Polyfunctional pyrazoles. 8*. Synthesis of 6-alkyl-2-aryl-2H- pyrazolo[4,3-d]pyrimidine-5,7(4H,6H)-diones based on ethyl 1-aryl-4- isocyanatopyrazole-3-carboxylates

Article abstract of DOI:10.1007/s10593-013-1383-1

A method for the preparation of 6-alkyl-2-aryl-2H-pyrazolo[4,3-d] pyrimidine-5,7(4H,6H)-diones in reaction of ethyl 1-aryl-4-isocyanatopyrazole-3- carboxylates with aliphatic amines followed by cyclization of the obtained 4-ureidopyrazole-3-carboxylic acid esters in the presence of bases is proposed.

Full text of DOI:10.1007/s10593-013-1383-1

Chemistry of Heterocyclic Compounds, Vol. 49, No. 9, December, 2013 (Russian Original Vol. 49, No. 9, September, 2013)
POLYFUNCTIONAL PYRAZOLES. 8*. SYNTHESIS OF
6-ALKYL-2-ARYL-2H-PYRAZOLO[4,3-d]PYRIMIDINE-
5,7(4H,6H)-DIONES BASED ON ETHYL 1-ARYL-
4-ISOCYANATOPYRAZOLE-3-CARBOXYLATES
M. K. Bratenko1**, M. M. Barus1, and M. V. Vovk2
A method for the preparation of 6-alkyl-2-aryl-2H-pyrazolo[4,3-d]pyrimidine-5,7(4H,6H)-diones in
reaction of ethyl 1-aryl-4-isocyanatopyrazole-3-carboxylates with aliphatic amines followed by cyclization
of the obtained 4-ureidopyrazole-3-carboxylic acid esters in the presence of bases is proposed.
Keywords: 6-alkyl-2-arylpyrazolo[4,3-d]pyrimidine-5,7-diones, 1-aryl-3-ethoxycarbonylpyrazole-
4-carboxylic acids, 1-aryl-4-ureidopyrazole-3-carboxylic acids, ethyl 1-aryl-4-formylpyrazole-
3-carboxylates, ethyl 1-aryl-4-isocyanatopyrazole-3-carboxylates, intramolecular cyclization.
Pyrazolo[4,3-d]pyrimidine-5,7-diones are pharmacologically promising heterocyclic systems. An
important reason for their systematic investigation is the discovery among them of the C-nucleoside antibiotic
oxoformycin B [2], stimulants of insulin secretion [3], corticotropin-releasing factor receptor antagonists [4],
and selective calcitonin inducers [5]. Representatives of pyrazolo[4,3-d]pyrimidine-5,7-diones are also
important synthons for the design of adenosine receptor antagonists [6, 7] and fluorescent probes in receptor-
binding enzymatic systems [8].
Two methods are usually employed for the preparation of pyrazolo[4,3-d]pyrimidine-5,7-diones. The first
method is based on pyrazole annelation of polyfunctional uracils [5, 9-11]. The second is based on the principle of
the formation of a pyrimidine ring as a result of intramolecular condensation of amides [12-15] or esters [16] of
4-aminopyrazole-3-carboxylic acids. It should be mentioned that in the last case toxic and challenging alkyl
isocyanates are used as electrophilic component for the closure of the pyrimidine ring. Moreover, the synthetic value
of the method is low due to the complexity of isolation of the initial 4-aminopyrazole-5-carboxylates, which are
formed in a mixture with the isomeric 4-aminopyrazole-5-carboxylates.
We have proposed a more effective and scalable method for the synthesis of 6-alkyl-2-arylpyrazolo-
[4,3-d]pyrimidine-5,7-diones that requires the use of ethyl 4-isocyanatopyrazole-3-carboxylates 3a,b as key
_______
*For Communication 7, see [1].
**To whom correspondence should be addressed, e-mail: bratenko@gmail.com.
1Bukovinsk State Medical University, 2 Teatral'naya Sq., Chernovtsy 58002, Ukraine.
2Institute of Organic Chemistry, National Academy of Sciences of Ukraine, 5 Murmanska St., Kyiv 02094,
Ukraine; e-mail: mvovk@i.com.ua.
_________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1443-1450, September, 2013.
Original article submitted April 24, 2013.
