A convenient synthesis method of 5-oxopyrazolo[4,3-b]pyridine-6-carboxylic acids and their nitriles

Article abstract of DOI:10.1007/s10593-019-02603-5

[Figure not available: see fulltext.] N-Boc-protected 5-formyl-1H-pyrazol-4-amines react with malonic acid in pyridine in the presence of pyrrolidine at 45–50°С or with malonic acid monomethyl ether in the presence of pyrrolidine in AcOH under reflux with

Full text of DOI:10.1007/s10593-019-02603-5

DOI 10.1007/s10593-019-02603-5
Chemistry of Heterocyclic Compounds 2019, 55(12), 1211–1216
A convenient synthesis method of 5-oxopyrazolo[4,3-b]pyridine-
6-carboxylic acids and their nitriles
Georgiy G. Yakovenko1,2*, Oleh А. Lukianov2,
Andriy V. Bol'but2,3, Mikhailo V. Vovk2
1 National University ''Kyiv-Mohyla Academy'',
2 Hrygorija Skorovody St., Kyiv 04655, Ukraine; e-mail: chemgeorge@i.ua
2 Institute of Organic Chemistry, National Academy of Sciences of Ukraine,
5 Murmanska St., Kyiv 02094, Ukraine; е-mail: mvovk@ioch.kiev.ua
3 Enamine Ltd.,
78 Chervonotkatskaya St., Kyiv 02094, Ukraine; e-mail: bolbut@ukr.net
Submitted June 6, 2019
Accepted August 3, 2019
Translated from Khimiya Geterotsiklicheskikh Soedinenii,
2019, 55(12), 1211–1216
N-Boc-protected 5-formyl-1H-pyrazol-4-amines react with malonic acid in pyridine in the presence of pyrrolidine at 45–50°С or with
malonic acid monomethyl ether in the presence of pyrrolidine in AcOH under reflux with the formation of 5-oxo-4,5-dihydro-1H-
pyrazolo[4,3-b]pyridine-6-carboxylic acids. The reaction of N-Boc-protected 5-formyl-1H-pyrazol-4-amines with cyanoacetic acid in
pyridine in the presence of pyrrolidine at 45–50°С leads to the formation of 5-oxo-4,5-dihydro-1H-pyrazolo[4,3-b]pyridine-
6-carbonitriles. The latter can also be obtained via cyclocondensation of N-Boc-protected 5-formyl-1H-pyrazol-4-amines with methyl
cyanoacetate in AcOH under reflux in the presence of pyrrolidine or in MeCN containing pyrrolidine and a catalytic amount of proline
heated under reflux.
Keywords: cyanoacetic acid, 5-formyl-1H-pyrazol-4-amine, malonic acid, methyl cyanoacetate, monomethyl malonate, pyrazolo[4,3-b]-
pyridine-6-carbonitrile, pyrazolo[4,3-b]pyridine-6-carboxylic acid, cyclocondensation.
Derivatives of 5-oxo-4,5-dihydro-1H-pyrazolo[4,3-b]-
pyridine are condensed nitrogen-containing heterocyclic
compounds with pronounced biological activity. Among
them, inhibitors of p38 mitogen-activated protein kinases,
promising agents for the treatment of viral diseases,
arthritis, Alzheimer's disease and dermatitis,1 inhibitors of
bromodomain and extraterminal proteins for the treatment
of autoimmune diseases, viral and inflammatory
infections,2 as well as NIK kinase inhibitors effective for
the treatment and prevention of inflammatory diseases3
were identified. There is also a report on the use of
derivatives of 5-oxo-4,5-dihydro-1H-pyrazolo[4,3-b]-
pyridine as important intermediates in the synthesis of
chemokine receptor antagonists pyrazolopiperidines.4
derivatives, the known methods for their synthesis are
multistage, require the use of expensive and aggressive
reagents, and, as a rule, include a series of successive
conversions to annulate the pyridine ring to the
pyrazole.1b,3,5 In particular, the condensation of 3,5-diacyl-
1-phenyl-1H-pyrazol-4-amines with cyanoacetic acid pro-
ceeds in Ac2O medium under the conditions of microwave
activation with the formation of 2-cyano-N-(3,5-diacyl-
1-phenyl-1H-pyrazol-4-yl)acetamides, which cyclize into
5-oxo-4,5-dihydro-1H-pyrazolo[4,3-b]pyridine-6-carbonitriles
only upon heating in DMF under reflux in the presence of
NaOAc.5a In turn, intramolecular copper-catalyzed
amidation of 4-iodopyrazoles does not exhibit high
selectivity and leads to the formation of 5-oxo-4,5-dihydro-
1H-pyrazolo[4,3-b]pyridine derivatives with relatively low
yields.5b In the context of the foregoing, it seems
However, despite the fairly wide pharmacological
profile of 5-oxo-4,5-dihydro-1H-pyrazolo[4,3-b]pyridine
0009-3122/19/55(12)-1211©2019 Springer Science+Business Media, LLC
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Chemistry of Heterocyclic Compounds 2019, 55(12), 1211–1216
Table 1. Synthesis of 5-oxo-4,5-dihydro-1H-pyrazolo-
reasonable to develop a preparatively convenient way to
[4,3-b]pyridine-6-carboxylic acids 4a–g
n-BuLi, DMF
access new representatives of this heterocyclic system,
additionally containing a carboxyl or nitrile functionality in
the pyridine ring, which can be effectively subjected to
structural modifications by pharmacophore groups. The
choice of the indicated functional groups as substituents is
also due to the powerful synthetic potential6 and biological
activity7 of isostere 3-carbo-functionalized quinolin-2-ones.
