Synthesis and biological activity of 1-alkyl(heteryl)-5-oxopyrrolidine-3-carboxylic acids

Full text of DOI:10.1134/S1070363216120203

ISSN 1070-3632, Russian Journal of General Chemistry, 2016, Vol. 86, No. 12, pp. 2693–2695. © Pleiades Publishing, Ltd., 2016.
Original Russian Text © V.L. Gein, T.A. Silina, A.A. Cherepanov, A.P. Shishkin, B.Ya. Syropyatov, E.V. Voronina, L.I. Varkentin, 2016, published in Zhurnal
Obshchei Khimii, 2016, Vol. 86, No. 12, pp. 2061–2063.
LETTERS
TO THE EDITOR
Synthesis and Biological Activity
of 1-Alkyl(heteryl)-5-oxopyrrolidine-3-carboxylic Acids
V. L. Gein*, T. A. Silina, A. A. Cherepanov, A. P. Shishkin,
B. Ya. Syropyatov, E. V. Voronina, and L. I. Varkentin
Perm State Pharmaceutical Academy, Ministry of Healthcare of the Russian Federation,
ul. Polevaya 2, Perm, 614990 Russia
*e-mail: geinvl48@mail.ru
Received July 14, 2016
Keywords: 2-methylenebutanedioic (itaconic) acid, 1-alkyl(heteryl)-5-oxo-pyrrolidine-3-carboxylic acids,
antimicrobial activity, anticoagulant activity
DOI: 10.1134/S1070363216120203
Biological activity of functional derivatives of
pyrrolidine depends essentially on the degree of
substitution of the heteroring and the nature of the
substituents, in particular at the heteroatom. Substituted
5-oxopyrrolidinecarboxylic acids derivatives are
promising compounds due to their availability and
wide spectrum of biological activity [1–6]. In this
regard, the synthesis of new derivatives of 5-
oxopyrrolidine-3-carboxylic acid as well as studying
their biological activity is of special interest.
Apparently in the first stage, the addition of the
amine to the double bond took place to form an
intermediate A, which then underwent cyclization to
provide the target compounds 1–6 (Scheme 1).
The resulting compounds 1–6 were colorless
crystalline substances, soluble in polar organic sol-
vents. Their structure and composition were confirmed
by IR , NMR, and mass spectra, and elemental analysis
data.
The IR spectra of compounds 1–6 contained the
absorption bands of stretching vibrations of carboxyl
OH (3150–3050 cm–1) and C=O groups (1750–
1730 cm–1) as well as those pyrrolidin-5-one fragment
1-Alkyl(heteryl)-5-oxopyrrolidine-3-carboxylic acids
were prepared by the method described previously in
[1–5, 7]. Heating a mixture of aliphatic amine with an
equimolar amount of itaconic acid without solvent
until water liberation ceased afforded 1-alkyl-5-
oxopyrrolidine-3-carboxylic acids 1–6. In the case of
heterocyclic amines acetic acid was used as a catalyst.
1-Heteryl-5-oxopyrrolidine-3-carboxylic acids 5 and 6
were isolated in good yields.
1
(1720–1688 cm–1). In the H NMR spectra of com-
pounds 1–6 there were the signals of oxopyrrolidine
moiety and carboxy group (10.05–12.58 ppm). The
peaks of molecular and fragment ions in the mass
spectra of compounds 1, 3–6 also confirmed the
structure of compounds obtained.
Scheme 1.
O
O
O
HO
OH
HO
H2NR
OH
HO
O
_H2O
O
N
R
HN
R
O
CH2
1_6
A
R = (CH2)7CH3 (1), CH2(CH2)14CH3 (2), cyclohexyl (3), i-Bu (4), 3-pyridyl (5), 2-benzothiazolyl (6).
2693

2694
GEIN et al.
