Synthesis and Quantification of 2-(Diethylamino)-N-(2-methylphenyl)acetamide Nitrate

Article abstract of DOI:10.1134/S1070428019100117

A procedure for the synthesis of 2-(diethylamino)-N-(2-methylphenyl)acetamide nitrate (monomecaine) exhibiting a pronounced antiarrhythmic activity has been optimized. A procedure for its identification and quality control of the drug substance by HPLC ha

Full text of DOI:10.1134/S1070428019100117

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2019, Vol. 55, No. 10, pp. 1532–1538. © Pleiades Publishing, Ltd., 2019.
Russian Text © The Author(s), 2019, published in Zhurnal Organicheskoi Khimii, 2019, Vol. 55, No. 10, pp. 1583–1591.
Synthesis and Quantification of 2-(Diethylamino)-
N-(2-methylphenyl)acetamide Nitrate
L. A. Chekryshkinaa, A. M. Deminb,* A. A. Tumashovb, c, E. A. Babikovad, and N. V. Slepovaa
a Perms State Pharmaceutical Academy, Ministry of Health of the Russian Federation, Perm, Russia
b Postovskii Institute of Organic Synthesis, Ural Branch, Russian Academy of Sciences, Yekaterinburg, Russia
*e-mail: demin@ios.uran.ru
c Institute of Natural Sciences and Mathematics, Ural Federal University, Yekaterinburg, Russia
d Pharmaceutical Branch, Sverdlovsk Regional Medical College, Yekaterinburg, Russia
Received April 15, 2019; revised August 14, 2019; accepted August 15, 2019
Abstract—A procedure for the synthesis of 2-(diethylamino)-N-(2-methylphenyl)acetamide nitrate
(monomecaine) exhibiting a pronounced antiarrhythmic activity has been optimized. A procedure for its
identification and quality control of the drug substance by HPLC has been developed, and the limit of detection
of o-toluidine impurity therein has been estimated at 0.02%. Procedures for HLPC and extraction–titration
quantification of monomekain in the drug substance have been proposed and validated. The obtained relative
standard deviation (RSD) indicates good specificity, linearity, and precision of the developed procedures.
Keywords: monomecaine, HPLC, extraction titration, validation.
DOI: 10.1134/S1070428019100117
Cardiovascular diseases constitute one of the
leading causes of death over the world. According to
statistical data, each thirteenth citizen of the Russian
Federation suffers from one or another cardiac or
vascular pathology, and the mortality caused by cardio-
vascular diseases amounts to 53% of all deaths in
Russia. These diseases are generally accompanied by
arrhythmia, i.e., heart rhythm rate disorders which
could aggravate the underlying disease. Although the
series of available antiarrhythmic drugs is sufficiently
large, many of them cause undesirable side effects;
therefore, development and introduction into medical
practice of new antiarrhythmic agents constitute an im-
portant problem [1, 2]. Various compounds are being
studied for this purpose. The most widely used
anesthetics and antiarrhythmics are represented by
derivatives of N-phenylacetamide and aromatic car-
boxylic acid amides [3–11], lidocaine being the most
known [12]. Of particular interest are N,N-diethyl-
aminoacetic acid o-toluidide [2-(diethylamino)-N-(2-
methylphenyl)acetamide] salts with inorganic acids.
A procedure for the preparation of 2-(diethylamino)-
N-(2-methylphenyl)acetamide hydrochloride was
described in [9, 13]. Later on, 2-(diethylamino)-N-(2-
methylphenyl)acetamide salts with HBr, HI, and
H3PO4 [9] and N-(2-methylphenyl)-2-(morpholin-4-yl)-
acetamide salt with salicylic acid [10] were synthe-
sized. Their antiarrhythmic activity was evaluated, and
prospects of further studies aimed at introducing them
into medical practice have been demonstrated. 2-(Di-
ethylamino)-N-(2-methylphenyl)acetamide nitrate arbi-
trarily called monomecaine is promising as a potential
antiarrhythmic drug. It exhibited the highest activity
among the above listed 2-(diethylamino)-N-(2-methyl-
phenyl)-acetamide salts [9–11] (Table 1), and it can
therefore be regarded as a potential antiarrhythmic.
