Chemical Synthesis and Efficient Scale-Up in Flow … Synthesis and Efficient Scale-Up in Flow...
Transcript of Chemical Synthesis and Efficient Scale-Up in Flow … Synthesis and Efficient Scale-Up in Flow...
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Chemical Synthesis and Efficient Scale-Up in Flow Reactors
Paul WattsDepartment of Chemistry, The University of Hull, Hull, HU6 7RX.
Chemtrix BV, Burgemeester Lemmensstraat 358, Geleen, The Netherlands.
IFPAC: The Cortona Conference on QbD and PAT, 19-22 September 2010
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Benefits of Micro Reactor Technology
• Increased reaction control– Efficient mixing– Accurate control of reaction time, temperature and pressure– Improved atom efficiency, product selectivity, yield and purity– Increased run-to-run and reactor-to-reactor reproducibility – Increased catalyst turnover and lifetimes
• Increased process safety– Due to rapid dissipation of heat of reaction– Low reactant hold-up– Real-time in-situ analytical evaluation of reactions
• Lower cost and shorter development cycles– Higher chemical selectivity leading to higher yield– Reducing the amount of reagents and catalyst– Reducing the size of the plant– Faster scale-up from lab to plant scale
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Benefits of Micro Reactor Technology
• Increased reaction control– Efficient mixing– Accurate control of reaction time, temperature and pressure– Improved atom efficiency, product selectivity, yield and purity– Increased run-to-run and reactor-to-reactor reproducibility – Increased catalyst turnover and lifetimes
• Increased process safety– Due to rapid dissipation of heat of reaction– Low reactant hold-up– Real-time in-situ analytical evaluation of reactions
• Lower cost and shorter development cycles– Higher chemical selectivity leading to higher yield– Reducing the amount of reagents and catalyst– Reducing the size of the plant– Faster scale-up from lab to plant scale
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Benefits of Micro Reactor Technology
• Increased reaction control– Efficient mixing– Accurate control of reaction time, temperature and pressure– Improved atom efficiency, product selectivity, yield and purity– Increased run-to-run and reactor-to-reactor reproducibility – Increased catalyst turnover and lifetimes
• Increased process safety– Due to rapid dissipation of heat of reaction– Low reactant hold-up– Real-time in-situ analytical evaluation of reactions
• Lower cost and shorter development cycles– Higher chemical selectivity leading to higher yield– Reducing the amount of reagents and catalyst– Reducing the size of the plant– Faster scale-up from lab to plant scale
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What is a Micro Reactor?• ‘Micro’ reactors
– Defined as a series of interconnecting channels formed in a planar surface
– Channel dimensions of 10-300 µm– Very small dimensions result in very
fast diffusive mixing– Rapid heat transfer– High throughput experimentation
• ‘Flow’ (or meso) reactors– Dimensions > 300 µm (up to 5 mm)– Mixing much slower
– Incorporate mixers– Throughput higher– More useful when packed with
catalysts• Reactors fabricated from polymers,
metals, quartz, silicon or glass• Why glass?
