New Structural Modifications of Cotarnine Alkaloid Derivatives: Cotarnone and Dihydrocotarnine

Article abstract of DOI:10.1134/S1070363220020127

Abstract: Simplest derivatives of the cotarnine alkaloid, like cotarnone and 1,2-dihydrocotarnine, undergo electrophilic Einhorn acylamidomethylation (with 60–95% yield) and sulfochlorination with chlorosulfonic acid at position 5. At the same time cotarnone and its derivatives undergo additional O-protodemethylation. Using these and some other reactions, we synthesized a number of previously unknown derivatives of two substrates with 5-chloroacetamidomethyl, 5-arylaminomethyl, 5-aminomethyl and 5-sulfamide groups.

Full text of DOI:10.1134/S1070363220020127

ISSN 1070-3632, Russian Journal of General Chemistry, 2020, Vol. 90, No. 2, pp. 238–243. © Pleiades Publishing, Ltd., 2020.
Russian Text © The Author(s), 2020, published in Zhurnal Obshchei Khimii, 2020, Vol. 90, No. 2, pp. 261–267.
New Structural Modifications of Cotarnine Alkaloid Derivatives:
Cotarnone and Dihydrocotarnine
V. G. Kartseva, A. A. Zubenkob, L. N. Divaevac,*, A. S. Morkovnikc,
T. K. Baryshnikovad , and V. Z. Shiriniand
a InterBioScreen Ltd, Chernogolovka, 142432 Russia
b North Caucasian Zonal Veterinary Research Institute, Federal Rostov Agrarian Scientific Center,
Novocherkassk, 346406 Russia
c Institute of Physical and Organic Chemistry of Southern Federal University, Rostov-on-Don, 344090 Russia
d N.D. Zelinsky Institute of Organic Chemistry of Russian Academy of Sciences, Moscow, 119991 Russia
*e-mail: divaevaln@mail.ru
Received July 22, 2019; revised July 22, 2019; accepted July 25, 2019
Abstract—Simplest derivatives of the cotarnine alkaloid, like cotarnone and 1,2-dihydrocotarnine, undergo elec-
trophilic Einhorn acylamidomethylation (with 60–95% yield) and sulfochlorination with chlorosulfonic acid at
position 5. At the same time cotarnone and its derivatives undergo additional O-protodemethylation. Using these
and some other reactions, we synthesized a number of previously unknown derivatives of two substrates with
5-chloroacetamidomethyl, 5-arylaminomethyl, 5-aminomethyl and 5-sulfamide groups.
Keywords: cotarnine, dihydrocotarnine, O-demethylation, amidoalkylation, sulfochlorination
DOI: 10.1134/S1070363220020127
The alkaloid cotarnine 1 and its derivatives have
considerable potential for transformation into biologi-
cally active structuresdue to possibility of the ring-chain
tautomerism of the piperidine fragment of the molecule
and the formation of a highly reactive minor bifunctional
form [1].
stituent at position 5. The 1,2,3,4-tetrahydroisoquinoline
derivatives have diverse biological activity, including, for
example, the ability to act as estrogen receptors antago-
nists [18] and antitumor agents (alkaloid noscapine [19]).
There are more complex variants of the reaction
of cotarnine with nucleophiles, proceeding via non-
degenerate recyclization. A typical case is a reaction
with CH-acids (barbituric acids), which in the basic
medium can cause recyclization of cotarnine into
5,6,7,8-tetrahydronaphtho[2,3-d][1,3]dioxole with spiro-
linked [12, 13, 20–23] or a fused [21] fragment of bar-
bituric acid. This feature of barbituric acids is due to
the special properties of arylidene intermediates formed
upon nucleophilic addition to the open-chain form of the
substrate and capable of undergoing cyclization under
certain conditions.
For a long time, the main direction in the development
of the chemistry of cotarnines was the study of the reac-
tions of cotarnine with C- [2–9] and N-nucleophiles, both
anionic [10] and electroneutral [7, 11–13]. Reactions with
electrophilic agents, with the exception of N-methylation
[12, 14] and N-acylation [13], have not been studied.