Preclinical trials of a chemical compound require
its standardization which includes development of
a procedure for its preparation ensuring high purity of
the product, efficient methods for quality evaluation of
both drug substance and dosage forms, and procedures
for its determination in biological media. No quality
control methods acceptable for the development of
a state pharmacopeial specification for a dosage form
have been reported. Therefore, the goal of the present
work was to optimize the procedure for the synthesis
of monomecaine and develop procedures for its
identification and purity evaluation by HPLC and for
1532

SYNTHESIS AND QUANTIFICATION OF 2-(DIETHYLAMINO)-
1533
Table 1. Antiarrhythmic activity of 2-(diethylamino)-N-(2-methylphenyl)acetamide salts and lidocaine
Antiarrhythmic index
Compound
LD50, mg/kg
65.0 (56–75)
46.0 (33–60)
81.5 (71–84)
60.0 (48–74)
ED50, mg/kg
1.4 (1.2–1.7)
1.4 (1.1–1.7)
17.8 (15–21)
35.5 (29–42)
LD50/ED50
2-(Diethylamino)-N-(2-methylphenyl)acetamide nitrate
46.4
(monomecaine)
2-(Diethylamino)-N-(2-methylphenyl)acetamide
32.8
04.6
01.7
hydrochloride
2-(Diethylamino)-N-(2-methylphenyl)acetamide
hydrobromide
2-(Diethylamino)-N-(2-methylphenyl)acetamide
hydroiodide
2-(Diethylamino)-N-(2-methylphenyl)acetamide
dihydrogen phosphate
44.7 (37–59)
39.5 (34–45)
20.5 (18–24)
7.7 (6–9)
02.2
05.1
Lidocaine
quantification in laboratory batches of the drug sub-
stance by HPLC and extraction–titration method.
concentrated nitric acid at 0°C to obtain monomecaine
(6). The structure and purity of the isolated compounds
1
were confirmed by elemental analyses and H NMR,
The key precursor to monomecaine, 2-(diethyl-
amino)-N-(2-methylphenyl)acetamide, was previously
synthesized by acylation of o-toluidine with chloro-
acetyl chloride in glacial acetic acid or acetone accord-
ing to a two-step procedure [13]. We improved this
method by carrying out the reaction in one step in
acetone or benzene by adding 1, 1.5, or 2 equiv of
chloroacetyl chloride (2) to o-toluidine (1) (Scheme 1).
The best yield was obtained in benzene (dried over
metallic sodium) using 1.5 equiv of 2. The acylation
was complete almost instantaneously; a white solid
precipitated immediately after addition of chloroacetyl
chloride to a solution of o-toluidine 1, and no initial
amine was detected in the reaction mixture. The subse-
quent reaction of anilide 3 with diethylamine (4) gave
2-(diethylamino)-N-(2-methylphenyl)acetamide (5)
which was dissolved in ethanol and treated with
HPLC, and TLC data.
In keeping with modern requirements, chromato-
graphic methods are important for drug quality control
at different stages of analysis of drug substance and
dosage forms [14–16]. We propose HPLC as a method
for quality control of monomecaine to be included in
a pharmacopeial article project. Taking into account
that monomecaine and possible related impurities
[o-toluidine (1) and 2-chloro-N-(2-methylphenyl)acet-
amide (3)] are polar compounds, the use of reversed-
phase HPLC seemed to be preferred. Initially, HPLC
conditions for the determination of monomecaine and
compounds 1 and 3 were found (Fig. 1). It was shown
that neither monomecaine nor 2-chloro-N-(2-methyl-
phenyl)acetamide synthesized according to the pro-
posed procedure contained related impurities. With the
Scheme 1.
Me
Me
H
H
Et2NH (4)
PhH, ∆
NH2
Me
N
N
O
Cl
NEt2
PhH
+
Cl
O
O
Cl
1
2
3, 76.7%
5, 88.8%
Me
H
67% HNO3
EtOH, 0°C
N
NHEt2
NO3
O
6, 78.5%
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 55 No. 10 2019

CHEKRYSHKINA et al.
(a)
1534
Peak area, rel. units
detection of o-toluidine in monomecaine substance
14.613
was estimated at 0.02%. Analysis of four laboratory
monomecaine batches according to the developed
procedure showed the absence of o-toluidine in the
examined samples. Taking into account considerable
difference in the retention times of monomecaine and
related impurities, the proposed method can also be
used for the identification of the former.
