Synthesis of Substituted Aminopyrimidines as Novel Promising Tyrosine Kinase Inhibitors

Article abstract of DOI:10.1134/S1070428019090094

A procedure has been proposed for the synthesis of a series of substituted N-(1,3-thiazol-2-yl)-pyrimidin-2-amines and N-(pyrimidin-2-yl)thioureas by reactions of diethyl 2-(ethoxymethylidene)malonate and ethyl 2-(ethyoxymethylidene)-3-oxobutanoate with 1

Full text of DOI:10.1134/S1070428019090094

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2019, Vol. 55, No. 9, pp. 1322–1328. © Pleiades Publishing, Ltd., 2019.
Russian Text © The Author(s), 2019, published in Zhurnal Organicheskoi Khimii, 2019, Vol. 55, No. 9, pp. 1406–1414.
Synthesis of Substituted Aminopyrimidines
as Novel Promising Tyrosine Kinase Inhibitors
N. V. Stolpovskayaa,* A. A. Kruzhilina, A. V. Zorinaa, Kh. S. Shikhalieva, I. V. Ledenevaa,
E. A. Koshelevaa, and D. Yu. Vandysheva
a Voronezh State University, Voronezh, Russia
*e-mail: stolpovskaya@chem.vsu.ru
Received February 25, 2019; revised April 18, 2019; accepted April 22, 2019
Abstract—A procedure has been proposed for the synthesis of a series of substituted N-(1,3-thiazol-2-yl)-
pyrimidin-2-amines and N-(pyrimidin-2-yl)thioureas by reactions of diethyl 2-(ethoxymethylidene)malonate
and ethyl 2-(ethyoxymethylidene)-3-oxobutanoate with 1,3-thiazol-2-ylguanidines and amidinothiourea,
respectively. Preliminary screening has revealed high inhibitory activity of ethyl 2-(carbamothioylamino)-4-
methylpyrimidine-5-carboxylate and ethyl 2-(carbamothioylamino)-6-oxo-1,6-dihydropyrimidine-5-carbox-
ylate toward several protein kinases.
Keywords: pyrimidines, thiazoles, protein kinase inhibitors, EGFR tyrosine kinase, amidinothiourea.
DOI: 10.1134/S1070428019090094
Nowadays, design of drugs for the treatment of
oncological diseases is one of the most important
directions of the synthesis of new organic compounds.
In recent years, main advances in this field have been
related to targeted kinase inhibitors that exert a selec-
tive pathogenetic effect. There is a trend of using
low-molecular-weight organic compounds as kinase
inhibitors.
Among numerous methods of cyclization of guani-
dine derivatives to pyrimidines, reactions of guani-
dines with ethoxymethylidene derivarives of dicar-
bonyl compounds occupy an important place. In most
cases, these reactions follow a general scheme accord-
ing to which in the first stage the ethoxy group is re-
placed by amino group of guanidine. The second stage
is cyclization involving one carbonyl group and imino
group of intermediate imino enamine (Scheme 1). As
a result, pyrimidines with various substituents in posi-
tions 4, 5, and 6 are formed [3–6]. Apart from 2-(al-
koxymethylidene)-1,3-dicarbonyl compounds, their
2-(arylmethylidene) analogs possess a high synthetic
potential. Their reactions with acetamidine, benzami-
dine, guanidine, and N,N-dimethylguanidine with the
formation of 4,5,6-trisubstituted pyrimidines were
studied. Different conditions of these reactions, includ-
Aminopyrimidine fragment is a structural unit of
the currently used EGFR tyrosine kinase inhibitors
erlotinib and gefitinib [1, 2]; therefore, it seemed
reasonable to search for new EGFR tyrosine kinase
inhibitors among 2-aminopyrimidine derivatives.
Herein, we report the synthesis of some pyrimidin-2-
ylthioureas and the results of their preliminary screen-
ing for inhibitory activity against several tyrosine
kinases.
Scheme 1.
O
O
O
O
O
O
NH
+
EtO
EtO
OEt
EtO
HN
OEt
HN
R1
OEt
R1
NH2
R2
N
H
R2
N
R2
R1
1a, 1b
2a, 2b
3a–3c
4a–4c
1, R1 = Me (a), Et (b); 2, R2 = Me (a), H (b); 4, R1 = Me, R2 = H (a), R1 = R2 = Me (b), R1 = Et, R2 = H (c).