The nucleophilic attack of cotarnine most often leads
to the formation of products of the formal addition of the
reagent or its residue at position 5 of the salt cyclic form
[15–17]. In the basic medium, which contributes to the
predominance of the pseudo-basic tautomeric form of
the alkaloid, the reaction proceeds predominantly by the
indirect scheme of the recyclization of the terahydroiso-
quinoline system. It includes the transition to the open-
chain form of the substrate, the addition of a nucleophile
to it at the formyl group, and the cyclization of the adduct
to 1,2,3,4-tetrahydroisoquinoline derivative with a sub-
In recent years, success has been achieved in the
study of the reactions of cotarnine and its derivatives
with electrophilic agents. In particular, the study of
quaternization of cotarnine was continued, which is not
impeded by the hemiaminal structure of the alkaloid [24,
25]. The quaternary salts of cotarnine have antitumor [24]
and anti-inflammatory properties [25]. Cotarnine [26], as
238

NEW STRUCTURAL MODIFICATIONS OF COTARNINE ALKALOID DERIVATIVES
239
Scheme 1.
well as its 5-bromo derivative [27], are easily undergo
the base-catalyzed pyridine-azepine recyclization in the
presence of RCH2Hlg (R = Ac, hetaryl), which in some
cases proceeds in the usual way, while in others it is ac-
companied by 1,2-acyl rearrangement. Other fused dihy-
dropyridinium salts or their pseudo-bases with the same
type of annelation underwent similar recyclization [26].
preparative methods for the synthesis of many relatively
simple representatives of the cotarnine series, as well as
the lack of data on the reactivity of the cotarnine system
in main organic reactions.
Herein, we studied the synthesis and reactivity of the
simplest derivatives of cotarnine, namely cotarnone 2 and
dihydrocotarnine 3 (Scheme 1).
Recyclization opens up the possibility of a simple
and effective one-pot transformation of cotarnines into
acyl-substituted dihydrobenz[3]azepines with an acyl
group in the azepine ring [1, 27, 28]. Dihydroazepines
are promising as biologically active structures [1] and as
highly active synthons for further transformations. An
alternative transition from cotarnine-like structures to
hydrogenated but non-functionalized benzo[3]azepines
is based on aziridination of the salt form of the substrate
with diazomethane at the C=N bond and subsequent
non-selective reduction of the aziridine derivative [29].
To obtain cotarnone 2, a modified method for the
oxidation of cotarnine 1 using iodine in a two-phase
water–chloroform medium as an oxidizing agent is
proposed. Compared to the oxidation of cotarnine with
N-bromosuccinimide [3], the yield of compound 2 in-
creases from 83 to 95%. In addition, simple and practi-
cally quantitative regeneration of the oxidizing agent is
possible by treating the acidified post-reaction aqueous
solution with hydrogen peroxide.
Analyzing the available data on the synthesis of di-
hydrocotarnine 3, we were able to propose an improved
method for the reduction of cotarnine 1 with formic
acid in boiling formamide. Compared to the best of the
Further development of the chemistry of cotarnines
substantially inhibits the absence or imperfection of
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240
KARTSEV et al.
previously described alkaloid reduction methods [30],
this method allows to increase the yield of compound
3 from 50 to 90%. Moreover, our method makes it pos-
sible to obtain analytically pure sample of 3, without
the low-melting impurities that are present when using
another method.
yield (81%). This modification of the Einhorn reaction
can be considered as a kind of synthetic equivalent of
direct Mannich amniomethylation with the prospect of
wider applicability. Compound 7 was characterized by
conversion to aroyl amides 8a–8c under the action of the
corresponding aroyl chlorides (Scheme 1).
We studied the electrophilic substitution reactions of
compounds 2 and 3, namely Einhorn acetamidomethyl-
ation with N-hydroxymethylacylamides in conc. H2SO4
[31] and sulfochlorination.Acylamidomethyl derivatives
of the cotarnine series can be used to obtain the corre-
sponding aminomethyl derivatives, since direct Mannich
aminomethylation of compounds 2 and 3 is unlikely due
to the insufficient reactivity of the benzene ring.
