U.S. patent application number 15/067865 was filed with the patent office on 2017-09-14 for alpha-hydroxy-beta-azido-tetrazoles.
The applicant listed for this patent is CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE, UNIVERSITE VERSAILLES SAINT-QUENTIN-EN-YVELINES. Invention is credited to Francois COUTY, Bruno DROUILLAT, Pierre QUINODOZ, Karen WRIGHT.
Application Number | 20170260171 15/067865 |
Document ID | / |
Family ID | 59788708 |
Filed Date | 2017-09-14 |
United States Patent
Application |
20170260171 |
Kind Code |
A1 |
WRIGHT; Karen ; et
al. |
September 14, 2017 |
ALPHA-HYDROXY-BETA-AZIDO-TETRAZOLES
Abstract
Alpha-hydroxy-beta-azido tetrazole compounds of formula (I):
##STR00001## a process for manufacturing alpha-hydroxy-beta-azido
tetrazoles of formula (I), and their use for synthesizing new
compounds, e.g. in "click" chemistry.
Inventors: |
WRIGHT; Karen; (Saint-Cloud,
FR) ; COUTY; Francois; (Malakoff, FR) ;
QUINODOZ; Pierre; (Saint-Julien-en-Genevois, FR) ;
DROUILLAT; Bruno; (Saint-Cloud, FR) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE
UNIVERSITE VERSAILLES SAINT-QUENTIN-EN-YVELINES |
Paris
Versailles Cedex |
|
FR
FR |
|
|
Family ID: |
59788708 |
Appl. No.: |
15/067865 |
Filed: |
March 11, 2016 |
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D 403/14 20130101;
C07D 409/06 20130101; C07D 257/04 20130101; C07D 403/08
20130101 |
International
Class: |
C07D 409/06 20060101
C07D409/06; C07D 403/08 20060101 C07D403/08; C07D 403/14 20060101
C07D403/14; C07D 257/04 20060101 C07D257/04 |
Claims
1. An alpha-hydroxy-beta-azido-tetrazole compound of formula (I):
##STR00097## wherein R.sup.1 and R.sup.2 are each independently
selected from the groups consisting of hydrogen, hydrocarbyl, aryl,
heteroaryl, hydrocarbylaryl, arylhydrocarbyl,
hydrocarbylheteroaryl, and heteroarylhydrocarbyl groups; or R.sup.1
and R.sup.2 form together a hydrocarbyl, aryl, heteroaryl,
hydrocarbylaryl, arylhydrocarbyl, hydrocarbylheteroaryl or
heteroarylhydrocarbyl group; wherein the group is optionally
substituted by at least one hydrocarbyl, aryl, heteroaryl, oxo,
hydroxyl, amido, amino, nitro, carboxylo, formyl, halo, thioxo or
sulfhydryl; and wherein the group is optionally interrupted or
terminated by at least one of --O--, --S-- or --NR.sup.N--, wherein
R.sup.N is hydrogen, hydrocarbyl, aryl, or a combination thereof,
and wherein the nitrogen and/or sulfur atoms are optionally
oxidized; or a stereoisomer, salt or solvent thereof.
2. The compound according to claim 1, wherein R.sup.1 and R.sup.2
are each independently selected from the group consisting of
hydrogen, alkyl, alkenyl, aryl, heteroaryl, alkylaryl, arylalkyl,
alkenylaryl, and arylalkenyl groups; wherein the groups are
optionally substituted by at least one hydroxyl, alkyl, alkenyl,
aryl, alkylaryl, arylalkyl, amino, nitro, halo and sulfhydryl; and
wherein the groups are optionally interrupted or terminated by at
least one of --O--, --S--, and --NR.sup.N--, wherein R.sup.N is
selected from the group consisting of hydrogen, alkyl, alkenyl, and
a combination thereof.
3. The compound according to claim 1, wherein R.sup.1 and R.sup.2
are each independently selected from the group consisting of
hydrogen, alkyl, alkenyl, aryl, heteroaryl, alkylaryl and
alkenylaryl groups; wherein the groups are optionally substituted
by at least one hydroxyl, alkyl, amino, nitro, halo and sulfhydryl;
and wherein the groups are optionally interrupted or terminated by
at least one of --O--, --S--, and --NR.sup.N--, wherein R.sup.N is
selected from the group consisting of hydrogen, alkyl, alkenyl,
aryl, alkylaryl, and arylalkyl.
4. The compound according to claim 1, wherein R.sup.1 and R.sup.2
are each independently selected from the group consisting of
hydrogen, alkyl, aryl and alkenylaryl groups; and the groups are
optionally substituted by at least one halo group.
5. The compound according to claim 1, wherein R.sup.1 and R.sup.2
form together a group selected from the group consisting of alkyl,
alkenyl, aryl, alkylaryl, arylalkyl, alkenylaryl and arylalkenyl;
wherein the group is optionally substituted by at least one
hydroxyl, alkyl, alkenyl, aryl, alkylaryl, arylalkyl, amino, nitro,
halo and sulfhydryl; and wherein the group is optionally
interrupted or terminated by at least one of --O--, --S--, and
--NR.sup.N--, wherein R.sup.N is selected from the group consisting
of hydrogen, alkyl, alkenyl, aryl, and a combination thereof.
6. The compound according to claim 1, wherein R.sup.1 and R.sup.2
form together a group selected from the group consisting of alkyl,
alkylaryl and arylalkyl; wherein the group is optionally
substituted by at least one hydroxyl, alkyl, amino, nitro and halo;
and wherein the group is optionally interrupted or terminated by at
least one of --O-- and --NR.sup.N--, wherein R.sup.N is selected
from the group consisting of hydrogen, alkyl, alkenyl, aryl,
alkylaryl, and arylalkyl.
7. The compound according to claim 1, wherein R.sup.1 and R.sup.2
form together an alkyl or aryl group.
8. The compound according to claim 1, selected from the group
consisting of: 2-azido-2-phenyl-1-(1H-tetrazol-5-yl)ethan-1-ol;
2-azido-2-(naphthalen-2-yl)-1-(1H-tetrazol-5-yl)ethan-1-ol;
2-azido-2-(4-chlorophenyl)-1-(1H-tetrazol-5-yl)ethan-1-ol;
2-azido-1-(1H-tetrazol-5-yl)-2-(thiophen-2-yl)ethan-1-ol;
2-azido-4-phenyl-1-(1H-tetrazol-5-yl)but-3-en-1-ol;
2-azido-1-(1H-tetrazol-5-yl)nonan-1-ol;
2-azido-2-ethyl-1-(1H-tetrazol-5-yl)butan-1-ol;
2-azido-2,2-diphenyl-1-(1H-tetrazol-5-yl)ethan-1-ol;
(1-azidocyclopentyl) (1H-tetrazol-5-yl)methanol;
(1-azidocyclohexyl)(1H-tetrazol-5-yl)methanol; (1-azidocycloheptyl)
(1H-tetrazol-5-yl)methanol;
(1-azidocyclooctyl)(1H-tetrazol-5-yl)methanol; and
(9-azido-9H-fluoren-9-yl) (1H-tetrazol-5-yl)methanol.
9. A process for manufacturing the compound of formula (I)
according to claim 1, the method comprising: starting from an
epoxynitrile of formula (II): ##STR00098## and performing the
following steps: (a) reacting the compound of formula (II) with an
azide in presence of an organometallic catalyst, and (b) performing
a hydrolysis reaction to afford compound (I).
10. The process of claim 9, wherein the azide is trimethylsilyl
azide.
11. The process of claim 9, wherein the organometallic catalyst is
dibutyltin oxide.
12. The process of claim 9, wherein step (a) is executed in a
solvent, said solvent being toluene.
13. The process of claim 9, wherein step (a) is executed at
60.degree. C. for 18 h.
14. The process of claim 9, wherein the hydrolysis of step (b) is
acidic hydrolysis.
15. An alpha-hydroxy-beta-triazole-tetrazole compound of formula
(III): ##STR00099## wherein R.sup.1 and R.sup.2 are each
independently selected from the group consisting of hydrogen,
hydrocarbyl, aryl, heteroaryl, hydrocarbylaryl, arylhydrocarbyl,
hydrocarbylheteroaryl, or heteroarylhydrocarbyl groups; or R.sup.1
and R.sup.2 form together a group being hydrocarbyl, aryl,
heteroaryl, hydrocarbylaryl, arylhydrocarbyl,
hydrocarbylheteroaryl, and heteroarylhydrocarbyl groups; wherein
the group is optionally substituted by at least one hydrocarbyl,
aryl, heteroaryl, oxo, hydroxyl, amido, amino, nitro, carboxylo,
formyl, halo, thioxo or sulfhydryl; wherein the group is optionally
interrupted or terminated by at least one of --O--, --S-- or
--NR.sup.N--, wherein R.sup.N is hydrogen, hydrocarbyl, aryl, or a
combination thereof, and wherein the nitrogen or sulfur atoms are
optionally oxidized; and wherein R.sup.3 is hydrogen, an organic
group or an organic molecule; or a stereoisomer, salt or solvent
thereof.
16. The compound according to claim 15, wherein R.sup.3 is
hydrogen, hydroxyl, amido, amino, cyano, tetrazolyl, triazolyl,
nitro, borono, carboxylo, formyl, halo, haloformyl, phosphono,
phosphate or sulfhydryl.
17. The compound according to claim 15, wherein R.sup.3 is
hydrogen, hydrocarbyl, aryl, heteroaryl, hydrocarbylaryl,
arylhydrocarbyl, hydrocarbylheteroaryl, or heteroarylhydrocarbyl;
wherein the group is optionally substituted by at least one group
being hydrocarbyl, aryl, heteroaryl, oxo, hydroxyl, amido, amino,
cyano, tetrazolyl, triazolyl, nitro, carboxylo, formyl, halo,
thioxo or sulfhydryl; wherein the group is optionally interrupted
or terminated by at least one of --O--, --S-- or --NR.sup.N--,
wherein R.sup.N is hydrogen, hydrocarbyl, aryl, or a combination
thereof, and wherein the nitrogen or sulfur atoms are optionally
oxidized.
18. The compound according to claim 15, wherein R.sup.3 is a
carbohydrate, an amino acid, a peptide or a nucleoside.
19. The compound according to claim 15, wherein R.sup.3 is selected
from the group consisting of alkyl, alkenyl, aryl, heteroaryl,
alkylaryl, arylalkyl, alkenylaryl, arylalkenyl, alkylheteroaryl,
and heteroarylalkyl groups; wherein the group is optionally
substituted by at least one alkyl, alkenyl, aryl, heteroaryl,
alkylaryl, arylalkyl, oxo, hydroxyl, amido, amino, tetrazolyl,
triazolyl, nitro, carboxylo, formyl, halo, thioxo or sulfhydryl;
and wherein the group is optionally interrupted or terminated by at
least one of --O--, --S-- or --NR.sup.N--, wherein R.sup.N is
selected from the group consisting of hydrogen, alkyl, alkenyl,
aryl, and a combination thereof.
20. The compound according to claim 15, selected from the group
consisting of:
(1-(4-phenyl-1H-1,2,3-triazol-1-yl)cyclohexyl)(1H-tetrazol-5-yl)methanol;
(1-(4-phenyl-1H-1,2,3-triazol-1-yl)cycloheptyl)
(1H-tetrazol-5-yl)methanol;
(1-(4-phenyl-1H-1,2,3-triazol-1-yl)cyclooctyl)(1H-tetrazol-5-yl)methanol;
tert-butyl
1-(1-(hydroxy(1H-tetrazol-5-yl)methyl)cyclooctyl)-1H-1,2,3-triazole-4-car-
boxylate;
(1-(4-(3-chloropropyl)-1H-1,2,3-triazol-1-yl)cyclooctyl)(1H-tetr-
azol-5-yl)methanol;
2-(1-(1-(hydroxy(1H-tetrazol-5-yl)methyl)cyclooctyl)-1H-1,2,3-triazol-4-y-
l)ethan-1-ol;
2-ethyl-2-(4-phenyl-1H-1,2,3-triazol-1-yl)-1-(1H-tetrazol-5-yl)butan-1-ol-
;
2-(4-hexyl-1H-1,2,3-triazol-1-yl)-2-phenyl-1-(1H-tetrazol-5-yl)ethan-1-o-
l;
2-(4-hexyl-1H-1,2,3-triazol-1-yl)-2,2-diphenyl-1-(1H-tetrazol-5-yl)etha-
n-1-ol;
2-(4-(3-chloropropyl)-1H-1,2,3-triazol-1-yl)-2,2-diphenyl-1-(1H-te-
trazol-5-yl)ethan-1-ol; and tert-butyl
1-(2-hydroxy-1,1-diphenyl-2-(1H-tetrazol-5-yl)ethyl)-1H-1,2,3-triazole-4--
carboxylate.
Description
FIELD OF INVENTION
[0001] The present invention pertains to chemistry, especially to
organic chemistry and to the synthesis of organic compounds.
[0002] The present invention relates to alpha, beta-substituted
tetrazole compounds, especially alpha-hydroxy-beta-azido-tetrazole
compounds, and their manufacturing process. The present invention
further relates to the use of alpha-hydroxy-beta-azido-tetrazoles
for synthesizing new compounds, especially but not limitatively in
"click" chemistry.
BACKGROUND OF INVENTION
[0003] Tetrazoles have found applications in various domains
including material science, energetic materials, coordination
chemistry, organic synthesis, and especially medicinal chemistry,
due to the fact that 5-substituted tetrazoles (5-ST) are
bioisosteres of carboxylic acids. Therefore, there is a need of
novel methods for introducing a tetrazole functional group in
compounds, e.g. in organic molecules.
[0004] The 1,3-dipolar cycloaddition (Huisgen reaction) of azides
and alkynes leads to 5-membered triazole heterocycles and has
gained considerable interest in the field of organic synthesis
since the development of copper (I)-catalysed procedures by Medal
and Tomoe. Copper-catalysed azide-alkyne cycloaddition (CuAAC) is a
well-known "click" reaction, which is very general and has many
attractive features, including: high or quantitative yields,
robustness, insensibility, orthogonality, and compatibly with
biological and polymerization conditions (Meldal, M. and Tomoe, C.
W., Chemical Reviews 2008, Vol. 108, pp. 2952-3015.). A
particularly advantageous aspect of CuAAC is that it allows
orthogonal ligation reactions, which means that a dedicated set of
reaction conditions will lead to a ligation reaction occurring
specifically on a functional group of a molecule, without affecting
the others.
[0005] Due to the popularity of CuAAC reaction, many libraries of
compatible azides and alkynes are available. However, there is a
need from improvement of the selectivity of CuAAC reactions and/or
reduction of the number of steps for the synthesis of complex
molecules. Therefore, there is still a need for novel reactants
having specific features advantageous for CuAAC and presenting a
variety of reactive groups, especially tetrazoles groups. There is
also a need for reactants comprising "latent" or "hidden"
functional groups, i.e. groups which will not react in CuAAC
conditions, but may be easily converted to azide or alkyne when
another reactive group is required, thus allowing sequential CuAAC
reactions.
[0006] The applicant surprisingly established that
alpha-hydroxy-beta-azido-tetrazoles could be useful molecular
scaffolds for chemical synthesis, in particular for sequenced
synthesis. Therefore, the applicant conceived and successfully
reduced to practice the manufacture of
alpha-hydroxy-beta-azido-tetrazoles and their use as reactant,
especially in "click" reactions.
SUMMARY
[0007] In a first aspect, the invention relates to an
alpha-hydroxy-beta-azido tetrazole compound of formula (I):
##STR00002##
wherein R.sup.1 and R.sup.2 are each independently hydrogen,
hydrocarbyl, aryl, heteroaryl, hydrocarbylaryl, arylhydrocarbyl,
hydrocarbylheteroaryl, or heteroarylhydrocarbyl groups; or R.sup.1
and R.sup.2 form together a group being hydrocarbyl, aryl,
heteroaryl, hydrocarbylaryl, arylhydrocarbyl, hydrocarbylheteroaryl
or heteroarylhydrocarbyl; [0008] wherein the group is optionally
substituted by at least one hydrocarbyl, heteroaryl, oxo, hydroxyl,
amido, amino, nitro, carboxylo, formyl, halo, thioxo or sulfhydryl;
[0009] wherein the group is optionally interrupted or terminated by
at least one group being --O--; --S--; or --NR.sup.N-- wherein
R.sup.N is hydrogen, hydrocarbyl, aryl, or a combination thereof;
and [0010] wherein the nitrogen or sulfur atoms substituting or
comprised in the group are optionally oxidized; and stereoisomers
thereof; and salts thereof; and solvates thereof.
[0011] According to an embodiment, R.sup.1 and R.sup.2 are each
independently selected from the group consisting of hydrogen,
alkyl, alkenyl, aryl, heteroaryl, alkylaryl, arylalkyl,
alkenylaryl, and arylalkenyl groups; wherein the groups are
optionally substituted by at least one group selected from the
group consisting of hydroxyl, alkyl, alkenyl, aryl, alkylaryl,
arylalkyl, amino, nitro, halo and sulfhydryl; and wherein the
groups are optionally interrupted or terminated by at least one
group selected from the group consisting of --O--; --S--; and
--NR.sup.N-- wherein R.sup.N is selected from the group consisting
of hydrogen, alkyl, alkenyl, aryl, and a combination thereof.
[0012] According to an embodiment, R.sup.1 and R.sup.2 are each
independently selected from the group consisting of hydrogen,
alkyl, alkenyl, aryl, heteroaryl, alkylaryl and alkenylaryl groups;
wherein the groups are optionally substituted by at least one group
selected from the group consisting of hydroxyl, alkyl, amino,
nitro, halo and sulfhydryl; and wherein the groups are optionally
interrupted or terminated by at least one group selected from the
group consisting of --O--; --S--; and --NR.sup.N-- wherein R.sup.N
is selected from the group consisting of hydrogen, alkyl, alkenyl,
aryl, alkylaryl, and arylalkyl.
[0013] According to an embodiment, R.sup.1 and R.sup.2 are each
independently selected from the group consisting of hydrogen,
alkyl, aryl and alkenylaryl groups; and the groups are optionally
substituted by at least one halo group.
[0014] According to an embodiment, R.sup.1 and R.sup.2 form
together a group selected from the group consisting of alkyl,
alkenyl, aryl, alkylaryl, arylalkyl, alkenylaryl and arylalkenyl;
wherein the group is optionally substituted by at least one group
selected from the group consisting of hydroxyl, alkyl, alkenyl,
aryl, alkylaryl, arylalkyl, amino, nitro, halo and sulfhydryl; and
wherein the group is optionally interrupted or terminated by at
least one group selected from the group consisting of --O--; --S--;
and --NR.sup.N-- wherein R.sup.N is selected from the group
consisting of hydrogen, alkyl, alkenyl, aryl, and a combination
thereof.
[0015] According to an embodiment, R.sup.1 and R.sup.2 form
together a group selected from the group consisting of alkyl,
alkylaryl and arylalkyl; wherein the group is optionally
substituted by at least one group selected from the group
consisting of hydroxyl, alkyl, amino, nitro and halo; and wherein
the group is optionally interrupted or terminated by at least one
group selected from the group consisting of --O-- and --NR.sup.N--
wherein R.sup.N is selected from the group consisting of hydrogen,
alkyl, alkenyl, aryl, alkylaryl, and arylalkyl.
[0016] According to an embodiment, R.sup.1 and R.sup.2 form
together a group selected from the group consisting of alkyl and
aryl.
[0017] According to an embodiment, the
alpha-hydroxy-beta-azido-tetrazole is selected from the group
consisting of: 2-azido-2-phenyl-1-(1H-tetrazol-5-yl)ethan-1-ol;
2-azido-2-(naphthalen-2-yl)-1-(1H-tetrazol-5-yl)ethan-1-ol;
2-azido-2-(4-chlorophenyl)-1-(1H-tetrazol-5-yl)ethan-1-ol;
2-azido-1-(1H-tetrazol-5-yl)-2-(thiophen-2-yl)ethan-1-ol;
2-azido-4-phenyl-1-(1H-tetrazol-5-yl)but-3-en-1-ol;
2-azido-1-(1H-tetrazol-5-yl)nonan-1-ol;
2-azido-2-ethyl-1-(1H-tetrazol-5-yl)butan-1-ol; and
2-azido-2,2-diphenyl-1-(1H-tetrazol-5-yl)ethan-1-ol;
(1-azidocyclopentyl)(1H-tetrazol-5-yl)methanol;
(1-azidocyclohexyl)(1H-tetrazol-5-yl)methanol; (1-azidocycloheptyl)
(1H-tetrazol-5-yl)methanol;
(1-azidocyclooctyl)(1H-tetrazol-5-yl)methanol; or
(9-azido-9H-fluoren-9-yl)(1H-tetrazol-5-yl)methanol.