1322

SYNTHESIS OF SUBSTITUTED AMINOPYRIMIDINES
1323
Scheme 2.
O
N
R1
N
Ph
O
O
NH
7
R2O
Me
+
R1
NH2
5a–5d
O
Me
OR2
Me
OR2
O
Me
OH
Ph
TsOH, reflux
N
OR2
N
O
N
6a, 6b
R1
N
Ph
R1
N
H
Ph
R1
N
H
Ph
H
8
9a–9e
5, R1 = Me (a), Ph (b), NH2 (c), NMe2 (d); 6, R2 = Et (a), t-Bu (b); 9, R1 = Me, R2 = Et (a), R1 = Me, R2 = t-Bu (b),
R1 = Ph, R2 = Et (c), R1 = NH2, R2 = Et (d), R1 = NMe2, R2 = Et (e).
ing fairly mild (stirring at room temperature), were
given in different publications (Scheme 2). Similar
reactions were reported for derivatives of thiourea and
2-(ethoxymethylidene)malonic acid [10]. These reac-
tions afforded pyrimidine-2-thiones with various sub-
stituents in positions 4, 5, and 6. Here, the sulfur atom
is not involved, and the reaction occurs at the amidine
fragment (Scheme 3).
malononitrile (compounds 11, 13, and 20, respectively)
with a view to obtaining pyrimidine-containing thio-
ureas and evaluating their inhibitory activity against
some tyrosine kinases.
As expected, the reactions involved the amidine
fragment of 19. Presumably, as in reactions with some
guanidines [11], the first stage is substitution of the
ethoxy group in the 1,3-dicarbonyl component by
nucleophilic amino group of the guanidine fragment of
19, and next follows intramolecular nucleophilic
addition of the imino nitrogen atom to the electrophilic
The goal of the present work was to study reactions
of amidinothiourea 19 with ethoxymethylidene deriva-
tives of diethyl malonate, ethyl acetoacetate, and
Scheme 3.
R1
N
S
S
S
O
O
HN
HN
HN
R3
11, 12
R2
15, 16
R1
N
X
NH
CN
S
EtO
R1
+
Y
13
H2N
N
R2
11–14
H
R2
10
17
R1
N
R1
N
NH
O
S
O
+
14
OEt
HN
CN
R2
R2
18
18'
10, R1 = H, Alk, cycloalkyl, Ar; 11, X = Y = COOEt; 12, X = COOEt, Y = COR3; 13, X = Y = CN; 14, X = CN, Y = COOEt;
11, 15, R2 = H, Me, Et, R3 = OEt; 12, 16, R2 = H, R3 = Me, Ph; 17, 18, R2 = H, Me, Et.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 55 No. 9 2019

STOLPOVSKAYA et al.
1324
Scheme 4.
O
O
Me
OEt
OEt
Me
N
O
O
20
S
S
N
OEt
OEt
H2N
N
H
21
O
S
NH
Dioxane, DMF, reflux
11
HN
H2N
N
H
NH2
H2N
N
H
N
19
22
NH2
CN
13
S
N
H2N
N
N
H
23
Scheme 5.
Me
O
O
20
S
N
OEt
OEt
Ph
N
N
N
H
N
O
HN
Dioxane
reflux, 7 h
Xylene, reflux
5–6 h
O
S
Br
26
HN
27
19
+
NH2
Ph
Ph
N
N
H
24
25
11
S
Ph
N
H
N
carbon atom of the intermediate (Scheme 4). Similar
reactions were studied for thiazolylguanidines 25 and
29 which were prepared according to known proce-
dures [12]. When the reactants were heated in o-xylene
for 5–6 h, cyclization involving the amidine fragment
of 25 and 29 afforded 2-(1,3-thiazol-2-ylamino)-
pyrimidine-5-carboxylates 26, 27, 30, and 31
(Schemes 5, 6). It should be noted that the cyclization
in the second stage of the reactions of 25 and 29 with
ethyl 2-(ethoxymethylidene)-3-oxobutanoate (20) is
possible with participation of both ketone and ester
carbonyl groups. According to [10], substituted thio-
ureas 10 reacted with 2-(ethoxymethylidene)-3-oxo
esters 12 in ethanol in the presence of sodium ethoxide
to give pyrimidinones 16 as a result of cyclization at
the ester fragment. We found that the reaction of thio-
urea 19 with keto ester 20 in a dioxane–DMF mixture
involved the ketone carbonyl group, as followed from
the H NMR spectra of compounds 21, 26, and 31,
which contained signals typical of ethoxy group. This
result was consistent with the data of [11].
