# US 9,434,699 B2 · Iodine(III)-mediated radiofluorination

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- Number: US 9,434,699 B2
- Document ID: US9434699B2
- Status: Granted
- Kind: B2
- Application number: 14/641,094
- Filed: 2015-03-06
- Published: 2015-09-10
- Granted: 2016-09-06
- Earliest claimed: 2014-03-07
- Assignees: The General Hospital Corporation
- Applicants: The General Hospital Corporation
- Inventors: Neil Vasdev; Benjamin H. Rotstein; Nickeisha A. Stephenson; Huan Liang
- Web page: https://patentgrep.com/patent/US9434699B2

## CPC

- C07D 213/57: Nitriles
- C07B 59/00: Introduction of isotopes of elements into organic compounds {; Labelled organic compounds per se}
- C07B 59/002: {Heterocyclic compounds}
- C07D 239/553: with halogen atoms or nitro radicals directly attached to ring carbon atoms, e.g. fluorouracil
- C07D 319/06: not condensed with other rings
- C07D 319/08: condensed with carbocyclic rings or ring systems
- C07D 405/12: linked by a chain containing hetero atoms as chain links
- C07J 1/0059: {substituted in position 17 by a keto group}
- C07J 17/00: Normal steroids containing carbon, hydrogen, halogen or oxygen, having an oxygen-containing hetero ring not condensed with the cyclopenta(a)hydrophenanthrene skeleton (cardanolide, bufanolide C07J19/00)
- C07J 51/00: Normal steroids with unmodified cyclopenta(a)hydrophenanthrene skeleton not provided for in groups C07J1/00 - C07J43/00
- C07B 2200/05: Isotopically modified compounds, e.g. labelled
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- C07B: GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR (preparation of carboxylic acid esters by telomerisation C07C67/47; telomerisation C08F)
- C07J: STEROIDS (seco-steroids C07C)

## Abstract

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

## Claims

### Claim 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:
Z1 is selected from the group consisting of NRZ1, O, and S;
Z2 is selected from the group consisting of NRZ2, O, and S;
RZ1 is selected from the group consisting of C3-10 cycloalkyl and C6-10 aryl, wherein said C3-10 cycloalkyl and C6-10 aryl forming RZ1 are each optionally substituted by 1, 2, 3, or 4 independently selected R20 groups;
RZ2 is selected from the group consisting of C3-10 cycloalkyl and C6-10 aryl, wherein said C3-10 cycloalkyl and C6-10 aryl forming RZ2 are each optionally substituted by 1, 2, 3, or 4 independently selected R20 groups;
RA 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, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-10 aryl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl, wherein each of said C3-10 cycloalkyl, C6-10 aryl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl forming RA is optionally substituted by 1, 2, 3, or 4 independently selected R20 groups;
RB is selected from the group consisting of H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-10 aryl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl, wherein each of said C3-10 cycloalkyl, C6-10 aryl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl forming RB is optionally substituted by 1, 2, 3, or 4 independently selected R20 groups;
or RA and RB in combination, together with the carbon atom to which RA and RB are attached, form an oxo group;
or RA and RB in combination, together with the carbon atom to which RA and RB 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 RA and RB is unsubstituted or substituted by 1, 2, or 3 substituents independently selected from halogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, and oxo; and
and each R20 is independently selected from the group consisting of OH, SH, CN, NO2, halo, oxo, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, C1-4 cyanoalkyl, C1-4 hydroxyalkyl, C1-4 alkoxy, —(C1-4 alkyl)-(C1-4 alkoxy), —(C1-4 alkoxy)-(C1-4 alkoxy), C1-4 haloalkoxy, C3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl, 5-6 membered heterocycloalkyl, amino, C1-4 alkylamino, di(C1-4 alkyl)amino, carbamyl, C1-4 alkylcarbamyl, di(C1-4 alkyl)carbamyl, carbamoyl, C1-4 alkylcarbamoyl, di(C1-4 alkyl)carbamoyl, C1-4 alkylcarbonyl, C1-4 alkoxycarbonyl, C1-4 alkylcarbonylamino, C1-4 alkylsulfonylamino, aminosulfonyl, C1-4 alkylaminosulfonyl, di(C1-4 alkyl)aminosulfonyl, aminosulfonylamino, C1-4 alkylaminosulfonylamino, di(C1-4 alkyl)aminosulfonylamino, aminocarbonylamino, C1-4 alkylaminocarbonylamino, and di(C1-4 alkyl)aminocarbonylamino.

### Claim 2 (depends on 1)

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.

