Iodine(III)-mediated radiofluorination

Patent metadata

Field	Value
Publication number	US-9434699-B2
Application number	US-201514641094-A
Country	US
Kind code	B2
Filing date	Mar 6, 2015
Priority date	Mar 7, 2014
Publication date	Sep 6, 2016
Grant date	Sep 6, 2016

Abstract

A process for fluorination of aromatic compounds employing iodonium ylides and applicable to radiofluorination using 18 F is described. Processes, intermediates, reagents and radiolabelled compounds are described.

First claim

What is claimed is:

1. A process for fluorodeiodination of an aromatic iodide compound comprising:
(a) oxidizing an aromatic iodide compound (Ar-I), to form an iodonium compound;
(b) reacting the iodonium compound with a compound of formula (A):

to form an iodonium ylide;
(c) reacting the iodonium ylide with a fluoride source to form an aromatic fluoride compound (Ar-F);
wherein:
Z 1 is selected from the group consisting of NR Z1 , O, and S;
Z 2 is selected from the group consisting of NR Z2 , O, and S;
R Z1 is selected from the group consisting of C 3-10 cycloalkyl and C 6-10 aryl, wherein said C 3-10 cycloalkyl and C 6-10 aryl forming R Z1 are each optionally substituted by 1, 2, 3, or 4 independently selected R 20 groups;
R Z2 is selected from the group consisting of C 3-10 cycloalkyl and C 6-10 aryl, wherein said C 3-10 cycloalkyl and C 6-10 aryl forming R Z2 are each optionally substituted by 1, 2, 3, or 4 independently selected R 20 groups;
R A is selected from the group consisting of H, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl; 2-methyl-1-butyl, n-pentyl, 3-pentyl, n-hexyl, 1,2,2-trimethylpropyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl, wherein each of said C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl forming R A is optionally substituted by 1, 2, 3, or 4 independently selected R 20 groups;
R B is selected from the group consisting of H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl, wherein each of said C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl forming R B is optionally substituted by 1, 2, 3, or 4 independently selected R 20 groups;
or R A and R B in combination, together with the carbon atom to which R A and R B are attached, form an oxo group;
or R A and R B in combination, together with the carbon atom to which R A and R B are attached, form a 3, 4, 5, 6, or 7-membered carbocyclic or heterocyclic ring containing 3 to 7 carbon atoms and 0, 1, or 2 ring heteroatoms, each independently selected from N, O, and S, wherein the ring formed by the combination of R A and R B is unsubstituted or substituted by 1, 2, or 3 substituents independently selected from halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, and oxo; and
and each R 20 is independently selected from the group consisting of OH, SH, CN, NO 2 , halo, oxo, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, C 1-4 cyanoalkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy, —(C 1-4 alkyl)-(C 1-4 alkoxy), —(C 1-4 alkoxy)-(C 1-4 alkoxy), C 1-4 haloalkoxy, C 3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl, 5-6 membered heterocycloalkyl, amino, C 1-4 alkylamino, di(C 1-4 alkyl)amino, carbamyl, C 1-4 alkylcarbamyl, di(C 1-4 alkyl)carbamyl, carbamoyl, C 1-4 alkylcarbamoyl, di(C 1-4 alkyl)carbamoyl, C 1-4 alkylcarbonyl, C 1-4 alkoxycarbonyl, C 1-4 alkylcarbonylamino, C 1-4 alkylsulfonylamino, aminosulfonyl, C 1-4 alkylaminosulfonyl, di(C 1-4 alkyl)aminosulfonyl, aminosulfonylamino, C 1-4 alkylaminosulfonylamino, di(C 1-4 alkyl)aminosulfonylamino, aminocarbonylamino, C 1-4 alkylaminocarbonylamino, and di(C 1-4 alkyl)aminocarbonylamino.

2. The process of claim 1 , wherein step (a) is performed in the presence of an oxidizing agent selected from the group consisting of sodium perborate, urea-hydrogen peroxide adduct, 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (Selectfluor®), potassium peroxymonosulfate (OXONE®), dimethyldioxirane, or meta-chloroperoxybenzoic acid.

3. The process of claim 2 , wherein step (a) is performed in the presence of a carboxylate source that is an acetate source or trifluoroacetate source.

4. The process of claim 1 , wherein said iodonium product of step (a) is an iodonium compound of Formula B or Formula C:

5. The process of claim 1 , wherein step (b) is carried out in the presence of a base.

6. The process of claim 5 , wherein step (b) is carried out in the presence of a carbonate base.

7. The process of claim 1 , wherein said iodonium ylide formed in step (b) is an iodonium ylide of Formula D:

8. The process of claim 1 , wherein the compound of Formula A is selected from compounds of the following formulae:

9. The process of claim 1 , wherein the compound of Formula A is selected from compounds of the following formulae:

10. The process of claim 1 , comprising isolating or purifying the iodonium ylide following step (b).

11. The process of claim 1 , wherein said fluoride source of step (c) is a fluoride salt.

12. The process of claim 1 , wherein said fluoride source comprises [ 18 F] fluoride.

13. The process of claim 12 , wherein said fluoride source is tetraethylammonium [ 18 F]fluoride.

14. The process of claim 1 , comprising isolating or purifying the aromatic fluoride following step (c).

15. A compound of Formula D:

wherein:
Ar is an aromatic group;
Z 1 is selected from the group consisting of NR Z1 , O, and S;
Z 2 is selected from the group consisting of NR Z2 , O, and S;
R Z1 is selected from the group consisting C 3-10 cycloalkyl and C 6-10 aryl, wherein said C 3-10 cycloalkyl and C 6-10 aryl forming R Z1 are each optionally substituted by 1, 2, 3, or 4 independently selected R 20 groups;
R Z2 is selected from the group consisting of C 3-10 cycloalkyl and C 6-10 aryl, wherein said C 3-10 cycloalkyl and C 6-10 aryl forming R Z2 are each optionally substituted by 1, 2, 3, or 4 independently selected R 20 groups;
R A is selected from the group consisting of H, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl; 2-methyl-1-butyl, n-pentyl, 3-pentyl, n-hexyl, 1,2,2-trimethylpropyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl, wherein each of said C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl forming R A is optionally substituted by 1, 2, 3, or 4 independently selected R 20 groups;
R B is selected from the group consisting of H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl, wherein each of said C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl forming R B is optionally substituted by 1, 2, 3, or 4 independently selected R 20 groups;
or R A and R B in combination, together with the carbon atom to which R A and R B are attached, form an oxo group;
or R A and R B in combination, together w

Assignees

• Massachusetts Gen Hospital

Inventors

• Vasdev Neil
• Rotstein Benjamin H
• Stephenson Nickeisha A
• Liang Huan

Classifications

• C07B2200/05

  Isotopically modified compounds, e.g. labelled · CPC title

• C07D319/08

  condensed with carbocyclic rings or ring systems · CPC title

• C07B59/00

  Introduction of isotopes of elements into organic compounds {; Labelled organic compounds per se} · CPC title

• C07D213/57 Primary

  Nitriles · CPC title

• C07D319/06

  not condensed with other rings · CPC title