Synthesis of novel 5-piperidyl-substituted 7-hydroxy-3H-1,2,3-triazolo [4,5-d]pyrimidines

Article abstract of DOI:10.1007/s10593-006-0078-2

A series of 8-azapurin-6-ones having a piperidine substituent at position 5 has been synthesized from pipecolinate esters, benzylazides, and cyanoacetamide. 2006 Springer Science+Business Media, Inc.

Full text of DOI:10.1007/s10593-006-0078-2

Chemistry of Heterocyclic Compounds, Vol. 42, No. 2, 2006
SYNTHESIS OF NOVEL 5-PIPERIDYL-
SUBSTITUTED 7-HYDROXY-3H-
1,2,3-TRIAZOLO[4,5-d]PYRIMIDINES
K. V. Kuleshov, K. Yu. Borovkov, O. G. Rodin, and V. P. Perevalov
A series of 8-azapurin-6-ones having a piperidine substituent at position 5 has been synthesized from
pipecolinate esters, benzylazides, and cyanoacetamide.
Keywords: 8-azapurin-6-one, benzylazides, piperidine, triazole, dopamine receptors.
In the last 20 years a large number of different analogs of natural nucleosides have been prepared. Many
of the analogous compounds have specific antiviral, anticancer [1], and antihistamine activity [2]. Hence, for
example, 9-(2,3-dihydroxypropyl)adenine and 9-(2-hydroxyethoxymethyl)guanine (acyclovir, Zovirax®) are able
to inhibit DNA and RNA viral replication and have selective activity against Herpes Simplex I and II
respectively [3, 4].
There are many examples in the literature of biologically active compounds in which a pyrimidine
fragment is C–C bonded with a piperidine residue [5-7], in fact with 3- and 4-piperidinecarboxylic acid residues.
A piperidine fragment gives a basic character to the compounds obtained and, along with a pyrimidine
fragment, can take part in the formation of hydrogen bonds between the purine bases of RNA and DNA. Similar
derivatives can also serve as ligands for dopamine receptors and, thus, can be used for treatment of dysfunctions
associated with the dopamine system such as schizophrenia, Parkinson’s disease, depression, and the side effects
of treatment with neuroleptics etc.
For the preparation of the azapurine ring from 4-amino-3-benzyl-5-carboxamide the method was used
that given in [6] and based on construction of a pyrimidine fragment through a three component reaction.
The reaction between the cyanoacetamide A and the benzylazide B forms the intermediate 4-amino-3-
benzyltriazole-5-carboxamide C which then reacts with ester component D to give the condensed azapurine
system E.
OH
O
O
H2N
N
N
O
N
N
N
+
R
O
CN
+
Ar
N3
N
H2N
R
N
H2N
N
B
D
A
C
Ar
E
Ar
__________________________________________________________________________________________
D. I. Mendeleev Russian University of Chemical Technology, Moscow 125047, Russia; e-mail:
kuleshov76@list.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 276-290, February,
2006. Original article submitted March 15, 2004.
246
0009-3122/06/4202-0246©2006 Springer Science+Business Media, Inc.