0009-3122/13/4909-1345©2013 Springer Science+Business Media New York
1345

synthetic intermediates. These compounds are formed smoothly by a modified Curtius reaction [17] from
3-ethoxycarbonylpyrazole-4-carboxylic acids 2a,b, which obtained through oxidation of the accessible [18]
4-formylpyrazole-3-carboxylates 1a,b. It was shown that the use of 4-isocyanatopyrazoles 3a,b has an
advantage over the use of 4-aminopyrazoles [16] since it is possible to obtain a wide range of pyrazolylureas
4a-m in reaction with primary amines, including those containing N-alkyl-functionalized substituents in the
ureide fragment. The presence of these substituents is essential for the subsequent modifications of the
pyrazolo[4,3-d]pyrimidinedione system.
Investigation toward intramolecular cyclization of compounds 4a-m showed that the substituent R in
the ureide fragment plays a significant role in a process. Thus, upon treatment with potassium hydroxide
(method A) or potassium tert-butoxide (method B) the ureido esters 4a-g,k-m containing sterically unhindered
alkyl substituents undergo intramolecular cyclization with the formation of pyrazolo[4,3-d]pyrimidinediones
5a-j with yields of 57-78% (Table 1). On the other hand, under analogous conditions N-cyclohexyl- or
N-arylureido esters (compounds 4h or 4i,j, respectively) are not susceptible to closure of the pyrimidine ring but
undergo hydrolysis of the ethoxycarbonyl group with the formation of the ureido acids 6a-c. This fact confirms
the predominant effect of the steric and electronic factors of the substituents at the N-3 atom of the ureide group
on the pyrimidine annelation of compound 4.
O
O
O
KMnO4
Me2CO, H2O
EtO
1) EtOCOCl, Et3N
THF, –10°C, 0.5 h;
O
EtO
OH
N
N
room temp., 12 h
2) NaN3, H2O
–10°C, 1 h;
3) PhMe, , 2 h
N
N
Ar
Ar
1a,b
2a,b
O
O
O
H
N=C=O
N
EtO
EtO
RNH2, PhMe
NHR
N
N
room temp., 3 h
or
N
N
Ar
Ar
, 1 h (for 4i,j)
3a,b
4a–m
R
6
O
A) KOH, EtOH
B) t-BuOK, THF
5
O
, 3 h
O
N
H
4
N
HO
O
NH
7
NHR
(from 4a–g,k–m)
(from 4h–j)
N
3
1 N
N
N 2
Ar
Ph
6a–c
5a–j
1–3 a, 4a–j, 5a–g, 6a–c Ar = Ph, 1–3 b, 4k–m, 5h–j Ar = 4-BrC6H4;
4, 5 a R = n-C4H9; b R = (CH2)2OH; с R = (CH2)2NMe2; е R = 4-ClC6H4CH2; f R = 4-MeC6H4CH2;
4d,k, 5d,h R = PhCH2; 4g,m, 5g,j R = 4-MeOC6H4(CH2)2; 4l, 5i R = 4-MeOC6H4CH2;
4h, 6a R = cyclo-C6H11; 4i, 6b R = Ph; 4j, 6c R = 4-MeC6H4
The starting isocyanates 3a,b are light-yellow crystals that are sensitive to atmospheric moisture and
1
require the use of dry solvents. Their structure is consistent with the results of H NMR spectroscopy and also
with the data from the IR spectra, in which strong absorption bands for the C=O (1730 cm-1) and N=C=O
(2250 cm-1) groups are observed. The structure and composition of the intermediate ureido carboxylates 4a-m
and also of the final products 5a-j, 6a-c were confirmed by complex physicochemical investigation using
elemental analysis, chromato-mass spectrometry, and IR and NMR spectroscopy (Tables 1-4).
