Development of Fluorine-18 Halofluorination and Fluorine-18 Fluoride Ion Displacement Reactions for the Synthesis of Fluorine-18 Labeled Radiopharmaceuticals (Spiperone, Spiroperidol, N-Alkylation, Radioactivity)
Chi, Dae Yoon
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Permalink
https://hdl.handle.net/2142/70342
Description
Title
Development of Fluorine-18 Halofluorination and Fluorine-18 Fluoride Ion Displacement Reactions for the Synthesis of Fluorine-18 Labeled Radiopharmaceuticals (Spiperone, Spiroperidol, N-Alkylation, Radioactivity)
Author(s)
Chi, Dae Yoon
Issue Date
1986
Department of Study
Chemistry
Discipline
Chemistry
Degree Granting Institution
University of Illinois at Urbana-Champaign
Degree Name
Ph.D.
Degree Level
Dissertation
Keyword(s)
Chemistry, Organic
Abstract
Two fluorine-18 labeling methods, ('18)F halofluorination and ('18)F fluoride ion displacement reactions, have been developed to assess their potential for labeling molecules with the positron-emitting radionuclide fluorine-18 at the no-carrier-added level.
Olefin halofluorination involves the in situ generation of a halogen-fluoride reagent and subsequent addition to an olefin. The characteristics of this reaction were investigated with three model olefins (allylbenzene, 1-hexene, and propene). The most favorable conditions for halofluorination utilized 1,3-dibromo-5,5-dimethylhydantoin with dichloromethane as solvent. By this reaction, allylbenzene was labeled with fluorine-18 in 32% yield, under either carrier-added or no-carrier-added conditions. Transformations of halofluorination products, by either dehalogenation or N-alkylation, provide fluoroalkyl compounds or N-fluoroalkylated nitrogen compounds, respectively.
A two-step method for the preparation of fluoroalkyl substituted amines and amides has been achieved. The sequence involves fluoride ion displacement of trifluoromethanesulfonates (triflates) from short-chain haloalkyl triflates, followed by fluoroalkylation of the amine or amide. Alternatively, short-chain fluoroalkyl halides can be prepared by halofluorination of a terminal olefin. These reactions have been used to prepare various fluoroalkyl derivatives of 1-phenylpiperazine and N-fluoroalkyl derivatives of the neuroleptic agent spiperone. The sequence is rapid, convenient, and efficient, even when fluoride ion is the limiting reagent.
A series of fluorine-18 labeled N-fluoroalkylated spiperone derivatives were synthesized by N-alkylation of spiperone with fluoroalkyl halides. The fluoroalkylating species 2- ('18)F fluoroethyl bromide and 3- ('18)F fluoropropyl bromide were prepared by ('18)F fluoride ion displacement of the corresponding triflates. By this method, 2- ('18)F fluoroethyl and 3- ('18)F fluoropropyl spiperone derivatives can be both prepared and purified rapidly and conveniently (within 40 min) in yields of 30-40%. An alternative approach, suitable for the preparation of 2- ('18)F fluoroalkyl (ethyl, propyl, butyl, pentyl and hexyl) spiperone derivatives, involves iodo ('18)F fluorination of terminal olefins, followed by N-alkylation of spiperone (overall yields, <5%). N-(3- ('18)F Fluoropropyl)spiperone shows excellent selectivity for target tissue uptake in vivo.
Olefin halofluorination and fluoride ion displacement of haloalkyl triflate are readily adaptable to the preparation of a variety of compounds labeled with the short half-life (t(, 1/2) = 110 min) positron-emitting radionuclide fluorine-18.
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