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Introducing Milligram Screening Reactions into the Kilogram World of Chemical Development Simon Yates, AstraZeneca. FreeSlate European User Meeting 24.

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Presentation on theme: "Introducing Milligram Screening Reactions into the Kilogram World of Chemical Development Simon Yates, AstraZeneca. FreeSlate European User Meeting 24."— Presentation transcript:

1 Introducing Milligram Screening Reactions into the Kilogram World of Chemical Development Simon Yates, AstraZeneca. FreeSlate European User Meeting 24 th September 2013

2 Our Journey so far…

3 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 What is Chemical Development?

4

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

6 What are scavengers?

7 But what kit? 10 reactions at a time Minimum volume ~2mL Integrity 10

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

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

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

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

12 Centrifuge for 5 min Scavenging Workflow Air Gap Backing Solvent Overshoot ICP sample HPLC sample RAS ICP = Inductively Coupled Plasma

13 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. Scavenging today

14

15 Cross Coupling R 1 -M R 2 -X R 1 -R 2

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

17 Pre-screening ~10 reactions Optimisation of continuous parameters DoE (24-plate) 96-well plate screening Discovery Life Cycle Management Development 96-well plate screening Optimisation of continuous parameters DoE (24-plate) What we developed

18 18 Developed ‘Generic plates’ for 5 different reaction types Based on literature and in house expertise Generic Reaction Plates

19 19 Manual Pipette Evaporate off carrier solvent Stock solutions of - Ligands - Metals - Internal std Generic plate formation -or - Automated dispensing and store

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

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

22 1 st sample will always be manual 2 nd sample could be automated – middle of night. Future improvements Reactions run on uL scale at 10C below bp Solvent loss / corrosion of sealing material Fully closed plate Can’t sample by CM2 Need a pierceable, but re-sealable, membrane Any ideas welcome!!

23 Material consumption 24 well - DoE type Expanding on 96 well hit(s) Continuous variables B A Discrete variables Profile reactionsStatistical Analysis

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

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

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

27 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 zones to ‘start’ reactions (Josh Denette and Kristin Price at Pfizer)

28 Data Handling RAS MDB

29 29

30 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

31 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

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

33 Acknowledgments

34 Freeslate, San Francisco, 2013

35 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) , F: +44 (0) ,

36 What it looks like under the hood

37 Time Out.… Accurate Sampling Accuracy and Precision of sampling critical for ICP analysis Narrower needle Use as small an airgap (20uL) No bubbles in your backing solvent Use a suitably large overshoot If sampling hot, aspirate an airgap before coming out of the vessel Dispense below solvent level if possible. Best syringe speeds (parameters) – varies for different solvents. Use DoE to define

38 Start Speed Top Speed Cut Off SpeedSlope Option Time Speed What are these syringe parameters? Speeds for 500uL syringe

39 A B C D Tare all 48 vials For each well Aspirate 100uL Toluene, plus 30uL overshoot from a 20mL vial Dispense into the 1mL vial using given parameters Immediately reweigh vial Calculate the volume dispensed by change in mass Randomised Speed Options, in triplicate Gravimetric checking

40 For 100uL of toluene, at 25C Start SpeedTop SpeedCut Off SpeedSlope Option The result…

41 For 100uL of toluene, at 25C Start SpeedTop SpeedCut Off SpeedSlope Option The result… 12 different solvents A range of speed options shown to be best 2-MeTHF – option 3 THF – option 16


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