1346

TABLE 1. Physicochemical Characteristics of the Synthesized
Compounds 4a-m, 5a-j
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
Yield, %
(method)
Mp, °С
C
H
N
C17H22N4O3
61.78
61.80
56.72
56.60
59.31
59.12
65.66
65.92
59.96
60.23
66.87
66.65
64.93
64.69
64.15
64.03
65.08
65.13
65.85
65.92
54.41
54.19
53.53
53.29
54.03
54.22
63.61
63.37
6.79
6.71
5.61
5.70
6.91
6.71
5.41
5.53
4.61
4.80
5.98
5.86
5.86
5.92
6.80
6.79
5.18
5.18
5.60
5.53
4.19
4.32
4.31
4.47
4.91
4.76
5.53
5.67
16.88
16.96
17.35
17.60
20.38
20.28
15.29
15.37
13.85
14.05
14.61
14.80
13.87
13.72
15.68
15.72
16.01
15.99
15.29
15.37
12.48
12.64
11.77
11.84
11.36
11.50
19.49
19.71
90-91
84
73
70
88
92
86
77
87
90
87
81
84
73
4а
4b
4c
4d
4e
4f
C15H18N4O4
C17H23N5O3
C20H20N4O3
C20H19ClN4O3
C21H22N4O3
C22H24N4O4
C19H24N4O3
C19H18N4O3
C20H20N4O3
C20H19BrN4O3
C21H21BrN4O4
C22H23BrN4O4
C15H16N4O2
155-157
103-104
160-162
178-179
182-183
105-106
100-101
134-135
148-149
160-161
185-187
150-151
190-191
4g
4h
4i
4j
4k
4l
4m
5a
63 (А)
68 (B)
70 (А)
C13H12N4O3
C15H17N5O2
C18H14N4O2
C18H13ClN4O2
C19H16N4O2
57.61
57.35
60.47
60.19
67.68
67.92
61.47
61.28
4.59
4.44
5.49
5.72
4.31
4.43
3.80
3.71
20.36
20.58
23.66
23.40
17.45
17.60
15.51
15.88
225-226
295-298
282-284
>300
5b
5c
5d
5e
5f
64 (B)
78 (B)
74 (А)
68.71
68.66
5.03
4.85
16.88
16.86
210-212
77 (А)
75 (B)
66 (B)
C20H18N4O3
66.07
66.29
54.70
54.43
53.17
53.41
54.19
54.44
5.10
5.01
3.16
3.30
3.62
3.54
3.70
3.88
15.30
15.46
14.31
14.10
12.81
13.11
12.85
12.70
259-262
279-283
268-271
259-261
5g
5h
5i
C18H13BrN4O2
C19H15BrN4O3
C20H17BrN4O3
67 (А)
61 (B)
57 (B)
5j
Thus, it was established that ethyl 1-aryl-4-isocyanatopyrazole-3-carboxylates are convenient new
starting compounds for the preparative synthesis of 6-alkyl-2-aryl-2H-pyrazolo[4,3-d]pyrimidine-5,7(4H,6H)-
diones.
EXPERIMENTAL
The IR spectra were recorded in CH2Cl2 (compounds 3a,b) and in pellets with KBr (the other
1
compounds) on a UR-20 spectrometer. The H and 13C NMR spectra were recorded on a Bruker Avance
DRX-500 spectrometer (500 and 125 MHz, respectively) in CDCl3 (compounds 3a,b) and DMSO-d6 (the other
1347

TABLE 2. The IR and Mass Spectra of Compounds 4a-m, 5a-j
IR spectrum, , cm-1
С=О NH
IR spectrum, , cm-1
С=О NH
Mass,
Mass,
Com-
pound
Com-
pound
spectrum
spectrum
m/z [M+H]+
m/z [M+H]+
1690, 1725 3255, 3340
1690, 1725 3260, 3345
1695, 1720 3240, 3335
1700, 1730 3255, 3365
1690, 1730 3250, 3360
1685, 1730 3270, 3355
1700, 1725 3270, 3350
1695, 1720 3245, 3345
1695, 1725 3250, 3360
1700, 1730 3245, 3355
1695, 1730 3245, 3365
1700, 1725 3250, 3360
331
319
346
365
399
379
409
357
351
365
444
474
1700, 1725 3255, 3345
488
285
273
300
319
353
333
363
398
428
442
4а
4b*
4с
4d
4e
4f
4m
5a
1675, 1715
3345
3360
3365
3350
3360
3370
3375
3365
3355
3360
5b*2 1675, 1720
1670, 1715
1670, 1715
1675, 1720
1675, 1720
1680, 1720
1675, 1715
1670, 1715
1675, 1720
5c
5d
5e
5f
4g
4h
4i
5g
5h
5i
4j
4k
4l
5j
_______
* (OH) 3430.
*2 (OH) 3405.
