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Introducing Milligram Screening Reactions into the Kilogram World of Chemical Development

Introducing Milligram Screening Reactions into the Kilogram World of Chemical Development. Simon Yates, AstraZeneca. FreeSlate European User Meeting 24 th September 2013. Our Journey so far …. What is Chemical Development?. We produce a scalable process, not just a compound

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Introducing Milligram Screening Reactions into the Kilogram World of Chemical Development

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  1. Introducing Milligram Screening Reactions into the Kilogram World of Chemical Development Simon Yates, AstraZeneca. FreeSlate European User Meeting24th September 2013

  2. Our Journey so far…

  3. What is Chemical Development? • We produce a scalable process, not just a compound • From a few grams in the lab to multi-kilo plant campaigns • Emphasis on SELECT criteria • Safety • Economics • Legal • Environment • Control • Throughput

  4. Scavenging Challenge? Transition Metals are toxic! In number of metal catalysed reactions in Med Chem Development time by using scavengers Time, effort and missed opportunity by automated screening The time to develop process for early compounds Conventional work up takes time to develop 100’s Of scavengers and carbons to choose from Reproducibility by screening under inert conditions

  5. What are scavengers?

  6. But what kit? Integrity 10 • 10 reactions at a time • Minimum volume ~2mL

  7. But what kit? • Inerted Glovebox • 20mL reaction tubes • 100mg reactions • 24 wells • Very manual • Lots of programming • 2x MT Mini Mapper • MT Flexiweigh

  8. Wanted to…. In number of reactions we could run (up from 24) Manual intervention, to make this as routine as possible Reaction scale Ease of programming and data analysis ‘Future proof’ our investment

  9. Purchased a Symyx CM2 • Solid Dispensing • 10G needle • (5mL syringe) • 9 heat-stir bays • Vial gripper • 16G to 20G needle (with N2 pressure) • - 1mL & 500uL syringes attached to 10 off deck solvents • Bespoke filter equipment • - Symyx filter too small

  10. Scavenging Workflow 96 x 1mL vials Seal, heat, stir 16 hours ~40 different scavengers Stock of reaction solution

  11. Scavenging Workflow Backing Solvent Air Gap Overshoot ICP sample HPLC sample RAS Centrifuge for5 min ICP = Inductively Coupled Plasma

  12. Scavenging today • We have run 20+ screens and saved projects time and money • Numerous examples of where scavengers used in all scales of manufacture • Pd is most common metal scavenged, now have a generic plate of 22 scavengers. • Improvements in whole workflow reduced time from 5 working days to 2 days.

  13. Cross Coupling R2-X R1-M R1-R2

  14. Background In number of reactions we could runcover more experimental space, quicker. • Original plan was to run X-Coupling Reaction scale Timing forced by closure of our existing facility Apply our previous learning

  15. What we developed • 96-well plate screening • Optimisation of continuous parameters • DoE (24-plate)

  16. Generic Reaction Plates • Developed ‘Generic plates’ for 5 different reaction types • Based on literature and in house expertise

  17. Generic plate formation Stock solutions of- Ligands - Metals - Internal std Manual Pipette Evaporate off carrier solvent -or - Automated dispensing and store

  18. Running a project… Define: Bases and Solvents Add in solid(s) Reactants Add in reaction solvent

  19. Running a project… Quickly add in Aq. Base ‘Start of reaction’ Seal up Heat and Stir 2 x Manual Sample Prep ~2hrs and 20hrs

  20. Future improvements Reactions run on 200-400uL scale at 10C below bp • Solvent loss / corrosion of sealing material • Fully closed plate • Can’t sample by CM2 1st sample will always be manual 2nd sample could be automated – middle of night. Need a pierceable, but re-sealable, membrane Any ideas welcome!!

  21. 24 well - DoE type • Expanding on 96 well hit(s) B A Discrete variables Continuous variables Material consumption • Profile reactions • Statistical Analysis

  22. 24 well – DoE type Catalyst Plate Weigh in LigandsMetal Cap, heat and stir, 60min. Add reaction solvent 24 x 4mL vials Reaction Plate Add reaction solvent/liquid reagents Weigh in Reactants, Bases Internal Standard 24 x 4mL vials

  23. 24 well – DoE type Transfer from Catalyst plate to reaction plate Reaction Plate Heat and Stir Automatically sample 4 times over 16 hours Run LC-Mass Spec on samples

  24. Future improvements • 1 Temperature (plate) per run • Lose a key factor Multiple Plates / run  sampled into 1 HPLC plate

  25. Future improvements • Sampling always run at the end, not good for fast reactions Allow sampling as part of ‘dispense’ And/or move vials to heat zonesto ‘start’ reactions(Josh Denette and Kristin Price at Pfizer)

  26. Data Handling MDB RAS

  27. Asymmetric Hydrogenation • Successfully built capability in Sodertalje, Sweden • site end of 2012 Opportunity to purchase new equipment • CM3 (in glovebox) and SPR • Off deck hydrogenation – make use of CM3 during long reactions • Knowledge of LEA / CM2 • CM2 / CM3 used as 1 resource for X-Coupling and Asymm. Hydrog. • Commissioning - NOW

  28. Conclusion • We have come along way since 2007 • Scavenger was the warm up act • Scavenging and X-Coupling saved millions of dollars already • Success led the way to keep Asymm. Hydrog. in house • Asymm. Hydrog. will have similar if not bigger impact • Continue to develop workflows • Keep control of the data • 96 x 2 x 5 x 50 = 48K data points / year

  29. Conclusion User community carry on sharing and learning What’s good for me, could be good for you too.

  30. Acknowledgments AstraZeneca John Leonard, Gair Ford, Barney Squires Phil Hogan, Keith Mulholland, Andy Campbell Rachel Munday, Kevin Leslie Sarah Thompson, Andy Poulton Ex AstraZeneca Paul Murray and co. (catsci.com) Per Ryberg and co. (SP Technical Research Institute of Sweden) Symyx/FreeSlateSteve Yemm, Zack Hogan, Colin Masui, AnnyTangkilisan, Rob Rosen, Eric Carlson Peter Huefner, Grant Gavranovic,Justin Fisher, Jonathan Harris Peter Gravil, Jos De Keijzer, Rick Sidler, Tony Mani, Guillaume Magan, Ludovic Edvard

  31. Confidentiality Notice This file is private and may contain confidential and proprietary information. If you have received this file in error, please notify us and remove it from your system and note that you must not copy, distribute or take any action in reliance on it. Any unauthorized use or disclosure of the contents of this file is not permitted and may be unlawful. AstraZeneca PLC, 2 Kingdom Street, London, W2 6BD, UK, T: +44(0)20 7604 8000, F: +44 (0)20 7604 8151, www.astrazeneca.com

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