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High Throughput Synthesis Within Flow Reactors. Paul Watts CPAC, Rome, March 19 th 2007. A. B. C. D. Micro Reactors. Defined as a series of interconnecting channels formed in a planar surface Channel dimensions of 10-300 m m Various pumping techniques available Hydrodynamic flow

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high throughput synthesis within flow reactors

High Throughput Synthesis Within Flow Reactors

Paul Watts

CPAC, Rome, March 19th 2007

micro reactors

A

B

C

D

Micro Reactors
  • Defined as a series of interconnecting channels formed in a planar surface
  • Channel dimensions of 10-300 mm
  • Various pumping techniques available
    • Hydrodynamic flow
    • Electroosmotic flow
  • Fabricated from polymers, metals, quartz, silicon or glass
  • Why glass?
    • Mechanically strong
    • Chemically resistant
    • Optically transparent
pet radiosynthesis
PET Radiosynthesis
  • Positron emission tomography (PET) is a radiotracer imaging technique used to provide quantitative information on physiological and biochemical phenomena in vivo
  • Applications in clinical research and drug discovery
  • Two of the most desirable radioisotopes are:
    • 11C (t1/2 20.4 minutes)
    • 18F (t1/2 109.7 minutes)
  • Syntheses must be conducted within 2-3 half-lives
  • Aims of miniaturisation:
    • Produce the desired quantity of radiotracer (< 1 mg) at point of use
    • Reduced reaction times will produce the product with enhanced specific activity
    • The PET ligand will have greater sensitivity in vivo

Collaboration with NIH, Washington DC

pet chemistry
PET Chemistry
  • Reaction of 3-(3-pyridinyl)propionic acid
  • Reaction optimised with 12CH3I (10 mM concentration) at RT
  • Hydrodynamic flow (syringe pump)
  • Reaction with 11CH3I
    • At 0.5 ml/min flow rate RCY 88%
  • Reaction of 18FCH2CH2OTs at 80 oC
    • At 0.5 ml/min flow rate RCY 10%

Lab Chip,2004, 4, 523

pet chemistry1
PET Chemistry
  • Esterification reaction
  • Reaction with 11CH3I (10 mM concentration) at RT
    • RCY 65% at 0.5 ml/min flow rate
  • Product isolated by preparative HPLC

Lab Chip,2004, 4, 523

electroosmotic flow eof

Transient positive ions

‘Double Layer’

Negative glass surface

Electroosmotic Flow (EOF)
  • Advantages of EOF:
    • No mechanical parts
    • Reproducible, pulse free flow
    • Minimal back pressure
    • Electrophoretic separation
      • See Chem. Commun.,2003, 2886 for peptide separation
18 f pet chemistry
18F PET Chemistry
  • 18F has a longer half-live than 11C
  • Produced from H218O
  • For nucleophilic reactions the fluoride needs to be separated from the water
    • Azeotropic distillation
  • Electrophoretic separation
  • Reaction

Electrophoresis

18F-

J. Lab. Compd. Radiopharm.,2007, 50, in press

stable radiosynthesis
Stable Radiosynthesis
  • Stable isotopes routinely used in drug discovery for drug metabolism studies (500 mg typically needed)
  • Amide synthesis
  • Optimise reaction with ‘normal’ (cheap) unlabelled reagents
stable radiosynthesis1
Stable Radiosynthesis
  • Acetylation of aniline
  • Reaction efficiency dependent of flow rate
  • Reaction repeated with other derivatives
stable radiosynthesis2
Stable Radiosynthesis
  • Once optimised substitute labelled precursor