TABLE 3. The 1H NMR Spectra of Compounds 4a-m, 5a-j
Com-
pound
Chemical shifts, δ, ppm (J, Hz)
1
2
0.89 (3Н, t, J = 6.8, (CH2)3СН3); 1.32-1.43 (7Н, m, СН2СН2СН2СН3, OCH2CH3);
3.11 (2Н, t, J = 6.6, NHСН2); 4.38 (2Н, q, J = 6.8, OСН2СН3);
7.37-7.55 (4Н, m, H Ph, NН); 7.83 (2Н, d, J = 8.2, H Ph);
8.39 (1Н, s, Н-5); 8.68 (1Н, s, NН)
4а
1.35 (3Н, t, J = 6.8, OСН2СН3); 3.19 (2Н, t, J = 5.8, NHСН2СН2ОН);
3.57 (2Н, t, J = 5.8, NHСН2СН2ОН); 4.38 (2Н, q, J = 6.8, OСН2СН3);
4.75 (1Н, br. s, ОН); 7.18-7.38 (4Н, m, H Ph, NН); 7.83 (2Н, d, J = 7.6, H Ph);
8.40 (1Н, s, Н-5); 8.82 (1Н, s, NН)
4b
1.37 (3Н, t, J = 6.8, OСН2СН3); 2.17 (6Н, s, N(СН3)2); 2.32 (2Н, t, J = 6.0, NНСН2СН2NMe2);
3.21 (2Н, t, J = 6.0, NНСН2СН2NMe2); 4.39 (2Н, q, J = 7.2, OСН2СН3);
7.39-7.55 (4Н, m, H Ph, NН); 7.84 (2Н, d, J = 8.0, H Ph); 8.48 (1Н, s, Н-5); 8.69 (1Н, s, NН)
1.36 (3Н, t, J = 6.8, OСН2СН3); 4.39 (2Н, d, J = 5.4, СН2Ph);
4.41 (2Н, q, J = 6.8, OСН2СН3); 7.26-7.90 (11Н, m, H Ph, NН); 8.52 (1Н, s, Н-5);
8.70 (1Н, s, NН)
4с
4d
4е
4f
1.36 (3Н, t, J = 7.2, OСН2СН3); 4.32 (2Н, d, J = 5.2, СН2Ar);
4.39 (2Н, q, J = 7.2, OСН2СН3); 7.31 (2Н, t, J = 7.6, H Ar); 7.33-7.44 (5Н, m, H Ph);
7.84-7.92 (3Н, m, H Ar, NН); 8.53 (1Н, s, Н-5); 8.69 (1Н, s, NН)
1.36 (3Н, t, J = 6.8, OСН2СН3); 2.29 (3Н, s, ArСН3); 4.28 (2Н, d, J = 5.4, СН2Ar);
4.39 (2Н, q, J = 6.8, OСН2СН3); 7.15 (2Н, d, J = 7.6, H Ar); 7.20 (2Н, d, J = 7.6, H Ar);
7.38 (1Н, t, J = 7.6, H Ph); 7.53 (2Н, t, J = 7.6, H Ph); 7.84-7.88 (3Н, m, H Ph, NН);
8.49 (1Н, s, Н-5); 8.70 (1Н, s, NН)
1.36 (3Н, t, J = 7.2, OСН2СН3); 2.70 (2Н, t, J = 6.8, NНСН2СН2Ar);
4g
3.31 (2Н, t, J = 6.8, NНСН2СН2Ar); 3.73 (3Н, s, ОCН3); 4.38 (2Н, q, J = 7.2, OСН2СН3);
6.87 (2Н, d, J = 8.0, H Ar); 7.16 (2Н, d, J = 8.0, H Ar); 7.37-7.56 (4Н, m, H Ph, NН);
7.85 (2Н, d, J = 8.0, H Ph); 8.42 (1Н, s, Н-5); 8.70 (1Н, s, NН)
1.06-1.08 (13Н, m, 5СН2, OСН2СН3); 3.48-3.53 (1Н, m, NHСН);
4.39 (2Н, q, J = 7.2, OСН2СН3); 7.28-7.55 (4Н, m, H Ph, NН); 7.83 (2Н, d, J = 7.2, H Ph);
8.38 (1Н, s, Н-5); 8.67 (1Н, s, NН)
4h
4i
1.38 (3Н, t, J = 6.8, OСН2СН3); 4.41 (2Н, q, J = 6.8, OСН2СН3); 6.99 (1Н, t, J = 7.2, H Ph);
7.29-7.42 (7Н, m, H Ph); 7.87 (2Н, d, J = 7.6, H Ph); 8.76 (1Н, s, Н-5); 8.82 (1Н, s, NН);
9.84 (1Н, s, NН)
1.35 (3Н, t, J = 7.0, OСН2СН3); 2.38 (3H, s, ArСН3); 4.42 (2Н, q, J = 7.0, OСН2СН3);
