Nucleophilic fluorination of aromatic compounds
View Patent ↗Iodylbenzene derivatives substituted with electron donating as well as electron withdrawing groups on the aromatic ring are used as precursors in aromatic nucleophilic substitution reactions. The iodyl group (IO 2 ) is regiospecifically substituted by nucleophilic fluoride to provide the corresponding fluoroaryl derivatives. No-carrier-added [F-18]fluoride ion derived from anhydrous [F-18](F/Kryptofix, [F-18]CsF or a quaternary ammonium fluoride (e.g., Me 4 NF, Et 4 NF, n-Bu 4 NF, (PhCH 2 ) 4 NF) exclusively substitutes the iodyl moiety in these derivatives and provides high specific activity F-18 labeled fluoroaryl analogs. Iodyl derivatives of a benzothiazole analog and 6-iodyl-L-dopa derivatives have been synthesized as precursors and have been used in the preparation of no-carrier-added [F-18]fluorobenzothiazole as well as 6-[F-18]fluoro-L-dopa.
1. A procedure for preparing F-18 labeled compounds identified as product in the table below comprising:
providing a benzene derivative containing an iodyl group and an aqueous solution of [F-18] fluoride ion
replacing the iodyl group by said F-18 ion to produce an F-18 containing benzene derivative, the F-18 ion being free of a fluoride ion carrier
wherein the benzene derivative containing an iodyl group is selected from the group listed in the left hand column of the table below and the F-18 containing benzene derivative produced therefrom is listed in the corresponding right hand column of the table below:
Benzene Derivative
Containing Iodine
Product
.
2. The procedure of claim 1 wherein [O-18]water in a cyclotron target body is bombarded by photons to produce the aqueous solution of the [F-18]fluoride ion free of a fluoride ion carrier.
3. The procedure of claim 2 wherein each [F-18]fluoride ion is treated with potassium carbonate and a ligand, the aqueous solution is evaporated to dryness and reacted with the benzene derivatives containing and iodyl group to form a dry composition containing [F-18]fluoride ion labeled benzene derivative.
4. The procedure of claim 3 wherein the [F-18] fluorobenzene derivative is purified to produce a ≧95% radiochemically pure [F-18] fluorobenzene derivative.
5. The procedure of claim 3 wherein the [F-18] fluorobenzene derivative is purified to produce a ≧99% radiochemically and chemically pure product.
6. A method of producing the F-18 compounds of the formula
by subjecting an iodine containing compound of the formula
to dry/anhydrous no-carrier-added F-18 fluoride ion using conventional dry heating procedures or under microwave heating where the [F-18] fluoride ion is derived from [F-18]KF/Kryptofix complex, [F-18]CsF or [F-18] quaternary ammonium fluoride, the quaternary ammonium groups selected from tetramethyl, tetraethyl, tetra n-butyl, and tetrabenzyl
wherein:
R 1 ═H, OCH 3 , OCH 2 Ph, O-Boc, O-Methoxytrityl
wherein R 2 is bonded to the iodine containing compound at a C atom identified by *.
7. The method of claim 6 wherein one or more ketone groups in the F-18 compounds are oxidized using the Baeyer-Villiger reaction to form one or more ester groups.
8. The method of claim 6 further comprising producing F-18 labeled amino acids, F-18 labeled amines or F-18 labeled amino alcohols by hydrolyzing the F-18 compounds using conventional dry heating or microwave heating with mineral acids or organic acids.
9. The method of claim 8 wherein the mineral acids comprise HCl, HBr or HI and the organic acids comprise methanesulfonic acid, or trifluoromethane sulfonic acid.