### Claim 3 (depends on 2)

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.

### Claim 4 (depends on 1)

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

### Claim 5 (depends on 1)

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

### Claim 6 (depends on 5)

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

### Claim 7 (depends on 1)

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

### Claim 8 (depends on 1)

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

### Claim 9 (depends on 1)

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

### Claim 10 (depends on 1)

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

### Claim 11 (depends on 1)

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

### Claim 12 (depends on 1)

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

### Claim 13 (depends on 12)

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

### Claim 14 (depends on 1)

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

### Claim 15

A compound of Formula D:
wherein:
Ar is an aromatic group;
Z1 is selected from the group consisting of NRZ1, O, and S;
Z2 is selected from the group consisting of NRZ2, O, and S;
RZ1 is selected from the group consisting C3-10 cycloalkyl and C6-10 aryl, wherein said C3-10 cycloalkyl and C6-10 aryl forming RZ1 are each optionally substituted by 1, 2, 3, or 4 independently selected R20 groups;
RZ2 is selected from the group consisting of C3-10 cycloalkyl and C6-10 aryl, wherein said C3-10 cycloalkyl and C6-10 aryl forming RZ2 are each optionally substituted by 1, 2, 3, or 4 independently selected R20 groups;
RA 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, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-10 aryl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl, wherein each of said C3-10 cycloalkyl, C6-10 aryl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl forming RA is optionally substituted by 1, 2, 3, or 4 independently selected R20 groups;
RB is selected from the group consisting of H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-10 aryl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl, wherein each of said C3-10 cycloalkyl, C6-10 aryl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl forming RB is optionally substituted by 1, 2, 3, or 4 independently selected R20 groups;
or RA and RB in combination, together with the carbon atom to which RA and RB are attached, form an oxo group;
or RA and RB in combination, together with the carbon atom to which RA and RB 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 RA and RB is unsubstituted or substituted by 1, 2, or 3 substituents independently selected from halogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, and oxo;
and each R20 is independently selected from the group consisting of OH, SH, CN, NO2, halo, oxo, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, C1-4 cyanoalkyl, C1-4 hydroxyalkyl, C1-4 alkoxy, —(C1-4 alkyl)-(C1-4 alkoxy), —(C1-4 alkoxy)-(C1-4 alkoxy), C1-4 haloalkoxy, C3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl, 5-6 membered heterocycloalkyl, amino, C1-4 alkylamino, di(C1-4 alkyl)amino, carbamyl, C1-4 alkylcarbamyl, di(C1-4alkyl)carbamyl, carbamoyl, C1-4 alkylcarbamoyl, di(C1-4 alkyl)carbamoyl, C1-4 alkylcarbonyl, C1-4 alkoxycarbonyl, C1-4 alkylcarbonylamino, C1-4 alkylsulfonylamino, aminosulfonyl, C1-4 alkylaminosulfonyl, di(C1-4 alkyl)aminosulfonyl, aminosulfonylamino, C1-4 alkylaminosulfonylamino, di(C1-4alkyl)aminosulfonylamino, aminocarbonylamino, C1-4 alkylaminocarbonylamino, and di(C1-4 alkyl)aminocarbonylamino; and
wherein Ar is connected to the iodonium group through an aromatic ring carbon atom.

### Claim 16 (depends on 15)

The compound of claim 15, wherein the compound of Formula D is selected from compounds of the following formulae:

### Claim 17 (depends on 15)

The compound of claim 15, wherein the compound of Formula D is selected from compounds of the following formulae:

### Claim 18 (depends on 15)

A process for preparing a compound according to claim 15 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):
wherein Z1, Z2, RA and RB are as defined in claim 15, to form a compound according to claim 15.

### Claim 19 (depends on 15)

A process for preparing an aromatic fluoride compound (Ar-F) comprising
(c) reacting a compound according to claim 15 with a fluoride source to form an aromatic fluoride compound.

### Claim 20 (depends on 19)

The process of claim 19, wherein said fluoride source of step (c) is a fluoride salt.

### Claim 21 (depends on 19)

The process of claim 19, wherein said fluoride source comprises [18F] fluoride.

### Claim 22 (depends on 21)

The process of claim 21, wherein said fluoride source is tetraethylammonium [18F]fluoride.

### Claim 23 (depends on 1)

The process of claim 1, wherein Z1 is NRZ1 and Z2 is NRZ2.

### Claim 24 (depends on 23)

The process of claim 23, wherein RZ1 and RZ2 are each independently selected C6-10 aryl groups.

### Claim 25 (depends on 23)

The process of claim 23, wherein RZ1 and RZ2 are each phenyl.