[0018] In a second aspect, the invention relates to a process for
manufacturing a compound of formula (I) according to claim 1
comprising: starting from an epoxynitrile of formula (II):
##STR00003##
and performing the following steps: [0019] (a) reacting compound
(II) with an azide in presence of an organometallic catalyst, and
[0020] (b) performing an hydrolysis reaction to afford compound
(I).
[0021] According to an embodiment, the azide is trimethylsilyl
azide. According to an embodiment, the organometallic catalyst is
dibutyltin oxide. According to an embodiment, step (a) is executed
in a solvent, said solvent being toluene. According to an
embodiment, step (a) is executed at 60.degree. C. during 18 h.
According to an embodiment, step (b) of hydrolysis is acidic
hydrolysis.
[0022] In others aspects, the invention relates to an
alpha-hydroxy-beta-triazole-tetrazole compound of formula
(III):
##STR00004##
wherein R.sup.1 and R.sup.2 are each independently hydrogen,
hydrocarbyl, aryl, heteroaryl, hydrocarbylaryl, arylhydrocarbyl,
hydrocarbylheteroaryl, or heteroarylhydrocarbyl groups; or R.sup.1
and R.sup.2 form together a group being hydrocarbyl, aryl,
heteroaryl, hydrocarbylaryl, arylhydrocarbyl,
hydrocarbylheteroaryl, or heteroarylhydrocarbyl; [0023] wherein the
groups are optionally substituted by at least one group being
hydrocarbyl, aryl, heteroaryl, oxo, hydroxyl, amido, amino, nitro,
carboxylo, formyl, halo, thioxo or sulfhydryl; [0024] wherein the
groups are optionally interrupted or terminated by at least one
group being --O--; --S--; and --NR.sup.N-- wherein R.sup.N is
hydrogen, hydrocarbyl, aryl, or a combination thereof; [0025]
wherein the nitrogen or sulfur atoms substituting or comprised in
the group are optionally oxidized; and wherein R.sup.3 is hydrogen,
an organic group or an organic molecule; and stereoisomers thereof;
and salts thereof; and solvates thereof.
[0026] According to an embodiment, R.sup.3 is hydrogen, hydroxyl,
amido, amino, cyano, tetrazolyl, triazolyl, nitro, borono,
carboxylo, formyl, halo, haloformyl, phosphono, phosphate or
sulfhydryl.
[0027] According to an embodiment, R.sup.3 is hydrogen,
hydrocarbyl, aryl, heteroaryl, hydrocarbylaryl, arylhydrocarbyl,
hydrocarbylheteroaryl, or heteroarylhydrocarbyl; wherein the group
is optionally substituted by at least one group being hydrocarbyl,
heteroaryl, oxo, hydroxyl, amido, amino, cyano, tetrazolyl,
triazolyl, nitro, carboxylo, formyl, halo, thioxo or sulfhydryl;
and wherein the group is optionally interrupted or terminated by at
least one group being --O--; --S--; and --NR.sup.N-- wherein
R.sup.N is hydrogen, hydrocarbyl, aryl, or a combination thereof;
and wherein the nitrogen or sulfur atoms substituting or comprised
in the group are optionally oxidized.
[0028] According to an embodiment, R.sup.3 is a carbohydrate, an
amino acid, a peptide or a nucleoside.
[0029] According to an embodiment, R.sup.3 is selected from the
group consisting of alkyl, alkenyl, aryl, heteroaryl, alkylaryl,
arylalkyl, alkenylaryl, arylalkenyl, alkylheteroaryl, and
heteroarylalkyl groups; wherein the group is optionally substituted
by at least one group selected from the group consisting of alkyl,
alkenyl, aryl, heteroaryl, alkylaryl, arylalkyl, oxo, hydroxyl,
amido, amino, tetrazolyl, triazolyl, nitro, carboxylo, formyl,
halo, thioxo and sulfhydryl; and the group is optionally
interrupted or terminated by at least one group selected from the
group consisting of --O--; --S--; and --NR.sup.N-- wherein R.sup.N
is selected from the group consisting of hydrogen, alkyl, alkenyl,
aryl, and a combination thereof.
[0030] According to an embodiment, the
alpha-hydroxy-beta-triazolo-tetrazole is selected from the group
consisting of:
(1-(4-phenyl-1H-1,2,3-triazol-1-yl)cyclohexyl)(1H-tetrazol-5-yl)methanol;
(1-(4-phenyl-1H-1,2,3-triazol-1-yl)cycloheptyl)(1H-tetrazol-5-yl)methanol-
;
(1-(4-phenyl-1H-1,2,3-triazol-1-yl)cyclooctyl)(1H-tetrazol-5-yl)methanol-
; tert-butyl
1-(1-(hydroxy(1H-tetrazol-5-yl)methyl)cyclooctyl)-1H-1,2,3-triazole-4-car-
boxylate;
(1-(4-(3-chloropropyl)-1H-1,2,3-triazol-1-yl)cyclooctyl)(1H-tetr-
azol-5-yl)methanol;
2-(1-(1-(hydroxy(1H-tetrazol-5-yl)methyl)cyclooctyl)-1H-1,2,3-triazol-4-y-
l)ethan-1-ol;
2-ethyl-2-(4-phenyl-1H-1,2,3-triazol-1-yl)-1-(1H-tetrazol-5-yl)butan-1-ol-
;
2-(4-hexyl-1H-1,2,3-triazol-1-yl)-2-phenyl-1-(1H-tetrazol-5-yl)ethan-1-o-
l;
2-(4-hexyl-1H-1,2,3-triazol-1-yl)-2,2-diphenyl-1-(1H-tetrazol-5-yl)etha-
n-1-ol;
2-(4-(3-chloropropyl)-1H-1,2,3-triazol-1-yl)-2,2-diphenyl-1-(1H-te-
trazol-5-yl)ethan-1-ol; or tert-butyl
1-(2-hydroxy-1,1-diphenyl-2-(1H-tetrazol-5-yl)ethyl)-1H-1,2,3-triazole-4--
carboxylate.
[0031] In others aspects, the invention relates to a triazole
alkyne of formula (IV):
##STR00005##
wherein R.sup.1 and R.sup.2 are each independently groups as
previously disclosed; or R.sup.1 and R.sup.2 form together a group
as previously disclosed; and R.sup.3 is a group as previously
disclosed; and stereoisomers thereof; and salts thereof; and
solvates thereof.
[0032] In others aspects, the invention relates to reactions,
especially CuAAC reactions, wherein compounds (I), (III) and/or
(IV) are used as reactants.
Definitions
[0033] In the present invention, the following terms have the
following meanings: [0034] "about" preceding a figure means plus or
less 10% of the value of said figure. [0035] "alkyl" refers to a
linear, cyclic or branched saturated hydrocarbon chain of general
formula --C.sub.nH.sub.2n+1 wherein n is a number greater than or
equal to 1, typically containing 1 to 16 carbon atoms, preferably 1
to 12 carbon atoms, more preferably 1 to 8 carbon atoms. When
concerning a group being bounded twice to the same carbon atom,
"alkyl" also refers to an alkylenyl derived from an alkyl by
removal of a hydrogen atom. Examples of alkyl groups are methyl,
ethyl, n-propyl, isopropyl, butyl, pentyl, hexyl, cyclopentyl and
2-ethylcyclohexyl. [0036] "alkenyl" refers to a linear, cyclic or
branched unsaturated hydrocarbon chain, typically containing 1 to
16 carbon atoms, preferably 1 to 12 carbon atoms, more preferably 1
to 8 carbon atoms, wherein the unsaturation arises from the
presence of one or more carbon-carbon double bonds. When concerning
a group being bounded twice to the same carbon atom, "alkenyl" also
refers to an alkenylenyl derived from an alkenyl by removal of a
hydrogen atom. Examples of alkenyl groups are propenyl, butenyl,
hexenyl and 3-ethylcyclohex-2-enyl. [0037] "alkynyl" refers to a
linear, cyclic or branched unsaturated hydrocarbon chain, typically
containing 1 to 16 carbon atoms, preferably 1 to 12 carbon atoms,
more preferably 1 to 8 carbon atoms, wherein the unsaturation
arises from the presence of one or more carbon-carbon triple bonds.
When concerning a group being bounded twice to the same carbon
atom, "alkynyl" also refers to an alkynylenyl derived from an
alkynyl by removal of a hydrogen atom. Examples of alkynyl groups
are propynyl, butynyl, hexynyl and 3-ethylcyclohex-2-ynyl. [0038]
"amido" refers to --C(.dbd.O)--NH.sub.2 group. [0039] "amino"
refers to --NH.sub.2 group. [0040] "aryl" refers to a
polyunsaturated, aromatic hydrocarbon chain having a single ring
(i.e. phenyl) or multiple rings fused together (e.g. naphtyl) or
linked covalently, wherein at least one ring is aromatic, typically
containing 5 to 16 carbon atoms, preferably 5 to 10 carbon atoms,
more preferably 5 or 6 carbon atoms. "Aryl" also refers to the
partially hydrogenated derivatives of the carbocyclic systems
enumerated herein. Examples of aryl comprise phenyl, biphenylyl,
biphenylenyl, 5- or 6-tetralinyl, naphthalen-1- or -2-yl, 4-, 5-, 6
or 7-indenyl, 1-2-, 3-, 4- or 5-acenaphtylenyl, 3-, 4- or
5-acenaphtenyl, 1- or 2-pentalenyl, 4- or 5-indanyl, 5-, 6-, 7- or
8-tetrahydronaphthyl, 1,2,3,4-tetrahydronaphthyl,
1,4-dihydronaphthyl, 1-, 2-, 3-, 4- or 5-pyrenyl. [0041] "azide"
refers to a molecule comprising the azido group. [0042] "azido"
refers to --N.sub.3 (--N.dbd.N.sup.(+).dbd.N.sup.(-)) group. [0043]
"borono" refers to --B(OH).sub.2 group. [0044] "carboxylo" refers
to carboxylic acid --COOH group. [0045] "cyano" or "carbonitrile"
refers to --C.ident.N group. [0046] "cycloalkyl", "cycloalkenyl"
and "cycloalkynyl" respectively refers to a cyclic or polycyclic
alkyl, alkenyl and alkynyl group, typically containing 5 to 16
atoms, optionally branched. Examples of cycloalkyl are cyclopropyl,
cyclopentyl and cyclohexyl. [0047] "hydrocarbyl" refers to any
alkyl, alkenyl or alkynyl group as defined above. Unless otherwise
stated, any term defined in this section which include this term
"hydrocarbyl" also define every corresponding term wherein
"hydrocarbyl" is substituted by "alkyl", "alkenyl" or "alkynyl".
For example, "halohydrocarbyl" as defined hereafter define
simultaneously by similarity "haloalkyl", "haloalkenyl" and
"haloalkynyl". [0048] "heteroaryl" refers to an aryl group as
defined above, wherein one or more carbon atoms in one or more
aromatic rings are replaced by oxygen, nitrogen or sulfur atoms,
and where the nitrogen and sulfur heteroatoms may optionally be
oxidized and the nitrogen heteroatoms may optionally be
quaternized. Non-limiting examples of such heteroaryl are pyrrolyl,
furanyl, thiophenyl and pyrazolyl. [0049] "hydrocarbylaryl" and
"arylhydrocarbyl" respectively refers to an aryl group substituted
by, or fused with, a hydrocarbyl group and to a hydrocarbyl group
substituted by, or fused with, an aryl group. [0050]
"hydrocarbylheteroaryl" and "heteroarylhydrocarbyl" respectively
refers to a heteroaryl group substituted by, or fused with, a
hydrocarbyl group and to a hydrocarbyl group substituted by, or
fused with, a heteroaryl group. [0051] "aryloxyl" refers to
--O-aryl group. [0052] "hydrocarbyloxyl" refers to --O-hydrocarbyl
group. [0053] "haloaryl" refers to an aryl group as defined above,
further comprising at least one halo group. [0054]
"halohydrocarbyl" refers to a hydrocarbyl group as defined above,
further comprising at least one halo group. [0055] "formyl" refers
to aldehyde --CHO group. [0056] "halo" refers to fluoride,
chloride, bromide or iodide atoms. [0057] "haloformyl" refers to
--C(.dbd.O)X group, wherein X is halo group as defined above.
[0058] "hydroxyl" refers to --OH group. [0059] "nitro" refers to
--NO.sub.2 group. [0060] "nitrile" refers to a molecule comprising
the cyano group. [0061] "oxo" refers to .dbd.O group, i.e. an
oxygen atom forming a double bond with a carbon atom. [0062]
"phosphono" refers to --P(.dbd.O)(OH).sub.2 group. [0063]
"phosphato" refers to --O--P(.dbd.O)(OH).sub.2 group. [0064]
"prodrug" refers to derivatives of a biologically active drug
compound, such as for example amides, whose in vivo
biotransformation product generates the biologically active drug.
Prodrugs are generally characterized by increased bio-availability
and are readily metabolized into biologically active compounds in
vivo. [0065] "protective group" refers to a functional group that
masks the characteristic reactivity of another group to which it
can later be converted. Examples of protecting groups are acetyl
(Ac), benzoyl (Bz), tert-butyloxycarbonyl (BOC), carbobenzoyloxy
(Cbz), p-methoxybenzyl ether (PMB), silyl ethers such as
trimethylsilyl (TMS), tert-butyldimethylsilyl (TBDMS) and
tetrahydropyranyl (THP). [0066] "solvate" refers to a compound that
contains stoichiometric or sub-stoichiometric amounts of one or
more solvent molecule such as ethanol. The term "hydrate" refers to
when the solvent is water. [0067] "sulfhydryl" refers to --SH
group. [0068] "tetrazole" refers to a molecule comprising the
tetrazolo group. [0069] "tetrazolo" refers to a 5-member
heterocyclic group, consisting of a ring of four nitrogen and one
carbon atom of general formula CRR'N.sub.4, wherein R and R' are
either hydrogen or other groups. [0070] "tetrazolyl" refers to the
5-member heterocyclic group --CHN.sub.4. [0071] "triazole" refers
to a molecule comprising the triazolo group. [0072] "triazolo"
refers to a 5-member heterocyclic group, consisting of a ring of
three nitrogen and two carbon atom, of general formula
C.sub.2RR'R''N.sub.3., wherein R, R' and R'' are either hydrogen or
other groups. [0073] "triazolyl" refers to the 5-member
heterocyclic group --CH.sub.2N.sub.3. [0074] "thioxo" refers to
.dbd.S group, i.e. a sulfur atom forming a double bond with a
carbon atom.
[0075] In the present invention, the following abbreviations have
the following meanings: [0076] "Ac" refers to acetyl group
--C(.dbd.O)CH.sub.3. [0077] "Bu.sub.2SnO" refers to dibutyltin
oxide (C.sub.4H.sub.9).sub.2Sn.dbd.O [No. CAS: 818-08-6] [0078]
"CuAAC" refers to a copper-catalysed azide-alkyne cycloaddition
reaction. [0079] "EDC" refers to
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide [No. CAS: 1892-57-5].
[0080] "Et" refers to ethyl --C.sub.2H.sub.5. [0081] "EtOAc" refers
to ethyl acetate [No. CAS: 141-78-6]. [0082] "DCC" refers to
N,N'-dicyclohexylcarbodiimide [No. CAS: 538-75-0]. [0083] "DIC"
refers to N, N'-diisopropylcarbodiimide [No. CAS: 693-13-0]. [0084]
"NaAs" refers to sodium ascorbate [No. CAS: 134-03-2 (L)]. [0085]
"Ph" refers to phenyl --C.sub.6H.sub.5. [0086] "TBTA" refers to
tris(benzyltriazolylmethyl)amine [No. CAS: 510758-28-8]. [0087]
"TMSN.sub.3" refers to trimethylsilyl azide
(CH.sub.3).sub.3SiN.sub.3 [No. CAS: 4648-54-8].
DETAILED DESCRIPTION
Alpha-Hydroxy-Beta-Azido Tetrazoles
[0088] In its first aspect, the invention relates to
alpha-hydroxy-beta-azido tetrazoles of formula (I):
##STR00006##
wherein R.sup.1 and R.sup.2 are each independently hydrogen,
hydrocarbyl, aryl, heteroaryl, hydrocarbylaryl, arylhydrocarbyl,
hydrocarbylheteroaryl, or heteroarylhydrocarbyl groups; or R.sup.1
and R.sup.2 form together a group being hydrocarbyl, aryl,
heteroaryl, hydrocarbylaryl, arylhydrocarbyl,
hydrocarbylheteroaryl, or heteroarylhydrocarbyl; and the group is
optionally substituted by at least one group being hydrocarbyl,
aryl, heteroaryl, oxo, hydroxyl, amido, amino, azido, cyano, nitro,
borono, carboxylo, formyl, halo, haloformyl, phosphono, phosphato,
thioxo or sulfhydryl; and the group is optionally interrupted or
terminated by at least one group being --B(OR.sup.B)-- with R.sup.B
being hydrogen, hydrocarbyl, aryl or a combination thereof; --O--;
--PR.sup.P-- with R.sup.P being hydrogen, hydrocarbyl, aryl or a
combination thereof; --P(OR.sup.OP)-- with R.sup.OP being hydrogen,
hydrocarbyl, aryl or a combination thereof; --S--; --NR.sup.N--
with R.sup.N being hydrogen, hydrocarbyl, aryl, or a combination
thereof; or a combination thereof; and the nitrogen, phosphorus or
sulfur atoms substituting or comprised in the group are optionally
oxidized.
[0089] The invention also relates to any stereoisomers, salts,
solvates, and prodrugs of a compound of formula (I), including
quaternary ammonium salts.
[0090] The compounds of the invention may contain one or more
asymmetric center and may thus exist as different stereoisomeric
forms. Accordingly, the present invention includes all possible
stereoisomers and includes not only racemic compounds but the
individual enantiomers and their non-racemic mixtures as well. When
a compound is desired as a single enantiomer, such may be obtained
by stereospecific synthesis, by resolution of the final product or
any convenient intermediate, or by chiral chromatographic methods
as each are known in the art. Resolution of the final product, an
intermediate, or a starting material may be performed by any
suitable method known in the art.
[0091] The compounds of the invention may be in the form of salts.
Salts of the compounds of the invention include the acid addition
and base salts thereof. Suitable acid addition salts are formed
from acids. Examples include the acetate, adipate, aspartate,
benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate,
borate, cams ylate, citrate, cyclamate, edisylate, esylate,
formate, fumarate, gluceptate, gluconate, glucuronate,
hexafluorophosphate, hibenzate, hydrochloride/chloride,
hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate,
malate, maleate, malonate, mesylate, methylsulphate, naphthylate,
2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate,
pamoate, phosphate/hydrogen, phosphate/dihydrogen, phosphate,
pyroglutamate, saccharate, stearate, succinate, tannate, tartrate,
tosylate, trifluoroacetate and xinofoate salts. Suitable base salts
are formed from bases. Examples include the aluminium, arginine,
benzathine, calcium, choline, diethylamine, diolamine, glycine,
lysine, magnesium, meglumine, olamine, potassium, sodium,
tromethamine, 2-(diethylamino)ethanol, ethanolamine, morpholine,
4-(2-hydroxyethyl)morpholine and zinc salts. Hemisalts of acids and
bases may also be formed, for example, hemisulphate and hemicalcium
salts. When the compounds of the invention contain an acidic group
as well as a basic group the compounds of the invention may also
form internal salts, and such compounds are within the scope of the
invention. When the compounds of the invention contain a
hydrogen-donating heteroatom (e.g. NH), the invention also covers
salts and/or isomers formed by transfer of said hydrogen atom to a
basic group or atom within the molecule. Preferred salts include
hydrochloride/chloride, hydrobromide/bromide, bisulphate/sulphate,
nitrate, citrate, and acetate.
