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

Patent metadata

Field	Value
Publication number	US-2017002012-A1
Application number	US-201515113730-A
Country	US
Kind code	A1
Filing date	Jan 26, 2015
Priority date	Jan 24, 2014
Publication date	Jan 5, 2017
Grant date	—

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 group
and 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

1 - 20 . (canceled)

21 . A process comprising reacting a (hetero)aryl 1,3-dipole compound with a (hetero)cycloalkyne, wherein:
a (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 σ p and/or the meta-Hammett substituent constant σ m , 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;

wherein 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; and wherein the (hetero)cycloalkyne is a (hetero)cyclooctyne or a (hetero)cyclononyne according to Formula (1):

wherein:
when the (hetero)cycloalkyne is a (hetero)cyclooctyne:
a is 1, 2, 3 or 4;
a′ is 1, 2, 3 or 4;
a″ is 1, 2, 3 or 4;
with the proviso that a+a′+a″=4; and
n is 0-8; or

when the (hetero)cycloalkyne is a (hetero)cyclononyne:
a is 1, 2, 3, 4 or 5;
a′ is 1, 2, 3, 4 or 5;
a″ is 1, 2, 3, 4 or 5;
with the proviso that a+a′+a″=5; and
n is 0-10;

R 1 is independently selected from the group consisting of —OR 2 , —NO 2 , —CN, —S(O) 2 R 2 , C 1 -C 24 alkyl groups, C 3 -C 24 cycloalkyl groups, C 2 -C 24 (hetero)aryl groups, C 3 -C 24 alkyl(hetero)aryl groups and C 3 -C 24 (hetero)arylalkyl groups, wherein the alkyl groups, cycloalkyl groups, (hetero)aryl groups, alkyl(hetero)aryl groups and (hetero)arylalkyl groups are optionally substituted, wherein the alkyl groups, cycloalkyl groups, alkyl(hetero)aryl groups and (hetero)arylalkyl groups are optionally interrupted by one or more heteroatoms selected from the group consisting of O, S and N, and wherein R 2 is independently selected from the group consisting of hydrogen, halogen, C 1 -C 24 alkyl groups, C 3 -C 24 cycloalkyl groups, C 2 -C 24 (hetero)aryl groups, C 3 -C 24 alkyl(hetero)aryl groups and C 3 -C 24 (hetero)arylalkyl groups;
B and B′ are independently selected from the group consisting of O, S, C(O), NR 3 and C(R 3 ) 2 , wherein R 3 is independently selected from the group consisting of hydrogen, R 1 or (L) p -(A) r ;
optionally, when n is 2 or more, two R 1 groups may together form a (hetero)cycloalkyl group, the (hetero)cycloalkyl group optionally being substituted with an (L) p -(A) r substituent;
optionally, when a″ is 2 or more and n is 2 or more, two R 1 groups present on adjacent a″-C-atoms may together form a (hetero)aryl group, the (hetero)aryl group optionally being substituted with an (L) p -(A) r substituent;
p is 0 or 1;
r is 1-4;
L is a linker;
A is independently selected from the group consisting of D, E and Q, wherein D, E and Q are as defined below;
q is 0-4;
with the proviso that if q is 0, then B and/or B′ is NR 3 wherein R 3 is (L) p -(A) r , and/or B and/or B′ is C(R 3 ) 2 wherein one or more R 3 is (L) p -(A) r , and/or n is 2 or more and two R 1 groups together form a (hetero)cycloalkyl group wherein the (hetero)cycloalkyl group is substituted with an (L) p -(A) r substituent, and/or a″ is 2 or more and n is 2 or more and two R 1 groups present on adjacent a″-C-atoms together form a (hetero)aryl group wherein the (hetero)aryl group is substituted with an (L) p -(A) r substituent;
D is a molecule of interest;
E is a solid surface; and
Q is a functional group.

22 . The process according to claim 21 , wherein the molecule of interest is selected from the group consisting of a reporter molecule, a diagnostic compound, an active substance, an enzyme, an amino acid, a (non-catalytic) protein, a peptide, a polypeptide, an oligonucleotide, a monosaccharide, an oligosaccharide, a polysaccharide, a glycan, a (poly)ethylene glycol diamine, a polyethylene glycol chain, a polyethylene oxide chain, a polypropylene glycol chain, a polypropylene oxide chain and a 1,x-diaminoalkane, wherein x is the number of carbon atoms in the alkane.

23 . The process according to claim 21 , wherein the solid surface is selected from the group consisting of a functional surface, a nanomaterial, a carbon nanotube, a fullerene, a virus capsid, a metal surface, a metal alloy surface and a polymer surface.

24 . The process according to claim 21 , wherein Q is selected from the groups consisting of hydrogen, halogen, R 11 , —CH═C(R 11 ) 2 , —C≡CR 11 , —[C(R 11 ) 2 C(R 11 ) 2 O] q —R 11 wherein q is in the range of 1 to 200, —CN, —N 3 , —
NCX, —XCN, —XR 11 , —N(R 11 ) 2 , — + N(R 11 ) 3 , —C(X)N(R 11 ) 2 , —C(R 11 ) 2 XR 11 , —C(X)R 11 , —C(X)XR 11 , —S(O)R 11 , —S(O) 2 R 11 , —S(O)OR 11 , —S(O) 2 OR 11 , —S(O)N(R 11 ) 2 , —S(O) 2 N(R 11 ) 2 , —OS(O)R 11 , —OS(O) 2 R 11 , —OS(O)OR 11 , —OS(O) 2 OR 11 , —P(O)(R 11 )(OR 11 ), —P(O)(OR 11 ) 2 , —OP(O)(OR 11 ) 2 , —Si(R 11 ) 3 , —XC(X) R 11 , —XC(X)XR 11 , —XC(X)N(R 11 ) 2 , —N(R 11 )C(X)R 11 , —N(R 11 )C(X)XR 11 and —N(R 11 )C(X)N(R 11 ) 2 , wherein X is oxygen or sulphur and wherein R 11 is independently selected from the group consisting of hydrogen, halogen, C 1 -C 24 alkyl groups, C 3 -C 24 cycloalkyl groups, C 2 -C 24 (hetero)aryl groups, C 3 -C 24 alkyl(hetero)aryl groups and C 3 -C 24 (hetero)arylalkyl groups, the C 1 -C 24 alkyl groups, C 3 -C 24 cycloalkyl groups, C 2 -C 24 (hetero)aryl groups, C 3 -C 24 alkyl(hetero)aryl groups and C 3 -C 24 (hetero)arylalkyl groups optionally substituted and optionally interrupted by one or more heteroatoms selected from O and N.

25 . The process according to claim 21 , 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 as defined in claim 21 ;
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, E and Q are as defined in claim 21 ;
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 σ p and/or the meta-Hammett substituent constant σ m ; 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, cycl

Assignees

• Synaffix Bv

Inventors

• Van Delft Floris Louis
• Dommerholt Frederik Jan

Classifications

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• A61K47/48061

  Human Necessities · mapped topic

• A61K47/48584

  Human Necessities · mapped topic

• C07H19/10

  with the saccharide radical esterified by phosphoric or polyphosphoric acids · CPC title

• C07K14/473

  alpha-Glycoproteins · CPC title