Process for deoxyfluorination of phenols

Patent metadata

Field	Value
Publication number	US-11046628-B2
Application number	US-201816635266-A
Country	US
Kind code	B2
Filing date	Jul 10, 2018
Priority date	Jul 31, 2017
Publication date	Jun 29, 2021
Grant date	Jun 29, 2021

Abstract

The present invention refers to a process for transition-metal-assisted 18F-deoxyfluorination of phenols. The transformation benefits from readily available phenols as starting materials, tolerance of moisture and ambient atmosphere, large substrate scope, and translatability to generate doses appropriate for positron emission tomography (PET) imaging.

First claim

The invention claimed is:

1. A method of replacing a hydroxyl group on an aryl or heteroaryl compound bearing the hydroxyl group with a fluorine atom, the method comprising contacting a compound of Formula (I):

with a Cp-Ru-(aryl or heteroaryl)-complex in the presence of a fluorine source under conditions sufficient to fluorinate the aryl or heteroaryl compound bearing the hydroxyl group compound, thereby providing a fluorinated (aryl or heteroaryl) compound, wherein, in Formula (I):
R 1 and R 2 are independently selected from the group consisting of C1-30 aliphatic, aromatic, heteroaliphatic or heteroaromatic hydrocarbons, each of which is optionally substituted with at least one substituent selected from C1-20 straight chain, branched or cyclic alkyl, alkenyl, alkynyl, aryl, heteroaryl, each being optionally further substituted by one or more heteroatoms, or heteroatoms,
R 3 and R 4 are independently selected from the group consisting of C1-30 aliphatic, aromatic, heteroaliphatic or heteroaromatic hydrocarbons, each of which is optionally substituted with at least one substituent selected from C1-20 straight chain, branched or cyclic alkyl, alkenyl, alkynyl, aryl, heteroaryl, each being optionally further substituted by one or more heteroatoms, or heteroatoms, or
R 3 and R 4 together with N—C═N to which they are bonded form a C4-20 ring which may be saturated or unsaturated aliphatic or aromatic, which C4-20 ring is optionally substituted with at least one substituent selected from C1-20 straight chain, branched or cyclic alkyl, alkenyl, alkenyl, aryl, heteroaryl, the C4-20 ring being optionally further substituted by one or more heteroatoms, or heteroatoms, and the C4-20 ring optionally fused to a C5-20 hydrocarbon ring which may be unsaturated or saturated aliphatic or aromatic including heteroatoms, which C5-20 hydrocarbon ring is optionally substituted by at least one substituent selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, nitro, cyano, halo, C1-6 haloalkyl, C1-6 alkoxy, optionally substituted C6-10 aryl, optionally substituted C6-10 aralkyl, optionally substituted 5-10 membered heteroaryl, optionally substituted 4-10 membered heterocyclyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclylalkyl, and acyl, each substituent for the C5-20 hydrocarbon ring being optionally further substituted by one or more heteroatoms;
X being an anion; and
L being a leaving group,
wherein the Cp-Ru-(aryl or heteroaryl)-complex is a Ru complex with a C5 to C30 aromatic or heteroaromatic mono- to polycyclic ring system having at least one aromatic or heteroaromatic ring with one hydroxyl group on said ring, said ring system optionally being further substituted with straight chain, branched or cyclic alkyl, alkenyl or alkynyl having 1 to 20 carbon atoms, or heteroatoms being selected from halogen, N, O or S, each of said alkyl, alkenyl, alkynyl, or heteroatoms being optionally further substituted or each of said alkyl, alkenyl, alkynyl, or heteroatoms being optionally part of an aliphatic or aromatic ring system, and at least one further ligand optionally being further substituted by one or more heteroatoms or by C1-6 alkyl, optionally being further substituted with halogen.