[0092] Salts of compounds of the invention may be prepared by one
or more of these methods: [0093] (i) by reacting the compound of
the invention with the desired acid; [0094] (ii) by reacting the
compound of the invention with the desired base; [0095] (iii) by
removing an acid- or base-labile protecting group from a suitable
precursor of the compound of the invention or by ring-opening a
suitable cyclic precursor, for example, a lactone or lactam, using
the desired acid; or [0096] (iv) by converting one salt of the
compound of the invention to another by reaction with an
appropriate acid or by means of a suitable ion exchange column.
[0097] Optionally, one or more alkene, alkyne, oxo, hydroxyl,
amido, amino, azido, nitro, borono, carboxylo, formyl, halo,
haloformyl, phosphono, phosphato, thioxo or sulfhydryl being
present in compound (I) is protected by any suitable protecting
group known by a skilled person of the art.
[0098] According to an embodiment, R.sup.1 and R.sup.2 are each
independently hydrogen, hydrocarbyl, aryl, heteroaryl,
hydrocarbylaryl, arylhydrocarbyl, hydrocarbylheteroaryl, or
heteroarylhydrocarbyl groups; and
the groups are optionally substituted by at least one group being
hydrocarbyl, aryl, heteroaryl, oxo, hydroxyl, amido, amino, nitro,
carboxylo, formyl, halo, thioxo or sulfhydryl; and the groups are
optionally interrupted or terminated by at least one group being
--O--; --S--; and --NR.sup.N-- with R.sup.N being hydrogen,
hydrocarbyl, aryl, or a combination thereof; and the nitrogen or
sulfur atoms substituting or comprised in the groups are optionally
oxidized.
[0099] According to a specific embodiment, R.sup.1 and R.sup.2 are
each independently selected from the group consisting of hydrogen,
alkyl, alkenyl, aryl, heteroaryl, alkylaryl, arylalkyl,
alkenylaryl, and arylalkenyl groups;
the groups are optionally substituted by at least one group
selected from the group consisting of hydroxyl, alkyl, alkenyl,
aryl, alkylaryl, arylalkyl, amino, nitro, halo and sulfhydryl; and
the groups are optionally interrupted or terminated by at least one
group selected from the group consisting of --O--; --S--; and
--NR.sup.N-- with R.sup.N being selected from the group consisting
of hydrogen, alkyl, alkenyl, aryl, and a combination thereof.
[0100] According to a more specific embodiment, R.sup.1 and R.sup.2
are each independently selected from the group consisting of
hydrogen, alkyl, alkenyl, aryl, heteroaryl, alkylaryl and
alkenylaryl groups; and the groups are optionally substituted by at
least one group selected from the group consisting of hydroxyl,
alkyl, amino, nitro, halo and sulfhydryl; and the groups are
optionally interrupted or terminated by at least one group selected
from the group consisting of --O--; --S--; and --NR.sup.N-- with
R.sup.N being selected from the group consisting of hydrogen,
alkyl, alkenyl, aryl, alkylaryl, and arylalkyl.
[0101] According to a furthermore specific embodiment, R.sup.1 and
R.sup.2 are each independently selected from the group consisting
of hydrogen, alkyl, aryl and alkenylaryl groups; and the groups are
optionally substituted by at least one halo group.
[0102] According to a furthermore specific embodiment, the
alpha-hydroxy-beta-azido tetrazole is selected from the group
consisting of: [0103]
2-azido-2-phenyl-1-(1H-tetrazol-5-yl)ethan-1-ol; [0104]
2-azido-2-(naphthalen-2-yl)-1-(1H-tetrazol-5-yl)ethan-1-ol; [0105]
2-azido-2-(4-chlorophenyl)-1-(1H-tetrazol-5-yl)ethan-1-ol; [0106]
2-azido-1-(1H-tetrazol-5-yl)-2-(thiophen-2-yl)ethan-1-ol; [0107]
2-azido-4-phenyl-1-(1H-tetrazol-5-yl)but-3-en-1-ol; [0108]
2-azido-1-(1H-tetrazol-5-yl)nonan-1-ol; [0109]
2-azido-2-ethyl-1-(1H-tetrazol-5-yl)butan-1-ol; and [0110]
2-azido-2,2-diphenyl-1-(1H-tetrazol-5-yl)ethan-1-ol.
[0111] According to an embodiment, R.sup.1 and R.sup.2 form
together a group being hydrocarbyl, aryl, heteroaryl,
hydrocarbylaryl, arylhydrocarbyl, hydrocarbylheteroaryl, or
heteroarylhydrocarbyl; and
the group is optionally substituted by at least one group being
hydrocarbyl, aryl, heteroaryl, oxo, hydroxyl, amido, amino, nitro,
carboxylo, formyl, halo, thioxo or sulfhydryl; and the group is
optionally interrupted or terminated by at least one group being
--O--; --S--; and --NR.sup.N-- with R.sup.N being hydrogen,
hydrocarbyl, aryl, or a combination thereof; and the nitrogen or
sulfur atoms substituting or comprised in the group are optionally
oxidized.
[0112] According to a specific embodiment, R.sup.1 and R.sup.2 form
together a group selected from the group consisting of alkyl,
alkenyl, aryl, alkylaryl, arylalkyl, alkenylaryl and
arylalkenyl;
the group is optionally substituted by at least one group selected
from the group consisting of hydroxyl, alkyl, alkenyl, aryl,
alkylaryl, arylalkyl, amino, nitro, halo and sulfhydryl; and the
group is optionally interrupted or terminated by at least one group
selected from the group consisting of --O--; --S--; and
--NR.sup.N-- with R.sup.N being selected from the group consisting
of hydrogen, alkyl, alkenyl, aryl, and a combination thereof.
[0113] According to a more specific embodiment, R.sup.1 and R.sup.2
form together a group selected from the group consisting of alkyl,
alkylaryl and arylalkyl; and the group is optionally substituted by
at least one group selected from the group consisting of hydroxyl,
alkyl, amino, nitro and halo; and the group is optionally
interrupted or terminated by at least one group selected from the
group consisting of --O-- and --NR.sup.N-- with R.sup.N being
selected from the group consisting of hydrogen, alkyl, alkenyl,
aryl, alkylaryl, and arylalkyl.
[0114] According to a furthermore specific embodiment, R.sup.1 and
R.sup.2 form together a group selected from the group consisting of
alkyl and aryl.
[0115] According to a furthermore specific embodiment,
alpha-hydroxy-beta-azido tetrazole is: [0116]
(1-azidocyclopentyl)(1H-tetrazol-5-yl)methanol; [0117]
(1-azidocyclohexyl)(1H-tetrazol-5-yl)methanol; [0118]
(1-azidocycloheptyl)(1H-tetrazol-5-yl)methanol; [0119]
(1-azidocyclooctyl)(1H-tetrazol-5-yl)methanol; or [0120]
(9-azido-9H-fluoren-9-yl)(1H-tetrazol-5-yl)methanol.
[0121] According to an embodiment, one or more amino, hydroxyl, or
sulfhydryl group being present in compound (I) is protected by any
suitable protecting group known by a skilled person of the art.
[0122] According to a specific embodiment, one or more amino group
being present in compound (I) is protected by a protective group
selected from: benzyl (CH.sub.2Ph), p-methoxybenzyl ether (PMB),
tert-butyloxycarbonyl (BOC), carbobenzoyloxy (Cbz) and tosyl
(Ts).
[0123] According to a specific embodiment, one or more hydroxyl
group being present in compound (I) is protected by a protective
group being benzyl (CH.sub.2Ph), p-methoxybenzyl ether (PMB),
tetrahydropyranyl (THP) and silyl ethers such as trimethylsilyl
(TMS, SiMe.sub.3), tert-butyldimethylsilyl (TBDMS,
SitBu(Me).sub.2), triethylsilyl (TES, SiEt.sub.3),
methyldiphenylsilyl (SiPh.sub.2Me) or tri-isopropylsilyl (TIPS,
Si(iPr).sub.3).
[0124] According to a specific embodiment, one or more sulfhydryl
group being present in compound (I) is protected by a protective
group being benzyl (CH.sub.2Ph), p-methoxybenzyl ether (PMB),
triphenylmethyl ((C.sub.6H.sub.5).sub.3C) or tetrahydropyranyl
(THP).
[0125] The alpha-hydroxy-beta-azido tetrazoles according to the
invention may be prepared by the process of manufacturing according
to the invention, as disclosed hereafter.
[0126] The alpha-hydroxy-beta-azido tetrazoles according to the
invention may be used as reactants, as disclosed hereafter.
Synthesis of Alpha-Hydroxy-Beta-Azido Tetrazoles
[0127] The most popular way to efficiently produce tetrazoles is
the cycloaddition of azides with nitriles. Various improvements
have appeared, including the use of sodium azide or trimethylsilyl
azide (TMSN.sub.3) with ammonium chloride, zinc dibromide,
trimethyl aluminium, or silver nitrate. However, these reactions
are promoted either by Bronsted or Lewis acids and may thus be
unsuitable for cycloaddition of sensible nitriles. Some of the
azide sources may also cause safety issues. Microwave irradiation
has also been used, but this reaction requires elevated
temperatures (above 100.degree. C.).
[0128] Another possibility lies in the use of dibutyltin oxide
(Bu.sub.2SnO) as a catalyst, in conjunction with trimethylsilyl
azide (TMSN.sub.3), as described by Wittenberger et al.
(Wittenberger, S. J. et al., Journal of Organic Chemistry, 1993,
Vol. 58, pp. 4139-4141.). In contrast to the above methods, this
reaction involves neutral reaction medium and a weak Lewis acid,
thus allowing cycloaddition of nitriles fitted with a Lewis base.
This reaction has been applied to the synthesis of aryl tetrazoles
and of unsubstituted aliphatic tetrazoles, but had never been
applied to the synthesis of
alpha-hydroxy-beta-azido-tetrazoles.
[0129] In its second aspect, the invention relates to a process for
manufacturing an alpha-hydroxy-beta-azido-tetrazole as disclosed in
previous section entitled "Alpha-hydroxy-beta-azido-tetrazoles",
comprising carrying out the reaction between an alpha,
beta-epoxynitrile and an azide in presence of a catalyst.
[0130] According to an embodiment, the invention relates to a
process for manufacturing an alpha-hydroxy-beta-azido tetrazole of
formula (I):
##STR00007##
comprising starting from an epoxynitrile of formula (II):
##STR00008##
wherein R.sup.1 and R.sup.2 are each independently groups as
disclosed in previous section; or R.sup.1 and R.sup.2 form together
a group as disclosed in previous section; and performing the
following steps: [0131] (a) reacting compound (II) with an azide in
presence of an organometallic catalyst, [0132] (b) performing a
hydrolysis reaction to afford compound (I).
[0133] This process is schematically represented below:
##STR00009##
[0134] Epoxynitriles compounds (II) can be synthesized by any
suitable process known by the skilled person of the art, e.g. by
Darzens reaction as proposed by Arai et al. (Arai, S. et al.,
Tetrahedron Lett., 1995, 36, 5417.).
[0135] According to an embodiment, the azide is organic, inorganic
or organometallic. According to a specific embodiment, the azide is
sodium azide or trimethylsilyl azide (TMSN.sub.3). According to a
more specific embodiment, the azide is trimethylsilyl azide.
[0136] According to an embodiment, the azide/epoxynitrile molar
ratio in the reaction medium ranges from 20 to 1. According to a
specific embodiment, the azide/epoxynitrile ratio ranges from 6 to
4. According to a more specific embodiment, the azide/epoxynitrile
ratio is about 3 (i.e. about 3 equiv. of azide for 1 equiv. of
epoxynitrile).
[0137] According to an embodiment, the catalyst is a metal oxide.
According to a specific embodiment, the catalyst an dialkyltin
oxide of general formula (alkyl).sub.2SnO, such as dibutyltin oxide
(Bu.sub.2SnO) and dimethyltin oxide (Me.sub.2SnO). According to a
more specific embodiment, the catalyst is dibutyltin oxide.
[0138] According to an embodiment, the catalyst/epoxynitrile molar
ratio in the reaction medium ranges from 5 to 0.01. According to
another specific embodiment, the catalyst/epoxynitrile ratio ranges
from 2 to 0.1. According to a more specific embodiment, the
catalyst/epoxynitrile ratio is about 0.5 (i.e. about 0.5 equiv. of
catalyst for 1 equiv. of epoxynitrile).
[0139] According to an embodiment, the step of reacting an
epoxynitrile with an azide is executed in a solvent. According to a
specific embodiment, the solvent is tetrahydrofurane (THF),
chloroform, 1,2-dichloroethane, 1,4-dioxane, toluene or mixtures
thereof. According to a more specific embodiment, the solvent is
toluene.
[0140] According to an embodiment, the step of reacting an
epoxynitrile with an azide is executed in a duration ranging from 4
h to 72 h. According to a specific embodiment, the duration ranges
from 12 h to 24 h. According a more specific embodiment, the
duration is about 18 h.
[0141] According to an embodiment, the step of reacting an
epoxynitrile with an azide is executed at a temperature ranging
from 25 to 100.degree. C. According to a specific embodiment, the
temperature ranges from 40 to 80.degree. C. According to a more
specific embodiment, the temperature is about 60.degree. C.
[0142] According to a specific embodiment, the hydrolysis reaction
is an acidic hydrolysis reaction. According to a specific
embodiment, the reaction is performed by using an acid being
sulphuric acid, acetic acid, trifluoroacetic acid or hydrochloric
acid (HCl); or aqueous solutions thereof; or organic solutions
thereof. According to a more specific embodiment, the hydrolysis is
achieved through treatment by an aqueous hydrochloric acid
solution, such as a 2N HCl solution.
[0143] According to a specific embodiment, the invention relates to
a process for manufacturing an alpha-hydroxy-beta-azido tetrazole
of formula (I) as previously disclosed, comprising starting from an
epoxynitrile of formula (II) as previously disclosed and performing
the following steps: [0144] (a) reacting compound (II) with
TMSN.sub.3 in toluene in presence of Bu.sub.2SnO, [0145] (b)
performing an acidic hydrolysis reaction to afford compound
(I).
[0146] According to an embodiment, the reaction between the
epoxynitrile and the azide is regioselective. According to an
embodiment, the reaction between the epoxynitrile and the azide is
stereoselective.
[0147] According to a specific embodiment, the reaction between the
epoxynitrile and the azide is both regioselective and
stereoselective.
Use of Alpha-Hydroxy-Beta-Azido-Tetrazoles in "Click" Reactions
[0148] The invention also relates to the use of
alpha-hydroxy-beta-azido-tetrazoles as reactants for synthesis,
especially in "click" reactions such as CuAAC.
Alpha-Hydroxy-Beta-Triazolo-Tetrazoles--CuAAC Reaction
[0149] In its third aspect, the invention relates to an
alpha-hydroxy-beta-triazolo-tetrazole of formula (III):
##STR00010##
wherein R.sup.1 and R.sup.2 are each independently groups as
disclosed in previous section; or R.sup.1 and R.sup.2 form together
a group as disclosed in previous section; and wherein R.sup.3 is
hydrogen; an organic group such as alkyl, hydroxyl or amino; an
organic molecule such as a polymer, a carbohydrate, a protein, an
amino acid, a peptide, a nucleoside; an inorganic compound such as
a metal salt; or an organometallic compound such as a metal
complex.
[0150] The invention also relates to any stereoisomers, salts,
solvates, and prodrugs of a compound of formula (III), including
quaternary ammonium salts.
[0151] According to an embodiment, R.sup.3 is hydrogen, an organic
group or an organic molecule.
[0152] According to an embodiment, R.sup.3 is hydrogen, hydroxyl,
amido, amino, cyano, tetrazolyl, triazolyl, nitro, carboxylo,
formyl, halo or sulfhydryl.
[0153] According to an embodiment, R.sup.3 is any independent
R.sup.1 or R.sup.2 group as previously disclosed.
[0154] According to an embodiment, R.sup.3 is hydrogen,
hydrocarbyl, aryl, heteroaryl, hydrocarbylaryl, arylhydrocarbyl,
hydrocarbylheteroaryl, or heteroarylhydrocarbyl group;
the group is optionally substituted by at least one group being
hydrocarbyl, aryl, heteroaryl, oxo, hydroxyl, amido, amino, azido,
cyano, tetrazolyl, triazolyl, nitro, borono, carboxylo, formyl,
halo, haloformyl, phosphono, phosphato, thioxo or sulfhydryl; the
group is optionally interrupted or terminated by at least one group
being --B(OR.sup.B)-- with R.sup.B being hydrogen, hydrocarbyl,
aryl or a combination thereof; --O--; --PR.sup.P-- with R.sup.P
being hydrogen, hydrocarbyl, aryl or a combination thereof;
--P(OR.sup.OP)-- with R.sup.OP being hydrogen, hydrocarbyl, aryl or
a combination thereof; --S--; --NR.sup.N-- with R.sup.N being
hydrogen, hydrocarbyl, aryl or a combination thereof; or a
combination thereof; and the nitrogen, phosphorus or sulfur atoms
substituting or comprised in the group are optionally oxidized.
[0155] According to an embodiment, R.sup.3 is hydrogen,
hydrocarbyl, aryl, heteroaryl, hydrocarbylaryl, arylhydrocarbyl,
hydrocarbylheteroaryl, or heteroarylhydrocarbyl group;
the group is optionally substituted by at least one group being
hydrocarbyl, aryl, heteroaryl, oxo, hydroxyl, amido, amino,
tetrazolyl, triazolyl, nitro, carboxylo, formyl, halo, thioxo or
sulfhydryl; and the group is optionally interrupted or terminated
by at least one group being --O--; --S--; and --NR.sup.N-- with
R.sup.N being hydrogen, hydrocarbyl, aryl, or a combination
thereof; and the nitrogen or sulfur atoms substituting or comprised
in the group are optionally oxidized.
[0156] According to a specific embodiment, R.sup.3 is selected from
the group consisting of alkyl, alkenyl, aryl, heteroaryl,
alkylaryl, arylalkyl, alkenylaryl, arylalkenyl, alkylheteroaryl,
and heteroarylalkyl groups; and
the group is optionally substituted by at least one group selected
from the group consisting of alkyl, alkenyl, aryl, heteroaryl,
alkylaryl, arylalkyl, oxo, hydroxyl, amido, amino, tetrazolyl,
triazolyl, nitro, carboxylo, formyl, halo, thioxo and sulfhydryl;
and the group is optionally interrupted or terminated by at least
one group selected from the group consisting of --O--; --S--; and
--NR.sup.N-- with R.sup.N being selected from the group consisting
of hydrogen, alkyl, alkenyl, aryl, and a combination thereof.
[0157] According to a more specific embodiment, R.sup.3 is selected
from the group consisting of alkyl, aryl, and alkylaryl groups; and
the groups are optionally substituted by at least one group
selected from the group consisting of oxo, hydroxyl, alkyl, amino
and halo; and the groups are optionally interrupted or terminated
by at least one group selected from the group consisting of --O--
and --NR.sup.N-- with R.sup.N being selected from the group
consisting of hydrogen, alkyl, alkenyl, aryl, alkylaryl, and
arylalkyl.
[0158] According to a furthermore specific embodiment, R.sup.3 is
selected from the group consisting of alkyl and aryl; and the
groups are optionally substituted by at least one group selected
from the group consisting of oxo, hydroxyl, alkyloxyl, and
halo.
[0159] According to a furthermore specific embodiment, compound
(III) is selected from the group consisting of: [0160]
(1-(4-phenyl-1H-1,2,3-triazol-1-yl)cyclohexyl)(1H-tetrazol-5-yl)methanol;
[0161]
(1-(4-phenyl-1H-1,2,3-triazol-1-yl)cycloheptyl)(1H-tetrazol-5-yl)m-
ethanol; [0162]
(1-(4-phenyl-1H-1,2,3-triazol-1-yl)cyclooctyl)(1H-tetrazol-5-yl)methanol;
[0163] tert-butyl
1-(1-(hydroxy(1H-tetrazol-5-yl)methyl)cyclooctyl)-1H-1,2,3-triazole-4-car-
boxylate; [0164]
(1-(4-(3-chloropropyl)-1H-1,2,3-triazol-1-yl)cyclooctyl)(1H-tetrazol-5-yl-
)methanol; [0165]
2-(1-(1-(hydroxy(1H-tetrazol-5-yl)methyl)cyclooctyl)-1H-1,2,3-triazol-4-y-
l)ethan-1-ol; [0166]
2-ethyl-2-(4-phenyl-1H-1,2,3-triazol-1-yl)-1-(1H-tetrazol-5-yl)butan-1-ol-
; [0167]
2-(4-hexyl-1H-1,2,3-triazol-1-yl)-2-phenyl-1-(1H-tetrazol-5-yl)et-
han-1-ol; [0168]
2-(4-hexyl-1H-1,2,3-triazol-1-yl)-2,2-diphenyl-1-(1H-tetrazol-5-yl)ethan--
1-ol; [0169]
2-(4-(3-chloropropyl)-1H-1,2,3-triazol-1-yl)-2,2-diphenyl-1-(1H-tetrazol--
5-yl)ethan-1-ol; and [0170] tert-butyl
1-(2-hydroxy-1,1-diphenyl-2-(1H-tetrazol-5-yl)ethyl)-1H-1,2,3-triazole-4--
carboxylate.