1
Ethyl 4-methyl-2-(4-phenyl-1,3-thiazol-2-ylamino)-
pyrimidine-5-carboxylate (26) and ethyl 6-oxo-2-(4-
phenyl-1,3-thiazol-2-ylamino)-1,6-dihydropyrimidine-
5-carboxylate (27) were also synthesized indepen-
dently, by reaction of thioureas 21 and 22 with
phenacyl bromide (24). The reactions were carried out
by heating the initial compounds in boiling dioxane for
1
5–6 h (Scheme 7). The H NMR spectra of 26 and 27
obtained by the two methods were identical. These
findings provide an additional support to the participa-
tion of the amidine fragment of 19 in the reactions with
ethoxymethylidene derivatives 11, 13, and 20.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 55 No. 9 2019

SYNTHESIS OF SUBSTITUTED AMINOPYRIMIDINES
1325
Scheme 6.
O
Me
O
O
EtO
20
11
S
S
N
OEt
Me
O
N
O
N
H
N
O
Xylene, reflux
5–6 h
Dioxane
reflux, 7 h
O
O
EtO
HN
S
30
19
+
Me
OEt
NH2
Me
N
N
EtO
Me
Cl
H
28
29
HN
OEt
N
O
N
H
31
N
Scheme 7.
Me
O
O
Me
PhC(O)CH2Br (24)
dioxane, reflux, 5–6 h
S
S
N
OEt
OEt
S
S
N
OEt
OEt
Ph
Ph
N
N
H2N
N
H
N
N
H
N
O
21
26
O
O
PhC(O)CH2Br (24)
dioxane, reflux, 5–6 h
HN
HN
H2N
N
H
N
N
H
N
22
27
maximal inhibitory concentrations IC50 were deter-
mined in duplicate (Table 1). Compound 31 showed no
inhibitory activity against the above listed tyrosine
kinases or its activity was insignificant. The highest
inhibitory effect was observed for thiourea 21 with
respect to EGFR [L858R] (IC50 = 1.52 μM).
Thioureas 21–22 and thiazolylamino derivatives 30
and 31 obtained therefrom were tested for inhibitory
activity against NPM1-ALK (anaplastic lymphoma
kinase), mutated forms of EGFR (epidermal growth
factor receptor) tyrosine kinase (EGFR[L858R], EGFR
T790M/L858R), and signal transducer and activator of
transcription kinases (Janus kinases JAK2, JAK3).
This panel of tyrosine protein kinases was selected
taking into account that many inhibitors of these
kinases contain an aminopyrimidine fragment [15–17].
Enzyme-linked immunosorbent assay (ELISA) was
performed in two steps: preliminary screening in
a single experiment, and validation of the results in
duplicate provided that the inhibition percentage in the
preliminary experiment was higher than 50%; the half
Thus, we were the first to reveal inhibitory activity
of some substituted pyrimidin-2-ylthioureas against
several tyrosine kinases. In the future, we plan to
optimize the structure of the synthesized pyrimidine
derivatives in order to extend the series of compounds
promising for use as protein kinase inhibitors, as well
as to obtain hybrid molecules exhibiting various
physiological activities, including anticoagulant
activity.
Table 1. Tyrosine kinase inhibitory activity of compounds 21, 22, and 31
Inhibition, %
Compound no.
NPM1-ALK
ALK
EGFR [L858R] [T790]
EGFR [L858R]
21
22
31
35
36
–
70
70
–
62
76
11
89
86
10
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 55 No. 9 2019

STOLPOVSKAYA et al.
succession with anti-phospho-Histone H3 antibodies
1326
EXPERIMENTAL
(0.3 ng/μL; Millipore, 04-746) and with specific anti-
bodies conjugated to enzyme label (peroxidase) (Anti-
rabbit IgG, HRP-linked Antibody, 1/5000; Cell
Signaling, 7074). After each incubation stage (60 min
at room temperature with continuous stirring), the
plates were washed thrice with PBS/Tween-20 to
remove unbound antibodies, and 100 μL of TMB sub-
strate (Sigma, T8768) was added, which was prepared
according to manufacturer’s manual.
