BOCEPOXIDE

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PHOENIX CHEMICALS
Applications of Real Time in-situ Reaction
Analysis in the Development of Continuous
Chemical Process Systems
Presented at the Eurokin Workshop Milan 21-22
September 2000
Lee Proctor Phoenix Chemicals Ltd.
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Three Fundamental Reactor Types
Batch Reactor
Plug Flow Reactor
CSTR Reactor
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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

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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

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Example 1 Development of a Multi-Stage Continuous
Process

• Synthetic targets
• 4-carbon fragments that are key intermediates to
  HIV protease inhibitors

Examples include
Nelfinavir (Agouron) Amprenavir
(Glaxo-Wellcome) Saquinavir (Roche)
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Synthetic Route
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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 Cadä data
  analysis
• HPLC/GC/GC-MS/UV/RI
• Gas-phase FT-IR and liquid FT-IR

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Stage 3 3D Waterfall Plot of Diazo Region
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Stage 3 Reverse Plot of Diazo region
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ConcIRT Generated Spectra
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Standard Spectra
Diazoketone
Diazomethane
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ConcIRT Generated Concentration Profiles
Diazoketone
Diazomethane
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Continuous On-line Plant Analysis
Chloroketone
Diazoketone
Mixed anhydride
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Continuous On-line Plant Analysis
Mixed anhydride
Diazoketone
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Plant Data collected during Start-up
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Plant Profiles collected during Start-up
Relative Concentration
Time (h)
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Quantitative Analysis (Process IR-MP)
DAK Concentration (w/w)
Time (min)
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Example 2 Arndt - Eistert Reaction
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Acknowledgements
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
Chemistry Alistair Anderson Mike Aslet Paul
Dawson David Justice Sean Kitson Elliot
Latham Derek Palmer Eddie Palmer
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)