J. Lab. Compd. Radiopharm.,2007, 50, 189-196

electrosynthesis kolbe reaction
Electrosynthesis - Kolbe Reaction
  • Radical dimerisation (Kolbe reaction)
  • Reactor diameter 1 mm
    • 1 mm platinum electrodes separated by 1 mm
    • Surface area in cell ca. 3 mm2
    • Current 5 mA cm-2
reaction efficiency
Reaction Efficiency
  • Reaction conducted continuously for 12 hours
  • A base is needed to deprotonate the acid
  • Pyridine most successful
    • Stops contamination of electrode surface
    • Also works for other dimerisation reactions
electrochemical debrominations
Electrochemical Debrominations
  • Parallel plate electrochemical reactor
  • Electrode area 25 mm2
    • Electrodes 160 mm apart
    • Flow rate 40 ml min-1
coupling reactions
Coupling Reactions

Flow Rate = 10 ml min-1

Electro. Commun.,2005, 7, 918 Angew. Chem. Int. Ed., 2006, 45, 4146

Green Chem., 2007, 9, 20 Lab. Chip, 2007, 7, 141

fine chemical synthesis

But always require purification

  • Generally batch work up required
Fine Chemical Synthesis
  • New methodology for fine chemical synthesis
  • Enhanced yields of more pure products etc
knoevenagel reaction
Knoevenagel Reaction
  • Solution phase Knoevenagel reaction
  • 1:1 Ratio of reagents (0.5 M) in MeCN
  • EOF
  • 100 % conversion
  • Reaction very ‘atom efficient’
  • BUT product contaminated with base!!
    • Traditional solvent extraction needed
    • This clearly reduces the advantages of flow reactors
functionally intelligent reactors
Functionally Intelligent Reactors
  • Fabricate micro reactors which enable catalysts and/or supported reagents to be spatially positioned
  • Quantitative conversion to analytically pure product
multi step synthesis

A-15

Silica-supported piperazine

Multi-Step Synthesis
enzymatic reactions

Novozyme 435 (ca. 100 mg)

Enzymatic Reactions
  • Enzymatic esterification

Flow reactor

Reaction Conditions:

  • Acid: Hexanoic acid, octanoic acid or lauric acid
  • Alcohol: Methanol, Ethanol or Butanol
  • 1:1 ratio in hexane (0.2 M)
  • Room temperature
synthesis of butyl hexanoate
Synthesis of Butyl Hexanoate
  • Esterification reaction is equilibrium dependent
  • With time conversion can increase then decrease
  • In flow the reaction mixture is removed so equilibrium is controlled
    • 96% yield
  • Gain knowledge about substrate specificity
  • Link solution phase and catalysed reactions
scale out and catalyst screening

200 mm

Scale Out and Catalyst Screening

Scale-out of reactions:

  • 4 channels operating in parallel produces 4 times the product
  • Larger packed reactors also feasible (5 mm diameter)

Synthesise arrays of compounds:

conclusions
Conclusions
  • Micro reactors allow the rapid optimisation of reactions
    • High-throughput combinatorial synthesis
  • Immobilised reagents (catalysts and enzymes) allow the synthesis of analytically pure compounds
  • Micro reactors are suitable for a wide range of reactions
    • Electrochemical synthesis
    • Catalysed reactions
    • Enzyme screening
  • Micro reactors generate products in:
    • Higher purity
    • Higher conversion
    • Higher selectivity
  • In situ formation of reagents

P. D. I. Fletcher et al., Tetrahedron,2002, 58, 4735

K. Jahnischet al.,Angew. Chem. Int. Ed., 2004, 43, 406

H. Pennemann et al., OPRD, 2004, 8, 422

P. Watts et al., Chem. Soc. Rev.,2005, 34, 235

research workers and collaborators
Dr. Charlotte Wiles

Dr. Nikzad Nikbin

Dr. Ping He

Dr. Victoria Ryabova

Dr. Vinod George

Dr. Leanne Marle

Dr. Joe Dragavon

LioniX

Astra Zeneca

Novartis

Mairead Kelly

Gareth Wild

Tamsila Nayyar

Julian Hooper

Linda Woodcock

Haider Al-Lawati

Ben Wahab

EPSRC

Sanofi-Aventis

EU FP6

Research Workers and Collaborators