The H and 13C NMR spectra were recorded at
30°C on a Bruker DRX 500 spectrometer (500 and
125 MHz, respectively) using DMSO-d6 as solvent and
tetramethylsilane as internal standard. HPLC/MS
analyses were performed with an Agilent Infinity 1260
liquid chromatograph coupled with an Agilent 6230
TOF mass-selective detector; Poroshell 120 EC-C18
column, 4.6 × 50 mm, grain size 2.7 μm; eluent
0.1% formic acid in acetonitrile (A)/0.1% formic acid
in water (B), gradient 0–100%: A, 3.5 min, 50%; A,
1.5 min, 50–100%; B, 3.5 min, 50%; B, 1.5 min, 50–
0%; flow rate 0.4 mL/min; column temperature 28°C;
electrospray ionization, positive ion detection, capil-
lary voltage –3.5 kV; fragmentor voltage +191 V;
OctRF voltage +66 V. The IR spectra were recorded on
a Bruker Vertex-70 spectrometer with Fourier trans-
form. The melting points were measured with a Stuart
SMP30 melting point apparatus. The progress of reac-
tions and the purity of the initial reactants and reaction
products were monitored by TLC on Silufol UV-254
plates using chloroform, methanol, or their mixtures at
different ratios as eluents; spots were visualized under
UV light and by treatment with iodine vapor.
1
Before measuring the optical density, the reaction
was terminated with 0.5 M H2SO4. The optical density
was measured at λ 450 nm with a Tecan Safire micro-
plate reader. The data were processed and imported
into HTSCalc.
Ethyl 2-(carbamothioylamino)-4-methylpyrimi-
dine-5-carboxylate (21). A mixture of 0.35 g
(3 mmol) of thiourea 19, 0.59 g (3 mmol) of ester 20,
10 mL of dioxane, and 2 mL of DMF was refluxed for
5–6 h. The mixture was poured into 100 mL of water,
and the precipitate was filtered off. Acetone was added
to the product, and the mixture was heated to the
boiling point and filtered while hot. After cooling, the
precipitate was filtered off and dried. Yield 0.53 g
(74%), white crystals, mp 232–234°C. IR spectrum, ν,
cm–1: 1716 (C=O), 1568 (pyrim.), 1519 (δNH2), 1280
(NCSN), 1228 (C–O), 1012 (pyrim.), 798 (pyrim.),
Amidinothiourea 19 (Alinda Chemical) and ethyl
2-chloro-3-oxobutanoate (28) (Sigma–Aldrich) were
commercial products. Ethoxymethylidene derivatives
11, 13, 20, and 30 were synthesized according to the
procedure described in [14].
1
576 (NCSN). H NMR spectrum, δ, ppm: 1.33 t (3H,
CH2CH3, J = 7.1 Hz), 2.69 s (3H, 4-CH3), 4.30 q (2H,
OCH2, J = 7.1 Hz), 8.95 s (1H, 6-H), 9.32 br.s (1H,
NH), 10.23 br.s (1H, NH), 10.88 br.s (1H, NH).
13C NMR spectrum, δC, ppm: 13.93 (CH2CH3), 24.02
(4-CH3), 60.95 (OCH2), 116.99 (C5), 157.66 (C6),
159.97 (C2), 163.82 (C4), 169.79 (C=O), 180.82 (C=S).
Found: m/z 241.0759 [M + H]+. C9H12N4O2S. Calculat-
ed: [M + H] 241.0754.
The kinase inhibitory activity was evaluated using
polypropylene microplates (Costar, 3363) in a reaction
buffer consisting of 20 mM HEPES, pH 7.5,
15 mM MgCl2, 2 mM DTT, 0.2 mM Na3VO4, and
0.005% Triton X-100 for 60 min at 30°C under vigor-
ous stirring. The final concentrations were 0.05 μg/mL
kinase, 5 nM substrat Histone H3 (1–21) biotinylated
substrate (Anaspec, 61702), 150 μM ATP (Sigma,
A6419), 10 μM compound to be tested, 5% DMSO.