7.09 (2Н, d, J = 7.6, H Ar); 7.39-7.56 (5Н, m, H Ph); 7.87 (2Н, d, J = 7.6, H Ar);
8.76 (1Н, s, Н-5); 8.81 (1Н, s, NН); 9.74 (1Н, s, NН)
4j
1348

TABLE 3 (continued)
1
2
4k
1.35 (3Н, t, J = 7.2, OСН2СН3); 4.34 (2Н, d, J = 5.6, СН2Ph);
4.40 (2Н, q, J = 7.2, OСН2СН3); 7.24-7.39 (5Н, m, H Ph); 7.72 (2Н, d, J = 7.8, H Ar);
7.86-7.91 (3Н, m, H Ar, NН); 8.51 (1Н, s, NН); 8.73 (1Н, s, Н-5)
4l
1.35 (3Н, t, J = 6.8, OСН2СН3); 3.74 (3Н, s, OCН3); 4.25 (2Н, d, J = 5.6, СН2Ar);
4.38 (2Н, q, J = 6.8, OСН2СН3); 6.86 (2Н, d, J = 8.2, H Ar); 7.23 (2Н, d, J = 8.2, H Ar);
7.70 (2Н, d, J = 8.4, H Ar); 8.81-8.86 (3Н, m, H Ar, NН); 8.47 (1Н, s, NН);
8.74 (1Н, s, Н-5)
4m
5a
1.35 (3Н, t, J = 7.2, OСН2СН3); 2.70 (2Н, t, J = 6.6, NНСН2СН2Ar);
3.31-3.38 (2Н, m, NНСН2СН2Ar); 4.38 (2Н, q, J = 7.2, OСН2СН3); 6.86 (2Н, d, J = 8.4, H Ar);
7.16 (2Н, d, J = 8.4, H Ar); 7.44 (1Н, s, NН); 7.71 (2Н, d, J = 8.4, H Ar);
7.84 (2Н, d, J = 8.4, H Ar); 8.41 (1Н, s, NН); 8.72 (1Н, s, Н-5)
0.93 (3Н, t, J = 7.0, NH(СН2)3СН3); 1.40-1.47 (4Н, m, СН2СН2СН2СН3);
3.62 (2Н, J = 6.2, NHCH2); 7.38-7.54 (3Н, m, H Ph); 7.88 (2Н, d, J = 8.0, H Ph);
8.42 (1Н, s, Н-3); 11.22 (1Н, s, NН)
5b
5c
3.55 (2Н, t, J = 6.0, NСН2СН2OH); 3.99 (2Н, t, J = 6.0, NСН2СН2OH); 4.80 (1Н, br. s, ОН);
7.42-7.51 (3Н, m, H Ph); 7.95 (2Н, d, J = 7.8, H Ph); 8.39 (1Н, s, Н-3); 11.32 (1Н, s, NН)
2.20 (6Н, s, N(СН3)2); 3.42 (2Н, t, J = 6.0, NСН2СН2NMe2); 4.00 (2Н, t, J = 6.0, NСН2СН2NMe2);
7.27-7.43 (3Н, m, H Ph); 7.94 (2Н, d, J = 7.6, H Ph); 8.37 (1Н, s, Н-3); 11.38 (1Н, br. s, NН)
5d
5e
5.10 (2Н, s, СН2Ph); 7.25-7.84 (10Н, m, H Ph); 8.41 (1Н, s, Н-3); 11.46 (1Н, s, NН)
5.07 (2Н, s, СН2Ar); 7.36-7.57 (7Н, m, H Ar); 7.95 (2Н, d, J = 7.6, H Ar);
8.41 (1Н, s, Н-3); 11.49 (1Н, s, NН)
5f
5.05 (2Н, s, СН2Ar); 7.10-7.56 (7Н, m, H Ar); 7.96 (2Н, d, J = 7.8, H Ar);
8.39 (1Н, s, Н-3); 11.46 (1Н, s, NН)
5g
2.81 (2Н, t, J = 6.8, NHСН2СН2Ar); 3.73 (3Н, s, OCН3); 4.07 (2Н, t, J = 6.8, NHСН2СН2Ar);
6.84 (2Н, d, J = 8.4, H Ar); 7.15 (2Н, d, J = 7.6, H Ph); 7.44 (1Н, t, J = 7.8, H Ph);
7.57 (2Н, d, J = 8.0, H Ph); 7.96 (2Н, d, J = 8.4, H Ar); 8.38 (1Н, s, Н-3);
11.35 (1Н, s, NН)
5h
5i
5.09 (2Н, s, СН2Ph); 7.25-7.35 (5Н, m, H Ph); 7.72 (2Н, d, J = 8.0, H Ar);
7.94 (2Н, d, J = 8.0, H Ar); 8.44 (1Н, s, Н-3); 11.49 (1Н, s, NН)