Using the example of dihydrocotarnine 3, the first
sulfochlorination reaction in the cotarnine series was
carried out using chlorosulfonic acid as the sulfochlori-
nating agent. In the free state, 5-sulfochloride is unstable;
therefore, it was converted into sulfamides 9a, 9b by the
action of amines (Scheme 1).
Composition and structure of the obtained compounds
were confirmed by elemental analysis, IR and NMR
spectroscopy data.
N-(Hydroxymethyl)chloroacetamide was chosen as
the acylamidomethylating reagent in order to obtain
substitution products with a reactive chloromethyl group
suitable for conjugation of cotarnone or dihydrocotarnine
systems with various pharmacologically attractive groups.
In conclusion, the studies performed allowed us to
improve the methods for the synthesis of the simplest
derivatives of cotarnine, namely cotarnone and dihydro-
cotarnine, as well as to demonstrate their ability to cer-
tain electrophilic substitution reactions such as Einhorn
acetamidomethylation, sulfochlorination and methoxy
group acidolysis (for cotarnone and its derivatives) due
to the effect of the C=O group. In addition, previously
unknown 9-aminomethyl derivatives were obtained,
which is important for molecular design in the cotarnine
derivatives series.
Chloroacetamidomethylation of compound 2 led to
the formation of 9-chloroacetamidomethyl derivative
4 with a fairly satisfactory yield (60%). Hydrolytic
cleavage of this compound upon boiling in a mixture of
hydrochloric and acetic acids led to its N-deacylation.
Acidolysis of a methoxy group (protodemethylation)
proceeded simultaneously. The yield of the resulting
4-hydroxy-9-aminomethyl derivative 5 hydrochloride
was 77%. Under the same conditions, cotarnone 2 was
readily demethylated yielding 4-hydroxy derivative 6,
while cotarnine did not react under the same conditions.
The reason for such differences may be the effect of pro-
moting the closely located C=O group, which additionally
binds the attacking proton, which lowers the energy of
the transition state of demethylation process.
EXPERIMENTAL
1H NMR spectra were recorded on a Bruker Fou-
rier-300 instrument (300 MHz) from DMSO-d6 solutions.
IR spectra were recorded on a Varian Excalibur 3100 FT-
IR instrument for sample suspensions in liquid paraffin.
Melting points were determined on a Fisher–Johns Melt-
ing Point Apparatus. Elemental analysis was performed
by the classical microanalysis method. The reaction
progress and the purity of the obtained compounds were
monitored by thin-layer chromatography (plates coated
with Al2O3 having an activity grade Brockman III, elu-
ent – CHCl3, developing with iodine vapor in a humid
chamber).
Dihydro derivative 3 exhibits a different behavior dur-
ing chloroacetamidomethylation. Due to the presence of
two reactive groups in the molecule, the substitution prod-
uct is unstable and, apparently, is prone to polymerization
via intermolecular quaternization. Therefore, it was not
possible to be isolated in pure form. Similar problems
have been described in [31]. The authors reported a fuzzy
melting point of the chloroacetamidomethylation product
with an interval of 50°C.
6-Methyl-4-methoxy-5,6,7,8-tetrahydro[1,3]di-
oxolo[4,5-g]isoquinolin-5-one (2). To a mixture of
94.9 g (0.4 mol) of cotarnine 1, 300 mL of chloroform
and 114.3 g (0.45 mol) of finely ground iodine was
added 50 mL of a solution of 88.0 g (2.2 mol) of NaOH
in 300 mL of water. The resulting mixture was vigor-
ously stirred for 3 h at 30–35°C, then 25 mL of a NaOH
solution were added every 2 h until the initial cotarnine
It was possible to prove the chloroacetamidometh-
ylation of dihydrocotarnine 3 by replacing conc. H2SO4
with HCl, when performing a one-pot reaction in combi-
nation with subsequent N-deacylation.As a result, 5-ami-
nomethyl derivative 7 was obtained with a good overall
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NEW STRUCTURAL MODIFICATIONS OF COTARNINE ALKALOID DERIVATIVES
241
1 (TLC) disappeared in the reaction mixture. The excess
of iodine was reduced with sodium sulfite, the organic
layer was separated, washed with water (3×50 mL), then
5% sulfuric acid (2×100 mL), water (2×50 mL) and dried
with Na2SO4. The solvent was distilled off in vacuum
at 50–60°С. Yield 89.3 g (95%), mp 77‒78°C (cyclo-
hexane). 1Н NMR spectrum, δ, ppm: 2.78 t (2Н, H8, J =
6.3 Hz), 2.97 s (3Н, NСН3), 3.40‒3.42 m (2Н, Н7), 3.83 s
(3Н, ОCН3), 6.04 s (2Н, Н2), 6.61 s (1Н, Н9). Found, %:
C 59.95; H 5.20; N 5.73. C12H13NO4. Calculated, %: C
61.27; H 5.57; N 5.95.
