Synthesis of 4-[ 18 F]Fluorobenzaldehyde using Diaryliodonium Salt Precursors in a Microreactor

Transcription

1 Synthesis of 4-[ ]Fluorobenzaldehyde using Diaryliodonium Salt Precursors in a Microreactor CHO [ ]fluoride Michael Charlton michael.charlton1@ncl.ac.uk RSC Radiochemistry Group YRM 27/28 th March 2012

2 Overview Introduction to Positron Emission Tomography (PET) Introduction to Prosthetic Groups and 4-[ ]FBA Diaryliodonium Salts and their Synthesis Automated Microfluidic Synthesis Automated Synthesis of 4-[ ]FBA Future Work and Conclusions

3 Fluorine-18 Introduction and PET Fluorine-18 (β + emitter, half-life min) the nuclide of choice for PET. - Low energy positron. - Range of biological processes. - Transportation.

4 to Prosthetic Groups Prosthetic groups are radiolabelled compounds used to indirectly label a target of interest. O OH O Br O O O N O CHO Prosthetic groups are used where direct labelling methods aren t applicable. CHO N H 2 N 4-[ ]FBA can also be converted to several useful synthons.

5 Uses Introduction of 4-[ ]FBA OH CHO OH OH OH halogenation reduction CHO X oxidation Br reductive amination NR 2 X = H or MEM

6 Current Synthetic Routes to 4-[ ]FBA 4-[ ]FBA can be synthesised from 4-nitrobenzaldehyde or 4-formyl- N,N,N-trimethylbenzenaminium trifluoromethanesulfonate 1. O F 3 C S O O CHO [ ]Fluoride CHO NMe [ ]FBA has been obtained in a yield of up to 81% using the nitro precursor, 1 or 90% using 1. 2 Using 1 could result in the formation of volatile [ ]methylfluoride. Unable to label the meta position! [1] B. Shen, D. Löffler, K.-P. Zeller, M. Übele, G. Reischl and H.-J. Machulla, J. Fluorine Chem., 2007, 128, [2] X. Li, J. M. Link, S. Stekhova, K. J. Yagle, C. Smith, K. A. Krohn and J. F. Tait, Bioconjugate Chem., 2008, 19,

7 Introduction to Diaryliodonium Salts Diaryliodonium salts have proven useful precursors to the single-step synthesis of electron-rich and electron-poor arenes. 1 No restriction on the position of the label. 2 R 1 I X [ ]fluoride R 1 /I /I R 2 R 2 The selectivity of the process can be affected by modifying the steric and electron properties of the non-participating-arene. 3 [1] F. I. Aigbirhio, V. W. Pike, S. L. Waters and R. J. N. Tanner, J. Fluorine Chem., 1995, 70, [2] F. Basuli, H. Wu and G. L. Griffiths, J. Labelled Compd. Radiopharm., 2011, 54, [3] M. A. Carroll, S. Martin-Santamaria, V. W. Pike, H. S. Rzepa and D. A. Widdowson, J. Chem. Soc. Perkin Trans. 2, 1999,

8 Diaryliodonium Salt Synthesis Diaryliodonium salts used in the study synthesised from a diacetoxyiodoarene and an organostannane. Ar I(OAc )2 1) TFA, DCM, -30 o C to RT 1.5 h 2) 4-Tributylstannylbenzaldehyde -30 o C to RT overnight CF 3 COO I Ar CHO Ar = Phenyl Ar = 4-Anisyl Ar = 2-Thienyl Ar = Phenyl, 1, 32% Ar = 4-Anisyl, 2, 48% Ar = 2-Thienyl, 3, 38% 3 Non-participating-arene varied.

9 Synthetic Radiochemistry Microfluidic production - Single batch of [ ]fluoride - Multi-step - Flexible system

10 Automated Synthesis Optimisation Variation of multiple reaction parameters Rapid optimisation of protocols (>30 runs per batch of [ ]fluoride) Robust performance Introduction of Et 4 N.HCO 3 as a new phase transfer reagent. 1 [1] Carroll, M.A. Launay, G.G. Reed, C.D. Hobson, S.J. J. Labelled Compd. Radiopharm., 2011, 54, S554,.