– Mechanically strong– Chemically resistant– Optically transparent
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Labtrix• Rapid reaction optimisation
Features• Syringe pumps• Automated sample collection and
control• Tests at pressures of 25 bar and
temperatures of -15 to 195°C• Standard interchangeable
reactors:
• Catalyst reactors:
10µl10µl
1µl 5µl 10µl
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Rapid Reaction Evaluation: 1,2-Azole Synthesis
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Optimal conditions: • Micro reactor: 180 sec, 125 °C, 100% conversion• Batch stirred reactor 1 h, 125 °C cf. 93.6 % conversionInvestigation:• Number of reactions: 200• Time taken to generate samples: 27 h• Volume of reactants employed: 5.97 ml (94.3 mg 1,3-diketone)
MeOH
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PET - Rapid Reaction Optimisation• Reaction of 3-(3-pyridinyl)propionic acid
• Reaction optimised with one equivalent of 12CH3I (10 mM concentration) at RT
• Hydrodynamic flow (syringe pump)
• Reaction with 11CH3I– At 0.5 µl/min flow rate RCY 88%
• Reaction of 18FCH2CH2OTs at 80 oC• At 0.5 µl/min flow rate RCY 10%
• Product isolated by preparative HPLC
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Bu4NOH, DMF
Lab Chip, 2004, 4, 523 J. Lab. Compd. Radiopharm., 2007, 50, 597
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Total Synthesis of PET agents• Micro ‘reactors’ used for synthesis steps only• Other steps often performed using traditional approaches
• Need to develop better integration of all steps
• EU FP7 project: Radiochemistry on a Chip (ROC)• 4M Euro project
• Also on-line measurement/detection technology would add value
http://www.roc-project.eu
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Temperature (°C)
Flow Rate (µLmin-1)
Indole (%)
90 1 60.795 1 81.3105 1 85.7105 0.5 93.3115 0.5 98.9
• Core structure of many pharmaceuticals• Reaction conditions:• 0.1M Phenylhydrazine, cyclohexanone, methanesulphonic acid inDMF• Heat
Indole Synthesis: Atom Efficient Synthesis
O
+
NH
NH2 NH
H+
• Note that excess reagents were not necessary • Similar results for other unfunctionalised ketonesTetrahedron, 2010, 66, 3861
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• Reaction of ethyl pyruvate • Acid caused product degradation - very low yields of product
• Reactor incorporating a solid supported acid: Amberlite IR-120
• 56% isolated yield at 70 oC in EtOH• Easier product isolation
NH
NH2 NH
EtO
O
O OEt
O
NH
N
O
OEt
Indole Synthesis: Atom Efficient Synthesis
Tetrahedron, 2010, 66, 3861
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• Aim to incorporate radiolabel
• Challenge for continuous flow reactors:– Solvent compatibility between reaction steps
• Screening study found MeCN to be the best compromise for both reactions
• 46% overall yield at 75 oC in MeCN
Multi-Step Indole Synthesis
Tetrahedron, 2010, 66, 3861
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• Epoxides are very useful reaction intermediates• Traditionally prepared using organic peracids
– Hazardous on a large scale• Enzyme ‘greener’ but usually denatured by the reaction conditions• Avoided using a flow reactor where peracid generated in situ
Experimental set-up:• Reactor packed with Novozyme 435 • Alkene 0.1 M and H2O2 0.2 M in EtOAc
Epoxidation of Alkenes
Beilstein Journal of Organic Chemistry, 2009, 5, No 27
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• Evaluation of optimum reaction conditions• Alkene 0.1 M and H2O2 0.2 M in EtOAc
• Optimum conditions:– Temperature 70 oC– Residence time 2.6 minutes
• Higher temperatures denatured the enzyme
Epoxidation of Alkenes: Rapid Evaluation
Beilstein Journal of Organic Chemistry, 2009, 5, No 27
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• Reactor continually used for 25 hours to evaluate performance atoptimum experimental conditions
• No loss in activity observed• RSD 0.08%• Library synthesis
Epoxidation of Alkenes: Catalyst Lifetime
Beilstein Journal of Organic Chemistry, 2009, 5, No 27
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(+)−γ-Lactamase Enzymes
• Hydrolysis of amides