3.73 (3Н, s, OCН3); 5.03 (2Н, s, СН2Ar); 6.86 (2Н, d, J = 7.8, H Ar);
7.29 (2Н, d, J = 7.8, H Ar); 7.73 (2Н, d, J = 8.0, H Ar); 7.91 (2Н, d, J = 8.0, H Ar);
8.34 (1Н, s, Н-3); 11.29 (1Н, s, NН)
5j
2.79 (2Н, t, J = 7.0, NHСН2СН2Ar); 3.73 (3Н, s, OCН3);
4.05 (2Н, t, J = 7.0, NHСН2СН2Ar); 6.86 (2Н, d, J = 8.0, H Ar);
7.15 (2Н, d, J = 8.0, H Ar); 7.74 (2Н, d, J = 8.4, H Ar); 7.93 (2Н, d, J = 8.4, H Ar);
8.40 (1Н, s, Н-3); 11.37 (1Н, s, NН)
compounds) with TMS as internal standard. The mass spectra were recorded on an Agilent LC/MSD SL chromato-
mass spectrometer; Zorbax SB-C18 column, 4.6×15 mm, 1.8 μm (PN 82(c)75-932). Solvents: A – MeCN–H2O,
95:5, 0.1% trifluoroacetic acid; B – 0.1% aqueous trifluoroacetic acid; eluent flow rate 3 ml/min; injection volume 1
μl; UV detectors 215, 254, 285 nm; chemical ionization at atmospheric pressure, scan range m/z 80-1000. Elemental
analysis was performed on a Perkin-Elmer CHN Analyzer in the analytical laboratory of the Institute of Organic
Chemistry, National Academy of Sciences of Ukraine. The melting points were determined on a Kofler hot bench
and were not corrected. Compounds 1a,b were obtained by the described method [18].
1-Aryl-3-(ethoxycarbonyl)-1H-pyrazole-4-carboxylic acids 2a,b (General Method). The ester 1a,b
(0.05 mol) in acetone (50 ml) was added with stirring to a suspension of KMnO4 (7.90 g, 0.05 mol) in acetone (50
ml) and water (10 ml) at such a rate that the temperature of the reaction mixture did not exceed 20°C. The reaction
mixture was stirred at room temperature for 12 h and poured into iced water (200 ml). The solid precipitate was
filtered off and washed with of H2O (100 ml), and the filtrate was acidified with 20% HCl (10 ml). The solid
precipitate was filtered off, washed with water (3×50 ml), dried, and recrystallized from EtOH.
Compound 2a. Yield 9.44 g (73%). White crystals, mp 139-140°С. IR spectrum, ν, cm-1: 1730 (С=О),
1
2540-2850 (СООН). H NMR spectrum, δ, ppm (J, Hz): 1.39 (3Н, t, J = 7.2, ОСН2СН3); 4.34 (2Н, q, J = 7.2,
ОСН2СН3); 7.39-7.42 (1Н, m, Н Ph); 7.50-7.55 (2Н, m, Н Ph); 7.92 (2Н, d, J = 7.8, Н Ph); 9.18 (1Н, s, Н-5);
11.98 (1Н, s, СООН). Found, %: С 60.23; Н 4.76; N 10.90. С13Н12N2О4. Calculated, %: С 60.00; Н 4.65;
N 10.76.