In a previous report, we showed that the Friedlander
reaction of N-Boc-protected 1-alkyl- or 1-aryl-5-formyl-1H-
pyrazol-4-amines with various methylene-containing
ketones can be used to obtain 5-substituted pyrazolo[4,3-b]-
pyridines.8 Considering these revelations, as well as the
literature data on the cyclocondensation of aromatic o-amino-
aldehydes or ketones with CH acids as an effective method
for the synthesis of 3-substituted quinolones,6a,7a,b,9 we
investigated the reactions of N-Boc-protected 1-alkyl- or
1-aryl-5-formyl-1H-pyrazol-4-amines 1a–g with malonic
acid (2a), its methyl ester 2b, and also cyanoacetic acid
(2c) and its methyl ester 2d in this work.
THF, 78°C,
then rt, 12 h
or
R2
N
NH2
R2
N
NHBoc
R2
N
NHBoc
CHO
Boc2O
DMAP
THF
rt, 4 6 h,
then 40°C, 1 h
72–95%
n-BuLi, HC(O)Et
THF
–78°C, 15 min
58–90%
N
R1
N
R1
N
R1
1a–g
8a–g
Method I
(R3 = H)
R1
N
R2
NH
R2
N
N
NHBoc
CO2H
Pyrrolidine
2 N HCl
CO2H
Py
45–50°C
N
CO2H
CO2R3
2a,b
R1
HO2C
4a–g
O
3a g
Method II (R3 = Me)
Pyrrolidine
AcOH, rt, 3 h, then
In search of the optimal conditions for cyclo-
condensation of 5-formyl-1H-pyrazol-4-amines 1a–g with
malonic acid (2a), it was found that the use of pyridine as
the solvent and an equimolar amount of pyrrolidine as the
catalyst is the most effective. In this medium, the reaction
is complete at 45–50°С within 8–12 h and proceeds via the
intermediate products 3a–g, which can be observed by
1H NMR spectroscopy (Table 1, method I). Subsequent treat-
ment with 2 N aqueous HCl removes the N-Boc protection
to effect cyclization to the desired 5-oxo-4,5-dihydro-1H-
pyrazolo[4,3-b]pyridine-6-carboxylic acids 4a–g in 54–86%
yields. Carrying out the reaction under reflux in the AcOH–
pyrrolidine system, which was previously used to condense
N-Boc-protected 1-alkyl- or 1-aryl-5-formyl-1H-pyrazol-
4-amines with ketones,8 was ineffective. Thus, after
carrying out the reaction of 5-formyl-1H-pyrazol-4-amine
1a with acid 2a under these conditions, it was found that
the content of the target product 4a in the reaction mixture
was only 18% according to LC-M spectrometry. However,
the replacement of malonic acid (2a) with its monomethyl
ether 2b allowed to successfully effect cyclocondensation
with N-Boc-protected 1-alkyl- or 1-aryl-5-formyl-1H-
pyrazol-4-amines 1a–e by stirring in AcOH–pyrrolidine at
room temperature for 3 h, followed by heating under reflux
for 5–6 h (method II). Most probably that under these
conditions the cyclization stage proceeds noticeably faster
than the competing decarboxylation reaction of the malo-
nate carboxyl group of the crotonic condensation inter-
mediate, although the target compounds 4a–e are obtained
in 4–15% lower yields than when using method I. Formation
of the pyridine ring as a result of the studied cyclization is
confirmed by the presence in the IR spectra of compounds
4a–g of absorption bands of N–H in the 3201–3217 cm–1
range, carboxylic C=O in the 1721–1739 cm–1 range,
pyridone C=O in the 1652–1665 cm–1 range, whereas the
1H NMR spectra contained the singlet signals of protons of
7-CH at 8.70–8.97 (for compounds 4a–d,f,g) and 9.63 ppm
(for compound 4e), of NH at 13.26–13.61 ppm, and of
СО2Н at 15.20–15.50 ppm.
Method I
Method II
Com-
pound
R1
R2
Time, h Yield, % Time, h Yield, %
Me
Et
H
H
9
8
86
82
62
59
60
62
54
5
5
6
6
6
–
–
71
68
58
52
48
–
4a
4b
4c
4d
4e
4f
t-Bu
Ph
H
12
10
12
9
H
2-Py
Me
Me
H
OMe
Ph
10
–
4g
The reactivity of cyanoacetic (compound 2c) and
malonic acid (compound 2a) with 5-formyl-1H-pyrazol-
4-amines 1a,c,e,g are practically the same. 5-Oxo-4,5-di-
hydro-1H-pyrazolo[4,3-b]pyridine-6-carbonitriles 1a,c,e,g
are formed as a result of this reaction in the pyridine–
pyrrolidine system at 45–50°С in 48–74% yields (Table 2,
method I). At the same time, methyl cyanoacetate (2d)
does not react with 5-formyl-1H-pyrazol-4-amines 1a–g
under these conditions. A positive result, however, was
achieved by carrying out the reaction in AcOH under reflux
in the presence of an equimolar amount of pyrrolidine
(method II).
The use of the pyrrolidine–proline catalytic system,
which proved to be effective when using MeCN as a
solvent, is also noteworthy. Using the reaction of
bifunctional pyrazoles 1a–d with ester 2d in MeCN under
reflux as an example, it was demonstrated that the use of an
equimolar amount of pyrrolidine and 0.1 equiv of proline
leads to the desired products 5a–d in 52–72% yields
(Table 2, method III). It should be noted that the yields of
compounds 5a–d decrease by 8–11% in the absence of
proline.