• Resolutions
• CLEA from a cloned thermophilic enzyme – Comomonas acidovorans
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Substrate Screening• Experimental conditions
• Optimum temperature 80 oC• Substrate 10 mmol/L concentration in phosphate buffer pH 7• Flow rate 1 µl/min
Biotechnology J., 2009, 4(4), 510-516
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Synthesis of α-Aminonitriles: Increased Control
Strecker Reaction:
• Low yields, complex reaction mixtures laborious purification required– Problematic with aromatic aldehydes due to slow imine formation
Expensive Catalyst
• Difficult to recover and recycle• Generation of acidic waste
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Continuous Flow Synthesis
Aims of Flow Reaction
• Enable optimisation of imine formation– To minimise or prevent cyanohydrin formation
• Employ a stoichiometric quantity of TMSCN and amine • Recycle catalyst efficiently
– Reduce degradation due to absence of stirring
Immobilised catalyst
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Reaction Conditions– 0.4 M Stock Solutions in MeCN– Micro Channel Dimensions = 150 µm (wide) x 50 µm (deep)
• Reaction products analysed, off-line, by GC-MS – Identify optimal conditions for imine formation
Flow Synthesis of Imines
Product (0.2 M)
25 µl min-1
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Continuous Flow Addition to Imine0.2 M Stock Solutions in MeCN
TMSCN
Strecker Reaction
Reagent Mixing
0.1 M Product
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Multi-Step Reactor Design
TMSCN
Imine Formation
Strecker Reaction
Reagent Mixing
Reaction Conditions: Total flow rate 5.0 µl min-1, 0.4 M aldehyde and amine, 0.2 M TMSCN
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Library of 51 compounds
Multi-Step Reaction
Flow: Quantitative Conversion (by NMR), 9.45 mg hr-1 (5.0 µl min-1)Batch: 64 % Conversion, stirred for 24 hr (1.5 eq. TMSCN)ICP-MS Analysis:
– Stirred Batch Reaction: 440 ppm Ru– Micro Reaction: No observable difference from the blank (MeCN)
OPRD, 2008, 12, 1001 Eur. J. Org. Chem., 2008, 5597
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Scale-Up: Plantrix Meso Reactors• Glass reactors 15 cm x 15 cm:
– Six layers (Reactor layer, 2 heat transfer layers and a top/bottom plate)
– Reaction channels of 1 mm (wide) x 0.7 mm (deep) x 10.5 m (long)• Holder is constructed from stainless steel and PEEK
– All wetted parts are chemically resistant and metal-free
• Reactor can be used for multi-input and operated at 10 bar• Temperatures of -40 to 200°C (depending on tubing material)
• Pre-heater and cooler modules are also available to increase/decrease reactant temperature ahead of reaction zone or upon collection
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Efficient Scale Up - Mixing Technology• Need to ensure that the mixing is the same in all reactor designs• Staggered Oriented Ridges (SOR) fabricated in the channels
1 Unit
2 Units
3 Units
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Conclusions• Micro reactors allow the rapid optimisation of reactions
– Rapid process development• Increased reaction control
– Higher purity– Higher conversion– Higher selectivity
• More reproducible synthetic procedures– Suitable for library synthesis
• Increased catalyst turnovers and lifetimes– Easier purification/isolation
• Increased process safety– Due to rapid dissipation of heat of reaction– Low reactant hold-up
• Equipment for scale-up being developed Chem. Commun., 2007, 443Org. Biomol. Chem., 2007, 5, 733Chem. Rev., 2007, 107, 2300
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• Researchers
• Dr. Charlotte Wiles• Dr. Bongkot Ngamsom• Dr. Joe Dragavon• Dr. Vicki Hammond• Dr. Gareth Wild• Dr. Tamsila Nayyar• Dr. Julian Hooper• Dr. Linda Woodcock• Dr. Haider Al-Lawati• Dr. Nikzad Nikbin• Dr. Ping He• Dr. Victoria Ryabova• Dr. Vinod George• Dr. Leanne Marle• Mairead Kelly• Ben Wahab• Francesco de Leonardis
• Collaborators
• Hull colleagues• Prof. J. A. Littlechild• TNO• TUe
• Funding
• EPSRC• Sanofi-Aventis• LioniX• Astra Zeneca• EU FP6• EU FP7• Yorkshire Concept
Research Workers and Collaborators