Process for the cycloaddition of a (hetero)aryl 1,3-dipole compound with a (hetero)cycloalkyne

Patent metadata

Field	Value
Publication number	US-12084448-B2
Application number	US-202117503138-A
Country	US
Kind code	B2
Filing date	Oct 15, 2021
Priority date	Jan 24, 2014
Publication date	Sep 10, 2024
Grant date	Sep 10, 2024

Abstract

A process is provided, comprising reacting a (hetero)aryl 1,3-dipole compound with a (hetero)cycloalkyne, wherein the (hetero)aryl 1,3-dipole compound comprises a 1,3-dipole functional group bonded to a (hetero)aryl group, and wherein the (hetero)aryl 1,3-dipole compound is a (hetero)aryl azide or a (hetero)aryl diazo compound; wherein:(i) the (hetero)aryl group of the (hetero)aryl 1,3-dipole compound comprises a substituent(ii) the (hetero)aryl group of the (hetero)aryl 1,3-dipole compound is an electron-poor (hetero)aryl groupand wherein the (hetero)cycloalkyne is a (hetero)cyclooctyne or a (hetero)cyclononyne according to Formula (1). The invention also relates to the products obtainable by the process according to the invention.

First claim

What is claimed is:

1. A process for preparing a product of a 1,3-dipolar cycloaddition reaction comprising reacting a (hetero)aryl 1,3-dipole compound with a (hetero)cycloalkyne,
wherein:
the (hetero)aryl 1,3-dipole compound is defined as a compound comprising a 1,3-dipole functional group, wherein the 1,3-dipole functional group is bonded to a (hetero)aryl group, and wherein the (hetero)aryl 1,3-dipole compound is a (hetero)aryl azide or a (hetero)aryl diazo compound;
wherein:
(i) the (hetero)aryl group of the (hetero)aryl 1,3-dipole compound comprises one or more substituents having a positive value for the para-Hammett substituent constant op and/or the meta-Hammett substituent constant om, and/or
(ii) the (hetero)aryl group of the (hetero)aryl 1,3-dipole compound is an electron-poor (hetero)aryl group, wherein an electron-poor (hetero)aryl group is:
(ii-a) a (hetero)aryl group wherein the (hetero)aromatic ring system is bearing a positive charge, and/or
(ii-b) a (hetero)aryl group wherein the ratio {number of π-electrons present in the (hetero)aromatic ring system}: {number of protons present in the nuclei of the (hetero)aromatic ring system} is lower than 0.167 for a 6-membered ring, or lower than 0.200 for a 5-membered ring;
the (hetero)cycloalkyne is an aliphatic (hetero)cycloalkyne, wherein an aliphatic (hetero)cycloalkyne is defined as a (hetero)cycloalkyne wherein both sp 1 C-atoms of the (hetero)cycloalkyne carbon-carbon triple bond are bonded to an sp 3 C-atom.

2. The process according to claim 1 , wherein the (hetero)cycloalkyne is an aliphatic cycloalkyne interrupted by heteroatoms selected from oxygen, nitrogen, or sulfur.

3. The process according to claim 2 , wherein the heteroatom is sulfur.

4. The process according to claim 1 , wherein the (hetero)aryl 1,3-dipole compound is according to Formula (2):

wherein:
t is 0 or 1;
u is 1-4;
g is 0 or 1;
m is 0-8;
with the proviso that when m is 0, then T is an electron-poor (hetero)aryl group, wherein an electron-poor (hetero)aryl group is:
(ii-a) a (hetero)aryl group wherein the (hetero)aromatic ring system is bearing a positive charge, and/or
(ii-b) a (hetero)aryl group wherein the ratio {number of π-electrons present in the (hetero)aromatic ring system}: {number of protons present in the nuclei of the (hetero)aromatic ring system} is lower than 0.167 for a 6-membered ring, or lower than 0.200 for a 5-membered ring;
Z is an azide functional group or a diazo functional group;
L′ is a linker;
A′ is independently selected from the group consisting of D, E and Q, wherein D is a molecule of interest, E is a solid surface, and Q is a functional group;
T is selected from the group consisting of (hetero)aryl groups;
R 4 is independently selected from the group consisting of electron-withdrawing substituents having a positive value for the para-Hammett substituent constant op and/or the meta-Hammett substituent constant σm; and
W is selected from the group consisting of C 1 -C 24 alkylene groups, C 2 -C 24 alkenylene groups, C 3 -C 24 cycloalkylene groups, C 2 -C 24 (hetero)arylene groups, C 3 -C 24 alkyl(hetero)arylene groups and C 3 -C 24 (hetero)arylalkylene groups, wherein the alkylene groups, alkenylene groups, cycloalkylene groups, (hetero)arylene groups, alkyl(hetero)arylene groups and (hetero)arylalkylene groups are optionally substituted, and wherein the alkylene groups, alkenylene groups, cycloalkylene groups, (hetero)arylene groups, alkyl(hetero)arylene groups and (hetero)arylalkylene groups are optionally interrupted by one or more heteroatoms selected from the group consisting of O, S and N.

