1. Presented at the Eurokin Workshop Milan 21-22 September 2000 PHOENIX CHEMICALS Applications of Real Time in-situ Reaction Analysis in the Development of Continuous Chemical Process Systems Lee Proctor Phoenix Chemicals Ltd.

2. Batch Reactor Plug Flow Reactor CSTR Reactor Three Fundamental Reactor Types PHOENIX CHEMICALS

3. Advantages of Continuous Processing Concentration of reactants/product/intermediates is constant Reaction rates can be optimised to maximise throughput Low inventory of hazardous materials Low-cost plant allowing full containment Remote automated plant control Continuous monitoring of all process flows and temperatures Continuous on-line monitoring of process streams Improved product consistency Reduced cross-contamination Reduced waste Reduced environmental emissions PHOENIX CHEMICALS

4. Suitable Chemistry Fast energetic reactions are ideal Gas liquid reactions Reactions involving toxic reactants/intermediates Reactions requiring careful process control to achieve high chemical yield, selectivity and if relevant chiral and/or diastereomeric purity Hazardous reactions involving unstable intermediates Reactions limited by heat transfer PHOENIX CHEMICALS

5. PHOENIX CHEMICALS Example 1 Development of a Multi-Stage Continuous Process Synthetic targets: 4-carbon fragments that are key intermediates to HIV protease inhibitors Nelfinavir (Agouron) Amprenavir (Glaxo-Wellcome) Saquinavir(Roche) Examples include:

6. PHOENIX CHEMICALS Synthetic Route

7. Continuous Processing Laboratory Development Principal focus on reaction times and reaction kinetics: ReactIR ™ system allows real-time in-situ reaction analysis Variable temperature high field NMR Heat flow calorimetry linked to Batch Cad  data analysis HPLC/GC/GC-MS/UV/RI Gas-phase FT-IR and liquid FT-IR PHOENIX CHEMICALS

8. Stage 3 3D Waterfall Plot of Diazo Region PHOENIX CHEMICALS

9. PHOENIX CHEMICALS Stage 3 “Reverse Plot of Diazo region”

10. ConcIRT Generated Spectra PHOENIX CHEMICALS

11. Diazomethane Diazoketone Standard Spectra PHOENIX CHEMICALS

12. PHOENIX CHEMICALS Diazoketone Diazomethane ConcIRT Generated Concentration Profiles

13. Continuous On-line Plant Analysis Mixed anhydride Diazoketone Chloroketone PHOENIX CHEMICALS

14. Diazoketone Mixed anhydride PHOENIX CHEMICALS Continuous On-line Plant Analysis

15. PHOENIX CHEMICALS Plant Data collected during Start-up

16. Relative Concentration Time (h) Plant Profiles collected during Start-up PHOENIX CHEMICALS

17. 2.5 3 3.5 4 4.5 5 5.5 6 1535557595115135155 DAK Concentration (%w/w) Time (min) PHOENIX CHEMICALS Quantitative Analysis (Process IR-MP)

18. Example 2 Arndt - Eistert Reaction PHOENIX CHEMICALS

19. PHOENIX CHEMICALS Acknowledgements Chemistry: Alistair Anderson Mike Aslet Paul Dawson David Justice Sean Kitson Elliot Latham Derek Palmer Eddie Palmer Engineering: Les Herring Steve Hill Ron Walker Tony Warr Harry Williamson Production: Graham Bishop Stewart Cairns Richard Chappell Chris Davies John Downing Dave Hall Paul Kemp Rich Kevlin Colin Leece Stella Lewis Rob McCool Mal Phillips Analytical: Jayne Blythin Andrew Burrows Alison Daniel Jamie Darker Rob Owens Other: Richard Bambrey (University of Wales) Geraint Thomas (University of Wales) Bernard Golding (University of Newcastle) Ken Stares (Mettler Toledo)