2000
1500
1000
500
Me
H
N
NHEt2
NO3
O
The use of HPLC for the quantification of mono-
mecaine in the drug substance and possible dosage
forms developed at the preclinical trial stage, as well as
for studying its metabolism and pharmacokinetic, also
seemed reasonable. Validation is necessary for the
HPLC procedure to be used in pharmacokinetic studies
of drug dosage forms or included in a pharmacopeial
article for a dosage form [15–17]. For this purpose,
HPLC analyses of monomecaine solutions with dif-
ferent concentrations and a blank solution (containing
no monomecaine) were performed (Fig. 2). The proce-
dure was validated with respect to the following
parameters: selectivity, linearity, analytical range,
precision, and reproducibility.
0
0
5
10
15
τ, min
(b)
20.774
600
500
400
300
200
100
0
H
N
Cl
O
Me
The selectivity was estimated by analyzing the
solvent used for the preparation of monomecaine solu-
tions. The obtained chromatogram showed no peaks
with a retention time corresponding to that of mono-
mecaine (Fig. 2c). The linearity was checked by
plotting a calibration curve (Fig. 3) for solutions con-
taining 0.001, 0.0107, 0.0535, 0.214, and 1.07 mg/mL
of monomecaine. Each solution was analyzed in trip-
licate. A linear dependence was observed between the
chromatographic peak area and monomecaine concen-
tration in the given range. The linear dependence is
described by the equation y = 26859.6 x + 131, and the
correlation coefficient is 0.9997. The analytical range
was defined as 0.8–1.2 mg/mL.
0
5
10
15
11.177
20τ, min
(c)
3.0
140
2.8
120
NH2
Me
2.6
100
2.4
0.02% solution
10.9 11.0 11.1 11.2 τ, min
80
60
40
20
0
2.2
0
5
10
15
τ, min
The precision of the proposed procedure was deter-
mined by statistical processing of the results of deter-
mination of monomecaine concentration in 3 model
solutions containing 0.80, 1.00, and 1.20 mg/mL of the
substrate on different working days. Standard devia-
tions (Sδ) and relative standard deviations (Sδav) were
calculated; the latter did not exceed 3% (Table 2),
indicating acceptable precision of monomecaine quan-
tification by the proposed procedure.
Fig. 1. HPLC chromatograms of (a) monomecaine (6),
(b) 2-chloro-N-(2-methylphenyl)acetamide (3), and
(c) 1% and 0.02% (in the insert) solutions of o-toluidine (1).
goal of estimating the o-toluidine detection limit in
samples of 6, model solutions of 6 containing 0.01 and
0.02% of 1 were prepared and analyzed.
The high resolution of peaks of 6 and 1 (R = 8.8)
allowed us to successfully solve the problem. The peak
of 1 on the chromatogram of the first solution (0.01%
o-toluidine) insignificantly exceeded the background
level, whereas the signal-to-noise (S/N) ratio for
a 0.02% solution of 1 was 10.4 (Fig. 1c). Thus, in
accordance with OFS.1.1.0012.15 [14], the limit of
The reproducibility was estimated by statistical
treatment of the results of analysis of samples from
three laboratory batches of the drug substance.
Student’s t tests were calculated for the number of
degrees of freedom f = L – 1 = 4 and a confidence
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 55 No. 10 2019

SYNTHESIS AND QUANTIFICATION OF 2-(DIETHYLAMINO)-
Peak area, rel. units
1535
(a)
probability P of 0.95. In all cases, the calculated t
1000
800
600
400
200
0
values were lower than the reference value, indicating
that the bias is insignificant with respect to random
dispersion; therefore, it was assumed to be zero, and
the relative error for the mean value (εm) did not
exceed 3% (Table 3). Thus, the procedure gives
accurate and reproducible results.
We can conclude that the proposed reversed-phase
HPLC procedure for quantification of monomecaine
is characterized by acceptable specificity, linearity,
precision, and reproducibility; therefore, it can be used
for analytical purposes.
(b)
We previously described another procedure for
the quantification of monomecaine by nonaqueous
acidimetry [18]. Herein, we propose one more method
based on two-phase extraction–titration using sodium
lauryl sulfate. Monomecaine is a salt formed by
an organic base; therefore, it forms an associate with
the titrant, which is extracted into organic phase
(chloroform). The main factors affecting the extraction
process are pH of the aqueous phase, aqueous and
organic phase volume ratio, and selected indicator. The
optimal conditions were found by varying one param-
eter, the other parameters being maintained constant.