The BOC-protected ethyl piperidinecarboxylates (ethyl nipecotate and ethyl isonipecotate) 2a,b were
used as the ester component.
COOEt
R
CONH2
i-PrONa
+
+
CN
N
Boc
2a,b
N3
1a–c
OH
OH
N
N
N
N
N
N
dioxane / HCl
R
N
N
N
N
R
.
HCl
N
N
Boc
4a–f
3a–f
Starting compounds
Reaction products
1
2
3, 4
a R = 2-Cl
b R = H
a 4-CO2Et
b 3-CO2Et
a R = 2-Cl, 4-piperidyl
b R = 2-Cl, 3-piperidyl
a 4-CO2Et
b 3-CO2Et
c R = H, 4-piperidyl
d R = H, 3-piperidyl
c R = 4-F
a 4-CO2Et
b 3-CO2Et
e R = 4-F, 4-piperidyl
f R = 4-F, 3-piperidyl
According to data in [6] benzylazides are suitable azide-containing components. Because of the steric
hindrance brought about by the benzyl substituents a possible Dimroth rearrangement, which occurs in the case
of usual alkyl and aryl substituents, was excluded.
O
O
H2N
H2N
R
N
N
N
N
H2N
N
N
R
N
H
H
R = Alk; Ar
The benzylazides 1a-c were prepared by the reaction of the corresponding benzyl chlorides with sodium
azide and they were used in subsequent reactions without further purification. It was found that the highest
yields of benzylazides were achieved when carrying out the reaction between the components over 4-5 h in a
mixture of acetone and acetonitrile. In the preparation of the benzylazides it is also possible to use other polar
solvents such as DMF and DMSO but, in this case, the yields of benzylazides are markedly reduced.
The N-BOC derivatives 3a-f were separated from the reaction mixture by acidification with hydrochloric
acid. It should be born in mind that too powerful acidification leads to removal of the protecting group and loss
of the target material:
247

ONa
N
OH
N
HCl
N
N
N
N
N
N
N
N
–NaCl
R
R
Ar
Ar
Boc
Boc
N
;
N
R =
Removal of the BOC protection was carried out in dioxane saturated with hydrogen chloride (refluxing
for 2 h) since use of another known method (in trifluoroacetic acid) did not give the desired result [8].
TABLE 1. Analytical Data for the Compounds Synthesized
Found, %
Calculated, %
Mass
spectrum[M+1],
m/z*
——————
Com-
pound
Empirical
formula
C
3
H
4
N
5
1
4a
4b
4c
4d
4e
4f
2
C16H17ClN6O·HCl
C16H18N6O·HCl
C16H17FN6O·HCl
C16H17ClN6O·HCl
C16H18N6O·HCl
C16H17FN6O·HCl
C22H21ClN6O2S
C24H23ClN6O2
C20H21ClN6O2
C20H22N6O2
6
50.90
50.41
55.88
55.41
52.91
52.68
50.90
50.41
55.89
55.41
52.25
52.68
56.81
56.35
62.53
62.27
58.42
58.18
63.10
63.48
59.51
59.98
58.51
58.97
61.05
61.45
58.10
58.39
59.51
59.08
55.89
55.44
4.72
4.76
5.40
5.52
4.99
4.97
4.80
4.76
5.41
5.52
5.10
4.97
4.41
4.51
5.10
5.01
5.01
5.13
5.79
5.86
4.89
4.79
4.00
4.09
5.75
5.65
4.77
4.68
5.31
5.43
4.10
4.21
22.21
22.04
24.39
24.23
23.22
23.04
22.23
22.04
24.02
24.23
23.20
23.04
17.79
17.92
18.35
18.15
20.53
20.35
22.39
22.21
20.19
19.99
17.75
17.94
20.68
20.47
18.40
18.57
19.50
19.69
18.32
18.47
345
311
329
345
311
329
5a
5b
5c
5d
5e
5f
470
463.9
413.8
379.5
421.3
469.3
411.3
453.6
428
C21H20ClN6O2S
C23H19F3N6O2
C21H23FN6O2
5g
5h
6a
6b
6c
6d
6e
6f
C22H21FN6O2S
C21H23ClN6O2
C21H19ClN6O2S
C23H21ClN6O2
C24H24N6O2
456
61.74
61.54
67.30
67.27
63.90
63.48
66.85
66.65
4.62
4.72
5.59
5.65
5.80
5.86
5.45
5.35
18.58
18.72
19.79
19.61
22.04
22.21
20.42
20.28
450
429.7
379.5
415.3
C20H22N6O2
C23H22N6O2
248