The enzymatic reaction was terminated with a buffer
containing 20 mM HEPES (Sigma, H4034), pH 7.5,
and 150 mM EDTA (Sigma, E5513). To detect the
phosphorylated substrate, the reaction mixtures were
transferred to preliminarily prepared microplates
(Nunc, 468667) covered with NeutrAvidin (1 ng per
well; Pierce, 31000) and treated with bovine serum
albumin (BSA) to block nonspecific binding sites. The
microplates were incubated for 1 h at room tempera-
ture, washed three times with phosphate-buffered
saline (PBS) containing Tween-20, and incubated in
Ethyl 2-(carbamothioylamino)-6-oxo-1,6-dihy-
dropyrimidine-5-carboxylate (22). A mixture of
0.35 g (3 mmol) of thiourea 19, 0.65 g (3 mmol) of
diester 11, 10 mL of dioxane, and 2 mL of DMF was
refluxed for 5–6 h. The mixture was poured into
100 mL of water, and the precipitate was filtered off.
Acetone was added to the product, and the mixture was
heated to the boiling point and filtered while hot. After
cooling, the precipitate was filtered off and dried. Yield
0.46 g (64%), white crystals, mp 254–256°C. IR spec-
trum, ν, cm–1: 1699 (C=O), 1633 (pyrim.), 1498
(pyrim.), 1244 (COEt), 1186 (NHCSNH), 1037
1
(pyrim.), 808 (pyrim.). H NMR spectrum, δ, ppm:
1.25 t (3H, CH2CH3, J = 7.1 Hz), 4.20 q (2H, OCH2,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 55 No. 9 2019

SYNTHESIS OF SUBSTITUTED AMINOPYRIMIDINES
1327
J = 7.1 Hz), 8.45 s (1H, 4-H), 9.55 br.s (1H, NH),
9.90 br.s (1H, NH), 11.80 br.s (1H, NH), 12.80 br.s
(1H, NH). 13C NMR spectrum, δC, ppm: 14.05
(CH2CH3), 60.07 (OCH2), 109.54 (C5), 152.93 (C4),
155.36 (C6), 158.77 (C2), 162.94 (5-C=O), 180.09
(C=S). Found: m/z 243.0552 [M + H]+. C8H10N4O3S.
Calculated: M + H 243.0547.
164.91 (C2′), 170.05 (C=O). Found: m/z 341.1071
[M + H]+. C17H16N4O2S. Calculated: M + H 341.1067.
Ethyl 6-oxo-2-(4-phenyl-1,3-thiazol-2-ylamino)-
1,6-dihydropyrimidine-5-carboxylate (27). A mix-
ture of 0.65 g (3 mmol) of guanidine 25 and 0.65 g
(3 mmol) of diester 11 in 15 mL of xylene was
refluxed for 5–6 h. The precipitate was filtered off and
recrystallized from toluene. Yield 0.72 g (70%), white
crystals, mp > 300°C. IR spectrum, ν, cm–1: 1689
(C6=O), 1654 (C=O, ester), 1633 (pyrim.), 1566
(C=Carom), 1517 (pyrim.), 1423 (arom.), 1280
(COOEt), 1186 (NHCSNH), 1012 (pyrim.), 719
N-(4-Amino-5-cyanopyrimidin-2-yl)thiourea
(23). A mixture of 0.35 g (3 mmol) of thiourea 19,
0.37 g (3 mmol) of dinitrile 13, 10 mL of dioxane, and
2 mL of DMF was refluxed for 5–6 h. The mixture was
poured into 100 mL of water, and the precipitate was
filtered off. Acetone was added to the product, and the
mixture was heated to the boiling point and filtered
while hot. After cooling, the precipitate was filtered off
and dried. Yield 0.34 g (58%), yellow crystals,
mp 290–292°C. IR spectrum, ν, cm–1: 2229 (CN),
1573 (pyrim.), 1521 (δNH2), 1280 (NHCSN), 1014
1
(pyrim.). H NMR spectrum, δ, ppm: 1.27 t (3H,
CH2CH3, J = 7.1 Hz), 4.22 m (2H, OCH2), 7.36 t (1H,
Harom, J = 7.4 Hz), 7.45 t (2H, Harom, J = 7.7 Hz), 7.61 s
(1H, 5′-H), 7.89 d (2H, Harom, J = 7.7 Hz), 8.50 s (1H,
4-H), 12.00 br.s (2H, NH). Found: m/z 343.0854
[M + H]+. C16H14N4O3S. Calculated: M + H 343.0860.