2. The method according to claim 1 , wherein the compound of Formula (I) has the Formula (II):

and the method comprises contacting a compound of Formula (II) with the Cp-Ru-(aryl or heteroaryl)-complex and a fluorine source under conditions sufficient to fluorinate the aryl or heteroaryl compound bearing the hydroxyl group, thereby providing a fluorinated aryl compound,
wherein, in Formula (II):
R 1 and R 2 are independently selected from the group consisting of C1-6 alkyl, C6-10 aryl, C6-10 aralkyl, 5-10 membered heteroaryl, 5-10 membered heteroaralkyl, 4-10 membered heterocyclyl, 4-10 membered heterocyclylalkyl, 3-10 membered carbocyclyl, and 3-10 membered carbocyclylalkyl, each being optionally further substituted by one or more heteroatoms;
R 5 and R 6 are independently selected from the group consisting of hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, nitro, cyano, halo, C1-6 haloalkyl, C1-6 alkoxy, optionally substituted C6-10 aryl, optionally substituted C6-10 aralkyl, optionally substituted 5-10 membered heteroaryl, optionally substituted 4-10 membered heterocyclyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclylalkyl, acyl, each being optionally further substituted by one or more heteroatoms; or
R 5 and R 6 may form together a C5-20 hydrocarbon ring which may be unsaturated or saturated aliphatic or aromatic including heteroatoms, optionally being substituted by C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, nitro, cyano, halo, C1-6 haloalkyl, C1-6 alkoxy, optionally substituted C6-10 aryl, optionally substituted C6-10 aralkyl, optionally substituted 5-10 membered heteroaryl, optionally substituted 4-10 membered heterocyclyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclylalkyl, acyl, each being optionally further substituted by one or more heteroatoms;
X being an anion; and
L is a leaving group,
wherein the Cp-Ru-(aryl or heteroaryl)-complex is a Ru complex comprising an aryl or heteroaryl compound bearing a hydroxyl group as a ligand and at least one further ligand optionally being substituted by C1-6 alkyl, haloalkyl or halogen.

3. The method according to claim 2 , wherein in Formula (II):
R 1 and R 2 are independently selected from the group consisting of C6-10 aryl, C6-10 aralkyl, 5-10 membered heteroaryl, 5-10 membered heteroaralkyl, each of which is optionally substituted at least one substituent selected from the group consisting of halogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 alkoxy, optionally substituted with at least one heterosubstituent;
R 5 and R 6 are independently selected from the group consisting of hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 alkoxy, optionally substituted C6-10 aryl, optionally substituted C6-10 aralkyl, optionally substituted 5-10 membered heteroaryl, optionally substituted 4-10 membered heterocyclyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclylalkyl, acyl, optionally substituted with at least one heterosubstituent,
L is a leaving group which is not detrimentally interacting in the method; and
X represents an anion.

4. The method according to claim 2 , wherein the compound of Formula (II) is represented by the following formula (III):

wherein each R 7 is independently selected from halogen, optionally substituted C1-8 alkyl, in particular iso-propyl, C1-8 haloalkyl, C1-8 alkoxy, optionally substituted C6-12 aryl, and optionally substituted 6-12 membered heteroaryl, and wherein “substituted” refers to substituted with a substituent selected from the group consisting of alkyl, cycloalkyl, haloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, heterocyclyl, alkenyl, alkynyl, cycloalkenyl, heterocycloalkenyl, alkoxy, haloalkoxy, halogen, hydroxy, carboxy, carboxylate, cyano, nitro, amino, alkylamino, dialkylamino, sulfate, phosphate, methylenedioxy —O—CH 2 —O— wherein oxygens are attached to vicinal atoms, ethylenedioxy, oxo, thioxo (e.g., C═S), imino (alkyl, aryl, aralkyl), S(O) n -alkyl (where n is 0-2), S(O) n -aryl (where n is 0-2

Assignees

• Studiengesellschaft Kohle Mbh
• Harvard College

Inventors

• Ritter Tobias
• Neumann Constanze
• Beyzavi Mohammad Hassan
• Strebl-Bantillo Martin Georg
• Mandal Debashis

Classifications

• C07D451/04

  with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system · CPC title

• C07C231/12

  by reactions not involving the formation of carboxamide groups · CPC title

• C07C17/16 Primary

  of hydroxyl groups · CPC title

• C07D279/30

  with acyl radicals attached to the ring nitrogen atom · CPC title

• C07D487/04

  Ortho-condensed systems · CPC title