TABLE 1 (continued)
1
2
3
4
5
6
6g
C22H27FN6O2
C20H21FN6O2
C23H21FN6O2
61.75
61.96
60.10
60.60
63.44
63.88
52.91
52.54
50.54
50.87
48.72
48.28
59.00
59.47
58.24
58.65
52.94
52.57
54.54
54.75
52.11
52.54
50.43
50.87
55.91
55.49
55.74
55.36
6.47
6.38
5.22
5.34
4.81
4.89
3.94
4.01
3.80
3.88
4.40
4.53
5.28
5.21
4.80
4.92
5.10
5.19
4.49
4.40
4.10
4.01
3.80
3.88
4.45
4.36
4.56
4.65
19.88
19.70
21.00
21.20
19.61
19.43
16.60
16.71
16.37
16.18
19.70
19.87
18.27
18.09
18.93
18.65
21.42
21.63
15.78
15.96
16.50
16.71
16.00
16.18
17.50
17.33
16.70
16.84
427.5
397.6
433.6
504
6h
6i
7a
7b
7c
7d
7e
7f
C22H20ClFN6O3S
C22H20Cl2N6O3
C17H19ClN6O3S
C23H24N6O3S
520.3
424
465.6
451.6
389.6
527.7
504
C22H22N6O3S
C17H20N6O3S
7g
7h
8a
8b
8с
C24H23FN6O5S
C22H20ClFN6O3S
C22H20Cl2N6O3S
C23H23ClN6O3S
С23H23ClN6O3S
520.5
486.1
500.1
8d
C23H24N6O3S
C22H21ClN6O3S
C22H22N6O3S
C23H23FN6O3S
C23H23FN6O3S
C23H23FN6O4S
C23H28ClN7O2
C21H24ClN7O3
C21H25N7O3
59.10
59.47
54.90
54.49
58.20
58.65
57.73
57.25
57.61
57.25
55.00
55.41
58.43
58.78
55.53
55.08
59.13
59.56
63.90
63.43
57.53
57.32
54.66
54.19
58.50
58.78
58.40
57.95
65.50
65.00
63.31
63.79
5.30
5.21
4.30
4.36
5.05
4.92
4.71
4.80
4.69
4.80
4.58
4.65
6.10
6.01
5.20
5.28
6.03
5.95
6.60
6.71
4.32
4.39
4.11
3.98
6.10
6.01
4.40
4.46
5.52
5.68
5.85
5.77
18.29
18.09
17.21
17.33
18.85
18.65
17.30
17.42
17.21
17.42
16.70
16.86
20.71
20.86
21.60
21.41
23.30
23.15
22.32
22.51
20.51
20.35
18.21
18.43
20.71
20.86
19.90
19.71
22.30
22.11
20.20
20.03
465.6
485.9
451.6
483.5
483.6
499.6
471
8e
8f
8g
8h
8i
9a
9b
458.9
424.5
436.6
483
9c
9d
C23H29N7O2
10a
10b
10c
10d
10e
10f
10g
C22H21ClFN7O2
C24H21ClF3N7O2
C23H28ClN7O2
C24H22F3N7O2
C24H25N7O2
532.9
471
498.6
444.6
490.7
476.6
C26H28FN7O2
C25H26FN7O2
63.66
63.15
5.40
5.51
20.71
20.62
_______
* Irel = 100%.
249