In the case of method III, the reaction most likely
proceeds through the formation of Knoevenagel product 6,
detected by LC-M spectrometry. Subsequently, intra-
molecular acylation of intermediate 6 occurs by the action
of pyrrolidine as a base, with the formation of intermediate
1212

Chemistry of Heterocyclic Compounds 2019, 55(12), 1211–1216
Table 2. Synthesis of 5-oxo-4,5-dihydro-1H-pyrazolo-
[4,3-b]pyridin-6-carbonitriles 5a–g
intermediates, 5-oxo-4,5-dihydro-1H-pyrazolo[4,3-b]pyridine-
6-carboxylic acids and their nitriles. This approach is based
on the cyclocondensation of N-Boc-protected 1-alkyl- or
1-aryl-5-formyl-1H-pyrazol-4 amines with malonic or
cyanoacetic acids and their esters.
Method I (R3 = H)
Pyrrolidine
Py, 45–50°C
Experimental
R2
Method II (R3 = Me)
Pyrrolidine
IR spectra were registered on a Bruker Vertex 70 FT-IR
spectrometer in KBr pellets. 1H and 13C NMR spectra were
acquired on a Varian VXR-400 spectrometer (400 and
126 MHz, respectively) in CDCl3 (compounds 1b,f,g and
9b,f,g) or DMSO-d6 (compounds 4a–g and 5a–g), with
TMS as internal standard. Mass spectra were recorded on a
Agilent LC/MSD SL LC-MS system equipped with a
Zorbax SB-C18 column (4.6 × 150 mm, 1.8 μm), atmo-
spheric pressure electrospray ionization, DMSO solvent.
Elemental analysis was performed on a PerkinElmer Series II
2400 Elemental analyzer. Melting points were determined
on a Kofler bench and are uncorrected.
H
N
CO2R3
CN
O
1a–g
+
N
AcOH, rt, 2 h,
N
CN
then 
R1
2c d
5a g
–
,
Method III (R3 = Me)
Pyrrolidine, proline
MeCN, rt, 23 h,
then 
Method I
Method IІ
Yield,
Method IІІ
Yield,
Com-
pound
R1
R2
Yield,
%
Time, h
Time, h
Time, h
The starting pyrazoles 1а,12 1с–е,8 and 8b,f,g8 were
obtained according to published methods. 1-Ethyl-1Н-
pyrazol-4-amine, 3-methoxy-1-methyl-1Н-pyrazol-4-amine,
and 1-methyl-3-phenyl-1Н-pyrazol-4-amine used in the
synthesis of N-Boc-protected 1-alkyl-5-formyl-1H-pyrazol-
4-amines 1b,f,g were supplied by Enamine Ltd.
Synthesis of N-Boc-substituted 1-alkyl-1H-pyrazol-
4-amines 8b,f,g (General method).8 DMAP (1.22 g,
0.01 mol) was added with stirring and cooling to 0°С to a
solution of pyrazol-4-amine (0.257 mol) in THF (400 ml),
followed by di-tert-butyl dicarbonate (56.8 g, 0.260 mol)
over 20 min. The reaction mixture was stirred at 0°C for
1 h, then at room temperature for 4–6 h, and finally at 40°С
for 1 h. The solvent was evaporated under reduced pressure,
the residue was extracted with MTBE (300 ml). MTBE–
hexane, 3:2 mixture (300 ml) was added to the resulting
oily product. The precipitate formed after stirring was
filtered off and air-dried.
tert-Butyl (1-ethyl-1Н-pyrazol-4-yl)carbamate (8b) was
obtained from 1-ethyl-1Н-pyrazol-4-amine (35.4 g,
0.319 mol). Yield 61.3 g (91%), light-pink powder, mp 68–
69°C. IR spectrum, ν, cm–1: 3376 (N–H), 1725 (С=О).
1H NMR spectrum, δ, ppm (J, Hz): 1.41–1.48 (12H, m,
CH3, С(CH3)3); 4.08 (2H, q, J = 7.2, CH2); 6.40 (1H, br. s,
NH); 7.28 (1H, s, H-5); 7.65 (1H, s, Н-3). 13C NMR
spectrum, δ, ppm: 14.9; 27.8; 46.7; 79.5; 118.9; 121.1;
129.2; 152.8. Mass spectrum, m/z (Irel, %): 212 [М+Н]+
(100). Found, %: C 56.39; H 8.20; N 19.68. C10H17N3O2.
Calculated, %: C 56.85; H 8.11; N 19.89.
tert-Butyl (3-methoxy-1-methyl-1Н-pyrazol-4-yl)carba-
mate (8f) was obtained from 3-methoxy-1-methyl-
1Н-pyrazol-4-amine (24.9 g, 0.196 mol). Yield 42.3 g
(95%), colorless crystals, mp 69–70°C. IR spectrum, ν, cm–1:
3285 (N–H), 1714 (С=О). 1H NMR spectrum, δ, ppm: 1.47
(9H, s, С(CH3)3); 3.66 (3H, s, NCH3); 3.89 (3H, s, ОCH3);
6.08 (1H, br. s, NH); 7.48 (1H, s, H-5). 13C NMR spectrum,
δ, ppm: 28.3; 38.9; 56.3; 80.1; 105.7; 123.1; 153.1; 153.7.
