Fast and reliable method for the preparation of ortho-and para-[18 F] fluorobenzyl halide derivatives: key intermediates for the preparation of no-carrier-added PET aromatic radiopharmaceuticals (original) (raw)
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Journal of Fluorine Chemistry, 1990
Nucleophilic aromatrc substrtutron by [' 8F]fluoride ion has been demonstrated OI rings containing electron donating groups in addition to the necessary electron withdrawing and leaving groups. The reaction of ' 8F with a series of aromatic nitro aldehydes having protected hydroxyl substituents on the ring was studied. The reactivity of the aromatic ring towards nucleophilic substrtution to give ' 8F-labeled aromatic fluoroaldehyde derivatives is correlated with electron density at the reaction center. The effect of a number of protected hydroxyl substituents IS reported. t3C-NMR was used as a sensitive probe for the changes in electron distribution at the ring carbon atoms. Radiochemical yield correlates with ppm values at the reaction center. This methodology has been applied to the synthesis of no-carrier-added (NCA) 6-[18F]fluoro-L-DOPA. The extention of this strategy to the syntheses of other labeled pharmaceuticals appears promising.
International Journal of Radiation Applications and Instrumentation. Part A. Applied Radiation and Isotopes, 1991
No-carrier-added ~~-a-methyl-~-4-['8F]fluorophenyl-N-methyl-N-propynylethylamine (DL-4-['*F]fluorodeprenyl) was synthesized via the following 3-step procedure: (1) nucleophilic aromatic substitution by ['sF]fluoride on 4-nitrobenzaldehyde to produce 4-[r8F]fluorobenzaldehyde (yield 65%); (2) the reaction of 4-['8F]fluorobenzaldehyde with (I-chloro-I-(trimethylsilyl)ethyl)lithium followed by hydrolysis to give 4-['8F]fluorophenylacetone (yield 50%); and (3) reductive alkylation of 4-['8F]fluorophenylacetone with N-methyl-propynylamine in the presence of NaBH,CN (yield 35%) followed by HPLC purification to give a racemic mixture of 4-['8F]fluorodeprenyl. The overall yield was 11% (EOB corrected), the synthesis time was 90 min and the specific activity ~-0.57 Ci/pmol (end of synthesis). This synthesis approach, the conversion of an aromatic aldehyde to a homologous methyl ketone, extends the flexibility of the nucleophilic aromatic substitution reaction by applying it to the synthesis of radiotracers which do not bear electron-withdrawing activating groups on the aromatic ring. The tissue distribution of DL-4-['sF]fluorodeprenyl in mice at 1, IO and 60 min was also measured and showed that metabolic defluorination was not signifcant. Clearance of radioactivity from brain after injection of oL-4-['8F]fluorodeprenyl was more rapid than that previously observed for ["C]L-deprenyl.
International Journal of Radiation Applications and Instrumentation. Part A. Applied Radiation and Isotopes, 1992
The synthesis of no-carrier-added 3-['8F]fluoroanisole, 2-["F]fluoroanisole, ['*F]fluorohenzene and 4-['*F]fluoroveratrole are reported. The strategy consists of ammo-polyether supported nucleophilic substitution with ['*F]F-on activated nitro aromatic aldehyde precursors followed by decarbonylation using Tns(triphenylphosphme) rhodium (I) chloride The experimental parameters for this reaction have been studied and optimized with 2-['8qfluoro-4-methoxybenzaldehyde and then successfully applied to four other '*F-fluorinated aromatic aldehydes. The decarbonylation yields obtamed were 84 f 5% (corrected for decay) wlthm 15 mm at 150°C m 1,4-dloxan
Fluorine-18 chemistry for PET: A concise introduction
2010
Fluorine-18 is the most important radionuclide used in positron emission tomography (PET) today, largely due to its attractive physical and nuclear characteristics. Agents such as the clinical oncology tracer 2-[ 18 F]fluoro-2-deoxy-Dglucose ([ 18 F]FDG), the most widely used PET-radiopharmaceutical, are driving an increasing interest in the chemistry of radiopharmaceuticals utilizing fluorine-18. This review outlines the methods for production of fluorine-18, and the development of agents for performing radiofluorination reactions. With a few exceptions, radiofluorinations can be classified as either electrophilic or nucleophilic. The electrophilic reactions mainly use molecular [ 18 F]fluorine of moderately low specific radioactivity, or reagents prepared from it, and include additions to alkenes, reactions with carbanions and especially fluorodehydrogenation and fluorodemetallation. The nucleophilic reactions usually involve no-carrier-added (highspecific-radioactivity) [ 18 F]fluoride as its K[ 18 F]F-K 222 complex and include S N 2-type substitutions in the aliphatic series and S N Ar-type substitutions in the aromatic and heteroaromatic series. Key examples from each class of radiofluorination reaction will be described, highlighting the potential of this radioisotope in the design and preparation of fluorine-18labeled probes for PET imaging.