The prepared amine hydrochlorides 4a-f are generally compounds with a high melting point, poorly
soluble in organic solvents and limited in hot water. These properties of the hydrochlorides cause certain
problems for amine acylation. Preparation of the amides and sulfamides initially used a heterophasic system of
methylene chloride – acylating agent – water – potassium carbonate – amine hydrochloride. However, in these
OH
OH
N
N
N
N
O
N
+
N
N
R2
N
N
N
N
R2
N
Ar
Ar
6a–i
5a–h
O
R2COCl
OH
OH
N
N
N
R3
O
N
N
N
N
N
+
S
R3SO2Cl
N
N
N
O
4a–f
O
N
O
Ar
N
Ar
S
R3
8a–i
7a–h
OH
R4NCO
OH
N
N
N
N
O
N
N
+
R4
N
N
N
N
N
H
H
Ar R4
N
N
Ar
9a–d
10a–g
9
O
3-Piperidyl
5
7
R2
Ar
R3
Ar
R4
Ar
Thiophenemethyl 2-СlC6H4
2-FC6H4
2-СlC6H4
2-СlC6H4
2-СlC6H4
Ph
c-Hex
2-СlC6H4
a
b
c
d
e
f
CH2Ph
c-Pr
2-СlC6H4
2-СlC6H4
Ph
3-ClC6H4
Ме
Morpholyl 2-СlC6H4
Morpholyl Ph
c-Pr
CH2Ph
Ph
c-Hex
Ph
SPh
Ph
Ph
2,6-F2C6H3
c-Bu
4-FC6H4
4-FC6H4
Me
Ph
2,3-(OC2H4O)C6H3
3-ClC6H4
4-FC6H4
4-FC6H4
g
h
Thiophenemethyl 4-FC6H4
4- Piperidyl
6
8
10
R2
Ar
R3
Ar
R4
Ar
c-Bu
SPh
Ph
2-ClC6H4 3-ClC6H4
2-ClC6H4 Ph
2-ClC6H4
2-ClC6H4
2-ClC6H4
Ph
2-FC6H4
2-ClC6H4
2-ClC6H4
2-ClC6H4
Ph
a
b
c
d
e
f
2-CF3C6H4
c-Hex
2-ClC6H4 4-MeC6H4
CH2Ph
c-Pr
Ph
Ph
CH2Ph
4-CF3C6H4
3-MeC6H4
4-i-PrC6H4
2-EtC6H4
Ph
3-ClC6H4
Me
Ph
Ph
Ph
Ph
4-FC6H4
4-FC6H4
2,2-Diethylpentyl
4-FC6H4
4-FC6H4
4-FC6H4
CH2Ph
4-FC6H4
4-FC6H4
4-FC6H4
g
h
i
c-Pr
4-MeC6H4
4-MeOC6H4
Ph
250