[0171] According to an embodiment, R.sup.3 is a carbohydrate, an
amino acid, a peptide or a nucleoside.
[0172] According to an embodiment, one or more amino, hydroxyl or
sulfhydryl group being present in compound (III) is protected by
any suitable protecting group known by a skilled person of the art.
According to a specific embodiment, one or more amino group being
present in compound (III) is protected by a protective group being
benzyl (CH.sub.2Ph), p-methoxybenzyl ether (PMB),
tert-butyloxycarbonyl (BOC), carbobenzoyloxy (Cbz) or tosyl (Ts).
According to another specific embodiment, one or more hydroxyl
group being present in compound (III) is protected by a protective
group being benzyl (CH.sub.2Ph), p-methoxybenzyl ether (PMB),
tetrahydropyranyl (THP) or silyl ether such as trimethylsilyl (TMS,
SiMe.sub.3), tert-butyldimethylsilyl (TBDMS, SitBu(Me).sub.2),
triethylsilyl (TES, SiEt.sub.3), methyldiphenylsilyl (SiPh.sub.2Me)
or tri-isopropylsilyl (TIPS, Si(iPr).sub.3). According to another
specific embodiment, one or more sulfhydryl group being present in
compound (III) is protected by a protective group being benzyl
(CH.sub.2Ph), p-methoxybenzyl ether (PMB), triphenylmethyl
((C.sub.6H.sub.5).sub.3C) or tetrahydropyranyl (THP).
[0173] In its fourth aspect, the invention relates to a process for
manufacturing a alpha-hydroxy-beta-triazolo-tetrazole, comprising
carrying out the reaction between an
alpha-hydroxy-beta-azido-tetrazole and a terminal alkyne in
presence of a copper(I) source and a tertiary amine.
[0174] According to an embodiment, the invention relates to a
process for manufacturing an alpha-hydroxy-beta-triazolo-tetrazole
of formula (III):
##STR00011##
comprising starting from an alpha-hydroxy-beta-azido-tetrazole of
formula (I):
##STR00012##
wherein R.sup.1 and R.sup.2 are each independently groups as
previously disclosed; or R.sup.1 and R.sup.2 form together a group
as previously disclosed; and a terminal alkyne of formula
R.sup.3--C.ident.C--H, wherein R.sup.3 is as previously disclosed;
and carrying out the reaction of compound (I) with alkyne
R.sup.3--C.ident.C--H in presence of a copper(I) source and a
tertiary amine, wherein the copper(I) source is either: [0175] a
combination of a copper(I) salt and a base, or [0176] a combination
of a copper(II) salt and a reducing agent.
[0177] This process is schematically represented below (L referring
to the tertiary amine):
##STR00013##
[0178] According to an embodiment, the copper(I) salt is copper(I)
chloride, copper(I) bromide (CuBr) or copper(I) acetate; and the
base is a basic amine such as N,N-diisopropylethylamine (DIEA).
According to a specific embodiment, the copper salt is copper(I)
bromide and the base is N,N-diisopropylethylamine.
[0179] According to another embodiment, the copper(II) salt is
copper(II) chloride, copper(II) bromide, copper(II) acetate or
copper(II) sulphate (Cu.sup.IISO.sub.4); and the reducing agent is
sodium ascorbate (NaAs) or tri(2-carboxyethyl)phosphine (TECP).
According to a specific embodiment, the copper salt is copper(II)
sulphate and the reducing agent is sodium ascorbate.
[0180] According to an embodiment, the tertiary amine is
tris(benzyltriazolylmethyl)amine (TBTA),
tris(tertbutyltriazolylmethyl)amine (TTTA),
tris(benzimidazole)methyl amine (TBIA),
4,7-diphenyl-1,10-phenanthroline-disulfonic acid disodium salt,
tris [2-(N,N-dibenzylamino)ethyl]amine or
tris(benzyltriazolylmethyl)amine. According to a specific
embodiment, the tertiary amine is tris(benzyltriazolylmethyl)amine
(TBTA).
[0181] According to an embodiment, the alkyne/azide molar ratio in
the reaction medium ranges from 1 to 10. According to a specific
embodiment, the alkyne/azide ratio ranges from 2 to 5. According to
a more specific embodiment, the alkyne/azide ratio is about 3 (i.e.
about 3 equiv. of alkyne for 1 equiv. of azide).
[0182] According to an embodiment, the copper salt/azide molar
ratio in the reaction medium ranges from 0.01 to 2. According to a
specific embodiment, the copper salt/azide ratio ranges from 0.05
to 0.2. According to a more specific embodiment, the copper
salt/azide ratio is about 0.1 (i.e. about 0.1 equiv. of copper salt
for 1 equiv. of azide).
[0183] According to an embodiment, the copper salt/tertiary amine
molar ratio in the reaction medium ranges from 0.1 to 10. According
to a specific embodiment, the copper salt/tertiary amine ratio
ranges from 0.5 to 2. According to a more specific embodiment, the
copper salt/tertiary amine ratio is about 1 (i.e. about 1 equiv. of
copper salt for 1 equiv. of tertiary amine).
[0184] According to an embodiment, the copper salt/reducing agent
molar ratio in the reaction medium ranges from 0.1 to 2. According
to a specific embodiment, the copper salt/reducing agent ratio
ranges from 0.25 to 0.75. According to a more specific embodiment,
the copper salt/reducing agent ratio is about 0.5 (i.e. about 0.5
equiv. of copper salt for 1 equiv. of reducing agent).
[0185] According to an embodiment, the step of carrying out the
reaction between the alpha-hydroxy-beta-azido-tetrazole and the
terminal alkyne is executed in a solvent. According to a specific
embodiment, the solvent is ethanol, tetrahydrofuran (THF),
N,N'-dimethylformamide (DMF), acetonitrile, n-butyl alcohol
(n-BuOH), water or mixtures thereof. According to a more specific
embodiment, the solvent is a mixture of n-butyl alcohol and
water.
[0186] According to an embodiment, the step of carrying out the
reaction between the alpha-hydroxy-beta-azido-tetrazole and the
terminal alkyne is executed in a duration ranging from 12 h to 5
days. According to a specific embodiment, the duration ranges from
24 h to 72 h. According a more specific embodiment, the duration is
about 48 h.
[0187] According to an embodiment, the step of carrying out the
reaction between the alpha-hydroxy-beta-azido-tetrazole and the
terminal alkyne is executed at a temperature ranging from 0 to
50.degree. C. According to a specific embodiment, the temperature
ranges from 15 to 30.degree. C. According to a more specific
embodiment, the temperature is room temperature, i.e. about
25.degree. C.
[0188] According to an embodiment, the step of carrying out the
reaction between the alpha-hydroxy-beta-azido-tetrazole and the
terminal alkyne is executed under a suitable inert gas, such as
argon.
[0189] According to a specific embodiment, the invention relates to
a process for manufacturing a alpha-hydroxy-beta-triazolo-tetrazole
of formula (III) as previously disclosed comprising starting from
an alpha-hydroxy-beta-azido-tetrazole of formula (I) and a terminal
alkyne of formula R.sup.3--C.ident.C--H as previously disclosed,
and carrying out the reaction of compound (II) with alkyne
R.sup.3--C.ident.C--H in presence of Cu.sup.IISO.sub.4, TBTA and
NaAs in a n-BuOH/H.sub.2O mixture.
[0190] During the reaction described in this aspect of the
invention, the hydroxy-tetrazole group acts as a "latent" or
"hidden" alkyne group, meaning that it may be easily converted to
an alkyne (as described hereafter) but does not react under CuAAC
conditions.
Triazole Alkynes--Hydroxy-Tetrazole to Alkyne Reaction
[0191] Wardrop et al. described the conversion of
alpha-hydroxy-tetrazoles to alkynes through a [1,2]-rearrangement
process using carbodiimides, which are compounds of general formula
RN.dbd.C.dbd.NR, as dehydrating agents (Wardrop, D. J. et al.,
Organic Letters, 2012, Vol. 14, No. 6, pp. 1548-1551.). From
alpha-hydroxy-alpha-aryl tetrazoles, this reaction allowed the
preparation of internal alkynes substituted by at least one aryl
group, most conveniently using diisopropylcarbodiimide (DIC).
However, instead of forming this alkyne, this process could also
lead to a 5-membered cycle or heterocycle, by a cyclisation
mechanism involving an [1,5]--C--H insertion.
[0192] In its fifth aspect, the invention relates to a triazole
alkyne of formula (IV):
##STR00014##
wherein R.sup.1 and R.sup.2 are each independent groups as
disclosed in previous section; or R.sup.1 and R.sup.2 form together
a group as disclosed in previous section; and R.sup.3 is as
disclosed in previous section.
[0193] The invention also relates to any stereoisomers, salts,
solvates, and prodrugs of a compound of formula (IV), including
quaternary ammonium salts.
[0194] According to a furthermore specific embodiment, the triazole
alkynes manufactured by the process are selected from the group
consisting of: [0195]
1-(1-ethynylcyclohexyl)-4-phenyl-1H-1,2,3-triazole; [0196]
1-(1-ethynylcycloheptyl)-4-phenyl-1H-1,2,3-triazole; [0197]
1-(1-ethynylcyclooctyl)-4-phenyl-1H-1,2,3-triazole; [0198]
tert-butyl 1-(1-ethynylcyclooctyl)-1H-1,2,3-triazole-4-carboxylate;
[0199]
4-(3-chloropropyl)-1-(1-ethynylcyclooctyl)-1H-1,2,3-triazole;
[0200] 2-(1-(1-ethynylcyclooctyl)-1H-1,2,3-triazol-4-yl)ethan-1-ol;
[0201] 1-(3-ethylpent-1-yn-3-yl)-4-phenyl-1H-1,2,3-triazole; [0202]
4-hexyl-1-(1-phenylprop-2-yn-1-yl)-1H-1,2,3-triazole; and [0203]
1-(1,1-diphenylprop-2-yn-1-yl)-4-hexyl-1H-1,2,3-triazole.
[0204] In its sixth aspect, the invention relates to a process for
manufacturing a triazole alkyne, comprising carrying out the
reaction between an alpha-hydroxy-beta-triazolo-tetrazole and a
carbodiimide.
[0205] According to an embodiment, the invention relates to a
process for manufacturing a triazole alkyne of formula (IV):
##STR00015##
comprising starting from an alpha-hydroxy-beta-triazolo-tetrazole
of formula (III):
##STR00016##
wherein R.sup.1 and R.sup.2 are each independent groups as
previously disclosed; or R.sup.1 and R.sup.2 form together a group
as previously disclosed; and R.sub.3 is as previously disclosed;
and carrying out the reaction of compound (III) with a
carbodiimide.
[0206] This process is schematically represented below:
##STR00017##
[0207] According to an embodiment, the carbodiimide is
N,N'-dicyclohexylcarbodiimide (DCC), N, N'-diisopropylcarbodiimide
(DIC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), phenyl
ethyl carbodiimide (PEC), phenyl isopropyl carbodiimide (PIC),
tert-butyl ethyl carbodiimide (BEC) or tert-butyl methyl
carbodiimide (BMC). According to a specific embodiment, the
carbodiimide is EDC.
[0208] According to an embodiment, the carbodiimide/tetrazole molar
ratio in the reaction medium ranges from 0.5 to 5. According to a
specific embodiment, the carbodiimide/tetrazole ratio ranges from 1
to 1.5. According to a more specific embodiment, the
carbodiimide/tetrazole ratio is about 1.2 (i.e. about 1.2 equiv. of
carbodiimide for 1 equiv. of tetrazole).
[0209] According to an embodiment, the step of carrying out the
reaction between the alpha-hydroxy-beta-triazolo-tetrazole and the
carbodiimide is executed in a solvent. According to a specific
embodiment, the solvent is: chloroform, 1,2-dichloroethane,
dichloromethane or mixture thereof. According to a more specific
embodiment, the solvent is dichloromethane.
[0210] According to an embodiment, the step of carrying out the
reaction between the alpha-hydroxy-beta-triazolo-tetrazole and the
carbodiimide is executed in a duration ranging from 4 h to 72 h.
According to a specific embodiment, the duration ranges from 12 h
to 24 h. According a more specific embodiment, the duration is
about 18 h.
[0211] According to an embodiment, the step of carrying out the
reaction between the alpha-hydroxy-beta-triazolo-tetrazole and the
carbodiimide is executed at a temperature ranging from 0 to
50.degree. C. According to a specific embodiment, the temperature
ranges from 15 to 30.degree. C. According to a more specific
embodiment, the temperature is room temperature, i.e. about
25.degree. C.
[0212] According to a specific embodiment, the invention relates to
a process for manufacturing an triazole alkyne of formula (IV) as
previously disclosed, comprising starting from an
alpha-hydroxy-beta-triazolo-tetrazole of formula (III) as
previously disclosed, and carrying out the reaction of compound
(III) with EDC in dichloromethane.
[0213] The reaction described in this aspect of the invention
allows the conversion of the hydroxy-tetrazole to an alkyne,
revealing the "latent" or "hidden" alkyne group of the
alpha-hydroxy-beta-azido-tetrazole.
Multi-Triazoles--Further CuAAC Reactions
[0214] In its seventh aspect, the invention relates to a process
for manufacturing molecules comprising starting from a triazole
alkyne of formula (IV), and carrying out the reaction of the
compound (IV) with an azide.
Synthesis of Di-Triazoles
[0215] According to a first embodiment, the invention relates to a
process for manufacturing a di-triazole of formula (V):
##STR00018##
comprising starting from a triazole alkyne of formula (IV):
##STR00019##
wherein R.sup.1 and R.sup.2 are each independent groups as
previously disclosed; or R.sup.1 and R.sup.2 form together a group
as previously disclosed; and R.sup.3 is as previously disclosed;
and from an azide of formula R.sup.4--N.sub.3, wherein R.sup.4 is
any R.sup.3 group as previously disclosed; and carrying out the
reaction of compound (IV) with azide R.sup.4--N.sub.3 in the
presence of a copper(I) source.
[0216] This process is schematically represented below:
##STR00020##
[0217] In this first embodiment, the compounds and the conditions
of the step of reaction of compound (IV) with azide
R.sup.4--N.sub.3 may be as previously disclosed in any embodiment
of previous paragraph entitled "CuAAC reaction--Alpha
hydroxy-beta-triazolo-tetrazoles", except that the presence of a
tertiary amine ligand may not be required.
[0218] According to a specific embodiment, R.sup.4 is a
carbohydrate.
[0219] According to a specific embodiment, R.sup.4 is a metal
complex.
[0220] According to a specific embodiment, R.sup.4 is an alkyl or
alkylaryl group optionally substituted by at least one group being
alkyl, oxo, hydroxyl, tetrazolyl or halo and optionally interrupted
or terminated by at least one group being --O-- or --NH--.
[0221] According to a more specific embodiment, the di-triazoles
manufactured by this process are selected from the group consisting
of: [0222]
1-octyl-4-(1-(4-phenyl-1H-1,2,3-triazol-1-yl)cyclohexyl)-1H-1,2,3--
triazole; [0223]
1-[bis(.eta.5-cyclopentadienyl)iron]-4-(1-(4-phenyl-1H-1,2,3-triazol-1-yl-
)cyclohexyl)-1H-1,2,3-triazole; [0224]
2-(acetoxymethyl)-6-(4-(1-(4-phenyl-1H-1,2,3-triazol-1-yl)cyclohexyl)-1H--
1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,4,5-triyl triacetate;
[0225] methyl
2-((tert-butoxycarbonyl)amino)-3-(4-(1-(4-phenyl-1H-1,2,3-triazol--
1-yl)cyclohexyl)-1H-1,2,3-triazol-1-yl)propanoate; [0226]
1-octyl-4-(1-(4-phenyl-1H-1,2,3-triazol-1-yl)cyclooctyl)-1H-1,2,3-triazol-
e; [0227] ethyl
4-(4-(1-(4-phenyl-1H-1,2,3-triazol-1-yl)cyclooctyl)-1H-1,2,3-triazol-1-yl-
)butanoate; [0228]
4-phenyl-1-(1-(1-(pyren-1-ylmethyl)-1H-1,2,3-triazol-4-yl)cyclooctyl)-1H--
1,2,3-triazole; [0229]
1-benzyl-4-(1-(4-phenyl-1H-1,2,3-triazol-1-yl)cyclooctyl)-1H-1,2,3-triazo-
le; [0230]
2-ethyl-2-(4-(1-(4-phenyl-1H-1,2,3-triazol-1-yl)cyclooctyl)-1H--
1,2,3-triazol-1-yl)-1-(1H-tetrazol-5-yl)butan-1-ol.
Synthesis of Poly-Triazoles
[0231] According to a second embodiment, the invention relates to a
process for manufacturing an alpha-hydroxy-tetrazole of formula
(VI):
##STR00021##
comprising starting from a triazole alkyne of formula (IV):
##STR00022##
and from an alpha-hydroxy-beta-azido tetrazole of formula (I):
##STR00023##
wherein R.sup.1 and R.sup.2 are each independent groups as
previously disclosed; or R.sup.1 and R.sup.2 form together a group
as previously disclosed; and R.sub.3 is as previously disclosed;
and carrying out the reaction of the compound (IV) with compound
(I) in presence of a copper(I) source and a tertiary amine.
[0232] According to a third embodiment, the invention relates to a
process for manufacturing a poly-triazole compound of formula
(VII):
##STR00024##
comprising starting from a triazole alkyne of formula (IV):
##STR00025##
and from an alpha-hydroxy-beta-azido tetrazole of formula (I):
##STR00026##
wherein R.sup.1 and R.sup.2 are each independent groups as
previously disclosed; or R.sup.1 and R.sup.2 form together a group
as previously disclosed; and R.sub.3 is as previously disclosed;
and performing n iterations of the following steps (a) and (b):
[0233] (a) carrying out the reaction of the compound (IV) with
compound (I) in the presence of a copper(I) source and a tertiary
amine. [0234] (b) carrying out the reaction of resulting compound
with a carbodiimide.
[0235] This process is schematically represented below (L referring
to the tertiary amine):
##STR00027##
[0236] According to a specific embodiment, n ranges from 0 to 100.
According to a more specific embodiment, n ranges from 1 to 10.
According to another more specific embodiment, n ranges from 2 to
5.
[0237] According to a more specific embodiment, the poly-triazoles
manufactured by this process are selected from the group consisting
in:
1-(3-ethylpent-1-yn-3-yl)-4-(1-(4-phenyl-1H-1,2,3-triazol-1-yl)cyclooctyl-
)-1H-1,2,3-triazole;
1-(1-ethynylcyclooctyl)-4-(3-(4-(1-(4-phenyl-1H-1,2,3-triazol-1-yl)cycloo-
ctyl)-1H-1,2,3-triazol-1-yl)pentan-3-yl)-1H-1,2,3-triazole; and
1-benzyl-4-(1-(4-(3-(4-(1-(4-phenyl-1H-1,2,3-triazol-1-yl)cyclooctyl)-1H--
1,2,3-triazol-1-yl)pentan-3-yl)-1H-1,2,3-triazol-1-yl)cyclooctyl)-1H-1,2,3-
-triazole.
[0238] In these second and third embodiments, the compounds and the
conditions of step (a) may be as previously disclosed in any
embodiment of previous paragraph entitled "CuAAC reaction--Alpha
hydroxy-beta-triazolo-tetrazoles".
[0239] In this third embodiment, the compounds and the conditions
of steps (b) may be as previously disclosed in any embodiment of
previous paragraph entitled "Triazole alkynes--Hydroxy-tetrazole to
alkyne reaction".