### Claim 26 (depends on 23)

The process of claim 23, wherein RA and RB in combination, together with the carbon atom to which RA and RB are attached, form an oxo group.

### Claim 27 (depends on 1)

The process of claim 1, wherein Z1 and Z2 are each 0.

### Claim 28 (depends on 27)

The process of claim 27, wherein RA is ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl; 2-methyl-1-butyl, n-pentyl, 3-pentyl, n-hexyl, or 1,2,2-trimethylpropyl and RB is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl; 2-methyl-1-butyl, n-pentyl, 3-pentyl, n-hexyl, or 1,2,2-trimethylpropyl.

### Claim 29 (depends on 27)

The process of claim 27, wherein RA is ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl; 2-methyl-1-butyl, n-pentyl, 3-pentyl, n-hexyl, or 1,2,2-trimethylpropyl and RB is ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl; 2-methyl-1-butyl, n-pentyl, 3-pentyl, n-hexyl, or 1,2,2-trimethylpropyl.

### Claim 30 (depends on 27)

The process of claim 27, wherein RA is n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl; 2-methyl-1-butyl, n-pentyl, 3-pentyl, n-hexyl, or 1,2,2-trimethylpropyl and RB is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl; 2-methyl-1-butyl, n-pentyl, 3-pentyl, n-hexyl, or 1,2,2-trimethylpropyl.

### Claim 31 (depends on 27)

The process of claim 27, wherein RA and RB in combination, together with the carbon atom to which RA and RB are attached, form a 3, 4, 5, 6, or 7-membered carbocyclic ring containing 3 to 7 carbon atoms wherein the ring formed by the combination of RA and RB is unsubstituted or substituted by 1, 2, or 3 substituents independently selected from halogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, and oxo.

### Claim 32 (depends on 27)

The process of claim 27, wherein RA and RB in combination, together with the carbon atom to which RA and RB are attached, form a 3, 4, 5, 6, or 7-membered carbocyclic ring containing 3 to 7 carbon atoms wherein the ring formed by the combination of RA and RB is unsubstituted.

### Claim 33 (depends on 15)

The compound of claim 15, wherein Z1 is NRZ1 and Z2 is NRZ2.

### Claim 34 (depends on 33)

The compound of claim 33, wherein RZ1 and RZ2 are each independently selected C6-10 aryl groups.

### Claim 35 (depends on 33)

The compound of claim 33, wherein RZ1 and RZ2 are each phenyl.

### Claim 36 (depends on 33)

The compound of claim 33, wherein RA and RB in combination, together with the carbon atom to which RA and RB are attached, form an oxo group.

### Claim 37 (depends on 15)

The compound of claim 15, wherein Z1 and Z2 are each 0.

### Claim 38 (depends on 37)

The compound of claim 37, wherein RA is ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl; 2-methyl-1-butyl, n-pentyl, 3-pentyl, n-hexyl, or 1,2,2-trimethylpropyl and RB is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl; 2-methyl-1-butyl, n-pentyl, 3-pentyl, n-hexyl, or 1,2,2-trimethylpropyl.

### Claim 39 (depends on 37)

The compound of claim 37, wherein RA is ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl; 2-methyl-1-butyl, n-pentyl, 3-pentyl, n-hexyl, or 1,2,2-trimethylpropyl and RB is ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl; 2-methyl-1-butyl, n-pentyl, 3-pentyl, n-hexyl, or 1,2,2-trimethylpropyl.

### Claim 40 (depends on 37)

The compound of claim 37, wherein RA is n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl; 2-methyl-1-butyl, n-pentyl, 3-pentyl, n-hexyl, or 1,2,2-trimethylpropyl and RB is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl; 2-methyl-1-butyl, n-pentyl, 3-pentyl, n-hexyl, or 1,2,2-trimethylpropyl.

### Claim 41 (depends on 37)

The compound of claim 37, wherein RA and RB in combination, together with the carbon atom to which RA and RB are attached, form a 3, 4, 5, 6, or 7-membered carbocyclic ring containing 3 to 7 carbon atoms wherein the ring formed by the combination of RA and RB is unsubstituted or substituted by 1, 2, or 3 substituents independently selected from halogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, and oxo.

### Claim 42 (depends on 37)

The compound of claim 37, wherein RA and RB in combination, together with the carbon atom to which RA and RB are attached, form a 3, 4, 5, 6, or 7-membered carbocyclic ring containing 3 to 7 carbon atoms wherein the ring formed by the combination of RA and RB is unsubstituted.