251

252

253

254

255

conditions, the amide and sulfamide reaction products were contaminated by unreacted amine. Hence, in place of
the potassium carbonate, strong organic bases such as DBU (diazabicycloundecane) were used. In the presence
of DBU the solubility of the amine hydrochlorides in organic solvents was increased and the acylation reaction
occurs fully in the homogeneous system formed. For these reasons specific difficulties also arose in the reaction
of the amines 4a-f with isocyanates. The use of a heterophase system containing water and potassium carbonate
in this reaction is precluded because of the ready hydrolysis of the isocyanates and the accompanying formation
of symmetrical aryl ureas. The use of triethylamine as base did not lead to solution of the starting amine
hydrochlorides hence, as in the preceding examples, DBU was used.
Hence it was found that the acylation of the amines 4a-f has to be carried out in aprotic, polar solvents.
We have used various solvents for the acylation: DMF, DMSO, acetonitrile, dioxane, acetone, and methylene
chloride. It was turned out that the most useful solvent is acetonitrile in the presence of the organic base (DBU).
Choice of the acetonitrile resulted from the quite high solubilizing properties, relatively low boiling point, and
polarity. The use of such solvents as DMF and DMSO was complicated because of problems of product isolation
from the reaction solutions.
EXPERIMENTAL
1H NMR spectra were recorded on a Varian Mercury (USA) spectrometer (400 MHz) using DMSO-d6
and TMS as internal standard. Mass spectra were taken on a Thermo Finnigan (USA) MSQ Surveyor
spectrometer with a WatersXterra MS C18 (2.1 x 30 mm) column and photodiode array detector (190-800 nm).
TLC analysis was carried out on Sorbfil UV-254 plates using the systems methylene chloride, methylene
chloride–methanol (10:1).
Melting points were measured in a sealed capillary on a Gallenkamp Sanyo (UK) instrument and are not
corrected. All commercially available reagents were used in the syntheses without preliminary purification.
Solvents used in the syntheses were purified and dried by known methods. Compounds 5-10 were recrystallized
from a mixture of acetone and isopropanol. The characteristics of the compounds synthesized are given in Tables
1 and 2.
Benzylazides 1a-c (General Method). Sodium azide (150 mmol) was added to a solution of the
corresponding benzyl chloride (100 mmol) in acetonitrile (500 ml) and refluxed for 2 h. The solvent was
distilled off in vacuo and the residue was dissolved in water and extracted with methylene chloride. The extract
was dried using sodium sulfate and evaporated. The obtained benzylazide was used in further reactions without
additional purification.
2-Chorobenzylazide (1a), yield 15 g (89%).
Benzylazide (1b), yield 10 g (75%).
4-Fluorobenzylazide (1e), yield 12 g (79%).
N-BOC-substituted Ethyl Piperidinecarboxylates 2a-b (General Method). tert-Butoxypyro-
carbonate (100 mmol) was added to a solution of the corresponding ethyl piperidinecarboxylate (100 mmol) in
methylene chloride and stirred for 1 h. The solvent was distilled off and the residue was used for further
reactions without additional purification.
N-BOC-Ethylisonipecotate (ethyl N-tert-butoxycarbonyl-4-piperidinecarboxylate) (2a), yield 22 g
(86%).
N-BOC-Ethylnipecotate (ethyl N-tert-butoxycarbonyl-3-piperidinecarboxylate) (2b), yield 20 g (78%).
N-BOC-5-Piperidyl-substituted 7-Hydroxy-3H-1,2,3-triazolo[4,5-d]pyrimidines 3a-f (General
Method). Sodium (300 mmol) was dissolved with heating in 2-propanol (500 ml). Cyanoacetamide (100 mmol)
and the corresponding benzylazide (100 mmol) were introduced with stirring into the solution of sodium
isopropylate formed and the suspension obtained was heated for 2 h. The corresponding ethyl N-BOC-
256