[0240] The triazole heterocycle is an analogue of the peptidic
bound, therefore oligomeric or polymeric compounds of general
formula (VII) are peptides analogues. Such biomimetic compounds may
thus present valuable applications in medicinal chemistry, and more
generally in the biotechnologies field.
Examples
[0241] The present invention is further illustrated by the
following examples.
General Materials and Methods
Materials
[0242] Starting aldehydes, alkynes and ketones are commercially
available from ordinary chemical compounds suppliers, and were
purchased from Sigma-Aldrich, Alfa Aesar, Acros Organics or TCI
Chemicals.
[0243] Azides were prepared using known methods of the literature:
Octyl azide (Org. Biomol. Chem., 2012, 10, 5993-6002.), Ferrocenyl
azide (J. Organometal. Chem., 1970, 23, 225-228.), Pyrene azide (J.
Org. Chem. 2008, 73, 8212-8218.), Methyl
3-azido-2-(tertbutoxycarbonyl-amino)propanoate (Bioorg. Med. Chem.,
2010, 18, 7338-7347.),
2,3,4,6-Tetra-O-acetyl-1-azido-.beta.-D-glucopyranoside (Tet. Lett.
2007 48 3953-3957.), Ethyl 4-azido-butyrate (Eur. J. Org. Chem.,
2011, 229-233.). Benzyl azide was purchased from Sigma-Aldrich.
[0244] Other reactants and solvent are commercially available from
ordinary chemical compounds suppliers, and were purchased from
Sigma-Aldrich, Alfa Aesar, Acros Organics or TCI Chemicals.
Methods
[0245] Column chromatography were performed on a silica gel 230-400
mesh by using various mixtures of dichloromethane (DCM), ethyl
acetate (EtOAc), methanol (MeOH), acetic acid (AcOH) and petroleum
ether (PE). Thin Layer chromatographies (TLCs) were run on
Kieselgel 60F.sub.254 plates and revealed by UV light and potassium
permanganate (epoxides) or ninhydrin (azido tetrazoles).
[0246] .sup.1H and .sup.13C NMR spectra were collected on a Bruker
Avance spectrometer respectively at 200 or 300 MHz and 75 MHz. Data
are presented as follows: chemical shift (in ppm on the .delta.
scale relative to STMS=0), multiplicity (s=singlet, d=doublet,
t=triplet, m=multiplet, b=broad), coupling constant (J/Hz),
integration and attribution. High resolution mass spectra (HR-MS)
were obtained on a Waters Micromass Q-TofMicro instrument. Melting
points are uncorrected.
Example 1: Epoxynitriles
[0247] Hereafter are provided epoxynitriles according to the
invention. R.sup.1 and R.sup.2 groups refer to formula (II):
##STR00028##
TABLE-US-00001 # R.sup.1 R.sup.2 Formula Name 1 Ph H ##STR00029##
trans-3- phenyloxirane-2- carbonitrile 2 Ph H ##STR00030## cis-3-
phenyloxirane-2- carbonitrile 3 naphthalen- 2-yl H ##STR00031##
trans-3- (naphthalen-2- yl)oxirane-2- carbonitrile 4 naphthalen-
2-yl H ##STR00032## cis-3-(naphthalen- 2-yl)oxirane-2- carbonitrile
5 4- chlorophenyl H ##STR00033## trans-3-(4- chlorophenyl)
oxirane-2-carbonitrile 6 4- chlorophenyl H ##STR00034## cis-3-(4-
chlorophenyl)oxirane- 2-carbonitrile 7 thiophenyl H ##STR00035##
3-(thiophen-2- yl)oxirane-2- carbonitrile 8 styryl H ##STR00036##
3-styryloxirane-2- carbonitrile 9 heptyl H ##STR00037##
3-heptyloxirane-2- carbonitrile 10 Et Et ##STR00038##
3,3-diethyloxirane- 2-carbonitrile 11 butyl (cyclopentyl)
##STR00039## 1- oxaspiro[2.4]heptane- 2-carbonitrile 12 pentyl
(cyclohexyl) ##STR00040## 1- oxaspiro[2.5]octane- 2-carbonitrile 13
hexyl (cycloheptyl) ##STR00041## 1- oxaspiro[2.6]nonane-
2-carbonitrile 14 heptyl (cyclooctyl) ##STR00042## 1-
oxaspiro[2.7]decane- 2-carbonitrile 15 Ph Ph ##STR00043## 3,3-
diphenyloxirane-2- carbonitrile 16 fluorenyl ##STR00044##
spiro[fluorene-9,2'- oxirane]-3'- carbonitrile
[0248] These compounds may be prepared as disclosed in Example
2.
Example 2: Synthesis of Epoxynitriles
Materials and Methods
Procedure (a) for the Synthesis of Epoxynitriles:
[0249] A solution of starting aldehyde or ketone (1 mol equiv.) and
chloroacetonitrile (1.2 equiv.) in THF (15 mL/10 mmol) was added
dropwise to a suspension of freshly crushed NaOH (3 equiv.) in THF
(5 mL/10 mmol of NaOH). The reaction was stirred at room
temperature and followed by TLC until full conversion of the
aldehyde or ketone. Water (100 mL) and dichloromethane (100 mL)
were added to the reaction mixture and the organic layer was washed
with brine. The organic layer was concentrated under reduced
pressure and the crude residue was purified by flash chromatography
on silica gel or alumina.
Results
[0250] Hereafter are provided the yield and physical
characterization of epoxynitriles #1-16 according to the invention,
prepared from the appropriate aldehyde or ketone, by the above
procedure.
TABLE-US-00002 # Name Characterization Yield 1 trans-3- .sup.1H NMR
(200 MHz, CDCl.sub.3) .delta.7.45-7.40 (m, 3H), 7.35- 29%
phenyloxirane-2- 7.25 (m, 2H), 4.30 (d, J = 1.8 Hz, 1H), 3.43 (d, J
= 1.8 Hz, carbonitrile 1H). .sup.13C NMR (75 MHz, CDCl.sub.3)
.delta.132.75, 129.84, 128.99, 125.66, 116.03, 58.49, 44.64. HRMS
(ESI, TOF MS) m/z calculated for [M + Na]+: 168.0426, found:
168.0427. 2 cis-3- .sup.1H NMR (200 MHz, CDCl.sub.3)
.delta.7.50-7.35 (m, 5H), 4.26 32% phenyloxirane-2- (d, J = 3.7 Hz,
1H), 3.79 (d, J = 3.7 Hz, 1H). .sup.13C NMR (75 carbonitrile MHz,
CDCl.sub.3) .delta.131.41, 129.73, 128.70, 126.32, 115.07, 57.72,
45.12. HRMS (ESI, TOF MS) m/z calculated for [M + Na]+: 168.0426,
found: 168.0427. 3 trans-3- .sup.1H NMR (200 MHz, CDCl.sub.3)
.delta. 7.95-7.80 (m, 4H), 7.60- 32% (naphthalen-2- 7.50 (m, 2H),
7.35-7.25 (m, 1H), 4.46 (d, J = 1.7 Hz, yl)oxirane-2- 1H), 3.52 (d,
J = 1.7 Hz, 1H). .sup.13C NMR (75 MHz, carbonitrile CDCl.sub.3)
.delta. 133.87, 132.93, 130.04, 129.09, 127.98, 127.91, 127.08,
126.98, 126.15, 121.84, 116.06, 58.79, 44.71. HRMS (ESI, TOF MS)
m/z calculated for [M + H]+: 196.0762, found: 196.0759. 4 cis-3-
.sup.1H NMR (200 MHz, CDCl.sub.3) .delta. 7.80-7.00 (m, 4H), 7.65-
33% (naphthalen-2- 7.45 (m, 3H), 4.43 (d, J = 3.7 Hz, 1H), 3.87 (d,
J = 3.7 Hz, yl)oxirane-2- 1H). .sup.13C NMR (75 MHz, CDCl.sub.3)
.delta.133.89, 132.88, carbonitrile 128.81, 128.70, 128.18, 127.90,
126.93, 126.76, 126.31, 122.99, 115.06, 57.96, 45.28. HRMS (ESI,
TOF MS) m/z calculated for [M + H]+: 196.0762, found: 196.0759. 5
trans-3-(4- .sup.1H NMR (200 MHz, CDCl.sub.3) .delta. 7.39 (d, J =
8.5 Hz, 2H), 14% chloro- 7.23 (d, J = 8.5 Hz, 2H), 4.29 (d, J = 1.7
Hz, 1H), 3.41 (d, phenyl)oxirane- J = 1.7 Hz, 1H). .sup.13C NMR (75
MHz, CDCl3) .delta.135.85, 2-carbonitrile 131.26, 129.28, 127.01,
115.73, 57.89, 44.66. HRMS (ESI, TOF MS): not detected. 6 cis-3-(4-
.sup.1H NMR (200 MHz, CDCl.sub.3) .delta. 7.43 (d, J = 8.6 Hz, 2H)
28% chloro- 7.37 (d, J = 8.6 Hz, 2H), 4.25 (d, J = 3.7 Hz, 1H),
3.80 (d, phenyl)oxirane- J = 3.7 Hz, 1H). .sup.13C NMR (75 MHz,
CDCl.sub.3) .delta.135.74, 2-carbonitrile 129.96, 129.02, 127.71,
114.84, 57.14, 45.11. HRMS (ESI, TOF MS): not detected. 7
3-(thiophen-2- .sup.1H NMR (200 MHz, CDCl.sub.3) .delta. 7.40 (dd,
J = 5.0, 1.2 Hz, 89% yl)oxirane-2- 1H.sub.cis), 7.36 (dd, J = 5.0,
0.9 Hz, 1H.sub.trans), 7.29 (dd, J = carbonitrile 2.4, 1.9 Hz,
1H.sub.cis), 7.22 (dd, J = 3.6, 0.8 Hz, 1H.sub.trans), 7.08 (dd, J
= 5.4, 4.0 Hz, 1H.sub.cis), 7.04 (dd, J = 5.0, 3.6 Hz,
1H.sub.trans), 4.54 (d, J = 1.8 Hz, 1H.sub.trans), 4.45 (d, J = 3.5
Hz, 1H.sub.cis), 3.82 (d, J = 3.5 Hz, 1H.sub.cis), 3.61 (d, J = 1.8
Hz, 1H.sub.trans). .sup.13C NMR (75 MHz, CDCl.sub.3) .delta. 135.86
(trans), 134.20 (cis), 128.26 (trans), 127.75 (cis), 127.61
(trans), 127.45(cis), 127.10 (cis), 127.03 (trans), 115.63 (trans),
115.12 (cis), 55.59 (trans), 54.89 (cis), 45.82 (cis),
45.43(trans). HRMS (ESI, TOF MS) m/z calculated for [M + H].sup.+:
152.0170, found: 152.0172. 8 3-styryloxirane-2- Trans stereoisomer:
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.26 31% carbonitrile (m,
5H), 6.81 (d, J = 16.0 Hz, 1H), 5.67 (dd, J = 16.0, 7.8 Hz, 1H),
3.83 (dd, J = 7.8, 1.7 Hz, 1H), 3.32 (d, J = 1.8 Hz, 1H). .sup.13C
NMR (75 MHz, CDCl.sub.3) .delta. 138.21, 134.98, 129.13, 128.89,
126.84, 121.49, 116.20, 58.94, 43.31. Cis stereoisomer: .sup.1H NMR
(300 MHz, CDCl.sub.3) .delta. 7.33 (m, 5H), 6.92 (d, J = 15.9 Hz,
1H), 5.98 (dd, J = 15.9, 8.1 Hz, 1H), 3.76 (dd, J = 8.1, 3.7 Hz,
1H), 3.65 (d, J = 3.7 Hz, 1H). .sup.13C NMR (75 MHz, CDCl.sub.3)
.delta. 139.42, 135.04, 129.12, 128.82, 126.97, 120.30, 115.54,
57.54, 43.64. HRMS (ESI, TOF MS) m/z calculated for [M + H].sup.+:
172.0762, found: 172.0763. 9 3-heptyloxirane-2- Trans stereoisomer:
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 3.34 59% carbonitrile
(td, J = 6.0, 1.9 Hz, 1H), 3.17 (d, J = 1.9 Hz, 1H), 1.71- 1.20 (m,
12H), 0.89 (t, J = 6.5 Hz, 3H). .sup.13C NMR (75 MHz, CDCl.sub.3)
.delta. 116.80, 59.17, 40.95, 31.63, 31.01, 29.08, 29.02, 25.26,
22.57, 14.04. Cis stereoisomer: .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 3.46 (d, J = 3.8 Hz, 1H), 3.19 (td, J = 6.0, 3.7 Hz, 1H),
1.88- 1.17 (m, 12H), 0.90 (t, J = 6.6 Hz, 3H). .sup.13C NMR (75
MHz, CDCl.sub.3) .delta. 115.94, 57.44, 41.74, 31.66, 29.75, 29.15,
29.06, 25.72, 22.59, 14.07. HRMS (ESI, TOF MS) m/z calculated for
[M + H].sup.+: 168.1388, found: 168.1387. 10 3,3- .sup.1H NMR (300
MHz, CDCl.sub.3) .delta. 3.27 (s, 1H), 1.96-1.62 55%
diethyloxirane-2- (m, 4H), 1.09 (td, J = 7.5, 1.3 Hz, 3H), 0.92
(td, J = 7.5, carbonitrile 1.3 Hz, 3H). .sup.13C NMR (75 MHz,
CDCl.sub.3) .delta. 116.48, 67.34, 46.21, 25.44, 25.12, 9.07, 8.31.
HRMS (ESI, TOF MS) m/z calculated for [M + H].sup.+: 126.0919,
found: 126.0917. 11 1- .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.
3.46 (s, 1H), 2.17-1.60 82% oxaspiro[2.4]heptane- (m, 8H). .sup.13C
NMR (75 MHz, CDCl.sub.3) .delta. 116.59, 71.43, 2-carbonitrile
45.78, 31.84, 30.62, 25.33, 24.92. HRMS (ESI, TOF MS) m/z
calculated for [M + H].sup.+: 124.0762, found: 124.0766. 12 1-
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 3.24 (s, 1H), 1.83-1.49
86% oxaspiro[2.5]octane- (m, 10H). .sup.13C NMR (75 MHz,
CDCl.sub.3) .delta. 116.27, 65.46, 2-carbonitrile 47.39, 33.17,
31.07, 24.75, 24.58. HRMS (ESI, TOF MS) m/z calculated for [M +
H].sup.+: 138.0919, found: 138.0913 13 1- .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 3.25 (s, 1H), 2.12-1.44 85%
oxaspiro[2.6]nonane- (m, 12H). .sup.13C NMR (75 MHz, CDCl.sub.3)
.delta. 116.46, 66.79, 2-carbonitrile 48.58, 35.46, 33.17, 28.84,
28.68, 24.33, 23.99. IR (cm.sup.-1) .nu..sub.max: 2930, 2859, 2244,
1468, 1448, 943. HRMS (ESI, TOF MS) m/z calculated for [M +
H].sup.+: 152.1075, found: 152.1071. 14 1- .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 3.28 (s, 1H), 2.01-1.46 48%
oxaspiro[2.7]decane- (m, 14H). .sup.13C NMR (75 MHz, CDCl.sub.3)
.delta. 116.50, 66.29, 2-carbonitrile 49.11, 33.76, 31.74, 26.45,
25.89, 24.96, 24.35, 22.69. HRMS (ESI, TOF MS) m/z calculated for
[M + H].sup.+: 166.1232, found: 166.1233. 15 3,3- Mp: 75.degree. C.
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.41-7.21 (m, 88%
diphenyloxirane- 10H), 3.83 (s, 1H). .sup.13C NMR (75 MHz,
CDCl.sub.3) .delta. 2-carbonitrile 136.44, 134.48, 129.34, 129.32,
128.81, 128.65, 127.72, 127.34, 115.27, 67.68, 50.11. HRMS (ESI,
TOF MS) m/z calculated for [M + H].sup.+: 222.0919, found:
222.0919. 16 spiro[fluorene- Mp: 122.degree. C. .sup.1H NMR (300
MHz, CDCl.sub.3) .delta. 7.65-7.02 42% 9,2'-oxirane]-3'- (m, 8H),
4.12 (s, 1H). .sup.13C NMR (75 MHz, CDCl.sub.3) .delta.
carbonitrile 141.57, 141.35, 137.30, 135.48, 130.86, 130.78,
128.15, 127.99, 123.78, 121.55, 120.82, 120.78, 115.17, 67.20,
48.31. HRMS (ESI, TOF MS) m/z calculated for [M + H].sup.+:
220.0762, found: 220.0759.
Example 3: Alpha-Hydroxy-Beta-Azido Tetrazoles
[0251] Hereafter are provided alpha-hydroxy-beta-azido tetrazoles
according to the invention. R.sup.1 and R.sup.2 groups refer to
formula (I):
##STR00045##
TABLE-US-00003 # R.sup.1 R.sup.2 Formula Name 17 Ph H ##STR00046##
anti-2-azido-2- phenyl-1-(1H- tetrazol-5-yl)ethan- 1-ol 18 Ph H
##STR00047## syn-2-azido-2- phenyl-1-(1H- tetrazol-5-yl)ethan- 1-ol
19 naphthalen- 2-yl ##STR00048## anti-2-azido-2- (naphthalen-2-yl)-
1-(1H-tetrazol-5- yl)ethan-1-ol 20 naphthalen- 2-yl H ##STR00049##
syn-2-azido-2- (naphthalen-2-yl)- 1-(1H-tetrazol-5- yl)ethan-1-ol
21 4- chlorophenyl H ##STR00050## anti-2-azido-2-(4-
chlorophenyl)-1- (1H-tetrazol-5- yl)ethan-1-ol 22 4- chlorophenyl H
##STR00051## syn-2-azido-2-(4- chlorophenyl)-1- (1H-tetrazol-5-
yl)ethan-1-ol 23 thiophenyl H ##STR00052## 2-azido-1-(1H-
tetrazol-5-yl)-2- (thiophen-2- yl)ethan-1-ol 24 styryl H
##STR00053## (E)-2-azido-4- phenyl-1-(1H- tetrazol-5-yl)but-3-
en-1-ol 25 heptyl H ##STR00054## 2-azido-1-(1H- tetrazol-5-
yl)nonan-1-ol 26 Et Et ##STR00055## 2-azido-2-ethyl-1-
(1H-tetrazol-5- yl)butan-1-ol 27 butyl (cyclopentyl) ##STR00056##
(1- azidocyclopentyl) (1H-tetrazol-5- yl)methanol 28 pentyl
(cyclohexyl) ##STR00057## (1- azidocyclohexyl) (1H-tetrazol-5-
yl)methanol 29 hexyl (cycloheptyl) ##STR00058## (1-
azidocycloheptyl) (1H-tetrazol-5- yl)methanol 30 heptyl
(cyclooctyl) ##STR00059## (1- azidocyclooctyl) (1H-tetrazol-5-
yl)methanol 31 Ph Ph ##STR00060## 2-azido-2,2- diphenyl-1-(1H-
tetrazol-5-yl)ethan- 1-ol 32 fluorenyl ##STR00061## (9-azido-9H-
fluoren-9-yl)(1H- tetrazol-5- yl)methanol
[0252] These compounds may be prepared as disclosed in Example
4.
Example 4: Synthesis of Alpha-Hydroxy-Beta-Azido-Tetrazoles
Materials and Methods
Procedure (b) for the Synthesis of
Alpha-Hydroxy-Beta-Azido-Tetrazoles
[0253] A solution of epoxynitrile (1 equiv.), Bu.sub.2SnO (0.5
equiv.) and TMSN.sub.3 (3 equiv.) in toluene (10 mL/mmol of
epoxide) was stirred at 60.degree. C. for 18 h. The solvent was
removed under reduced pressure and a 1:1 THF/2N aqueous HCl mixture
(20 mL) was added to the crude and stirred for 30 min. Water and
EtOAc were added and the aqueous layer was extracted (EtOAc),
washed with brine and dried over MgSO.sub.4.
[0254] Evaporation gave a residue that was washed by trituration
with small portions of dichloromethane. Further purification could
be done by flash chromatography over silica gel using
dichloromethane/MeOH/Acetic acid: 9/0.5/0.5 mixture as eluent
(spots were revealed with ninhydrin).
Results
[0255] Hereafter are provided the yield and physical
characterization of alpha-hydroxy-beta-azido tetrazoles according
to the invention, prepared by the above procedure.
