much larger reaction space being examined

25 Projects by Reaction Type
Templated : Suzuki Couplings Buchwald Couplings Amide Couplings Heck Couplings Carbonylations Classical Resol. Alkylations Hydrogenation Sonogashira Ullman Couplings Halogenations etc...

26 Speeding the Workflow For templated chemistry (60%) the workflow is significantly faster…. …but analytical samples have increased by a magnitude… Reaction Design Reaction Execution Semi- Automated and fast 30% Analysis and Visualisation Semi- Automated but slow 60% Templated Chemistry 10% 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 conclusions iChemExplorer Data Capture Rapid Resolution 1200 LC/MSD Per sample cycle-time dropped from 4 to 0.8mins data points per reaction screen. 100 reactions take 1.5hrs report and then capture in CeN as well as in-house reaction screening database Mention the lack of marker in Discovery Spotfire Visualization with Data Display Data to knowledge in 1 hour 6Mathews, 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 Chemistry Days per Screen Explain Reaction Optimization workflow and its evolution over time A 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 couplings Large numbers of coupling agents are commercially available Which one?

31 Difficult Amide Bond Formations - Discovery
70% 1. T3P 2. 1Cl2MPyI 60% 1. Cyanuric Fluoride 2. 2C-DMI-TFB Sterically hindered Selectivity Amide Coupling Protocol : 36 Coupling Agents 2 Solvents, 2 Temperatures, 1 Additive 150 reactions = 90mg total (300MW) 0.5 FTE Days 2 Days Start to Finish 50% 1. (COCl)2 2. CDMT 3. iBuCOCl 4. HATU 60% 1. TPTU 2. TDBTU 3. TOTT Point 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. Electron poor amine Selectivity

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… ArCOOH 6441 ArCl, Br, I, OTf 14136 Traditional Coupling Overlap 725 (3.5%) Carboamidation Coupling

33 Carboamidation – Accessing New Chemical Space
Carbonylation Screen Details Method required for primary, secondary and non-nucleophilic amines 78 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 CO Technology

34 Carbonylation Library Validation
Conclusions Ligand system works across all demonstration monomers Library 1 = 88 designed products 82 / 88 achieved = 93% success 0.05mmol scale. How would acid compare? 500 products have since been prepared using these conditions (2 weeks) Carbonylation Screen Details Take top eight ligands from initial screen and run under actual library conditions 78 Conditions (0.05mmol=10mg per reaction) 8 catalyst/ligand combinations 3 monomers (3eq.) DMAc (0.1M), DIPEA (5eq.), 100C, 4Bar CO Comments SM 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 / 18hrs Issue Team tried DME / H2O / Pd(dppf)2Cl2 / 80°C but gave only 50% conversion after 2 days Screen Design 96 conditions (0.003mmol, 1.13mg) 110mg for screen 6 catalyst/ligand combinations 4 bases and 4 solvents 80C, 18hrs, glove box Results 1/96 conditions gave >80% in-situ yield MeOH, 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 = 1day Scaled to 200mg, 90% isolated yield Request to Registration Time = 2days Original Conditions Mass Ion Count Product Des Bromo

Maximize information per reaction Minimize material consumption Minimize time to explore any given chemical space Using HTE Workflows, optima within a given parameter space can be quickly identified to focus resource at any stage across the portfolio 1g/rxn X 10 100mg/rxn X 50 10mg/rxn X 100 1mg/rxn X 200 0.05mg/rxn. X 1000 1998 2001 2004 2007 2012

38 Acknowledgements Technology Chemistry Special Thanks Carol Baines
David Bernhardson Klaus Dress David Damon Bill Farell Stuart Field Steve Fussell Rob Maguire Ben Matthews Andrew Morrell Paul Richardson Steve Trudel Alex Wilder Katie Wilford Alex Yanovsky Chemistry Kevin Bunker Laurence Harris Bob Hoffman Peter Huang Sarah Lewandowski Sacha Ninkovic Dan Richter Hong Shen John Tatlock Special Thanks Simon Bailey Rob Crook Peter Dunn Klaus Dress Martin Edwards Paul Higginson Jennifer Lafontaine Ivan Marziano Steve Trudel Paul Richardson Pete Spargo David Waite Mike Williams Alex Yanovsky

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