A simplified synthesis of 2,3,5,6-tetrafluorophenyl 2-(2-nitroimidazol-1-yl) acetate

Article abstract of DOI:10.1002/jlcr.691

2,3,5,6-Tetrafluorophenyl 2-(2-nitroimidazol-1-yl) acetate has been synthesized via an improved route which involves the direct coupling of 2-(2-nitroimidazol-1-yl) acetic acid with 2,3,5,6-tetrafluorophenol. Copyright

Full text of DOI:10.1002/jlcr.691

JOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS
J Label Compd Radiopharm 2003; 46: 511–513.
Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/jlcr.691
Note
A simplified synthesis of 2,3,5,6-
tetrafluorophenyl 2-(2-nitroimidazol-1-yl)
acetate
Hanna Wilson*
Imaging Research Solutions Ltd., Cyclotron Building, Hammersmith Hospital,
DuCane Road, London W12 0NN, UK
Summary
2,3,5,6-Tetrafluorophenyl 2-(2-nitroimidazol-1-yl) acetate has been synthesized
via an improved route which involves the direct coupling of 2-(2-nitroimidazol-
1-yl) acetic acid with 2,3,5,6-tetrafluorophenol. Copyright # 2003 John Wiley
& Sons, Ltd.
Key Words: Hypoxia; Nitroimidazole; Fluoroetanidazole; EF3
Introduction and Discussion
Fluorine-18 labelled 2-nitroimidazoles are used in the visualization of
hypoxic tissue by positron emission tomography.1 2,3,5,6-Tetrafluor-
ophenyl 2-(2-nitroimidazol-1-yl) acetate is a precursor used in the
synthesis of hypoxia markers such as N-(2-[18F]fluoroethyl)-2-(2-
nitroimidazol-1-yl)-acetamide ([18F] fluoroetanidazole)2 and 2-(2-nitroi-
midazol-1-yl)-N-([18F]3,3,3-trifluoropropyl)-acetamide ([18F] EF3).3
The current literature method for producing this precursor involves
the synthesis of 2,3,5,6-tetrafluorophenyl trifluoroacetate over 5 days,4
followed by reaction with 2-(2-nitroimidazol-1-yl) acetic acid.2,3 This
procedure appeared to be unnecessarily lengthy, given that 2,3,5,6-
*Correspondence to: H. Wilson, Imaging Research Solutions Ltd., Cyclotron Building, Hammer-
smith Hospital, DuCane Road, London W12 0NN, UK. E-mail: hanna.wilson@ic.ac.uk
Copyright # 2003 John Wiley & Sons, Ltd.
Received 11 November 2002
Revised 29 November 2002
Accepted 2 December 2002

512
H. WILSON
tetrafluorophenol may be directly coupled to other carboxylic acids
using 1,3-dicyclohexylcarbodiimide (DCC).5 This note reports a simple
synthesis of 2,3,5,6-tetrafluorophenyl 2-(2-nitroimidazol-1-yl) acetate (I)
from 2-(2-nitroimidazol-1-yl) acetic acid (II) and commercially available
2,3,5,6-tetrafluorophenol (Scheme 1)
Scheme 1.
Experimental
Reagents, including anhydrous solvents, were obtained from Aldrich.
1H (500 MHz) and 19F NMR spectra were obtained using an 11.7 T
Eclipse+ (JEOL), with a broad band autotune 5 mm probe (JEOL).
Residual protic solvent was used as an internal reference. Chemical
shifts are reported in parts per million. Mass spectra were recorded on a
Micromass AUTOSPEC-Q instrument (CI+, ammonia).
2; 3; 5; 6-Tetrafluorophenyl 2-(2-nitroimidazol-1-yl) acetate (I)
Two hundred milligrams of 2-(2-nitroimidazol-1-yl) acetic acid (II)6 and
290 mg 2,3,5,6-tetrafluorophenol were dissolved in 4 ml anhydrous
THF. Three hundred and nine milligrams of DCC (1,3-dicyclohex-
ylcarbodiimide) was dissolved in 7 ml anhydrous THF. The two
solutions were mixed and left stirring overnight. The precipitate was
filtered out. The solvent was evaporated under vacuum to give a tan
solid. The crude product was purified immediately on a silica gel
column, eluted with ethyl acetate/hexane (1:2) until TLC (ethyl acetate/
hexane on silica TLC plate, visualized by UV) showed the absence of
starting materials. The product was then eluted from the column using
ethyl acetate. Evaporation of the solvent gave 210 mg (55%) of (I) as a
tan solid.
Copyright # 2003 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2003; 46: 511–513

A SIMPLIFIED SYNTHESIS OF
513
1H NMR data (CD3CN): d 7.4 (d, 1 H, imidazole proton), d7.2 (d,
1 H, imidazole proton), d 6.8 (m, 1 H, 4-phenyl proton), d 5.5 (s, 2 H,
CH2).
19F NMR data (CD3CN, referenced to CFCl3): d -141 (m, 2F), d -154
(m, 2F). Mass spec: Major peaks m/z 320 (I)H+, m/z 337 (I)NH4+.
Minor peak m/z 188 (II)H+.
Conclusion
The synthesis of 2,3,5,6-tetrafluorophenyl 2-(2-nitroimidazol-1-yl)
acetate by direct coupling of 2-(2-nitroimidazol-1-yl) acetic acid with
2,3,5,6-tetrafluorophenol, using the coupling agent, DCC, has been
carried out in a 55% yield. This method is both faster and requires fewer
steps (and reagents) than the method currently in use.
References
1. Ballinger JR. Semin Nucl Med 2001; 31(4): 321–329.
2. Tewson TJ. Nucl Med Biol 1997; 24(8): 755–760.
3. Josse O, Labar D, Georges B, Gregoire V, Marchand-Brynaert J. Bioorg
Med Chem 2001; 9(3): 665–675.
4. Gamper HB, Reed MW, Cox T, et al. Nucl Acids Res 1993; 21(1): 145–150
5. Glaser M, Howard MJ, Howland K, et al. J Chem Soc - Dalton Trans 1998
18: 3087–3092.
6. Webb P, Threadgill MD. J Labelled Compd Radiopharm 1990; 28(3):
265–271.
Copyright # 2003 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2003; 46: 511–513