20–30°С. Yield 19.13 g (77%). The product was con-
verted to hydrochloride by the action of conc. HCl in
acetone, mp 254–256°C (EtOH). IR spectrum, ν, cm–1:
3075 s (OH), 1668 s (C=O). 1Н NMR spectrum, δ, ppm:
2.99–3.04 m (5Н, NCH3, H8), 3.55 t (2Н, Н7, J = 6.9 Hz),
3.92 s (2Н, СH2NН2), 6.11 s (2Н, Н2), 8.45 br. s (3Н,
+NH3), 13.44 s (1Н, ОН). Found, %: C 50.12; H 5.43; Cl
.
12.09; N 9.44. C12H14N2O4 HCl. Calculated, %: C 50.27;
H 5.27; Cl 12.36; N 9.77.
4-Hydroxy-6-methyl-7,8-dihydro-6H-[1,3]di-
oxolo[4,5-g]isoquinolin-5-one (6). A mixture of 2.35 g
(10 mmol) of isoquinolone 2, 4 mL of glacial acetic acid
and 4 mL of conc. HCl was refluxed for 1.5 h. After
cooling, 20 mL of water was added, and the mixture
was neutralized with a NH4OH solution to pH = 5–6.
The precipitate was filtered off and dried. Yield 1.75 g
(79%), mp 136–137°C (EtOAc). IR spectrum, ν, cm–1:
3075 s (OH), 1668 s (C=O). 1Н NMR spectrum, δ, ppm:
2.85‒2.90 m (2Н, H8), 3.00 s (3Н, NCH3), 3.51 t (2Н, Н7,
J = 6.9 Hz), 6.03 s (2Н, Н2), 6.42 s (1Н, Н9), 13.05 s (1Н,
ОН). Found, %: C 59.80; H 5.20; N 6.60. C11H11NO4.
Calculated, %: C 59.73; H 5.01; N 6.33.
6-Methyl-4-methoxy-5,6,7,8-tetrahydro[1,3]di-
oxolo[4,5-g]isoquinoline hydrochloride (3). A mixture
of 23.72 g (0.1 mol) of cotarnine 1, 40 mL of formamide
and 40 mLof 90% formic acid was refluxed for 4 h.After
cooling, the mixture was neutralized with a 25% NaOH
solution to pH = 9, and then extracted with diethyl ether
(3×30 mL). The extract was dried with Na2SO4, then the
solvent was distilled off in vacuum at 30–40°С. Yield
89%, mp 49–50°С (mp 49–50°С [27]). Hydrochloride 3
was obtained by the action of dry HCl on a diethyl ether
solution of the base, mp 285–288°C (sealed capillary).
N-[(6-Methyl-4-methoxy-5-oxo-5,6,7,8-tetra-
hydro[1,3]dioxolo[4,5-g]isoquinolin-9-yl)methyl]-
2-chloroacetamide (4). To 200 mL of conc. H2SO4 was
added in portions with stirring 47.04 g (0.2 mol) of com-
pound 2. Next, 27.17 g (0.22 mol) of N-(hydroxymethyl)-
2-chloroacetamide was added with stirring at 25–30°C to
the resulting solution. The reaction mixture was stirred for
20 h at 25–30°С, then it was poured into 1 L of ice water
and cooled to 0°С. The precipitate was filtered off, washed
with water (4×50 mL) and dried. Yield 41.35 g (60%), mp
230–232°C (EtOH). IR spectrum, ν, cm–1: 3240 br (NH),
1674 s (С=О). 1Н NMR spectrum, δ, ppm: 2.76 t (2Н, H8,
J = 6.3 Hz), 2.98 s (3Н, NСН3), 3.37–3.42 m (2Н, Н7),
3.82 s (3Н, ОCН3), 4.03 s (2Н, СH2NН), 4.23–4.25 m
(2Н, СН2СО), 6.08 s (2Н, Н2), 8.43 s (1Н, NH). Found,
%: C 52.50; H 5.20; Cl 10.56; N 8.05. C15H17ClN2O5.
