Paul Watts High Throughput Synthesis within Flow R

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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: 

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 Chemistry: 

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): 

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

18F 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 J. Lab. Compd. Radiopharm., 2007, 50, in press Electrophoresis 18F-

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 Radiosynthesis: 

Stable Radiosynthesis Acetylation of aniline Reaction efficiency dependent of flow rate Reaction repeated with other derivatives

Stable Radiosynthesis: 

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: 

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: 

Multi-Step Synthesis

Enzymatic Reactions: 

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: 

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:

Combinations of Acids and Bases: 

Combinations of Acids and Bases


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. Jahnisch et 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

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