11 Synthesis of 4-[ ]FBA Microfluidic apparatus used to synthesise 4-[ ]FBA. Precursor Concentration [10 mg/ml], Reactor Length - 4m, P1:P3 Volume Ratio - 1 Isotope Volume - 10μL, Flow Rate - 10 μl/min, Transfer Rate 60 μl/min Phase transfer agent TEA.HCO 3

12 Synthesis of 4-[ ]FBA The non-participating-arene affects RCY in with phenyl>4-anisyl>2-thienyl RCY % Phenyl 1 4-Anisyl 2 2-Thienyl Temperature ( C) [ ]Fluorobenzene detected in < 1% quantities for 1. No [ 19 F]fluorobenzene detected in cold study! RCY needs to be improved, reproducibility could be improved.

13 Synthesis of 4-[ ]FBA The radical scavenger TEMPO has been shown to increase the reproducibility of the fluorination procedure mol% TEMPO added to the diaryliodonium salt solution RCY % Phenyl 1 4-Anisyl 2 2-Thienyl 3 O N Temperature ( C) TEMPO Increased reproducibility as expected, slight decrease in RCY! [1] Carroll, M.A. J, Nairne. Smith, G. Widdowson, D.A. J. Fluorine. Chem., 2007, 128,

14 Synthesis of 4-[ ]FBA It has been shown that diaryliodonium salts can be radiofluorinated in the presence of water. 1 Water added to 4-formylphenyl(phenyl)iodonium TFA, RCY % % Water 10% Water 20% Water No Water Temperature ( C) Dramatic increase in RCY observed, RCYs >80% have been obtained. [1] Wadsworth, H.J. Devenish, P.A. US , 2011.

15 Synthesis of 4-[ ]FBA The addition of 5% water to 1 enhances RCY dramatically. 5% water added to 2 and RCY % Anisyl, 5% water 4-Anisyl, no water 2-Thienyl, 5% water 2-Thienyl, no water Temperature ( C) Addition of water to 2 results in dramatic increase in RCY Increase in RCY when water added to 3 not as pronounced.

16 Synthesis of 4-[ ]FBA The simultaneous addition of 5% water and 10 mol% TEMPO to a solution of 1 is detrimental to the RCY! RCY % % Water 10 mol% TEMPO 5% Water and 10 mol% TEMPO No Water Temperature ( C)

17 Conclusions 4-[ ]FBA in RCYs of 83% attainable as a result of process optimisation. Diaryliodonium salts offer a practical alternative to synthesise the prosthetic group 4-[ ]FBA. Interestingly, phenyl>4-anisyl>2-thienyl with respect to RCY. Addition of 5% water dramatically increases RCY. Addition of TEMPO increases reproducibility. The simultaneous addition of both is detrimental to the RCY. Optimised conditions will be applied to the synthesis of 3-[ ]FBA, 2-[ ]FBA and other compounds.

18 Future Work Reactions with a range of biomolecules for preclinical PET imaging at Newcastle University Faculty of Medicine are underway: - Peptides; Institute of Neuroscience (anxiety, depression) - Antibodies; Clinical and Laboratory Sciences (liver fibrosis) - Oligonucleotides; Institute of Genetic Medicine (muscular dystrophy) - MR agents; Northern Institute of Cancer Research (combined PET-MR probes)

19 Acknowledgements MAC Group: Dr M. A. Carroll Dr L. I. Dixon Dr S. J. Hobson Dr G. D. G. Launay C. D. Reed D. Molyneux C. McCardle S. S. Bhatt Newcastle University: Funding Dr R. W. Harrington and Prof. W. Clegg (X-Ray) Dr C. Y. Wills (NMR) EPSRC: Funding and provision of EPSRC NMSSC RSC: Radiochemistry Group Thank-you for listening!