Mass spectrum, m/z (Irel, %): 228 [М+Н]+ (100). Found, %:
C 53.10; H 7.61; N 18.31. C10H17N3O3. Calculated, %:
C 52.85; H 7.54; N 18.49.
%
67
69
67
74
70
68
61
%
56
52
60
72
−
Me
Et
t-Bu
Ph
H
H
H
H
H
8
−
74
−
5
5
6
6
6
5
6
4
4
5
6
−
−
−
5a
5b
5c
5d
5e
5f
10
8
12
−
56
−
2-Py
48
−
Me OMe
Me Ph
−
12
49
−
5g
7.10 N-Boc protection is removed under the reaction
conditions (elevated temperature, the presence of a base
and formed H2O), which is consistent with published data11
(Scheme 1).
Scheme 1
Boc
Boc
N
R2
R2
NH
1a–d
O
CO2Me
CN
N
N
– H2O
– MeOH
2d
N
N
R
CN
R1
1 6ad
7a d

5a–d
– CO2
– t-BuOH
Replacing the carboxyl group in acids 4a–g with a
cyano group affects the spectral characteristics of nitriles
5a–g. Thus, in the IR spectra of products 5a–g, an
insignificant short-wavelength shift of the absorption bands
of N–H bonds (3205–3252 cm–1), a short-wavelength shift
of the absorption bands of C=O bonds of pyridone (1658–
1694 cm–1), as well as the appearance of medium intensity
absorption bands of С≡N groups in the 2220–2230 cm–1
range are observed. In the 1H NMR spectra of nitriles 5a–g,
the chemical shifts of the 7-CH proton singlet signals are
practically unchanged; however, the NH proton signal does
undergo a noticeable upfield shift of 1 ppm.
To conclude, we have proposed a simple and convenient
method for the synthesis of promising novel synthetic
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Chemistry of Heterocyclic Compounds 2019, 55(12), 1211–1216
Mass spectrum, m/z (Irel, %): 302 [М+Н]+ (100). Found, %:
tert-Butyl (1-methyl-3-phenyl-1Н-pyrazol-4-yl)carba-
mate (8g) was obtained from 1-methyl-3-phenyl-1Н-
pyrazol-4-amine (24.6 g, 0.142 mol). Yield 34.2 g (88%),
brown powder, mp 93–94°C. IR spectrum, ν, cm–1: 3301
C 63.58; H 6.40; N 13.78. C16H19N3O3. Calculated, %:
C 63.77; H 6.36; N 13.94.
Synthesis of pyrazolo[4,3-b]pyridine-6-carboxylic
acids 4a–g (General method). Method I. Malonic acid (2a)
(0.62 g, 6 mmol) followed by pyrrolidine (0.5 ml, 6 mmol)
was added to a solution of N-Boc-protected 1-alkyl- or
1-aryl-5-formyl-1H-pyrazol-4-amine 1а–g (5 mmol) in
pyridine (15 ml). The reaction mixture was heated at 45–
50°С for 8–12 h. Pyridine was evaporated under reduced
pressure, and the residue was treated with 2 N aqueous HCl
(10 ml). The formed precipitate was filtered off, washed
with H2O (10 ml) and MTBE (10 ml), air-dried, and
recrystallized from MeOH.
Method IІ. Monomethyl malonate (2b) (0.70 g, 6 mmol)
followed by pyrrolidine (0.5 ml, 6 mmol) was added to a
solution of N-Boc-protected 1-alkyl- or 1-aryl-5-formyl-1H-
pyrazol-4-amine (5 mmol) 1а–e (5 mmol) in glacial AcOH
(20 ml). The reaction mixture was stirred at room
temperature for 3 h, then heated under reflux for 5–6 h. The
solvent was evaporated under reduced pressure, H2O (30–
40 ml) was added to the oily residue, and stirred until a
loose precipitate formed. It was filtered off, washed with
H2O (10 ml) and MTBE (10 ml), air-dried, and re-
crystallized from MeOH.
1-Methyl-5-oxo-4,5-dihydro-1Н-pyrazolo[4,3-b]pyri-
dine-6-carboxylic acid (4а). Yield 0.83 g (86%, method I),
0.69 g (71%, method IІ), light-yellow powder, mp 264–
265°C. IR spectrum, ν, cm–1: 3201 (N–H), 1739 (C=О
carboxylic acid), 1652 (C=О pyridone). 1H NMR spectrum,
δ, ppm: 4.10 (3H, s, CH3); 7.69 (1H, s, H-3); 8.92 (1H, s,
7-CН); 13.26 (1H, s, NH); 15.38 (1H, s, CO2H). 13C NMR
spectrum, δ, ppm: 37.2; 115.2; 124.0; 127.3; 129.2; 131.4;
163.9; 165.6. Mass spectrum, m/z (Irel, %): 194 [M+H]+
(100). Found, %: C 49.95; H 3.57; N 21.91. C8H7N3O3.
Calculated, %: C 49.74; H 3.65; N 21.75.
1
(N–H), 1687 (С=О). H NMR spectrum, δ, ppm (J, Hz):
1.12 (9H, s, С(CH3)3); 3.89 (3H, s, NCH3); 7.25–7.40 (4H,
m, NH, H-3,4,5 Ph); 7.67 (2H, d, J = 7.2, H-2,6 Ph); 7.80
(1H, s, H-5). 13C NMR spectrum, δ, ppm: 27.8; 38.8; 80.0;
117.6; 122.7; 127.3; 128.5; 132.1; 140.8; 152.8. Mass
spectrum, m/z (Irel, %): 274 [М+Н]+ (100). Found, %:
C 65.68; H 7.08;N 15.49. C15H19N3O2. Calculated, %:
C 65.91; H 7.01; N 15.37.