The optimal pH value was in the range 2.18–2.60,
which corresponded to an initial HCl concentration of
0.02 M; the volume ratio of the aqueous and organic
phases was estimated at 1:1 and 1:2; and a 5:1 mix-
ture of Butter Yellow and Methylene Blue was used as
an indicator (a sharp color change from light yellow to
blue was observed at the equivalence point).
18
16
14
12
10
8
12
11
10
9
(c)
8
14.5
15.0
15.5
τ, min
This procedure was also validated with respect to
linearity of the results, analytical range, precision, and
reproducibility. Statistical treatment of the results of
quantification of monomecaine at 7 concentration
levels gave a strictly linear relation between the
concentration and equivalent titrant volume, which
is given by the equation y = 355.5 x – 0.028 with
a correlation coefficient of 0.9999. The analytical
range was defined as 80 to 120% of the concentration
0.03 mg/mL taken as 100%.
Fig. 2. HPLC chromatograms of solutions of monomecaine
(6) with a concentration of (a) 214 and (b) 2 μg/mL and
(c) blank solution.
Peak area, rel. units
25000
20000
15000
10000
5000
The precision of the extraction–titration method
was estimated by statistical processing of the results of
quantitation of monomecaine at three concentration
levels within the analytical range. The relative standard
deviation (Sδav) did not exceed 0.09% (Table 4), which
is acceptable at a substrate concentration close to
100%. Statistical treatment of the results of titration of
samples from three laboratory batches of mono-
mecaine (Table 5) showed good reproducibility; the
Correlation coefficient r = 0.99972
0
0.0
0.5
1.0
Concentration, mg/mL
Fig. 3. Calibration curve for HPLC quantification of mono-
mecaine (6).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 55 No. 10 2019

CHEKRYSHKINA et al.
Table 2. Statistical treatmenta of the results of HPLC quantification of monomecaine (6) in the substance (batch no. 250115)
1536
Concentration, mg/mL
x¯, mg/mL
Sδ, mg/mL
Sδav, %
Δx¯, mg/mL
0.80
1.00
1.20
0.79
1.01
1.20
0.016
0.021
0.023
2.00
2.10
1.91
0.044
0.059
0.064
a
P = 95%, f = 4.
Table 3. Statistical treatmenta of the results of HPLC quantification of monomecaine (6) in three batches
Batch no.
x¯, mg/mL
Sδ, mg/mL
Sδav, %
Δx¯, mg/mL
ε¯, %
250115
170314
050713
1.01
1.00
0.99
0.0095
0.0071
0.0095
0.94
0.71
0.96
0.026
0.020
0.026
2.61
1.97
2.66
a
P = 95%, f = 4.
Table 4. Statistical treatmenta of the results of extraction–titration quantification of monomecaine (6) in the substance (batch
no. 050713)
Concentration level, %
x¯, mg/mL
Sδ, mg/mL
Sδav, %
Δx¯, mg/mL
080
100
120
99.46
99.28
99.36
0.091
0.088
0.089
0.091
0.089
0.090
0.084
0.082
0.082
a
P = 95%, f = 6.
Table 5. Statistical treatmenta of the results of extraction–titration quantification of monomecaine (6) in three batches
Batch no.
x¯, mg/mL
Sδ, mg/mL
Sδav, %
Δx¯, mg/mL
ε¯, %
250712
050713
080813
99.35
99.28
99.35
0.068
0.086
0.096
0.026
0.033
0.036
0.063
0.080
0.089
0.17
0.21
0.24
a
P = 95%, f = 6.
methylphenyl)acetamide. The latter was obtained with
the highest yield in the reaction carried out in anhy-
drous benzene using 1.5 equiv of chloroacetyl
chloride. The purity and structure of the isolated com-
concentration of monomecaine in all samples was
close to 100%, and the relative error was insignificant.
The extraction–titration method has some advan-
tages over the nonaqueous titration procedure proposed
previously. It makes it possible to determine the main
component in the presence of decomposition products.
It is important here that the molecular weight of the
analyte should be no lower than 200. The extraction–
titration procedure is promising for use at the stage of
development of dosage forms of monomecaine such as
infusion solution.