[0256] Compounds #17-32 were respectively prepared from
epoxynitriles #1-16 disclosed in Examples 1 and 2.
TABLE-US-00004 # Name Characterization Yield 17 anti-2-azido-2- Mp:
175.degree. C. .sup.1H NMR (300 MHz, DMSO) .delta.7.40-7.20 85%
phenyl-1-(1H- (m, 5H), 6.76 (dl, J = 4.9 Hz, 1H), 5.33 (t, J = 5.3
Hz, tetrazol-5-yl)ethan- 1H), 5.16 (d, J = 6.0 Hz, 1H). .sup.13C
NMR (75 MHz, 1-ol DMSO) .delta.156.76, 135.34, 128.31, 127.85,
67.58, 67.39. HRMS (ESI, TOF MS) m/z calculated for [M + H].sup.+:
232.0947, found: 232.0950. 18 syn-2-azido-2- Mp: 176.degree. C.
.sup.1H NMR (300 MHz, DMSO) .delta.7.35-7.20 65% phenyl-1-(1H- (m,
5H), 6.88 (dl, J = 5.8 Hz, 1H), 5.28 (t, J = 5.6 Hz,
tetrazol-5-yl)ethan- 1H), 5.07 (d, 1H, J = 6.1 Hz). .sup.13C NMR
(75 MHz, 1-ol DMSO) .delta.135.71, 128.49, 127.89, 68.13, 68.05.
HRMS (ESI, TOF MS) m/z calculated for [M + H].sup.+: 232.0947,
found: 232.0950. 19 anti-2-azido-2- Mp: 211.degree. C. (dec.).
.sup.1H NMR (300 MHz, DMSO) .delta.8.00- 55% (naphthalen-2-yl)-1-
7.85 (m, 3H), 7.82 (s, 1H), 7.60-7.45 (m, 2H), 7.42 (d,
(1H-tetrazol-5- 1H, J = 8.6 Hz), 6.83 (dl, J = 4.7 Hz, 1H), 5.45
(t, J = 5.0 yl)ethan-1-ol Hz, 1H), 5.36 (d, J = 5.9 Hz, 1H).
.sup.13C NMR (75 MHz, DMSO) .delta.132.95, 132.66, 132.44, 127.92,
127.50, 127.17, 126.42, 126.36, 125.31, 67.78, 67.47. HRMS (ESI,
TOF MS) m/z calculated for [M + H].sup.+: 282.1103, found:
282.1101. 20 syn-2-azido-2- Mp: 209.degree. C. (dec.). .sup.1H NMR
(300 MHz, DMSO) .delta.7.90- 56% (naphthalen-2-yl)-1- 7.80 (m, 4H),
7.60-7.40 (m, 4H), 5.41 (d, J = 6.4 Hz, (1H-tetrazol-5- 1H), 5.36
(d, J = 6.4 Hz, 1H). .sup.13C NMR (75 MHz, yl)ethan-1-ol DMSO)
.delta.133.26, 64, 132.44, 128.02, 127.91, 127.51, 127.05, 126.46,
126.39, 125.35, 68.35, 68.11. HRMS (ESI, TOF MS) m/z calculated for
[M + H].sup.+: 282.1103, found: 282.1101. 21 anti-2-azido-2-(4- Mp:
198.degree. C. (dec.). .sup.1H NMR (300 MHz, DMSO) .delta.7.40 63%
chlorophenyl)-1- (d, J = 8.5 Hz, 2H), 7.28 (d, J = 8.5 Hz, 2H),
6.82 (dl, (1H-tetrazol-5- J = 3.2 Hz, 1H), 5.34 (t, J = 4.9 Hz,
1H), 5.22 (d, J = 5.7 yl)ethan-1-ol Hz, 1H). .sup.13C NMR (75 MHz,
DMSO) .delta.134.36, 132.93, 129.72, 128.27, 67.43, 66.75. HRMS
(ESI, TOF MS) m/z calculated for [M + H].sup.+: 266.0560, found:
266.0557. 22 syn-2-azido-2-(4- Mp: 203.degree. C. (dec.). .sup.1H
NMR (300 MHz, DMSO) .delta.7.42 51% chlorophenyl)-1- (d, J = 8.6
Hz, 2H), 7.34 (d, J = 8.6 Hz, 2H), 6.91 (dl, (1H-tetrazol-5- J =
5.5 Hz, 1H), 5.29 (t, J = 5.3 Hz, 1H), 5.14 (d, J = 6.0
yl)ethan-1-ol Hz, 1H). .sup.13C NMR (75 MHz, DMSO) .delta.134.73,
133.03, 129.74, 128.39, 67.93, 67.18. HRMS (ESI, TOF MS) m/z
calculated for [M + H].sup.+: 266.0560, found: 266.0557. 23
2-azido-1-(1H- Mp: 125.degree. C. .sup.1H NMR (300 MHz, DMSO)
.delta. 7.57 (d, J = 38% tetrazol-5-yl)-2- 5.1 Hz, 1H.sub.min),
7.51 (d, J = 5.1 Hz, 1H.sub.maj), 7.19 (d, J = (thiophen-2- 2.8 Hz,
1H.sub.min), 7.12 (d, J = 2.8 Hz, 1H.sub.maj), 7.07 (s,
yl)ethan-1-ol 1H), 7.03 (dd, J = 5.1, 3.6 Hz, 1H.sub.min), 6.99
(dd, J = 5.0, 3.6 Hz, 1H.sub.maj), 5.45 (d, J = 4.8 Hz,
1H.sub.maj), 5.36 (d, J = 4.5 Hz, 1H.sub.maj + 1H.sub.min), 5.32
(d, J = 4.3 Hz, 1H.sub.min). .sup.13C NMR (75 MHz, DMSO) .delta.
156.94 (maj), 156.21 (min), 137.18 (min), 136.35 (maj), 128.00
(maj), 127.84 (min), 127.34 (min), 127.23 (maj), 126.51 (min),
67.93 (min), 67.54 (maj), 63.35 (min), 63.32 (maj). HRMS (ESI, TOF
MS) m/z calculated for [M + H].sup.+: 238.0511, found: 238.0514. 24
(E)-2-azido-4- Mp: 134.degree. C. .sup.1H NMR (300 MHz, DMSO)
.delta. 7.52-7.23 52% phenyl-1-(1H- (m, 5H), 6.85 (s, 1H), 6.81 (d,
J = 16.0 Hz, 1H.sub.min), 6.69 tetrazol-5-yl)but-3- (d, J = 15.9
Hz, 1H.sub.maj), 6.38 (dd, J = 15.9, 8.0 Hz, en-1-ol 1H.sub.min),
6.31 (dd, J = 15.9, 8.0 Hz, 1H.sub.maj), 5.25 (bm, 1H.sub.min),
5.24 (bm, 1H.sub.maj), 4.66 (dd, J = 7.5, 4.5 Hz, 1H.sub.maj), 4.58
(dd, J = 7.8, 4.4 Hz, 1H.sub.min). .sup.13C NMR (75 MHz, DMSO)
.delta. 156.33, 135.55 (min), 135.52 (maj), 135.07 (maj), 134.89
(min), 128.69 (maj), 128.29 (min), 126.63 (min), 126.58 (maj),
122.79 (min), 122.27 (maj), 67.34 (min), 67.08 (maj), 66.68 (maj),
66.51(min). HRMS (ESI, TOF MS) m/z calculated for [M + H].sup.+:
258.1103, found: 258.1102. 25 2-azido-1-(lH- Mp: 146.degree. C.
.sup.1H NMR (300 MHz, DMSO) .delta. 6.69 (s, 70%
tetrazol-5-yl)nonan- 1H), 5.15 (d, J = 3.9 Hz, 1H), 3.85-3.75 (m,
1H), 1-ol 1.60-1.10 (m, 12H), 0.89-0.79 (m, 3H). .sup.13C NMR (75
MHz, DMSO) .delta. 156.27, 67.31, 65.57, 31.10, 29.01, 28.56,
28.45, 25.51, 22.02, 13.88. HRMS (ESI, TOF MS) m/z calculated for
[M + H].sup.+: 254.1729, found: 254.1732. 26 2-azido-2-ethyl-1- Mp:
128.degree. C. .sup.1H NMR (300 MHz, DMSO) .delta. 6.74 (d, J = 60%
(1H-tetrazol-5- 4.3 Hz, 1H), 5.10 (d, J = 4.2 Hz, 1H), 1.95-1.75
(m, yl)butan-1-ol 2H), 1.45-1.25 (m, 2H), 0.94 (t, J = 7.3 Hz, 3H),
0.80 (t, J = 7.3 Hz, 3H). .sup.13C NMR (75 MHz, DMSO) .delta.
156.27, 68.60, 24.24, 23.04, 7.55, 7.36. HRMS (ESI, TOF MS) m/z
calculated for [M + H].sup.+: 212.1260, found: 212.1262. 27 (1- Mp:
161.degree. C. .sup.1H NMR (300 MHz, DMSO) .delta. 6.78 (d, J = 53%
azidocyclopentyl)(1 4.5 Hz, 1H), 5.10 (d, J = 4.4 Hz, 1H),
1.97-1.75 (m, H-tetrazol-5- 2H), 1.45-1.22 (m, 6H). .sup.13C NMR
(75 MHz, DMSO) .delta. yl)methanol 156.68, 75.15, 70.60, 33.55,
33.11, 23.41, 23.30. HRMS (ESI, TOF MS) m/z calculated for [M +
H].sup.+: 210.1103, found: 210.1104. 28 (1- Mp: 175.degree. C.
.sup.1H NMR (300 MHz, DMSO) .delta. 6.80 (d, J = 75%
azidocyclohexyl)(1 4.8 Hz, 1H), 5.06 (d, J = 4.8 Hz, 1H), 2.23-0.91
(m, H-tetrazol-5- 10H). .sup.13C NMR (75 MHz, DMSO) .delta. 156.01,
71.40, yl)methanol 65.48, 30.23, 29.77, 24.54, 21.39, 21.14. HRMS
(ESI, TOF MS) m/z calculated for [M + H].sup.+: 224.1260, found:
224.1264. 29 (1- Mp: 172.degree. C. .sup.1H NMR (300 MHz, DMSO)
.delta. 6.81 (d, J = 76% azidocycloheptyl)(1 4.8 Hz, 1H), 5.00 (d,
J = 4.8 Hz, 1H), 2.19-1.04 (m, H-tetrazol-5- 12H). .sup.13C NMR (75
MHz, DMSO) .delta. 156.21, 70.95, yl)methanol 68.96, 33.67, 33.07,
28.91, 28.88, 21.75, 21.66. HRMS (ESI, TOF MS) m/z calculated for
[M + H].sup.+: 238.1416, found: 238.1408. 30 (1- Mp: 186.degree. C.
.sup.1H NMR (300 MHz, DMSO) .delta. 6.76 (d, J = 51%
azidocyclooctyl)(1 4.6 Hz, 1H), 5.06 (d, J = 4.6 Hz, 1H), 2.23-1.88
(m, H-tetrazol-5- 2H), 1.77-1.18 (m, 12H). .sup.13C NMR (75 MHz,
DMSO) yl)methanol .delta. 156.26, 70.09, 68.91, 29.79, 28.06,
27.71, 27.21, 24.10, 21.49, 21.26. HRMS (ESI, TOF MS) m/z
calculated for [M + H].sup.+: 252.1573, found: 252.1576. 31
2-azido-2,2- Mp: 205.degree. C. .sup.1H NMR (300 MHz, DMSO) .delta.
7.63-7.29 61% diphenyl-1-(1H- (m, 5H), 7.22-6.99 (m, 6H), 6.39 (d,
J = 4.2 Hz, 1H). tetrazol-5-yl)ethan- .sup.13C NMR (75 MHz, DMSO)
.delta. 155.27, 140.06, 128.56, 1-ol 127.95, 127.93, 127.71,
127.25, 126.11, 74.31, 69.88. HRMS (ESI, TOF MS) m/z calculated for
[M + H].sup.+: 308.1260, found: 308.1252. 32 (9-azido-9H- Mp:
213.degree. C. .sup.1H NMR (300 MHz, DMSO) .delta. 7.82 (d, J = 61%
fluoren-9-yl)(1H- 6.9 Hz, 2H), 7.57-7.35 (m, 6H), 7.31 (d, J = 5.0
Hz, tetrazol-5- 1H), 5.68 (d, J = 4.8 Hz, 1H). .sup.13C NMR (75
MHz, yl)methanol DMSO) .delta. 155.35 141.47, 140.69, 140.13,
139.92, 129.87, 127.94, 127.81, 125.47, 125.14, 120.44, 74.21,
69.45. HRMS (ESI, TOF MS) m/z calculated for [M + H].sup.+:
306.1103, found: 306.1111.
[0257] These results evidence that the applicant successfully
conceived and reduced to practice an efficient, straightforward and
stereospecific synthesis of alpha-hydroxy-beta-azido
tetrazoles.
[0258] Various combinations of R.sup.1 and R.sup.2 substituting
groups were used, confirming that the scope of procedure (b) is
very broad.
Example 5: Alpha-Hydroxy-Beta-Triazolo-Tetrazoles
[0259] Hereafter are provided
alpha-hydroxy-beta-triazolo-tetrazoles according to the invention.
R.sup.1, R.sup.2 and R.sup.3 groups refer to formula (III):
##STR00062##
TABLE-US-00005 # R.sup.1 R.sup.2 R.sup.3 Formula Name 33 pentyl
(cyclohexyl) Ph ##STR00063## (1-(4-phenyl-1H- 1,2,3-triazol-1-
yl)cyclohexyl)(1H- tetrazol-5- yl)methanol 34 hexyl (cycloheptyl)
Ph ##STR00064## (1-(4-phenyl-1H- 1,2,3-triazol-1-
yl)cycloheptyl)(1H- tetrazol-5- yl)methanol 35 heptyl (cyclooctyl)
Ph ##STR00065## (1-(4-phenyl-1H- 1,2,3-triazol-1-
yl)cyclooctyl)(1H- tetrazol-5- yl)methanol 36 heptyl (cyclooctyl)
--COOtBu ##STR00066## tert-butyl 1-(1- (hydroxy(1H- tetrazol-5-
yl)methyl)cyclo- octyl)-1H-1,2,3- triazole-4- carboxylate 37 heptyl
(cyclooctyl) 3- chloropropyl ##STR00067## (1-(4-(3-
chloropropyl)-1H- 1,2,3-triazol-1- yl)cyclooctyl)(1H- tetrazol-5-
yl)methanol 38 heptyl (cyclooctyl) 2- hydroxyethyl ##STR00068##
2-(1-(1- (hydroxy(1H- tetrazol-5- yl)methyl)cyclo- octyl)-1H-1,2,3-
triazol-4-yl)ethan- 1-ol 39 Et Et Ph ##STR00069## 2-ethyl-2-(4-
phenyl-1H-1,2,3- triazol-1-yl)-1-(1H- tetrazol-5-yl)butan- 1-ol 40
Ph H hexyl ##STR00070## 2-(4-hexyl-1H- 1,2,3-triazol-1-yl)-
2-phenyl-1-(1H- tetrazol-5-yl)ethan- 1-ol 41 Ph Ph hexyl
##STR00071## 2-(4-hexyl-1H- 1,2,3-triazol-1-yl)- 2,2-diphenyl-1-
(1H-tetrazol-5- yl)ethan-1-ol 42 Ph Ph 3- chloropropyl ##STR00072##
2-(4-(3- chloropropyl)-1H- 1,2,3-triazol-1-yl)- 2,2-diphenyl-1-
(1H-tetrazol-5- yl)ethan-1-ol 43 Ph Ph --COOtBu ##STR00073##
tert-butyl 1-(2- hydroxy-1,1- diphenyl-2-(1H- tetrazol-5-yl)ethyl)-
1H-1,2,3-triazole- 4-carboxylate
[0260] These compounds may be prepared as disclosed in Example
6.
Example 6: CuAAC Synthesis of
Alpha-Hydroxy-Beta-Triazolo-Tetrazoles
Materials and Methods
Procedures for the Synthesis of
Alpha-Hydroxy-Beta-Tetrazo-Tetrazoles
Procedure (c):
[0261] The alpha-hydroxy-beta-azido-tetrazole substrate (1 mmol)
was dissolved in n-BuOH (3 mL). An alkyne (3 mmol) and TBTA
(tris((1-benzyl-1H-1,2,3-triazolyl)methyl)amine) (0.1 mmol) were
added. A solution of sodium ascorbate (0.2 mmol in 1.5 mL water)
was added, followed by a solution of copper sulphate (0.1 mmol in
1.5 mL water). The mixture was stirred at room temperature for 48
hours. The organic phase was separated and concentrated under
reduced pressure. The residue was purified by flash chromatography
on silica gel.
Procedure (d):
[0262] A mixture of alpha-hydroxy-beta-azido-tetrazole substrate
(0.10 mmol), copper (I) bromide (0.01 mmol) and TBTA (0.011 mmol)
in THF (1 mL) was placed under argon atmosphere. An alkyne (0.30
mmol) and diisopropylethylamine (0.05 mL, 0.30 mmol) were added,
and the mixture was stirred for 24 hours. The mixture was
concentrated under reduced pressure. The residue was purified by
flash chromatography on silica gel.
Results
[0263] Hereafter are provided the yield and physical
characterization of alpha-hydroxy-beta-triazolo-tetrazoles
according to the invention, prepared by procedure (c) above.
Compound #35 was also prepared by procedure (d).
[0264] Compounds #33-43 were prepared from the corresponding
alpha-hydroxy-beta-azido-tetrazoles disclosed in Example 3 and 4
and from the appropriate R.sup.3--C.ident.CH terminal alkyne.
TABLE-US-00006 # Name Characterization Yield 33 (1-(4-phenyl-1H-
Mp: 210-212.degree. C. .sup.1H NMR (300 MHz, DMSO-d6) .delta. 8.60
84% 1,2,3-triazol-1- (s, 1H), 7.87 (m, 2H), 7.44 (m, 2H), 7.31 (m,
1H), 6.76 (c) yl)cyclohexyl)(1H- (d, J = 5.0 Hz, 1H), 5.15 (d, J =
5.0 Hz, 1H), 2.61-2.66 tetrazol-5- (m, 2H), 1.88-1.96 (m, 2H),
1.48-1.67 (m, 3H), 1.08-1.29 yl)methanol (m, 3H). .sup.13C NMR (75
MHz, DMSO-d6) .delta. 155.9, 145.6, 131.1, 128.7, 127.6, 125.1,
121.5, 70.9, 66.3, 30.3, 24.3, 20.9, 20.8. HRMS (ESI, TOF MS) m/z
calculated for C.sub.16H.sub.20N.sub.7O [M + H].sup.+: 326.1729,
found: 326.1719. 34 (1-(4-phenyl-1H- Mp: 119-120.degree. C. .sup.1H
NMR (300 MHz, DMF-d6) .delta. 8.74 (s, 98% 1,2,3-triazol-1- 1H),
7.98 (m, 2H), 7.47 (m, 2H), 7.35 (m, 1H), 7.03 (bs, (c)
yl)cycloheptyl)(1 1H), 5.46 (bs, 1H), 3.53 (bs, 1H), 2.32-2.36 (m,
2H), H-tetrazol-5- 1.88-1.96 (m, 2H), 1.45-1.54 (m, 8H). .sup.13C
NMR (75 yl)methanol MHz, DMF-d6) .delta. 147.3, 132.8, 130.0,
129.8, 128.6, 126.3, 122.6, 72.8, 71.9, 30.4, 23.2, 23.1, 21.7.