1
(pyrim.), 792 (pyrim.), 605 (NHCSNH). H NMR
Ethyl 2-(carbamimidoylamino)-4-methyl-1,3-
thiazole-5-carboxylate (29) was synthesized accord-
ing to the procedure described in [12]. Yield 60%,
spectrum, δ, ppm: 7.95 br.s (2H, NH2), 8.49 s (1H,
6-H), 9.25 br.s (1H, NH), 10.20 br.s (1H, NH),
12.85 br.s (1H, NH). 13C NMR spectrum, δC, ppm:
115.50 (CN), 155.40 (C5), 157.74 (C6), 161.98 (C4),
162.50 (C2), 180.70 (C=S). Found: m/z 195.0451
[M + H]+. C6H6N6S. Calculated: M + H 195.0448.
1
mp 271–273°C. H NMR spectrum, δ, ppm: 1.22 t
(3H, CH2CH3, J = 7.1 Hz), 2.46 s (3H, 4-CH3), 4.17 m
(2H, OCH2), 7.20 br.s (4H, NH, NH2). Found:
m/z 229.0758 [M + H]+. C8H12N4O2S. Calculated:
M + H 229.0754.
N-(4-Phenyl-1,3-thiazol-2-yl)guanidine (25) was
synthesized according to known procedure [12]. Yield
88%, mp 225–227°C. H NMR spectrum, δ, ppm:
Ethyl 2-[(5-ethoxycarbonyl-4-methyl-1,3-thiazol-
2-yl)amino]-4-methylpyrimidine-5-carboxylate (30).
A mixture of 0.68 g (3 mmol) of guanidine 29 and
0.56 g (3 mmol) of ester 20 in 15 mL of xylene was
refluxed for 5–6 h. The precipitate was filtered off and
recrystallized from toluene. Yield 0.68 g. (65%), white
crystals, mp 233–235°C. IR spectrum, ν, cm–1: 1704
(C=O), 1568 (pyrim.), 1519 (δNH2), 1440 (arom.),
1280 (NCSN), 1228 (COEt), 1012 (pyrim.), 798
1
6.90 br.s (4H, NH), 7.15 s (1H, 5-H), 7.27 t (1H, Harom
,
J = 7.3 Hz), 7.38 t (2H, Harom, J = 7.7 Hz), 7.83 d (2H,
Harom, J = 7.2 Hz). Found: m/z 219.0703 [M + H]+.
C10H10N4S. Calculated: M + H 219.0699.
Ethyl 4-methyl-2-(4-phenyl-1,3-thiazol-2-yl-
amino)pyrimidine-5-carboxylate (26). A mixture of
0.65 g (3 mmol) of 25 and 0.56 g (3 mmol) of 20 in
15 mL of xylene was refluxed for 5–6 h. The precip-
itate was filtered off and recrystallized from toluene.
Yield 0.76 g (75%), white crystals, mp 266–267°C. IR
spectrum, ν, cm–1: 1716 (C=O), 1591 (C=Carom), 1568
(pyrim.), 1519 (δNH2), 1440 (arom.), 1280 (NCSN),
1228 (COEt), 1012 (pyrim.), 798 (pyrim.), 576
1
(pyrim.), 576 (NCSN). H NMR spectrum, δ, ppm:
1.27–1.36 m (6H, CH2CH3), 2.52 s (3H, 4′-CH3),
2.73 s (3H, 4-CH3), 4.23–4.35 m (4H, OCH2), 9.00 s
13
(1H, 6-H), 12.40 br.s (1H, NH). C NMR spectrum,
δC, ppm: 14.50 and 14.73 (CH2CH3), 17.48 (CH3),
60.73 and 61.33 (OCH2), 115.12 (C5′), 116.94 (C5),
156.88 (C2′), 157.73 (C4), 160.55 (C4′), 161.39 (C6),
162.80 (C2), 164.74 and 170.18 (C=O). Found:
m/z 351.1117 [M + H]+. C15H18N4O4S. Calculated:
M + H 351.1122.