1
pounds were confirmed by H NMR, elemental anal-
yses, and HPLC and TLC data. A procedure for the
identification of monomecaine and control of its purity
by HPLC has been proposed, and the limit of detection
of o-toluidine in laboratory samples of monomecaine
has been estimated at 0.02%. HPLC and extraction–
titration methods have been validated for the quan-
tification of monomecaine. Both methods showed
good selectivity, linearity, precision, and repro-
ducibility and can therefore be recommended for the
development of a pharmacopeial specification for
monomecaine dosage form.
In summary, we have optimized the procedure for
the synthesis of 2-(diethylamino)-N-(2-methylphenyl)
acetamide nitrate, in particular improved the procedure
for the preparation of its precursor, 2-chloro-N-(2-
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 55 No. 10 2019

SYNTHESIS AND QUANTIFICATION OF 2-(DIETHYLAMINO)-
1537
EXPERIMENTAL
7.22 d (1H, Harom, J = 7.4 Hz), 7.90 d (1H, Harom
,
J = 7.9 Hz), 9.47 s (1H, NH). Found, %: C 70.46;
H 9.06; N 13.53. C13H20N2O. Calculated, %: C 70.87;
H 9.15; N 12.72.
1
The H NMR spectra were recorded at room
temperature on a Bruker Avance 500 spectrometer
(500 MHz, Germany) using DMSO-d6 as solvent and
tetramethylsilane as internal standard. The elemental
analyses were obtained on a Perkin Elmer PE 2400
Series II automated CHN analyzer (USA). Reversed-
phase HPLC analyses were carried out on an Agilent
1100 chromatograph (USA) equipped with a Kromasil
100-5C18 column (Sweden), 250×4.6 mm, grain size
5 μm; 0.1% aqueous CF3COOH (A) and acetonitrile
(B) were used as eluents at a flow rate of 0.8 mL/min
(elution conditions and retention times are given
below). Analytical TLC was performed on Sorbfil
plates (Imid Ltd., Russia); spots were visualized under
UV light or by treatment with iodine vapor. Com-
mercially available analytical grade o-toluidine,
chloroacetyl chloride, and diethylamine were used
without further purification.
2-(Dimethylamino)-N-(2-methylphenyl)acet-
amide nitrate (6). A solution of 9.69 g (43.98 mmol)
of 5 in 9 mL EtOH was cooled to 0°C, and 2.96 mL
(43.98 mmol) of 67% nitric acid was added dropwise.
A white crystalline solid separated in 5 min. The mix-
ture was evaporated, and the product was recrystallized
from acetone and dried. Yield 9.03 g (78.5%), white
crystals, mp 138.5–139.5°C, Rf 0.30 [benzene–
Et(i-Pr)2N, 3:0.05]. HPLC: 0–3 min, 5% B; 3–20 min,
5 to 60% B; 20–22 min, 60% B; τ = 14.61 min.
1H NMR spectrum, δ, ppm: 1.24 d (6H, CH2CH3, J =
7.2 Hz), 2.23 s (3H, CH3), 3.23 d (4H, CH2CH3, J =
6.9 Hz), 4.15 s (2H, CH2), 7.16 d.d (1H, Harom, J = 7.4,
1.2 Hz), 7.22 d.d (1H, Harom, J = 7.5, 1.2 Hz), 7.27 d
(1H, Harom, J = 7.5 Hz), 7.42 d (1H, Harom, J = 7.7 Hz),
9.45 br.s (1H, HNO3), 9.96 s (1H, NH). Found, %:
C 55.23; H 7.73; N 14.70. C13H21N3O4. Calculated, %:
C 55.11; H 7.47; N 14.83.