HRMS (ESI, TOF MS) m/z calculated for C.sub.17H.sub.22N.sub.7O [M +
H].sup.+: 340.1886, found: 340.1893. 35 (1-(4-phenyl-1H- Mp:
86-88.degree. C. .sup.1H NMR (300 MHz, DMF-d6) .delta. 8.71 (s, 98%
1,2,3-triazol-1- 1H), 7.96 (m, 2H), 7.44-7.49 (m, 2H), 7.34 (m,,
1H), (c) yl)cyclooctyl)(1H- 7.03 (bs, 1H), 5.48 (s, 1H), 3.66 (bs,
1H), 2.52-2.72 (m, 90% tetrazol-5- 3H), 2.36-2.43 (m, 1H),
1.47-1.77 (m, 12H). .sup.13C NMR (d) yl)methanol (75 MHz, DMF-d6)
.delta. 157.7, 146.9, 132.8, 129.8, 128.6, 126.3, 122.7, 80.2,
71.7, 71.6, 29.3, 28.5, 25.7, 22.8. HRMS (ESI, TOF MS) m/z
calculated for C.sub.18H.sub.24N.sub.7O [M + H].sup.+: 354.2042,
found: 354.2045. 36 tert-butyl 1-(1- Mp: 118-120.degree. C. .sup.1H
NMR (300 MHz, DMSO-d6) .delta. 8.60 98% (hydroxy(1H- (s, 1H), 6.83
(bs, 1H), 5.25 (s, 1H), 2.25-2.45 (m, 3H), (c) tetrazol-5-
1.26-1.66 (m, 20H). .sup.13C NMR (75 MHz, DMSO-d6) .delta.
yl)methyl)cyclo- 159.9, 139.5, 128.9, 81.1, 69.8, 29.1, 27.9, 26.3,
24.2, octyl)-1H-1,2,3- 21.3. HRMS (ESI, TOF MS) m/z calculated for
triazole-4- C.sub.17H.sub.28N.sub.7O.sub.3 [M + H].sup.+: 378.2254,
found: 378.2257. carboxylate 37 (1-(4-(3- Mp: 85-87.degree. C.
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.23 (s, 71%
chloropropyl)-1H- 1H), 5.51 (s, 1H), 3.45 (t, J = 5.9 Hz, 1H),
2.67-2.79 (m, (c) 1,2,3-triazol-1- 4H), 2.42-2.51 (m, 2H),
2.01-2.04 (m, 2H), 1.47-1.82 (m, yl)cyclooctyl)(1H- 10H). .sup.13C
NMR (75 MHz, CDCl.sub.3) .delta. 121.8, 72.1, 71.3, tetrazol-5-
43.7, 31.6, 30.4, 29.6, 28.2, 27.3, 24.9, 22.1, 22.0. HRMS
yl)methanol (ESI, TOF MS) m/z calculated for
C.sub.15H.sub.25N.sub.7OCl [M + H].sup.+: 354.1809, found:
354.1810. 38 2-(1-(1- .sup.1H NMR (300 MHz, CD.sub.3OD) .delta.
7.87 (s, 1H), 5.28 (s, 94% (hydroxy(1H- 1H), 3.83 (t, J = 6.7 Hz,
1H), 2.90 (t, J = 6.5 Hz, 1H), (c) tetrazol-5- 2.30-2.61 (m, 4H),
1.43-1.57 (m, 10H). .sup.13C NMR (75 yl)methyl)cyclo- MHz,
CDCl.sub.3) .delta. 158.7, 145.3, 124.4, 72.2, 72.0, 62.2,
octyl)-1H-1,2,3- 30.9, 30.2, 30.0, 29.6, 28.8, 26.0, 23.1. HRMS
(ESI, TOF triazol-4-yl)ethan- MS) m/z calculated for
C.sub.14H.sub.24N.sub.7O.sub.2 [M + H].sup.+: 322.1991, 1-ol found:
322.1995. 39 2-ethyl-2-(4- Mp: 103-105.degree. C. .sup.1H NMR (300
MHz, DMSO-d6) .delta. 8.56 99% phenyl-1H-1,2,3- (s, 1H), 7.87 (m,
2H), 7.43 (m,, 2H), 7.30 (m, 1H), 6.84 (c) triazol-1-yl)-1- (d, J =
5.4 Hz, 1H), 5.34 (d, J = 5.4 Hz, 1H), 2.18-2.36 (1H-tetrazol-5-
(m, 4H), 0.90 (t, J = 7.3 Hz, 3H), 0.83 (t, J = 7.4 Hz,
yl)butan-1-ol 3H). .sup.13C NMR (75 MHz, DMSO-d6) .delta. 156.2,
145.3, 131.1, 128.7, 127.6, 125.1, 121.5, 69.9, 68.3, 24.6, 23.8,
7.5. HRMS (ESI, TOF MS) m/z calculated for C.sub.15H.sub.20N.sub.7O
[M + H].sup.+: 314.1729, found: 314.1724. 40 2-(4-hexyl-1H- Mp:
157-159.degree. C. .sup.1H NMR (300 MHz, DMF-d6) .delta. 8.32 78%
1,2,3-triazol-1- (bs, 1H), 7.30-7.53 (m, 5H), 6.37 (b, 2H), 2.66
(t, J = 7.3 (c) yl)-2-phenyl-1- Hz, 1H), 1.61-1.64 (m, 2H), 1.30
(b, 6H), 0.87 (t, J = 5.8 (1H-tetrazol-5- Hz, 1H). .sup.13C NMR (75
MHz, DMF-d6) .delta. 136.7, 128.8, yl)ethan-1-ol 128.3, 122.2,
68.6, 66.9, 31.7, 28.9, 25.7, 22.6, 13.8. HRMS (ESI, TOF MS) m/z
calculated for C.sub.17H.sub.24N.sub.7O [M + H].sup.+: 342.2042,
found: 342.2049. 41 2-(4-hexyl-1H- .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 7.21-7.38 (m, 10H), 6.82- 60% 1,2,3-triazol-1-
6.93 (m, 3H), 2.63-2.65 (m, 1H), 1.57 (m, 2H), 1.26 (b, (c)
yl)-2,2-diphenyl- 6H), 0.85 (t, J = 5.8 Hz, 3H). .sup.13C NMR (75
MHz, CDCl.sub.3) 1-(1H-tetrazol-5- .delta. 162.8, 139.2, 138.4,
129.3, 128.7, 128.4, 127.8, 124.2, yl)ethan-1-ol 71.4, 31.3, 28.9,
28.7, 25.2, 22.4, 13.9. HRMS (ESI, TOF MS) m/z calculated for
C.sub.23H.sub.28N.sub.7O [M + H].sup.+: 418.2355, found: 418.2353.
42 2-(4-(3- Mp: 114-116.degree. C. .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 7.25-7.39 78% chloropropyl)-1H- (m, 12H), 7.02
(bs, 1H), 6.83 (b, 4H), 3.55 (m, 2H), 2.82 (c) 1,2,3-triazol-1- (m,
2H), 2.11 (m, 2H). .sup.13C NMR (75 MHz, CDCl.sub.3) .delta.
yl)-2,2-diphenyl- 139.1, 138.3, 129.5, 128.8, 128.5, 127.8, 125.2,
71.2, 1-(1H-tetrazol-5- 43.9, 31.4, 22.4. HRMS (ESI, TOF MS) m/z
calculated yl)ethan-1-ol for C.sub.20H.sub.21N.sub.7OCl [M +
H].sup.+: 410.1496, found: 410.1490. 43 tert-butyl 1-(2- Mp:
122-124.degree. C. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.69
(s, 49% hydroxy-1,1- 1H), 7.43 (b, 5H), 7.27 (b, 3H), 6.94-6.97 (m,
3H), 1.59 (c) diphenyl-2-(1H- (s, 9H). .sup.13C NMR (75 MHz,
CDCl.sub.3) .delta. 159.2, 155.5, tetrazol-5- 139.7, 138.1, 130.0,
129.5, 128.9, 128.8, 128.5, 127.6, yl)ethyl)-1H- 83.1, 70.7, 27.9.
HRMS (ESI, TOF MS) m/z calculated 1,2,3-triazole-4- for
C.sub.22H.sub.23N.sub.7ONa [M + Na].sup.+: 456.1760, found:
456.1754. carboxylate
[0265] These results evidence that the applicant successfully
conceived and reduced to practice a CuAAC reaction between the
alpha-hydroxy-beta-azido-tetrazoles and terminal alkynes.
[0266] Procedures (c) and (d) are thus efficient methods to prepare
a wide range of alpha-hydroxy-beta-triazolo-tetrazoles
compounds.
Example 7: Triazole Alkynes
[0267] Hereafter are provided triazoles alkynes according to the
invention. R.sup.1, R.sup.2 and R.sup.3 groups refer to formula
(IV):
##STR00074##
TABLE-US-00007 # R.sup.1 R.sup.2 R.sup.3 Formula Name 44 pentyl
(cyclohexyl) Ph ##STR00075## 1-(1- ethynylcyclo- hexyl)-
4-phenyl-1H- 1,2,3-triazole 45 hexyl (cycloheptyl) Ph ##STR00076##
1-(1- ethynylcyclo- heptyl)- 4-phenyl-1H- 1,2,3-triazole 46 heptyl
(cyclooctyl) Ph ##STR00077## 1-(1- ethynylcyclo- octyl)-4-
phenyl-1H- 1,2,3-triazole 47 heptyl (cyclooctyl) tBuAc ##STR00078##
tert-butyl 1-(1- ethynylcyclo- octyl)-1H- 1,2,3-triazole-
4-carboxylate 48 heptyl (cyclooctyl) 3- chloropropyl ##STR00079##
4-(3-chloro- propyl)- 1-(1- ethynylcyclo- octyl)-1H- 1,2,3-triazole
49 heptyl (cyclooctyl) 2- hydroxy- ethyl ##STR00080## 2-(1-(1-
ethynylcyclo- octyl)-1H- 1,2,3-triazol- 4-yl)ethan- 1-ol 50 Et Et
Ph ##STR00081## 1-(3-ethylpent- 1-yn-3-yl)-4- phenyl-1H-
1,2,3-triazole 51 Ph H hexyl ##STR00082## 4-hexyl-1-(1- phenylprop-
2-yn-1- yl)-1H-1,2,3- triazole 52 Ph Ph hexyl ##STR00083## 1-(1,1-
diphenylprop- 2-yn-1-yl)-4- hexyl-1H- 1,2,3-triazole
[0268] These compounds may be prepared as disclosed in Example
8.
Example 8: Synthesis of Triazole Alkenes
Materials and Methods
[0269] Procedures for the Reaction of
.alpha.-Hydroxy-.beta.-Triazole-Tetrazoles with Carbodiimides:
Procedure (e), with Diisopropylcarbodiimide (DIC):
[0270] The alpha-hydroxy-beta-triazole-tetrazole (0.35 mmol) was
dissolved in dichloromethane (10 mL). DIC (0.42 mmol) was added.
The mixture was stirred at room temperature for 18 hours, and then
concentrated under reduced pressure. The residue was purified by
flash chromatography on silica gel.
Procedure (f), with N-(3-Dimethylaminopropyl)-N'-Ethylcarbodiimide
(EDC):
[0271] The alpha-hydroxy-beta-triazole-tetrazole (0.1 mmol) was
dissolved in dichloromethane (5 mL). EDC (0.12 mmol) was added and
the mixture was stirred at room temperature for 18 hours. The
mixture was diluted with dichloromethane and the resulting solution
was washed successively with solutions of aqueous 0.5M HCl, aqueous
saturated NaCl and aqueous saturated NaHCO.sub.3. The organic layer
was dried over MgSO.sub.4 and concentrated under reduced pressure.
The residue was purified by flash chromatography on silica gel.
Results
[0272] Hereafter are provided the yield and physical
characterization of triazole alkynes according to the invention,
prepared by the above procedures.
[0273] Compounds #44-52 were prepared from the corresponding
alpha-hydroxy-beta-triazolo-tetrazoles disclosed in Example 5 and
6.
TABLE-US-00008 # Name Characterization Yield 44 1-(1- Mp:
114-116.degree. C. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.18
(d, J = 69% ethynylcyclohexyl)- 4.6 Hz, 1H), 7.85-7.89 (m, 2H),
7.26-7.47 (m, 3H), 2.78 (e) 4-phenyl-1H- (d, J = 4.7 Hz, 1H),
2.25-2.43 (m, 4H), 1.77-1.88 (m, 1,2,3-triazole 5H), 1.28-1.43 (m,
1H). .sup.13C NMR (75 MHz, CDCl.sub.3) .delta. 146.7, 130.7, 128.7,
128.0, 125.7, 118.5, 82.4, 76.2, 61.5, 38.6, 24.7, 23.1. HRMS (ESI,
TOF MS) m/z calculated for C.sub.16H.sub.18N.sub.3 [M + H].sup.+:
252.1501, found: 252.1498. 45 1-(1- Mp: 80-81.degree. C. .sup.1H
NMR (300 MHz, CDCl.sub.3) .delta. 8.18 (s, 61% ethynylcycloheptyl)-
1H), 7.85 (m, 2H), 7.40-7.45 (m, 2H), 7.33 (m, 1H), 2.79 (e)
4-phenyl-1H- (s, 1H), 2.59-2.63 (m, 2H), 2.27-2.34 (m, 2H),
1.66-1.87 1,2,3-triazole (m, 8H). .sup.13C NMR (75 MHz, CDCl.sub.3)
.delta. 146.5, 130.6, 128.7, 128.0, 125.7, 118.5, 83.7, 75.4, 64.6,
42.1, 27.9, 22.7. HRMS (ESI, TOF MS) m/z calculated for
C.sub.17H.sub.20N.sub.3 [M + H].sup.+: 266.1657, found: 266.1655.
46 1-(1- Mp: 78.degree. C. .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 8.15 (s, 1H), 73% ethynylcyclooctyl)- 7.85 (m, 2H),
7.40-7.45 (m, 2H), 7.33 (t, J = 7.2 Hz, 1H), (e) 4-phenyl-1H- 2.72
(s, 1H), 2.64-2.71 (m, 2H), 2.24-2.33 (m, 2H), 1.63- 1,2,3-triazole
1.81 (m, 12H). .sup.13C NMR (75 MHz, CDCl.sub.3) .delta. 146.7,
130.6, 128.7, 128.0, 125.7, 118.5, 83.9, 74.7, 64.3, 37.0, 27.7,
24.4, 22.4. HRMS (ESI, TOF MS) m/z calculated for
C.sub.18H.sub.22N.sub.3 [M + H].sup.+: 280.1814, found: 280.1817 47
tert-butyl 1-(1- .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.35 (s,
1H), 2.73 (s, 1H), 76% ethynylcyclooctyl)- 2.57-2.62 (m, 2H),
2.18-2.24 (m, 2H), 1.61-1.75 (m, (f) 1H-1,2,3- 21H). .sup.13C NMR
(75 MHz, CDCl.sub.3) .delta. 160.2, 140.5, 130.6, triazole-4-
125.9, 83.1, 82.2, 75.2, 64.8, 37.0, 28.2, 27.6, 24.3, 22.3.
carboxylate HRMS (ESI, TOF MS) m/z calculated for
C.sub.17H.sub.26N.sub.3O.sub.2 [M + H].sup.+: 304.2025, found:
304.2031. 48 4-(3- .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.69
(s, 1H), 3.59 (t, J = 75% chloropropyl)-1- 6.4 Hz, 2H), 2.89 (t, J
= 7.7 Hz, 2H), 2.67 (s, 1H), 2.57- (f) (1- 2.64 (m, 2H), 2.16-2.26
(m, 4H), 1.62-1.76 (m, 10H). .sup.13C ethynylcyclooctyl)- NMR (75
MHz, CDCl.sub.3) .delta. 145.6, 119.9, 83.9, 74.4, 63.9, 1H-1,2,3-
44.3, 36.9, 31.9, 27.7, 24.3, 22.7, 22.4. HRMS (ESI, TOF triazole
MS) m/z calculated for C.sub.15H.sub.23N.sub.3Cl [M + H].sup.+:
280.1581, found: 280.1587. 49 2-(1-(1- .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 7.76 (s, 1H), 3.95 (t, J = 46%
ethynylcyclooctyl)- 5.6 Hz, 1H), 2.86-2.98 (m, 3H), 2.67 (s, 1H),
2.55-2.64 (f) 1H-1,2,3-triazol- (m, 2H), 2.17-2.25 (m, 2H),
1.61-1.76 (m, 10H). .sup.13C 4-yl)ethan-1-ol NMR (75 MHz,
CDCl.sub.3) .delta. 144.5, 120.3, 83.8, 74.5, 64.0, 61.5, 36.9,
28.6, 27.7, 24.3, 22.4. HRMS (ESI, TOF MS) m/z calculated for
C.sub.14H.sub.22N.sub.3O [M + H].sup.+: 248.1763, found: 248.1770.
50 1-(3-ethylpent-1- Mp: 36-38.degree. C. .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 8.17 (s, 73% yn-3-yl)-4- 1H), 7.87-7.90 (m,
2H), 7.40-7.45 (m, 2H), 7.33 (m, 1H), (e) phenyl-1H-1,2,3- 2.79 (s,
1H), 2.38-2.50 (m, 2H), 2.07-2.19 (m, 2H), 0.89 triazole (t, J =
7.4 Hz 6H). .sup.13C NMR (75 MHz, CDCl.sub.3) .delta. 146.0, 130.7,
128.7, 127.9, 125.6, 120.6, 81.2, 76.3, 66.0, 34.8, 8.5. HRMS (ESI,
TOF MS) m/z calculated for C.sub.15H.sub.18N.sub.3 [M + H].sup.+:
240.1501, found: 240.1502 51 4-hexyl-1-(1- Mp: 59-61.degree. C.
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.37-7.48 75%
phenylprop-2-yn- (m, 6H), 6.67 (d, J = 2.0 Hz, 1H), 2.82 (d, J =
2.4 Hz, 1H), (e) 1-yl)-1H-1,2,3- 2.68 (t, J = 7.5 Hz, 2H),
1.59-1.69 (m, 2H), 1.28-1.36 (m, triazole 6H), 0.86 (t, J = 7.0 Hz,
3H). .sup.13C NMR (75 MHz, CDCl.sub.3) .delta. 149.0, 135.6, 129.2,
128.9, 127.0, 119.0, 78.1, 55.5, 31.4, 29.2, 28.8, 25.7, 22.5,
13.9. HRMS (ESI, TOF MS) m/z calculated for C.sub.17H.sub.22N.sub.3
[M + H].sup.+: 268.1814, found: 268.1812. 52 1-(1,1- Mp:
59-61.degree. C. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.
7.25-7.44 62% diphenylprop-2- (m, 11H), 3.09 (s, 1H), 2.74 (t, J =
8.0 Hz, 1H), 1.63-1.70 (f) yn-1-yl)-4-hexyl- (m, 2H), 1.29-1.33 (m,
6H), 0.80 (b, 3H). .sup.13C NMR (75 1H-1,2,3-triazole MHz,
CDCl.sub.3) .delta. 147.7, 140.3, 128.8, 128.4, 127.9, 121.6, 83.2,
77.6, 69.1, 31.5, 29.3, 28.9, 25.7, 22.5, 14.0. HRMS (ESI, TOF MS)
m/z calculated for C.sub.23H.sub.26N.sub.3 [M + H].sup.+: 344.2127,
found: 344.2132.
[0274] Surprisingly, the formation of a 5-membered cycle or
heterocycle was never observed by the applicant when carrying out
the reaction of alpha-hydroxy-beta-triazolo-tetrazoles with
carbodiimides. The triazoles alkyne is thus the only product of the
reaction.
[0275] These results evidence that the
alpha-hydroxy-beta-triazolo-tetrazoles according to the invention
may be efficiency converted to triazoles alkynes, by the very broad
procedures (e) and (f) according to the invention.