1349

TABLE 4. The 13C NMR Spectra of Compounds 4a-m, 5a-j
Com-
pound
Chemical shifts, δ, ppm
С-7а
С-3
С-3а
С-5
С-7
R, Ar
112.8 132.1 150.2 157.3 138.7 17.8; 20.8; 31.4; 46.5; 119.3; 126.6; 127.4; 129.4
112.7 132.2 150.1 157.4 138.9 44.4; 60.3; 119.9; 125.4; 127.0; 128.8
112.6 132.0 150.5 157.3 139.1 37.8; 45.0; 56.4; 119.4; 127.0; 127.6; 129.2
5a
5b
5c
5d
113.0 131.9 150.6 157.3 139.1 41.1; 119.4; 126.9; 127.1; 127.3; 127.8; 128.2;
129.5; 137.5
113.1 131.9 150.5 157.4 139.1 42.5; 119.5; 127.1; 128.2; 129.3; 129.6; 129.9;
131.6; 136.5
5e
5f
113.0 132.0 150.6 157.3 139.1 20.6; 45.8; 119.4; 127.1; 127.4; 127.8; 128.7;
129.6; 134.5; 136.0
112.7 132.0 150.4 157.1 139.1 32.6; 41.7; 54.7; 113.7; 119.3; 127.0; 127.8;
129.4; 129.5; 130.4; 157.7
5g
113.1 132.4 150.5 157.3 138.3 43.1; 120.4; 126.7; 126.9; 127.1; 127.2; 127.3
5h
5i
113.1 132.4 150.5 157.2 138.4 42.5; 55.0; 113.6; 120.4; 121.4; 127.1; 129.1;
129.5; 132.3; 158.3
112.8 132.1 150.4 157.3 139.0 32.7; 42.0; 54.4; 113.8; 120.3; 121.5; 127.3;
129.1; 130.0; 132.4; 158.6
5j
Compound 2b. Yield 10.30 g (61%). Light-yellow crystals, mp 168-170°С. IR spectrum, ν, cm-1: 1730
1
(С=О), 2520-2860 (СООН). H NMR spectrum, δ, ppm (J, Hz): 1.43 (3Н, t, J = 7.0, ОСН2СН3); 4.28 (2Н, q,
J = 7.0, ОСН2СН3); 7.63 (2Н, d, J = 8.2, Н Ar); 7.97 (2Н, d, J = 8.2, Н Ar); 9.16 (1Н, s, Н-5); 12.11 (1Н, s,
СООН). Found, %: С 45.80; Н 3.10; N 8.08. С13Н11BrN2О4. Calculated, %: С 46.04; Н 3.27; N 8.26.
Ethyl 1-Aryl-4-isocyanato-1H-pyrazole-3-carboxylates 3a,b (General Method). Ethyl chloro-
formate (1.65 g, 0.015 mol) was added to a solution of the acid 2a,b (0.010 mol) and Et3N (2.7 ml, 0.020 mol)
in THF (30 ml) with stirring and cooling to -10°C. The mixture was stirred at this temperature for 0.5 h, and
NaN3 (1.62 g, 0.025 mol) in H2O (10 ml) was then added. The mixture was stirred at -10°C for a further 1 h.
The reaction mixture was poured into iced water (100 ml), extracted with PhMe (3×25 ml), dried over
anhydrous MgSO4, filtered, and refluxed until the release of nitrogen had stopped (~2 h). The toluene was
evaporated under vacuum, and the solid residue was recrystallized from a 3:1 mixture of benzene and hexane.
Compound 3a. Yield 2.10 g (82%). Light-yellow crystals, mp 93-95°С. IR spectrum, ν, cm-1: 1730
1
(С=О), 2250 (N=С=О). H NMR spectrum, δ, ppm (J, Hz): 1.44 (3Н, t, J = 7.4, ОСН2СН3); 4.47 (2Н, q,
J = 7.4, ОСН2СН3); 7.34 (1Н, t, J = 7.6, Н Ph); 7.46 (2Н, t, J = 7.8, Н Ph); 7.66 (2Н, d, J = 7.8, Н Ph); 7.77
(1Н, s, Н-5). Found, %: С 60.30; Н 4.35; N 16.16. С13Н11N3О3. Calculated, %: С 60.70; Н 4.31; N 16.33.
Compound 3b. Yield 2.57 g (77%). Yellow crystals, mp 118-120°С. IR spectrum, ν, cm-1: 1730 (С=О),
1
2250 (N=С=О). H NMR spectrum, δ, ppm (J, Hz): 1.41 (3Н, t, J = 7.2, ОСН2СН3); 4.30 (2Н, q, J = 7.2,
ОСН2СН3); 7.61 (2Н, d, J = 8.4, Н Ar); 7.80 (1Н, s, Н-5); 7.95 (2Н, d, J = 8.4, Н Ar). Found, %: С 46.22;
Н 2.90; N 12.35. С13Н10BrN3О3. Calculated, %: С 46.45; Н 3.00; N 12.50.