Synthesis of N-Boc-protected 1-alkyl-5-formyl-1H-
pyrazol-4-amines 1b,f,g (General method).8 n-BuLi (2.5 M
solution in hexane, 159 ml, 0.40 mol) was added to a
cooled (–78°С) solution of carbamate 8b,f,g (0.18 mol) in
THF (600 ml) under argon atmosphere. The reaction
mixture was stirred at –78°С for 2–3 h. DMF (15.4 ml,
0.20 mol) was added to the reaction mixture at –78°C, then
stirring was continued at room temperature for 10–12 h.
Saturated aqueous NH4Cl (200 ml) was added to the mixture.
The formed mixture was stirred for additional 20–30 min
and extracted with MTBE (3×200 ml). The organic layer
was washed with saturated aqueous NaCl (2×150 ml),
dried over anhydrous Na2SO4, and filtered through a layer of
silica gel. The solvent was evaporated, MTBE–hexane, 3:2
mixture (150 ml) was added to the oily residue. The pre-
cipitate formed after stirring was filtered off and air-dried.
tert-Butyl (1-ethyl-5-formyl-1Н-pyrazol-4-yl)carba-
mate (1b). Yield 37.4 g (87%), light-pink powder, mp 68–
69°C. IR spectrum, ν, cm–1: 3376 (N–H), 1725 (С=О
aldehyde), 1698 (С=О carbamate). 1H NMR spectrum, δ, ppm
(J, Hz): 1.47–1.50 (12H, m, CH3, С(CH3)3); 4.39 (2H, q,
J = 7.2, CH2); 8.01 (1H, br. s, NH); 8.28 (1H, s, H-5); 9.98
(1H, s, СНО). 13C NMR spectrum, δ, ppm: 15.5; 27.7; 45.2;
80.7; 125.0; 128.2; 129.0; 152.0; 179.0. Mass spectrum,
m/z (Irel, %): 240 [М+Н]+ (100). Found, %: C 55.38;
H 7.21; N 17.49. C11H17N3O3. Calculated, %: C 55.22;
H 7.16; N 17.56.
1-Ethyl-5-oxo-4,5-dihydro-1Н-pyrazolo[4,3-b]pyri-
dine-6-carboxylic acid (4b). Yield 0.85 g (82%, method I),
0.70 g (68%, method IІ), yellow powder, mp 259–261°C.
IR spectrum, ν, cm–1: 3214 (N–H), 1732 (C=О carboxylic
tert-Butyl (5-formyl-3-methoxy-1-methyl-1Н-pyrazol-
4-yl)carbamate (1f). Yield 39.0 g (85%), colorless
crystals, mp 76–77°C. IR spectrum, ν, cm–1: 3239 (N–H),
1
acid), 1663 (C=О pyridone). H NMR spectrum, δ, ppm
(J, Hz): 1.39 (3H, t, J = 7.2, CH3); 4.50 (2H, q, J = 6.8,
CH2); 7.74 (1H, s, H-3); 8.97 (1H, s, 7-CH); 13.27 (1H, s,
NH); 15.39 (1H, s, CO2H). 13C NMR spectrum, δ, ppm:
15.6; 44.9; 115.3; 124.3; 126.5; 129.2; 131.2; 164.0; 165.6.
Mass spectrum, m/z (Irel, %): 208 [M+H]+ (100). Found, %:
C 52.32; H 4.23; N 20.46. C9H9N3O3. Calculated, %:
C 52.17; H 4.38; N 20.28.
1
1710 (С=О aldehyde), 1678 (С=О carbamate). H NMR
spectrum, δ, ppm: 1.49 (9H, s, С(CH3)3); 3.94 (3H, s,
NCH3); 3.98 (3H, s, OCH3); 6.05 (1H, br. s, NH); 9.90 (1H,
s, СНО). 13C NMR spectrum, δ, ppm: 27.6; 38.7; 56.1;
80.7; 109.5; 131.5; 153.6; 154.2; 180.6. Mass spectrum,
m/z (Irel, %): 256 [М+Н]+ (100). Found, %: C 51.05;
H 6.74; N 16.18. C11H17N3O4. Calculated, %: C 51.76;
H 6.71; N 16.46.
1-tert-Butyl-5-oxo-4,5-dihydro-1Н-pyrazolo[4,3-b]-
pyridine-6-carboxylic acid (4с). Yield 0.73 g (62%,
method I), 0.68 g (58%, method IІ), beige powder, mp 261–
263°C. IR spectrum, ν, cm–1: 3212 (N–H), 1725 (C=О
carboxylic acid), 1660 (C=О pyridone). 1H NMR spectrum,
δ, ppm: 1.69 (9H, s, С(CH3)3); 7.75 (1H, s, H-3); 8.87 (1H,
s, 7-CH); 13.38 (1H, s, NH); 15.39 (1H, s, CO2H).
13C NMR spectrum, δ, ppm: 30.1; 62.2; 114.7; 123.4; 125.2;
130.9; 132.2; 163.3; 165.6. Mass spectrum, m/z (Irel, %):
236 [M+H]+ (100). Found, %: C 55.93; H 5.65; N 17.75.