piperidinecarboxylate (100 mol) 2a-b was added to the solution obtained and heating was continued for 20 h.
Solvent was distilled off and the residue was diluted with water and carefully acidified with dilute hydrochloric
acid. The oil formed crystallized in methanol.
5-[(tert-Butoxycarbonyl)piperidin-3-yl]-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-ol
(3a), yield 20 g (45%); mp 69-71.5°C. Mass spectrum, m/z (I, %): 446 [M+H] (100).
5-[(tert-Butoxycarbonyl)piperidin-3-yl]-3-benzyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-ol
yield 16 g (39%); mp 60.5-62°C. Mass spectrum, m/z (I, %): 411.5 [M+H] (100).
(3b),
5-[(tert-Butoxycarbonyl)piperidin-3-yl)]-3-(4-fluorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-ol
(3c), yield 18 g (42%); mp 75-76.5°C. Mass spectrum, m/z (I, %): 429.6 [M+H] (100).
5-[tert-Butoxycarbonyl)piperidin-4-yl)]-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-ol
(3d), yield 19 g (43%); mp 68-69.5°C. Mass spectrum, m/z (I, %): 446.1 [M+H] (100).
3-Benzyl-5-[(tert-butoxycarbonyl)piperidin-4-yl]-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-ol
yield 15 g (36%); mp 60-62°C. Mass spectrum, m/z (I, %): 411.6 [M+H] (100).
(3e),
5-[(tert-Butoxycarbonyl)piperidin-4-yl]-3-(4-fluorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-ol
(3f), yield 17 g (40%); mp 71.5-72.5°C. Mass spectrum, m/z (I, %): 429.7 [M+H] (100).
7-Hydroxy-5-piperidyl-3H-[1,2,3]triazolo[4,5-d]pyrimidines (General Method). The solution of the
N-BOC derivative obtained in the previous experiment 3 (100 mmol) in dioxane (100 ml) saturated with
hydrogen chloride was refluxed for 1 h. The solvent was evaporated and the oily residue was dissolved in
isopropyl alcohol and refluxed to form the precipitated amine hydrochloride which was then filtered off.
3-(2-Chlorobenzyl)-5-(piperidin-3-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-ol Hydrochloride (4a),
yield 35 g (92%); mp 215-217°C.
3-Benzyl-5-(piperidin-3-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-ol Hydrochloride (4b), yield 31 g
(89%); mp 210-211.5°C.
3-(4-Fluorobenzyl)-5-(piperidin-3-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-ol Hydrochloride (4c),
yield 33 g (90%); mp 230-232°C.
3-(2-Chlorobenzyl)-5-(piperidin-4-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-ol Hydrochloride (4d),
yield 34 g (89%); mp 220-222°C.
3-Benzyl-5-(piperidin-4-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-ol Hydrochloride (4e), yield 30 g
(86%); mp 217-219.5°C.
3-(4-Fluorobenzyl)-5-(piperidin-4-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-ol Hydrochloride (4f),
yield 32 g (87%); mp 250-252°C.
Preparation of Amides 5 (General Method). DBU (2 mmol) was added to a suspension of the amine
hydrochloride (1 mmol) in acetonitrile (5 ml) and then the acid chloride (1 mmol). The reaction mixture was
refluxed, diluted with water, and the solid or oil produced was crystallized from a suitable solvent.
3-(2-Chlorobenzyl)-5-[(1-thiophenylmethylcarbonyl)piperidin-3-yl]-3H-[1,2,3]triazolo[4,5-d]-
pyrimidin-7-ol (5a), yield 0.3 g (60%); mp 160.5-161.5°C.
5-[(Benzylcarbonyl)piperidin-3-yl)-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-ol (5b),
yield 0.35 g (70%); mp 170-172°C.
3-(2-Chlorobenzyl)-5-[(cyclopropylcarbonyl)piperidin-3-yl]-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-
ol (5c), yield 0.29 g (73%); mp 139-141.5°C.
3-Benzyl-5-[(cyclopropylcarbonyl)piperidin-3-yl]-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-ol (5d),
yield 0.28 g (73%); mp 134.5-136.5°C.
3-Benzyl-5-[(1-thiophenylcarbonyl)piperidin-3-yl]-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-ol (5e),
yield 0.35 g (83%); mp 149-151.5°C.
5-[(2,6-Difluorophenylcarbonyl)piperidin-3-yl]-3-(4-fluorobenzyl)-3H-[1,2,3]triazolo[4,5-d]-
pyrimidin-7-ol (5f), yield 0.43 g (91%); mp 139-140.5°C.
5-[(Cyclobutylcarbonyl)piperidin-3-yl]-3-(4-fluorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-ol
(5g), yield 0.32 g (78%); mp 139-141.5°C.
257