1-Hexadecyl-5-oxopyrrolidine-3-carboxylic acid
Anticoagulant activity of 1-substituted 5-oxopyrrolidine-3-
carboxylic acids 1–6
(2). Yield 56%, mp 79.5–80.5°С. IR spectrum, ν, cm–1:
1
1705 (C=O), 3120 (СООН), 1730 (COOH). H NMR
Clotting time, s
Change in blood
spectrum, δ, ppm: 10.13 s (1Н, СООН), 3.49 m (2Н,
C2H), 3.16 m (1H, C3H), 2.51 m (2Н, С4Н), 0.86 t (3Н,
СН3, J = 3.0 Hz), 1.24 m [30Н, (СН2)15]. Found, %: С
71.25; Н 11.01; N 3.84. C21H39NO3. Calculated, %: С
71.34; Н 11.12; N 3.96.
Compound
coagulation, %
control
experiment
1
37.90±3.47 37.70±1.50
27.01±1.13 27.20±1.51
38.10±2.58 43.20±2.89
64.30±1.79 83.00±3.39
0.5
–0.4
2
4
6
–13.4
–29.1
–22.4
15.2
1-Cyclohexyl-5-oxopyrrolidine-3-carboxylic (3).
Yield 52%, mp 190–192°С. IR spectrum, ν, cm–1:
1
1688 (C=O), 3150 (СООН), 1710 (COOH). H NMR
Heparin
29.9±0.48
36.6±1.82
24.5±0.94
spectrum, δ, ppm: 11.07 s (1Н, СООН), 4.10 m (2Н,
C2H), 3.25 m (1H, C3H), 2.60 m (11Н, cyclohexyl),
2.54 m (2Н, С4Н). Mass spectrum, m/z (Irel, %): 225
(35) [М]+, 196 (4), 182 (68), 166 (7), 144 (100), 127
(7), 115 (27), 84 (15), 68 (14), 55 (22). Found, %: С
62.58; Н 8.14; N 6.59. С11Н17NO3. Calculated, %: С
62.54; Н 8.11; N 6.63.
Etamsylate 28.9±1.11
Taking into account the fact that this class of
compounds has not been studied in detail for the
presence of any kind of biological activity, we carried
preliminary testing pharmacological activity of the
synthesized compounds.
1-Isobutyl-5-oxopyrrolidine-3-carboxylic acid (4).
Yield 44%, mp 77–78°С. IR spectrum, ν, cm–1: 1720
(C=O), 3100 (СООН), 1710 (COOH). 1H NMR
spectrum, δ, ppm: 10.05 s (1Н, СООН), 3.57 m (2Н,
C2H), 3.17 m (1H, C3H), 3.05 m [1H, (CH3)2CHCH2],
2.52 d and 2.43 d [2H, (CH3)2CHCH2, J = 4.0 Hz],
2.48 m (2Н, С4Н), 0.83 d and 0.81 d [6H, (CH3)
2CHCH2, J = 4.0 Hz]. Mass spectrum, m/z (Irel, %): 199
(18) [М]+, 184 (16), 156 (100), 144 (6), 127 (50), 115
(4), 96 (12), 84 (9), 68 (22), 42 (24). Found, %: С
58.29; Н 8.15; N 7.48. С9Н15NO3. Calculated, %: С
58.36; Н 8.16; N 7.56.
Effects on blood coagulation system were studied
in vitro (see the table). According to the data obtained
1-alkyl(heteryl)-5-oxopyrrolidine-3-carboxylic acids 4
and 6 show the direct anticoagulant action since they
lengthen the time of citrated blood clotting, other
compounds exhibit no pronounced effect on blood
coagulation process.
Antibacterial activity of compounds 1–6 was deter-
mined with respect to the test cultures Staphylococcus
aureus ATCC 6538-P and Escherichia coli ATCC
25922. According to the results, the compounds do not
exhibit antibacterial activity.
General procedure for the synthesis of 1-heteryl-
5-oxopyrrolidine-3-carboxylic acids 5 and 6. A
mixture of 0.01 mol of 2-methylenebutanedioic acid,
0.01 mol of heterylamine and 1 mL of glacial acetic
acid was heated at 170°C for 1 h until water liberation
ceased. After cooling the reaction mixture was treated
with ethanol. The precipitate was filtered off, dried,
and recrystallized from ethanol.