C11H13N3O3. Calculated, %: C 56.16; H 5.57; N 17.86.
tert-Butyl (5-formyl-1-methyl-3-phenyl-1Н-pyrazol-
4-yl)carbamate (1g). Yield 31.4 g (58%), brown powder,
mp 105–106°C. IR spectrum, ν, cm–1: 3258 (N–H), 1759
(С=О aldehyde), 1671 (С=О carbamate). 1H NMR
spectrum, δ, ppm (J, Hz): 1.27 (9H, s, С(CH3)3); 3.94 (3H,
s, NCH3); 7.14–7.23 (3H, m, H-3,4,5 Ph); 7.50 (2H, d,
J = 7.6, H-2,6 Ph); 7.67 (1H, br. s, NH); 9.65 (1H, s,
СНО). 13C NMR spectrum, δ, ppm: 27.6; 39.6; 80.1;
126.4; 127.5; 127.9; 131.1; 133.0; 144.2; 154.1; 179.7.
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Chemistry of Heterocyclic Compounds 2019, 55(12), 1211–1216
5-Oxo-1-phenyl-4,5-dihydro-1Н-pyrazolo[4,3-b]pyri-
pyrazol-4-amine 1а–g (5 mmol) in AcOH (20 ml). The
reaction mixture was stirred at room temperature for 2 h,
then heated under reflux for 5–6 h. The solvent was
evaporated under reduced pressure. H2O (50 ml) was added
to the residue, and the mixture was stirred. The formed
precipitate was filtered off, washed with H2O (10 ml)
and MTBE (10 ml), air-dried, and recrystallized from
MeOH.
Method IІІ. Methyl cyanoacetate (2d) (0.5 ml, 6 mmol)
followed by pyrrolidine (0.5 ml, 6 mmol) and proline
(6 mg, 0.5 mmol) was added to a solution of N-Boc-
protected 1-alkyl- or 1-aryl-5-formyl-1H-pyrazol-4-amine
1а–d (5 mmol) in anhydrous MeCN (30 ml). The reaction
mixture was stirred at room temperature for 2 h, then
heated under reflux for 4–6 h. The solvent was evaporated
under reduced pressure. H2O (20 ml) was added to the
residue, and the mixture was stirred. The formed precipitate
was filtered off, washed with H2O (10 ml) and MTBE
(10 ml), air-dried, and recrystallized from MeOH.
1-Methyl-5-oxo-4,5-dihydro-1Н-pyrazolo[4,3-b]pyri-
dine-6-carbonitrile (5а). Yield 0.64 g (74%, method I),
0.58 g (67%, method II), 0.48 g (56%, method III), yellow
powder, mp 243–245°C. IR spectrum, ν, cm–1: 3251 (N–H),
2226 (C≡N), 1671 (C=O). 1H NMR spectrum, δ, ppm: 3.98
(3H, s, NCH3); 7.52 (1H, s, H-3); 8.81 (1H, s, 7-CH); 12.32
(1H, br. s, NH). 13C NMR spectrum, δ, ppm: 39.9; 103.4;
117.1; 123.7; 125.5; 130.1; 134.6; 159.2. Mass spectrum,
m/z (Irel, %): 175 [M+H]+ (100). Found, %: C 55.36;
H 3.57; N 32.32. C8H6N4O. Calculated, %: C 55.17;
H 3.47; N 32.17.
dine-6-carboxylic acid (4d). Yield 0.74 g (59%, method I),
0.66 g (52%, method IІ), brown powder, mp 269–272°C.
IR spectrum, ν, cm–1: 3213 (N–H), 1729 (C=О carboxylic
1
acid), 1658 (C=О pyridone). H NMR spectrum, δ, ppm
(J, Hz): 7.52 (1H, t, J = 7.2, H-4 Ph); 7.65 (2H, t, J = 7.6,
H-3,5 Ph); 7.76 (2H, d, J = 7.2, H-2,6 Ph); 8.07 (1H, s,
H-3); 8.70 (1H, s, 7-CH); 13.53 (1H, s, NH); 15.20 (1H, s,
CO2H). 13C NMR spectrum, δ, ppm: 116.5; 123.1; 125.8;
127.1; 128.5; 130.4; 130.8; 131.0; 138.6; 163.2; 165.3.
Mass spectrum, m/z (Irel, %): 256 [M+H]+ (100). Found, %:
C 60.98; H 3.58; N 16.33. C13H9N3O3. Calculated, %:
C 61.18; H 3.55; N 16.46.
5-Oxo-1-(pyridin-2-yl)-4,5-dihydro-1Н-pyrazolo[4,3-b]-
pyridine-6-carboxylic acid (4e). Yield 0.75 g (60%,
method I), 0.61 g (48%, method IІ), brown powder, mp 284–
287°C. IR spectrum, ν, cm–1: 3217 (N–H), 1724 (C=О
carboxylic acid), 1656 (C=О pyridone). 1H NMR spectrum,
δ, ppm (J, Hz): 7.44 (1H, t, J = 7.4, Н-5 Ру); 7.89 (1H, d,
J = 6.2, Н-3 Ру); 8.08 (1H, t, J = 5.4, Н-4 Ру); 8.14 (1H, s,
H-3); 8.63 (1Н, d, J = 5.4, Н-6 Ру); 9.63 (1H, s, 7-CH);
13.61 (1H, s, NH); 15.24 (1H, s, CO2H). 13C NMR
spectrum, δ, ppm: 113.1; 117.0; 122.5; 125.4; 128.8; 131.9;
134.4; 140.1; 148.5; 152.5; 163.8; 165.3. Mass spectrum,
m/z (Irel, %): 257 [M+H]+ (100). Found, %: C 56.16;
H 3.22; N 21.75. C12H8N4O. Calculated, %: C 56.25;
H 3.15; N 21.87.