3-(4-Fluorobenzyl)-5-[(1-thiophenylmethylcarbonyl)piperidin-3-yl]-3H-[1,2,3]triazolo[4,5-d]-
pyrimidin-7-ol (5h), yield 0.3 g (67%); mp 158-160°C.
3-(2-Chlorobenzyl)-5-[(cyclobutylcarbonyl)piperidin-4-yl]-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-ol
(6a), yield 0.4 g (93%); mp 137-139°C.
3-(2-Chlorobenzyl)-5-[(1-thiophenylcarbonyl)piperidin-4-yl]-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-
ol (6b), yield 0.42 g (93%); mp 145-147.5°C.
3-(2-Chlorobenzyl)-5-[(phenylcarbonyl)piperidin-4-yl]-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-ol (6c),
yield 0.42 g (93%); mp 169-171°C.
3-Benzyl-5-[(benzylcarbonyl)piperidin-4-yl]-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-ol
yield 0.4 g (93%); mp 165-167°C.
3-Benzyl-5-[(cyclopropylcarbonyl)piperidin-4-yl]-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-ol
yield 0.3 g (79%); mp 145-146.5°C.
3-Benzyl-5-[(phenylcarbonyl)piperidin-4-yl]-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-ol
yield 0.35 g, (85%); mp 174-176°C.
(6d),
(6e),
(6f),
5-[(2,2-Diethylpentylcarbonyl)piperidin-4-yl]-3-(4-fluorobenzyl)-3H-[1,2,3]triazolo[4,5-d]-
pyrimidin-7-ol (6g), yield 0.3 g (70%); mp 120-122°C.
5-[(Cyclopropylcarbonyl)piperidin-4-yl]-3-(4-fluorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-ol
(6h), yield 0.3 g (75%); mp 141-143.5°C.
3-(4-Fluorobenzyl)-5-[(phenylcarbonyl)piperidin-4-yl]-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-ol
(6i),
yield 0.33 g (77%); mp 178-180°C.
Preparation of Sulfamides 7 (General Method). A solution of potassium carbonate (4 mmol) in water
(5 ml) was added to a suspension of the amine hydrochloride (1 mmol) in methylene chloride (10 ml). The
biphasic system formed was then treated with the corresponding sulfochloride (1 mmol) with stirring. Methylene
chloride was evaporated off and the residue was filtered off and recrystallized from a mixture of acetone and
isopropyl alcohol.
3-(2-Chlorobenzyl)-5-[(2-fluorophenylsulfonyl)piperidin-3-yl]-3H-[1,2,3]triazolo[4,5-d]pyrimidin-
7-ol (7a), yield 0.4 g (82%); mp 182-184°C.
3-(2-Chlorobenzyl)-5-[(3-chlorophenylsulfonyl)piperidin-3-yl]-3H-[1,2,3]triazolo[4,5-d]pyrimidin-
7-ol (7b), yield 0.42 g (84%); mp 179-180.5°C.
3-(2-Chlorobenzyl)-5-[(methylsulfonyl)piperidin-3-yl]-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-ol (7c),
yield 0.33 g (79%); mp 165-167°C.
3-Benzyl-5-[(benzylsulfonyl)piperidin-3-yl]-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-ol (7d), yield 0.39 g
(83%); mp 169-171.5°C.
3-Benzyl-5-[(phenylsulfonyl)piperidin-3-yl]-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-ol (7e), yield 0.33 g
(73%); mp 181-182.5°C.
3-Benzyl-5-[(methylsulfonyl)piperidin-3-yl]-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-ol (7f), yield 0.29 g
(74%); mp 157-159.5°C.
5-[(2,3-Ethylenedioxyphenylsulfonyl)piperidin-3-yl]-3-(4-fluorobenzyl)-3H-[1,2,3]triazolo[4,5-d]-
pyrimidin-7-ol (7g), yield 0.36 g (72%); mp 187-189°C.
5-[(3-Chlorophenylsulfonyl)piperidin-3-yl]-3-(4-fluorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-
7-ol (7h), yield 0.26 g (52%); mp 174-175.5°C.
3-(2-Chlorobenzyl)-5-[3-chlorophenylsulfonyl)piperidin-4-yl]-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-
ol (8a), yield 0.3 g (60%); mp 169-171°C.
3-(2-Chlorobenzyl)-5-[(phenylsulfonyl)piperidin-4-yl]-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-ol
(8b),
yield 0.33 g (67%); mp 166-168°C.
3-(2-Chlorobenzyl)-5-[(4-methylphenylsulfonyl)piperidin-4-yl]-3H-[1,2,3]triazolo[4,5-d]pyrimidin-
7-ol (8c), yield 0.35 g (70%); mp 169.5-171°C.
258