1
(NCSN). H NMR spectrum, δ, ppm: 1.34 t (3H,
CH2CH3, J = 6.9 Hz), 2.75 s (3H, 4-CH3), 4.32 m (2H,
OCH2), 7.32 t (1H, Harom, J = 7.1 Hz), 7.43 t (2H,
Harom, J = 7.5 Hz), 7.60 s (1H, 5′-H), 7.93 d (2H, Harom,
J = 7.6 Hz), 8.97 s (1H, 6-H), 12.20 s (1H, NH).
13C NMR spectrum, δC, ppm: 14.55 (CH2CH3), 24.21
(4-CH3), 61.18 (OCH2), 108.61 (C5), 116.23 (C5′),
126.36 (Co), 128.10 (Cp), 129.05 (Cm), 135.26 (Ci),
150.07 (C4′), 158.17 (C4), 159.53 (C6), 160.65 (C2),
Ethyl 2-[(5-ethoxycarbonyl-4-methyl-1,3-thiazol-
2-yl)amino]-6-oxo-1,6-dihydropyrimidine-5-carbox-
ylate (31). A mixture of 0.68 g (3 mmol) of guanidine
29 and 0.65 g (3 mmol) of diester 11 in 15 mL of
xylene was refluxed for 5–6 h. The precipitate was
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 55 No. 9 2019

STOLPOVSKAYA et al.
1328
7. Cho, H., Shima, K., Hayashimatsu, M., Ohnaka, Y.,
Mizuno, A., and Takeuchi, Y., J. Org. Chem., 1985,
vol. 50, p. 4227. doi 10.1021/jo00222a009
8. Weis, A.L. and Frolow, F., J. Chem. Soc., Perkin
Trans. 1, 1986, p. 83. doi 10.1039/p19860000083
9. Pryadeina, M.V., Burgart, Yu.V., Kodess, M.I., Salo-
utin, V.I., and Chupakhin, O.N., Russ. Chem. Bull., Int.
Ed., 2004, vol. 53, p. 1261. doi 10.1023/
b:rucb.0000042284.03940.41
filtered off and recrystallized from toluene. Yield
0.63 g (60%), white crystals, mp 292–294°C. IR spec-
trum, ν, cm–1: 1703 (C6=O), 1666 (C=O, ester), 1523
(pyrim.), 1365, 1263 (COOEt), 1095 (pyrim.), 605
(pyrim.). 1H NMR spectrum, δ, ppm: 1.20–1.30 m (6H,
CH2CH3), 2.51 s (3H, 4′-CH3), 4.16–4.29 m (4H,
OCH2), 8.52 s (1H, 4-H), 12.20 br.s (2H, NH). Found:
m/z 353.0918 [M + H]+. C14H16N4O5S. Calculated:
M + H 353.0915.
10. Abdel Megid, M., Elmahdy, K.M., and Rashad, A.E.,
Global J. Sci. Front. Res., B: Chem., 2013, vol. 13, p. 7.
FUNDING
11. Kryl’skii, D.V., Shikhaliev, Kh.S., Kovygin, Yu.A., and
Potapov, A.Yu., Geterotsiklicheskie sistemy na osnove
proizvodnykh guanidina i ego strukturnykh analogov
(Heterocyclic Systems Based on Guanidine Derivatives
and Structural Analogs), Voronezh: Voronezh. Gos.
Univ., 2006, p. 71.
This study was performed under financial support
by the Russian Science Foundation (project no. 18-74-
10097).
CONFLICT OF INTERESTS
12. Beyer, H. and Hantschel, H., Chem. Ber., 1962, vol. 95,
p. 893. doi 10.1002/cber.19620950413
The authors declare the absence of conflict of
interests.
13. Han, C., Wan, L., Ji, H., Ding, K., Huang, Z., Lai, Y.,
Peng, S., and Zhang, Y., Eur. J. Med. Chem., 2014,
vol. 77, p. 75. doi 10.1016/j.ejmech.2014.02.032
14. Mezheritskii, V.V., Olekhnovich, E.P., Luk’yanov, S.M.,
and Dorofeenko, G.N., Ortoefiry v organicheskom
sinteze (Ortho Esters in Organic Synthesis), Rostov:
Rostov. Univ., 1976, p. 176.
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