2-Chloro-N-(2-methylphenyl)acetamide (3). A so-
lution of 1 mL (9.32 mmol) of o-toluidine in 10 mL of
anhydrous benzene (dried over metallic sodium) was
cooled to 0°C, and 1.11 mL (14.0 mmol) of chloro-
acetyl chloride was added. A white solid immediately
precipitated. The mixture was evaporated, and the pre-
cipitate was washed with water until neutral washings
and dried. Yield 1.31 g (76.7%), colorless crystals,
mp 111–113°C; published data [13]: mp 102–104°C;
Rf 0.57 (benzene–EtOAc, 9 : 1). HPLC: 0–3 min,
100% A; 3–20 min, 0 to 100% B; 20–22 min, 60% B;
τ = 20.77 min. 1H NMR spectrum, δ, ppm: 2.20 s (3H,
CH3), 4.30 s (1H, CH2), 7.10 d (1H, Harom, J = 7.3 Hz),
Quantification of 2-(dimethylamino)-N-(2-meth-
ylphenyl)acetamide nitrate (6) by HPLC. A 25-mL
volumetric flask was charged with 0.025 g of a sample
of 6, 95% of eluent A and 5% of eluent B were added
to 2/3 of the total volume, and the mixture was stirred
until complete dissolution of 6. The volume of the
mixture was adjusted to 25 mL by adding the same
eluent mixture, the mixture was stirred and filtered
through a membrane filter (pore diameter 0.45 μm),
and the first filtrate portions were discarded. A 20-μL
sample of the obtained solution was injected to
an HPLC instrument. Elution conditions: 0–3 min,
95% A–5% B; 3 to 20 min, 5 to 60% B; 20–23 min,
40% A–60% B; τ = 14.9–15.4 min (Fig. 2). The con-
centration of 6 was calculated by the formula
7.15 d (1H, Harom, J = 7.5 Hz), 7.20 d (1H, Harom
,
J = 7.4 Hz), 7.40 d (1H, Harom, J = 7.8 Hz), 9.65 s
(1H, NH). Found, %: C 58.86; H 5.48; N 7.65;
Cl 19.22. C9H10ClNO. Calculated, %: C 58.86; H 5.49;
N 7.63; Cl 19.31.
S1 a0 P
2-(Dimethylamino)-N-(2-methylphenyl)acet-
amide (5). Compound 3, 9.10 g (49.56 mmol), was
dissolved on heating in 110 mL of anhydrous benzene,
12.64 mL (123.9 mmol) of diethylamine was added,
and the mixture was refluxed for 5 h. The precipitate
of diethylamine hydrochloride was filtered off, the
filtrate was evaporated, and the residue was used in the
synthesis of 6 without further purification. Yield 9.69 g
(88.8%), brown mobile oil, Rf 0.40 (benzene–EtOAc,
X =
,
S0a1
where S1 is the average peak area of monomecaine in
the chromatogram of analyzed solution, S0 is the aver-
age peak area of monomecaine in the chromatogram of
standard solution; a0 is the amount of monomecaine in
the standard solution; a1 is the amount of sample in the
analyzed solution; and P is the concentration of mono-
mecaine in the standard sample, %.
1
9:1). H NMR spectrum, δ, ppm: 1.05 d (6H, CH2CH3,
J = 7.13 Hz), 2.23 s (3H, CH3), 2.61 d (4H, CH2CH3,
Quantification of monomecaine (6) by extrac-
tion–titration with sodium lauryl sulfate. A 0.03-g
sample of monomecaine substance preliminarily dried
J = 7.1 Hz), 3.14 s (2H, CH2), 7.03 d.d (1H, Harom
,
J = 7.5, 1.1 Hz), 7.18 d.d (1H, Harom, J = 7.6, 1.1 Hz),
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 55 No. 10 2019

CHEKRYSHKINA et al.
1538
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at 100°C until constant weight was dissolved in 10 mL
of 0.02 M aqueous HCl in a 100-mL conical flask,
10 mL of chloroform and two drops of a solution of
mixed indicator (Butter Yellow–Methylene Blue, 5:1)
were added, and the mixture was titrated with a 0.01 M
solution of sodium lauryl sulfate under vigorous shak-
ing until the organic phase changed from light yellow
to blue. All titrations were carried out in duplicate.
7. Khairullina, V.R., Tarasov, G.P., Gerchikov, A.Ya.,
Zarudiy, F.S., and Tyurina, L.A., Biochem. (Moscow)
Suppl. Ser. B, 2010, vol. 4, p. 130.
ACKNOWLEDGMENTS
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https://doi.org/10.1007/s11094-010-0493-7
The authors thank Dr. M.I. Kodess for recording the
NMR spectra.
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Syropyatov, B.Ya., and Vahrin, M.I., Pharm. Chem. J.,
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FUNDING
This study was performed in the frame work of state
assignment (project no. AAAA-A19-119011790130-3)
using the facilities of the “Spectroscopy and Analysis of
Organic Compounds” joint center (Institute of Organic
Synthesis, Ural Branch, Russian Academy of Sciences).
CONFLICT OF INTERESTS
The authors declare the absence of conflict of interests.
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RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 55 No. 10 2019