3-Methoxy-1-methyl-5-oxo-4,5-dihydro-1Н-pyrazolo-
[4,3-b]pyridine-6-carboxylic acid (4f). Yield 0.69 g (62%,
method I), white powder, mp 264–265°C. IR spectrum,
ν, cm–1: 3211 (N–H), 1725 (C=О carboxylic acid), 1665
1-Ethyl-5-oxo-4,5-dihydro-1Н-pyrazolo[4,3-b]pyri-
dine-6-carbonitrile (5b). Yield 0.65 g (69%, method IІ),
0.49 g (52%, method IІІ), beige powder, mp 251–253°C.
IR spectrum, ν, cm–1: 3232 (N–H), 2220 (C≡N), 1694
1
(C=О pyridone). H NMR spectrum, δ, ppm: 3.94 (3H, s,
NCH3); 3.97 (3H, s, OCH3); 8.85 (1H, s, 7-CH); 13.42 (1H,
s, NH); 15.50 (1H, s, CO2H). 13C NMR spectrum, δ, ppm:
36.6; 57.3; 114.2; 116.5; 128.6; 131.5; 148.1; 163.7; 165.6.
Mass spectrum, m/z (Irel, %): 224 [M+H]+ (100). Found, %:
C 48.24; H 4.01; N 18.78. C9H9N3O4. Calculated, %:
C 48.43; H 4.06; N 18.83.
1
(C=O). H NMR spectrum, δ, ppm (J, Hz): 1.38 (3H, t,
J = 7.2, CH3); 4.36 (2H, q, J = 6.8, CH2); 7.54 (1H, s, H-3);
8.83 (1H, s, 7-CH); 12.25 (1H, br. s, NH). 13C NMR
spectrum, δ, ppm: 15.0; 44.4; 103.0; 116.7; 123.5; 124.1;
129.7; 134.1; 158.8. Mass spectrum, m/z (Irel, %): 189
[M+H]+ (100). Found, %: C 57.28; H 4.31; N 29.66.
C9H8N4O. Calculated, %: C 57.44; H 4.29; N 29.77.
1-Methyl-5-oxo-3-phenyl-4,5-dihydro-1Н-pyrazolo-
[4,3-b]pyridine-6-carboxylic acid (4g). Yield 0.73 g
(54%, method I), brown powder, mp 290–293°C. IR spect-
rum, ν, cm–1: 3216 (N–H), 1721 (C=О carboxylic acid),
1-tert-Butyl-5-oxo-4,5-dihydro-1Н-pyrazolo[4,3-b]-
pyridine-6-carbonitrile (5с). Yield 0.61 g (56%, method I),
0.73 g (67%, method IІ), 0.65 g (60%, method IІІ), brown
powder, mp 279–281°C. IR spectrum, ν, cm–1: 3244 (N–H),
2228 (C≡N), 1674 (C=O). 1H NMR spectrum, δ, ppm: 1.64
(9H, s, С(CH3)3); 7.53 (1H, s, H-3); 8.97 (1H, s, 7-CH);
12.38 (1H, br. s, NH). 13C NMR spectrum, δ, ppm: 29.9;
61.6; 117.1; 122.8; 123.1; 131.7; 136.1; 158.7; 164.6. Mass
spectrum, m/z (Irel, %): 217 [M+H]+ (100). Found, %:
C 61.03; H 5.46; N 25.75. C11H12N4O. Calculated, %:
C 61.10; H 5.59; N 25.91.
1
1662 (C=О pyridone). H NMR spectrum, δ, ppm: 4.16
(3H, s, NCH3); 7.36–7.56 (3H, m, H-3,4,5 Ph); 7.75–7.95
(2H, m, H-2,6 Ph); 8.95 (1H, s, 7-CH); 13.28 (1H, s, NH);
15.25 (1H, s, CO2H). 13C NMR spectrum, δ, ppm: 38.8;
116.9; 128.1; 129.6; 130.8; 132.5; 133.0; 133.8; 136.6;
141.6; 166.2; 171.9. Mass spectrum, m/z (Irel, %): 270
[M+H]+ (100). Found, %: C 62.29; H 4.06; N 15.55.
C14H11N3O3. Calculated, %: C 62.45; H 4.12; N 15.61.
Synthesis of pyrazolo[4,3-b]pyridine-6-carbonitriles
5a–g (General method). Method I. Compounds 5a,c,e,g
were obtained by method I of the synthesis of compounds
4a–g from N-Boc-protected 1-alkyl- or 1-aryl-5-formyl-1H-
pyrazol-4-amines 1a,c,e,g (5 mmol) and cyanoacetic acid
(2c) (0.51 g, 6 mmol).
5-Oxo-1-phenyl-4,5-dihydro-1Н-pyrazolo[4,3-b]pyri-
dine-6-carbonitrile (5d). Yield 0.87 g (74%, method IІ),
0.85 g (72%, method IІІ), beige powder, mp 259–261°C.