5. The process according to claim 4 , wherein T is selected from the group consisting of phenyl groups, pyridinyl groups, pyridiniumyl groups, pyrimidinyl groups, pyrimidinium groups, pyrazinyl groups, pyradizinyl groups, pyrrolyl groups, pyrrolium groups, furanyl groups, thiophenyl groups, diazolyl groups, quinolinyl groups, imidazolyl groups, oxazolyl groups and oxazolium groups, said groups optionally substituted with one or more substituents independently selected from the group consisting of C 1 -C 12 alkyl groups, C 2 -C 12 alkenyl groups, C 2 -C 12 alkynyl groups, C 3 -C 12 cycloalkyl groups, C 5 -C 12 cycloalkenyl groups, C 8 -C 12 cycloalkynyl groups, C 1 -C 12 alkoxy groups, C 2 -C 12 alkenyloxy groups, C 2 -C 12 alkynyloxy groups, C 3 -C 12 cycloalkyloxy groups, amino groups and silyl groups, wherein the silyl groups can be represented by the formula (R Si ) 3 Si—, wherein R Si is independently selected from the group consisting of C 1 -C 12 alkyl groups, C 2 -C 12 alkenyl groups, C 2 -C 12 alkynyl groups, C 3 -C 12 cycloalkyl groups, C 1 -C 12 alkoxy groups, C 2 -C 12 alkenyloxy groups, C 2 -C 12 alkynyloxy groups and C 3 -C 12 cycloalkyloxy groups, wherein the alkyl groups, alkenyl groups, alkynyl groups, cycloalkyl groups, alkoxy groups, alkenyloxy groups, alkynyloxy groups and cycloalkyloxy groups are optionally substituted, the alkyl groups, the alkoxy groups, the cycloalkyl groups and the cycloalkoxy groups being optionally interrupted by one of more hetero-atoms selected from the group consisting of O, N and S.

6. The process according to claim 1 , wherein the (hetero)aryl 1,3-dipole compound is according to Formula (3a), (3b), (3c), (3d), (3e) or (3f):

wherein:
s is 0 or 1;
t is 0 or 1;
u is 1-4;
g is 0 or 1;
m is 0-8;
with the proviso that when m is 0, then T is an electron-poor (hetero)aryl group, wherein an electron-poor (hetero)aryl group is:
(ii-a) a (hetero)aryl group wherein the (hetero)aromatic ring system is bearing a positive charge, and/or
(ii-b) a (hetero)aryl group wherein the ratio {number of π-electrons present in the (hetero)aromatic ring system}: {number of protons present in the nuclei of the (hetero)aromatic ring system} is lower than 0.167 for a 6-membered ring, or lower than 0.200 for a 5-membered ring;
Z is an azide functional group or a diazo functional group;
L′ is a linker;
A′ is independently selected from the group consisting of D, E and Q, wherein D is a molecule of interest, E is a solid surface, and Q is a functional group;
R 4 is independently selected from the group consisting of electron-withdrawing substituents having a positive value for the para-Hammett substituent constant op and/or the meta-Hammett substituent constant σm;
W is selected from the group consisting of C 1 -C 24 alkylene groups, C 2 -C 24 alkenylene groups, C 3 -C 24 cycloalkylene groups, C 2 -C 24 (hetero)arylene groups, C 3 -C 24 alkyl(hetero)arylene groups and C 3 -C 24 (hetero)arylalkylene groups, wherein the alkylene groups, alkenylene groups, cycloalkylene groups, (hetero)arylene groups, alkyl(hetero)arylene groups and (hetero)arylalkylene groups are optionally substituted, and wherein the alkylene groups, alkenylene groups, cycloalkylene groups, (hetero)arylene groups, alkyl(hetero)arylene groups and (hetero)arylalkylene groups are optionally interrupted by one or more heteroatoms selected from the group consisting of O, S and N;
G is independently selected from the group consisting of N, CH, CR 4 , CR 5 , C-(W) g -[(L′) t -(A′) u ], N+R 5 and N+-(W) g -[(L′) t -(A′) u ], wherein R 5 is selected from the group consisting of C 1 -C 24 alkyl groups;
G′ is independently selected from the group consisting of O, S

Assignees

• Synaffix Bv

Inventors

• Van Delft Floris Louis
• Dommerholt Frederik Jan

Classifications

• C07K14/473

  alpha-Glycoproteins · CPC title

• C07C271/18

  to carbon atoms of hydrocarbon radicals substituted by doubly-bound oxygen atoms · CPC title

• C07C269/06

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

• A61K47/60

  the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol · CPC title

• A61K47/545

  Heterocyclic compounds (A61K47/558 takes precedence) · CPC title