Russian Chemical Bulletin
4,5 Bis(butoxy) 2 nitrobenzaldehyde and 4,5 bis(tert butoxycarbonyloxy) 2 nitrobenzal dehyde, as well as their fluorine 18 labeled derivatives (the half life of F 18 is T 1/2 = 110 min) were synthesized for use as precursors in the synthesis of fluorine 18 labeled catecholamines and 6 [ 18 F]fluoro L DOPA ((S) 3 [4,5 dihydroxy 2 [ 18 F]fluorophenyl] 2 aminopropionic acid), important radiopharmaceutical agents (RPAs) for positron emission tomography. An advantageous feature of the newly obtained substituted nitrobenzaldehydes is the presence of labile protective groups which can be removed without using aggressive chemicals and severe conditions, which is of fundamental importance for automation of the RPA synthesis in modern synthesis apparatus. A high and stable radiofluorination yield achieved under the optimum fluorination conditions (Kryptofix 222 [K/K2.2.2.] + [ 18 F-], DMF, 140 °C, 10 min) using 4,5 bis(butoxy) 2 nitrobenzaldehyde as a substrate (83±6%, the number of experiments was n = 15) makes this compound a precursor of choice for the radioactive synthesis.
18F-Labeled Aryl-Tracers through Direct Introduction of [18F]fluoride into Electron-Rich Arenes
Current Organic Chemistry, 2013
Rapid and efficient methods using no-carried-added [ 18 F]fluoride as the source of fluorine-18 for nucleophilic aromatic fluorination play an important role in the development of new radiopharmaceuticals for positron emission tomography (PET). Molecules that bear electron-rich aromatic moieties are especially difficult to label by direct single-step nucleophilic no-carrier-added radiofluorination. Classical Balz-Schiemann reaction with its modifications, Wallach reaction and diaryliodonium salts methodology are a few methods to enable this. The present review provides a critical overview of these chemical methods with the emphasis on diaryliodonium salt as precursors for the direct introduction of [ 18 F]fluoride into electron-rich arenes in synthesis of 18 F-labeled molecules for PET scanning.
Journal of Labelled Compounds and Radiopharmaceuticals, 2008
The radiosynthesis of a new [ 18 F]fluoroalkylating agent, [ 18 F]fluoroacetaldehyde, is described. It was produced using the Kornblum method by oxidation with dimethyl sulphoxide of 2-[ 18 F]fluoroethyl p-toluenesulphonate ([ 18 F]FETos). In these conditions the oxidation proceeds smoothly and rapidly to the selective conversion of tosyl esters of primary alcohols to aldehydes with no carboxylic acids being produced. The chemical identity of [ 18 F]fluoroacetaldehyde was determined by comparing its chromatographic properties as well as those of its 2,4-dinitrophenylhydrazone (2,4-DNPH) derivative with those of, respectively, the standard fluoroacetaldehyde and its 2,4-DNPH derivative. Standard fluoroacetaldehyde was prepared by oxidation of fluoroethanol with pyridinium dichromate and characterized as its 2,4-DNPH derivative by mass spectrometry. To test its reactivity with amines under reductive alkylation conditions, [ 18 F]fluoroacetaldehyde was reacted with benzylamine used as model substrate. The chemical identity of the resulting radiolabelled product was determined to be [ 18 F]N-(2-fluoroethyl)-benzylamine by comparing its chromatographic properties with those of the synthesized standard N-(2-fluoroethyl)-benzylamine characterized by 19 F and 1 H NMR spectroscopy and mass spectrometry. This new fluorine-18 labelled synthon may find applications in radiolabelling peptide, protein and antibody fragments as well as in aldol condensation or in the Mannich reaction.