General procedure for the synthesis of 1-alkyl-5-
oxopyrrolidine-3-carboxylic acids 1-4. A mixture of
0.01 mol of 2-methylenebutanedioic acid and 0.01 mol
of an aliphatic amine was heated at 170°C until water
liberation ceased. After cooling, the reaction mixture
was treated with ethanol. The precipitate was filtered
off, dried, and recrystallized from ethanol.
5-Oxo-1-(pyridin-3-yl)pyrrolidine-3-carboxylic acid
1-Octyl-5-oxopyrrolidine-3-carboxylic acid (1).
Yield 45%, mp 40–42°С. IR spectrum, ν, cm–1: 1700
(С=О), 3100 (СООН), 1740 (СOOH). 1H NMR
spectrum, δ, ppm: 11.14 s (1Н, СООН), 3.61 m (2Н,
С2H), 3.20 m (1Н, С3Н), 2.54 m (2Н, С4Н), 1.4 m
[14H, (CH2)7], 0.91 t (3Н, СН3, J = 3.0 Hz). Mass
spectrum, m/z (Irel, %): 255 (15) [М]+, 224 (7), 196
(22), 184 (20), 156 (100), 127 (42), 96 (12), 68 (18),
42 (16). Found, %: С 64.53; Н 10.00; N 5.62.
C13H23NO3. Calculated, %: C 64.70; H 9.61; N 5.80.
(5). Yield 68%, mp 180–183°С. IR spectrum, ν, cm–1:
1
1710 (C=O), 3050 (СООН), 1700 (COOH). H NMR
spectrum, δ, ppm: 10.26 s (1Н, СООН), 7.32 d and
7.72 d (4Н, pyridyl, J = 5.0 Hz), 4.1 m (2Н, C2H), 3.29
m (1H, C3H), 2.76 m (2Н, С4Н). Mass spectrum, m/z
(Irel, %): 220 (30) [М]+, 189 (2), 178 (2), 161 (5), 146
(2), 133 (7), 107 (100), 92 (5), 78 (12), 51 (6). Found,
%: С 58.35; Н 4.91; N 13.62. С10Н10N2O3. Calculated,
%: С 58.25; Н 4.89; N 13.59.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 86 No. 12 2016

SYNTHESIS AND BIOLOGICAL ACTIVITY
2695
1-(Benzo[d]thiazol-2-yl)-5-oxopyrrolidine-3-carbo-
xylic acid (6). Yield 83%, mp 225–227°С. IR spec-
trum, ν, cm–1: 1740 (C=O), 3050 (СООН), 1720
strain. Chloramine B and furacilin were used as
comparative compounds.
Anticoagulant activity was examined with use of a
Minilab 701 coagulometer. Citrated (3.8%) blood (9 : 1)
was used. Effect of the test compounds on blood
clotting was studied in the same concentration of
1.0 mg/mL using a solution of heparin (1.0 U/mL) as a
reference for anticoagulant activity or etamsylate
solution (1.0 mg/mL) as a reference for haemostatic
activity.
1
(COOH). H NMR spectrum, δ, ppm: 12.58 s (1Н,
СООН), 7.32 d, 7.44 d, 7.79 d and 7.98 d (4Н,
benzothiazolyl, J = 1.0 Hz), 4.32 m (2Н, C2H), 3.54 m
(1H, C3H), 2.48 m (2Н, С4Н). Mass spectrum, m/z (Irel,
%): 276 (78) [М]+, 245 (8), 217 (35), 189 (42), 163
(100), 150 (9), 136 (18), 108 (12), 69 (6), 55 (5).
Found, %: С 55.02; H 3.88; N 10.71; S 12.19.
C12H10N2O3S. Calculated, %: С 54.95; H 3.84; N 10.68;
S 12.23.
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analyzed by gas chromatography-mass spectrometry in
the form of methyl esters obtained by reacting the
corresponding acids with iodomethane. Elemental
analysis was performed on a Perkin Elmer 2400
analyzer. Melting points were measured on a PTP (M)
instrument.
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RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 86 No. 12 2016