Example 9: Di-Triazoles and Synthesis Thereof
Compounds
[0276] Hereafter are provided di-triazoles according to the
invention. R.sup.1, R.sup.2, R.sup.3 and R.sup.4 groups refer to
formula (V):
##STR00084##
TABLE-US-00009 # R.sup.1 R.sup.2 R.sup.3 R.sup.4 Formula Name 53
pentyl (cyclohexyl) Ph octyl ##STR00085## 1-octyl-4-(1-(4-
phenyl-1H-1,2,3- triazol-1- yl)cyclohexyl)- 1H-1,2,3-triazole 54
pentyl (cyclohexyl) Ph bis(cyclo- pentadienyl)iron ##STR00086##
1-[bis(.eta.5- cyclopentadienyl) iron]-4-(1-(4- phenyl-1H-1,2,3-
triazol-1- yl)cyclohexyl)- 1H-1,2,3-triazole 55 pentyl (cyclohexyl)
Ph carbohydrate ##STR00087## (2S,3S,4R,5S,6S)- 2- (acetoxymethyl)-
6-(4-(1-(4- phenyl-1H-1,2,3- triazol-1- yl)cyclohexyl)-
1H-1,2,3-triazol- 1-yl)tetrahydro- 2H-pyran-3,4,5- triyl triacetate
56 pentyl (cyclohexyl) Ph --CH.sub.2CH(COOMe)NHBoc ##STR00088##
methyl 2-((tert- butoxycarbonyl) amino)-3-(4-(1-(4-
phenyl-1H-1,2,3- triazol-1- yl)cyclohexyl)- 1H-1,2,3-triazol-
1-yl)propanoate 57 heptyl (cyclooctyl) Ph octyl ##STR00089##
1-octyl-4-(1-(4- phenyl-1H-1,2,3- triazol-1- yl)cyclooctyl)-
1H-1,2,3-triazole 58 heptyl (cyclooctyl) Ph EtCOO-propyl
##STR00090## ethyl 4-(4-(1-(4- phenyl-1H-1,2,3- triazol-1-
yl)cyclooctyl)- 1H-1,2,3-triazol- 1-yl)butanoate 59 heptyl
(cyclooctyl) Ph pyren-1-ylmethyl ##STR00091## 4-phenyl-1-(1-(1-
(pyren-1- ylmethyl)-1H- 1,2,3-triazol-4- yl)cyclooctyl)-
1H-1,2,3-triazole 60 heptyl (cyclooctyl) Ph benzyl ##STR00092##
1-benzyl-4-(1-(4- phenyl-1H-1,2,3- triazol-1- yl)cyclooctyl)-
1H-1,2,3-triazole 61 heptyl (cyclooctyl) Ph
--C(Et).sub.2--CH(OH)-Tz ##STR00093## 2-ethyl-2-(4-(1-
(4-phenyl-1H- 1,2,3-triazol-1- yl)cyclooctyl)- 1H-1,2,3-triazol-
1-yl)-1-(1H- tetrazol-5- yl)butan-1-ol
Materials and Methods
Procedure (g) for the CuAAC Reaction of Triazole Alkynes:
[0277] The triazole alkyne substrate (0.1 mmol) was dissolved in
n-BuOH (1 mL). An azide (0.3 mmol) was added. A solution of sodium
ascorbate (0.02 mmol in 0.25 mL water) was added, followed by a
solution of copper sulphate (0.01 mmol in 0.25 mL water). The
mixture was stirred at room temperature for 48 hours. The organic
phase was separated and concentrated under reduced pressure. The
residue was purified by flash chromatography on silica gel.
Results
[0278] Hereafter are provided the yield and physical
characterization of di-triazoles according to the invention,
prepared by the above procedure (g).
[0279] Compounds #53-61 were prepared from the corresponding
triazole alkynes disclosed in Examples 7 and 8 and from the
appropriate R.sup.4--N.sub.3 azide.
TABLE-US-00010 # Name Characterization Yield 53 1-octyl-4-(1-(4-
Mp: 110-112.degree. C. .sup.1H NMR .delta. 7.93 (s, 1H), 7.81-7.84
(m, 98% phenyl-1H-1,2,3- 2H), 7.26-7.42 (m, 4H), 4.26 (t, J = 6.9
Hz, 2H), 2.65- triazol-1- 2.80 (m, 4H), 1.84 (b, 2H), 1.57-1.64 (m,
6H), 1.23-1.27 yl)cyclohexyl)-1H- (m, 10H), 0.85 (t, J = 6.1 Hz,
3H). .sup.13C NMR (75 MHz, 1,2,3-triazole CDCl.sub.3) .delta.
150.8, 147.2, 130.5, 128.7, 128.0, 125.6, 121.1, 118.3, 62.3, 50.5,
35.7, 31.6, 30.1, 28.9, 28.8, 26.4, 24.8, 22.5, 22.0, 14.0. HRMS
(ESI, TOF MS) m/z calculated for C.sub.24H.sub.35N.sub.6 [M +
H].sup.+: 407.2923, found: 407.2924. 54 1-[bis(.eta.5- Mp:
157-163.degree. C. (dec.). .sup.1H NMR .delta. 7.92 (s, 1H),
7.80-7.83 75% cyclopentadienyl)iron]- (m, 2H), 7.27-7.40 (m, 4H),
5.22 (bs, 2H), 4.14-4.24 (m, 4-(1-(4-phenyl- 9H), 2.65-2.75 (m,
4H), 1.84 (b, 2H), 1.58-1.62 (m, 6H). 1H-1,2,3-triazol-1- .sup.13C
NMR (75 MHz, CDCl.sub.3) .delta. 150.8, 147.3, 130.6, 128.7,
yl)cyclohexyl)-1H- 127.9, 125.5, 120.6, 118.3, 80.4, 69.1, 68.8,
62.1, 50.1, 1,2,3-triazole 35.7, 24.8, 21.9. HRMS (ESI, TOF MS) m/z
calculated for C.sub.27H.sub.28N.sub.6Fe [M + H].sup.+: 492.1724,
found: 492.1729. 55 2-(acetoxymethyl)- .sup.1H NMR .delta.
7.86-7.84 (m, 3H), 7.66 (s, 1H), 7.30-7.42 (m, 93%
6-(4-(1-(4-phenyl- 3H), 5.82 (d, J = 9.0 Hz, 1H), 5.23-5.39 (m,
2H), 5.33 (m, 1H-1,2,3-triazol-1- 1H), 4.27-4.33 (m, 1H), 4.11-4.15
(m, 1H), 3.99-4.02 yl)cyclohexyl)-1H- (m, 1H), 2.70-2.81 (m, 4H),
2.07 (s, 3H), 2.05 (s, 3H), 1,2,3-triazol-1- 2.01 (s, 3H), 1.84 (s,
3H), 1.57-1.62 (m, 6H). .sup.13C NMR yl)tetrahydro-2H- (75 MHz,
CDCl.sub.3) .delta. 170.4, 169.8, 169.2, 168.8, 130.6, pyran-3,4,5-
128.7, 128.0, 125.5, 120.5, 85.9, 75.2, 72.2, 70.6, 67.6,
triyltriacetate 62.3, 61.4, 36.0, 35.6, 24.8, 22.0, 21.9, 20.6,
20.4, 20.0. HRMS (ESI, TOF MS) m/z calculated for
C.sub.30H.sub.37N.sub.6O.sub.9 [M + H].sup.+: 625.2622, found:
625.2626. 56 methyl 2-((tert- .sup.1H NMR .delta. 7.81-7.89 (m,
3H), 7.29-7.41 (m, 4H), 5.42 89% butoxycarbonyl)amino)- (d, J = 6.9
Hz), 4.66-4.76 (m, 3H), 3.72 (s, 3H), 2.61- 3-(4-(1-(4- 2.77 (m,
4H), 1.55-1.62 (m, 6H), 1.38 (s, 9H). .sup.13C NMR phenyl-1H-1,2,3-
(75 MHz, CDCl.sub.3) .delta. 169.3, 154.9, 130.4, 128.7, 128.0,
triazol-1- 125.6, 122.8, 118.4, 80.7, 62.2, 53.6, 53.0, 51.0, 35.8,
yl)cyclohexyl)-1H- 35.7, 28.1, 24.8, 22.0. HRMS (ESI, TOF MS) m/z
1,2,3-triazol-1- calculated for C.sub.25H.sub.34N.sub.7O.sub.4 [M +
H].sup.+: 496.2672, found: yl)propanoate 496.2669. 57
1-octyl-4-(1-(4- .sup.1H NMR .delta. 7.93 (s, 1H), 7.80-7.83 (m,
2H), 7.27-7.41 (m, 92% phenyl-1H-1,2,3- 4H), 4.29 (t, J = 6.9 Hz,
2H), 2.75-2.96 (m, 4H), 1.84- triazol-1- 1.89 (m, 2H), 1.65 (b,
10H), 1.24-1.28 (m, 10H), 0.86 (t, yl)cyclooctyl)-1H- J = 6.1 Hz,
3H). .sup.13C NMR (75 MHz, CDCl.sub.3) .delta. 151.2,
1,2,3-triazole 130.7, 128.7, 127.9, 125.5, 121.3, 118.6, 66.1,
50.4, 33.5, 31.6, 30.0, 28.9, 28.8, 27.9, 26.4, 24.6, 22.5, 22.0,
14.0. HRMS (ESI, TOF MS) m/z calculated for
C.sub.26H.sub.38N.sub.6Na [M + Na].sup.+: 457.3056, found:
457.3061. 58 ethyl 4-(4-(1-(4- .sup.1H NMR .delta. 7.95 (s, 1H),
7.80-7.83 (m, 2H), 7.27-7.46 (m, 83% phenyl-1H-1,2,3- 4H), 4.38 (t,
J = 6.7 Hz, 2H), 4.10 (m, 2H), 2.73-2.96 (m, triazol-1- 4H),
2.15-2.35 (m, 4H), 1.64 (b, 10H), 1.23 (m, J = 6.5
yl)cyclooctyl)-1H- Hz, 3H). .sup.13C NMR (75 MHz, CDCl.sub.3)
.delta. 172.1, 151.2, 1,2,3-triazol-1- 146.9, 130.6, 128.7, 127.9,
125.5, 121.7, 118.7, 66.1, yl)butanoate 60.7, 49.4, 33.5, 30.7,
27.9, 25.2, 24.6, 21.9, 14.1. HRMS (ESI, TOF MS) m/z calculated for
C.sub.24H.sub.32N.sub.6O.sub.2Na [M + Na].sup.+: 459.2484, found:
459.2479. 59 4-phenyl-1-(1-(1- .sup.1H NMR .delta. 8.02-8.25 (m,
8H), 7.73-7.94 (m, 4H), 7.27- 100% (pyren-1-ylmethyl)- 7.36 (m,
4H), 6.20 (bs, 2H), 2.62-2.85 (m, 4H), 1.55 (b, 1H-1,2,3-triazol-4-
10H). .sup.13C NMR (75 MHz, CDCl.sub.3) .delta. 151.3, 132.2,
131.1, yl)cyclooctyl)-1H- 130.5, 129.0, 128.7, 128.3, 128.0, 127.7,
127.2, 126.4, 1,2,3-triazole 126.3, 125.9, 125.8, 125.6, 125.0,
124.9, 124.4, 121.7, 121.6, 118.7, 66.3, 52.6, 33.3, 27.8, 24.6,
21.9. HRMS (ESI, TOF MS) m/z calculated for
C.sub.35H.sub.32N.sub.6Na [M + Na].sup.+: 559.2586, found:
559.2584. 60 1-benzyl-4-(1-(4- Mp: 133-134.degree. C. .sup.1H NMR
.delta. 7.97 (s, 1H), 7.82-7.85 (m, 90% phenyl-1H-1,2,3- 2H),
7.27-7.41 (m, 9H), 5.50 (bs, 2H), 2.73-2.95 (m, 4H), triazol-1-
1.65 (b, 10H). .sup.13C NMR (75 MHz, CDCl.sub.3) .delta. 151.5,
yl)cyclooctyl)-1H- 146.9, 134.1, 130.5, 129.1, 128.7; 128.0, 127.9,
125.5, 1,2,3-triazole 121.5, 118.6, 66.1, 54.2, 33.4, 27.9, 24.6,
21.9. HRMS (ESI, TOF MS) m/z calculated for C.sub.25H.sub.29N.sub.6
[M + H].sup.+: 413.2454, found: 413.2464 61 2-ethyl-2-(4-(1-(4-
.sup.1H NMR .delta. 8.59 (s, 1H), 8.33, (s, 1H), 8.18-8.21 (m, 2H),
91% phenyl-1H-1,2,3- 7.32-7.44 (m, 3H), 2.54-3.05 (m, 8H),
1.41-1.59 (b, triazol-1- 10H), 0.94-1.03 (m, 6H). .sup.13C NMR (75
MHz, pyridine- yl)cyclooctyl)-1H- d.sub.5) .delta. 151.2, 130.7,
128.7, 127.9, 125.5, 121.3, 118.6, 1,2,3-triazol-1-yl)- 66.1, 50.4,
33.5, 31.6, 30.0, 28.9, 28.8, 27.9, 26.4, 24.6, 1-(1H-tetrazol-5-
22.5, 22.0, 14.0. HRMS (ESI, TOF MS) m/z calculated yl)butan-1-ol
for C.sub.25H.sub.35N.sub.10O [M + H].sup.+: 491.2995, found:
491.2996.
[0280] These results evidence that the triazoles alkynes according
to the invention may be efficiency reacted with azides in CuAAC
conditions to prepare various di-triazoles compounds.
Example 10: Poly-Triazoles and Synthesis Thereof
Compounds
[0281] Hereafter are provided poly-triazoles according to the
invention.
TABLE-US-00011 # Formula Name 62 ##STR00094##
1-(3-ethylpent-1-yn-3-yl)- 4-(1-(4-phenyl-1H-1,2,3-
triazol-1-yl)cyclooctyl)- 1H-1,2,3-triazole 63 ##STR00095##
1-(1-ethynylcyclooctyl)-4- (3-(4-(1-(4-phenyl-1H- 1,2,3-triazol-1-
yl)cyclooctyl)-1H-1,2,3- triazol-1-yl)pentan-3-yl)-
1H-1,2,3-triazole 64 ##STR00096## 1-benzyl-4-(1-(4-(3-(4-(1-
(4-phenyl-1H-1,2,3- triazol-1-yl)cyclooctyl)- 1H-1,2,3-triazol-1-
yl)pentan-3-yl)-1H-1,2,3- triazol-1-yl)cyclooctyl)-
1H-1,2,3-triazole
Materials and Methods
Procedure for Synthesis of Bis-Triazole Alkyne #62:
[0282] 2-Azido-2-ethyl-1-(1H-tetrazol-5-yl)-butan-1-ol (28 mg, 0.18
mmol) #26 and 1-(1-ethynyl-cyclooctyl)-4-phenyl-1H-[1,2,3]triazole
(45 mg, 0.16 mmol) #46 were dissolved in nBuOH (2 mL). TBTA
(tris((1-benzyl-1H-1,2,3-triazolyl)methyl)amine) (10.5 mg, 0.02
mmol) was added. A solution of sodium ascorbate (11 mg, 0.05 mmol
in 0.5 mL water) was added, followed by a solution of copper
sulphate (5 mg, 0.02 mmol in 0.5 mL water). The mixture was stirred
at room temperature for 48 hours. The mixture was concentrated
under reduced pressure.
[0283] The residue was dissolved in 1,2-dichloroethane (3 mL). DIC
(0.035 mL, 0.22 mmol) was added. The mixture was stirred at
50.degree. C. for 3 hours, and then concentrated under reduced
pressure. The residue was purified by flash chromatography on
silica gel using petroleum ether/EtOAc: 90/10 as eluent (Rf=0.18).
The bis-triazole alkyne was isolated as a white solid (41 mg, 62%
yield).
Procedure for Synthesis of Tris-Triazole Alkyne #63:
[0284] (1-Azido-cyclooctyl)-(1H-tetrazol-5-yl)-methanol (30 mg,
0.12 mmol) #30 and the bis-triazole alkyne #62 (41 mg, 0.1 mmol)
were dissolved in n-BuOH (2 mL) and THF (1 mL). TBTA
(tris((1-benzyl-1H-1,2,3-triazolyl)methyl)amine) (8 mg, 0.015 mmol)
was added. A solution of sodium ascorbate (7 mg, 0.035 mmol in 0.5
mL water) was added, followed by a solution of copper sulphate (3
mg, 0.012 mmol in 0.5 mL water). The mixture was stirred at room
temperature for 5 days. The mixture was concentrated under reduced
pressure.
[0285] The residue was dissolved in 1,2-dichloroethane (2 mL). DIC
(0.02 mL, 0.14 mmol) was added. The mixture was stirred at room
temperature for 4 hours, and then concentrated under reduced
pressure. The residue was purified by flash chromatography on
silica gel using petroleum ether/EtOAc: 75/25 as eluent (Rf=0.27).
The tris-triazole alkyne was isolated as a white solid (31 mg, 52%
yield).
Procedure for Synthesis of Tetra-Triazole #64:
[0286] The tris-triazole alkyne #63 (19 mg, 0.032 mmol) was
dissolved in n-BuOH (1 mL). Benzyl azide (0.01 mL, 0.085 mmol) was
added. A solution of sodium ascorbate (3 mg, 0.015 mmol in 0.25 mL
water) was added, followed by a solution of copper sulphate (1.2
mg, 0.005 mmol in 0.25 mL water). The mixture was stirred at room
temperature for 24 hours. The mixture was concentrated under
reduced pressure. The residue was purified by flash chromatography
on silica gel using dichloromethane/MeOH: 98/2 as eluent (Rf=0.34).
The tetra-triazole was isolated as white foam (20 mg, 86%
yield).
Results
[0287] Hereafter are provided the yield and physical
characterization of poly-triazoles according to the invention,
prepared by the above procedures.
TABLE-US-00012 # Name Characterization Yield 62 1-(3-ethylpent-1-
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.90 (s, 1H), 7.80-7.83
62% yn-3-yl)-4-(1-(4- (m, 3H), 7.27-7.42 (m, 3H), 2.92-3.00 (m,
2H), 2.73-2.80 phenyl-1H-1,2,3- (m, 2H), 2.72 (s, 1H), 2.28-2.40
(m, 2H), 2.03-2.14 (m, triazol-1- 2H), 1.66 (b, 10H), 0.81 (m, 6H).
.sup.13C NMR (75 MHz, yl)cyclooctyl)- CDCl.sub.3) .delta. 149.3,
146.9, 130.7, 128.7, 127.9, 125.5, 122.6, 1H-1,2,3-triazole 118.5,
80.7, 76.7, 66.2, 66.1, 34.7, 33.5, 27.9, 24.7, 22.0, 8.5. HRMS
(ESI, TOF MS) m/z calculated for C.sub.25H.sub.32N.sub.6Na [M +
Na].sup.+: 439.2586, found: 439.2585. 63 1-(1- .sup.1H NMR (300
MHz, CDCl.sub.3) .delta. 7.91 (s, 1H), 7.79-7.82 52%
ethynylcyclooctyl)- (m, 3H), 7.57 (s, 1H), 7.27-7.42 (m, 3H),
2.89-2.97 (m, 4-(3-(4-(1-(4- 2H), 2.71-2.77 (m, 2H), 2.65 (s, 1H),
2.44-2.58 (m, 6H), phenyl-1H-1,2,3- 2.15-2.22 (m, 2H), 1.61-1.74
(m, 20H), 0.76 (m, 6H). .sup.13C triazol-1- NMR (75 MHz,
CDCl.sub.3) .delta. 150.2, 147.9, 146.9, 130.6, yl)cyclooctyl)-
128.7, 127.9, 125.6, 121.0, 121.0, 118.7, 83.4, 75.0, 67.0,
1H-1,2,3-triazol- 66.2, 64.4, 37.0, 33.5, 30.3, 27.9, 27.6, 24.7,
24.3, 22.4, 1-yl)pentan-3-yl)- 22.0, 7.8. HRMS (ESI, TOF MS) m/z
calculated for 1H-1,2,3-triazole C.sub.35H.sub.47N.sub.9Na [M +
Na].sup.+: 616.3852, found: 616.3859. 64 1-benzyl-4-(1-(4- .sup.1H
NMR (300 MHz, CDCl.sub.3) .delta. 7.91 (s, 1H), 7.80-7.82 86%
(3-(4-(1-(4- (m, 2H), 7.57 (s, 1H), 7.51 (s, 1H), 7.21-7.41 (m,
9H), phenyl-1H-1,2,3- 5.47 (s, 2H), 2.60-2.92 (m, 8H), 2.38-2.51
(m, 4H), 1.52- triazol-1- 1.60 (m, 20H), 0.68-0.72 (m, 6H).
.sup.13C NMR (75 MHz, yl)cyclooctyl)- CDCl.sub.3) .delta. 151.1,
148.1, 142.4, 142.2, 134.2, 130.5, 129.1, 1H-1,2,3-triazol- 128.8,
128.7, 128.0, 125.6, 121.5, 121.3, 121.2, 118.9, 1-yl)pentan-3-yl)-
118.7, 67.0, 66.4, 54.2, 33.6, 33.5, 30.3, 27.9, 27.8, 24.7,
1H-1,2,3-triazol- 24.6, 22.0, 21.9, 7.8. HRMS (ESI, TOF MS) m/z
1-yl)cyclooctyl)- calculated for C.sub.42H.sub.55N.sub.12 [M +
H].sup.+: 727.4673, found: 1H-1,2,3-triazole 727.4678.
[0288] These results evidence that successive iterations of the
reactions according to the invention may be used to efficiently
prepare poly-triazoles compounds substituted by different alkyl and
aryl groups.
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