Ethyl 4-({[Alkyl(aryl)amino]carbonyl}amino)-1-aryl-1H-pyrazole-3-carboxylates 4a-m (General
Method). The corresponding amine (0.002 mol) was added to a solution of the isocyanate 3a,b (0.002 mol) in
PhMe (5 ml) and left at room temperature for 3 h (in the case of aliphatic amines) or refluxed for 1 h (in the case
of aromatic amines). Hexane (5 ml) was added to the reaction mixture, and after 1 h the precipitate was filtered
off, washed with hexane, dried, and recrystallized from EtOH.
6-Alkyl-2-aryl-2H-pyrazolo[4,3-d]pyrimidine-5,7(4H,6H)-diones 5a-j and 1-Phenyl-4-ureido-1H-
pyrazole-3-carboxylic Acids 6a-c (General Method). The ureido ester 4a-m (0.001 mol) was added to a
solution of KOH (0.12 g, 0.002 mol) in EtOH (10 ml) (method A) or t-BuOK (0.12 g, 0.001 mol) in THF
(10 ml) (method B), and the mixture was refluxed for 3 h. The reaction mixture was acidified to pH 2 with 10%
HCl, and the precipitate was filtered off, washed with water, dried, and recrystallized from AcOH.
4-{[(Cyclohexylamino)carbonyl]amino}-1-phenyl-1H-pyrazole-3-carboxylic Acid (6a). Yield 0.21 g
(63%, method A). White crystals, mp 235-237°С. IR spectrum, ν, cm-1: 1665, 1710 (С=О), 2520-2830 (СООН),
1350

1
3230-3300 (NH). H NMR spectrum, δ, ppm (J, Hz): 1.18-1.95 (10Н, m, 5СН2); 3.48-3.52 (1Н, m, NHСН);
7.37-7.53 (4Н, m, Н Ph, NH); 7.83 (2Н, d, J = 7.8, Н Ph); 8.38 (1Н, s, Н-5); 8.65 (1Н, s, NH); 13.11 (1Н, s,
СООН). Mass spectrum, m/z (Irel, %): 329 [M+H]+. Found, %: С 62.18; Н 6.25; N 17.38. С17Н20N4О3.
Calculated, %: С 62.18; Н 6.14; N 17.06.
1-Phenyl-4-(3-phenylureido)-1H-pyrazole-3-carboxylic Acid (6b). Yield 0.24 g (75%, method B). White
1
crystals, mp 231-233°С. IR spectrum, ν, cm-1: 1670, 1705 (С=О), 2530-2870 (СООН), 3315-3345 (NH). H NMR
spectrum, δ, ppm (J, Hz): 6.99-7.88 (10Н, m, Н Ph); 8.78 (1Н, s, Н-5); 8.86 (1Н, s, NH); 9.88 (1Н, s, NH); 13.27 (1Н,
br. s, СООН). 13C NMR spectrum, δ, ppm: 117.5 (С-5); 118.0, 118.9, 121.9, 127.0, 127.2, 128.8, 129.7, 135.2, 139.8
(С Ph); 132.2 (С-4); 139.3 (С-3); 151.7 (СОNH); 164.5 (СООН). Mass spectrum, m/z (Irel, %): 323 [M+H]+. Found, %:
С 63.57; Н 4.50; N 17.16. С17Н14N4О3. Calculated, %: С 63.35; Н 4.38; N 17.38.
4-[3-(4-Methylphenylureido)]-1-phenyl-1Н-pyrazole-3-carboxylic Acid (6с). Yield 0.27 g (81%,
method А). White crystals, mp 239-241°С. IR spectrum, ν, cm-1: 1665, 1705 (С=О), 2560-2880 (СООН),
1
3310-3340 (NH). Н NMR spectrum, δ, ppm (J, Hz): 2.25 (3Н, s, СН3); 7.09 (2Н, d, J = 7.8, Н Ar); 7.39-7.54
(5Н, m, Н Ph); 7.87 (2Н, d, J = 7.8, Н Ar); 8.75 (1Н, s, Н-5); 8.82 (1Н, s, NH); 9.76 (1Н, s, NH). 13С NMR
spectrum, δ, ppm: 20.4 (СН3); 117.4 (С-5); 118.1, 118.9, 127.1, 127.2, 129.2, 129.7, 130.7, 137.2 (С Ar); 132.3
(С-4); 139.3 (С-3); 151.8 (СОNH); 164.5 (СООН). Mass spectrum, m/z: 337 [M+H]+. Found, %: С 64.03;
Н 4.66; N 16.47. С18Н16N4О3. Calculated, %: С 64.28; Н 4.79; N 16.66.
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