3-Benzyl-5-[(benzylsulfonyl)piperidin-4-yl]-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-ol (8d), yield 0.33 g
(70%); mp 168-170°C.
3-Benzyl-5-[(3-chlorophenylsulfonyl)piperidin-4-yl]-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-ol (8e),
yield 0.37 g (74%); mp 174.5-176°C.
3-Benzyl-5-[(phenylsulfonyl)piperidin-4-yl]-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-ol (8f), yield 0.34 g
(75%); mp 167-169°C.
5-[(Benzylsulfonyl)piperidin-4-yl]-3-(4-fluorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-ol (8g),
yield 0.33 g (69%); mp 168-170.5°C.
3-(4-Fluorobenzyl)-5-[(4-methylphenylsulfonyl)piperidin-4-yl]-3H-[1,2,3]triazolo[4,5-d]pyrimidin-
7-ol (8h), yield 0.36 g (75%); mp 173.5-175.5°C.
3-(4-Fluorobenzyl)-5-[(4-methoxyphenylsulfonyl)piperidin-4-yl]-3H-[1,2,3]triazolo[4,5-d]pyrimidin-
7-ol (8i), yield 0.37 g (74%); mp 170-172°C.
Preparation of Ureas 9 (General Method). DBU (2 mmol) was added to a suspension of the amine
hydrochloride (1 mmol) in acetonitrile (5 ml) and then the corresponding isocyanate (1 mmol). The reaction
mixture was refluxed, diluted with water, and the solid or oil produced was crystallized from a suitable solvent.
3-(2-Chlorobenzyl)-5-[(cyclohexylcarbamoyl)piperidin-3-yl]-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-
ol (9a), yield 0.25 g (53%); mp 165-167°C.
3-(2-Chlorobenzyl)-5-[(morpholinocarbamoyl)piperidin-3-yl]-3H-[1,2,3]triazolo[4,5-d]pyrimidin-
7-ol (9b), yield 0.21 g (46%); mp 127-129°C.
3-Benzyl-5-[(morpholinylcarbamoyl)piperidin-3-yl]-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-ol (9c),
yield 0.21 g (50%); mp 124.5-126.5°C.
3-Benzyl-5-[(cyclohexylcarbamoyl)piperidin-3-yl]-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-ol
(9d),
yield 0.26 g (59%); mp 164-166°C.
3-(2-Chlorobenzyl)-5-[(4-fluorophenylcarbamoyl)piperidin-4-yl]-3H-[1,2,3]triazolo[4,5-d]pyrimidin-
7-ol (10a), yield 0.3 g (62%) mp 161-163°C.
3-(2-Chlorobenzyl)-5-[(2-trifluoromethylphenylcarbamoyl)piperidin-4-yl]-3H-[1,2,3]triazolo[4,5-d]-
pyrimidin-7-ol (10b), yield 0.27 g (51%); mp 145-147.5°C.
3-(2-Chlorobenzyl)-5-[(cyclohexylcarbamoyl)piperidin-4-yl]-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-
ol (10c), yield 0.25 g (53%); mp 167-169°C.
3-Benzyl-5-[(4-trifluoromethylphenylcarbamoyl)piperidin-4-yl]-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-
ol (10d), yield 0.3 g (60%); mp 148-150°C.
3-Benzyl-5-[(3-methylphenylcarbamoyl)piperidin-4-yl]-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-ol (10e),
yield 0.35 g (78%); mp 169-171°C.
3-(4-Fluorobenzyl)-5-[(4-isopropylphenylcarbamoyl)piperidin-4-yl]-3H-[1,2,3]triazolo[4,5-d]-
pyrimidin-7-ol (10f), yield 0.36 g (74%); mp 168-170°C.
5-[(2-Ethylphenylcarbamoyl)piperidin-4-yl]-3-(4-fluorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-
ol (10g), yield 0.3 g (63%); mp 144-146°C.
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