IR spectrum, ν, cm–1: 3205 (N–H), 2230 (C≡N), 1662
1
Method IІ. Methyl cyanoacetate (2d) (0.5 ml, 6 mmol)
followed by pyrrolidine (0.5 ml, 6 mmol) was added to a
solution of N-Boc-protected 1-alkyl- or 1-aryl-5-formyl-1H-
(C=О). H NMR spectrum, δ, ppm (J, Hz): 7.45 (1H, t,
J = 7.2, H-4 Ph); 7.57 (2H, t, J = 7.6, H-3,5 Ph); 7.71 (2H,
d, J = 7.2, H-2,6 Ph); 7.88 (1H, s, H-3); 8.78 (1H, s, 7-CH);
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Chemistry of Heterocyclic Compounds 2019, 55(12), 1211–1216
12.90 (1H, br. s, NH). 13C NMR spectrum, δ, ppm: 104.8;
References
116.9; 122.8; 124.0; 127.2; 128.3; 130.3; 132.4; 135.2;
138.8; 159.3. Mass spectrum, m/z (Irel, %): 237 [M+H]+
(100). Found, %: C 65.97; H 3.45; N 23.56. C13H8N4O.
Calculated, %: C 66.10; H 3.41; N 23.72.
1. (a) Arora, N.; Billedeau, R. J.; Dewdney, N. J.; Gabriel, T.;
Goldstein, D. M.; O'Yang, C.; Soth, M. US Patent
20050197340. (b) Arora, N.; Billedeau, R. J.; Dewdney, N. J.;
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Volgin, A.; Gelovani, J. G.; Alauddin, M. M. Bioorg. Med.
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5-Oxo-1-(pyridin-2-yl)-4,5-dihydro-1Н-pyrazolo[4,3-b]-
pyridine-6-carbonitrile (5е). Yield 0.57 g (48%, method I),
0.83 g (70%, method IІ), pale-yellow powder, mp 286–
287°C. IR spectrum, ν, cm–1: 3247 (N–H), 2229 (C≡N),
1
1676 (C=O). H NMR spectrum, δ, ppm (J, Hz): 7.41 (1H,
t, J = 7.1, H-5 Ру); 7.89 (1H, d, J = 6.0, H-3 Ру); 8.04 (1H,
s, H-3); 8.06 (1H, t, J = 5.2, H-4 Ру); 8.56 (1Н, d, J = 5.2,
H-6 Ру); 9.34 (1H, s, 7-CH); 13.50 (1H, s, NH). 13C NMR
spectrum, δ, ppm: 105.0; 112.9; 116.7; 122.4; 123.4; 128.5;
132.7; 137.5; 140.1; 145.5; 152.2; 159.0. Mass spectrum,
m/z (Irel, %): 238 [M+H]+ (100). Found, %: C 60.55;
H 2.85; N 29.43. C12H7N5O. Calculated, %: C 60.76;
H 2.97; N 29.52.
3-Methoxy-1-methyl-5-oxo-4,5-dihydro-1Н-pyrazolo-
[4,3-b]pyridine-6-carbonitrile (5f). Yield 0.69 g (68%,
method IІ), light-beige powder, mp 252–254°C. IR spect-
rum, ν, cm–1: 3224 (N–H), 2224 (C≡N), 1658 (C=О).
1H NMR spectrum, δ, ppm: 3.82 (3H, s, NCH3); 3.92 (3H,
s, ОCH3); 8.73 (1H, s, 7-CH); 12.30 (1H, br. s, NH).
13C NMR spectrum, δ, ppm: 36.5; 57.2; 114.7; 117.1;
127.3; 134.4; 148.8; 152.6; 159.0. Mass spectrum, m/z
(Irel, %): 204 [M+H]+ (100). Found, %: C 52.84; H 4.01;
N 27.38. C9H8N4O2. Calculated, %: C 52.94; H 3.95;
N 27.44.
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Cordi, A. A. J. Med. Chem. 1996, 39, 197. (b) Shi, J.; Xiao, Z.;
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Bambal, R.; Chai, D.; Concha, N. O.; Darcy, M. G.; Dhanak, D.;
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Han, C.; Hoffmann, G. A.; Johnston, V. K.; Kaura, A. C.; Liu, N.;
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1-Methyl-5-oxo-3-phenyl-4,5-dihydro-1Н-pyrazolo-
[4,3-b]pyridine-6-carbonitrile (5g). Yield 0.61 g (49%,
method I), 0.76 g (61%, method IІ), white powder, mp 285–
288°C. IR spectrum, ν, cm–1: 3252 (N–H), 2230 (C≡N),
8. Yakovenko, G. G.; Lukianov, O. A.; Bol'but, A. V.; Vovk, M. V.
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1
1671 (C=O). H NMR spectrum, δ, ppm (J, Hz): 4.07 (3H,
s, NCH3); 7.38 (1H, t, J = 7.2, H-4 Ph); 7.47 (2H, t, J = 8.0,
H-3,5 Ph); 7.85–8.08 (2H, m, H-2,6 Ph); 8.85 (1H, s,
7-CH); 12.15 (1H, s, NH). 13C NMR spectrum, δ, ppm:
37.0; 116.9; 126.8; 127.1; 128.5; 129.2; 129.9; 131.3;
136.9; 155.1; 159.9; 167.7. Mass spectrum, m/z (Irel, %):
251 [M+H]+ (100). Found, %: C 67.41; H 4.09; N 22.30.
C14H10N4O. Calculated, %: C 67.19; H 4.03; N 22.39.
9. Watson, B. T.; Christiansen, G. E. Tetrahedron Lett. 1998, 39, 9839.
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Guillaumet, G. Tetrahedron Lett. 2006, 47, 8575.
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Kawabata, K.; Inoue, S.; Misumi, K.; Itoh, K.; Satoh, K. WO
Patent 2004101571.
1216