Calculated, %: C 52.87; H 5.03; Cl 10.40; N 8.22.
(6-Methyl-4-methoxy-5,6,7,8-tetrahydro[1,3]di-
oxolo[4,5-g]isoquinolin-9-yl)methylamine oxalate (7).
N-(Hydroxymethyl)-2-chloroacetamide(14.82g,0.11mol)
was added in portions with stirring and cooling to a solu-
tion of 22.12 g (0.1 mol) of dihydrocotarnine 3 in 50 mL
of conc. HCl. The resulting mixture was stirred for 2 h at
20–25°С, and then 100 mLof water was added and boiling
was continued for another 2 h. After cooling, the mixture
was neutralized with a K2CO3 solution. The reaction
product was extracted with CHCl3 (4×20 mL), the extract
was dried with Na2SO4, and the solvent was distilled off
in vacuum at 30–35°С. Yield 20.35 g (81%). The com-
pound was converted to oxalate by the action of a solu-
tion of oxalic acid in ethanol, mp 217–220°C (EtOH). 1Н
NMR spectrum, δ, ppm: 2.61 s (3Н, NCH3), 2.90‒2.94 m
(4Н, Н8, Н7), 3.72 s (2Н, Н5), 3.91 s (2Н, СH2NH2), 3.96 s
+
(3Н, ОСН3), 4.20 br. s (6Н, NH3), 6.02 s (2Н, Н2).
.
Found, %: C 57.29; H 6.02; N 9.34. C26H36N4O6 Н2С2О4.
9-(Aminomethyl)-4-hydroxy-6-methyl-7,8-di-
hydro-6H-[1,3]dioxolo[4,5-g]isoquinolin-5-one hydro-
chloride (5). A mixture of 34.07 g (0.1 mol) of amide
4, 60 mL of glacial CH3COOH and 60 mL of conc. HCl
was boiled for 2 h, then cooled and filtered. The filtrate
was poured into 200 mL of water and neutralized with
a K2CO3 solution. The reaction product was extracted
with chloroform (4×25 mL), the extract was dried with
Na2SO4, and the solvent was distilled off in vacuum at
Calculated, %: C 57.14; H 6.16; N 9.52.
N-[(6-Methyl-4-methoxy-5,6,7,8-tetrahydro[1,3]-
dioxolo[4,5-g]isoquinolin-9-yl)methyl]benzamide (8a).
To a solution of 2.50 g (10 mmol) of amine 7 in 20 mL of
CHCl3 was added 10 mLof a saturated solution of K2CO3,
then 1.6 g (11 mmol) of benzoyl chloride was added
dropwise with vigorous stirring at 5–10°С. The mixture
was stirred for 1 h at room temperature. The organic layer
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242
KARTSEV et al.
was separated, washed with water (3×10 mL) and dried
with Na2SO4. The solvent was distilled off in vacuum at
50–60°С. Yield 3.15 g (89%), mp 179–1818°C (EtOH).
1Н NMR spectrum, δ, ppm: 2.31 s (3Н, NCH3), 2.71 t (2Н,
Н8, J = 6.0 Hz), 3.31‒3.70 m (4Н, Н5, Н7), 3.90 s (3Н,
ОСН3), 4.38 s (2Н, СH2NН), 5.95 s (2Н, Н2), 7.40‒7.54 m
(3Н, Н3'–5'),1 7.83‒7.86 m (2Н, Н2',6'), 8.53 br. s (1H,
NH). Found, %: C 67.60; H 6.01; N 7.67. C20H22N2O4.
Calculated, %: C 67.78; H 6.26; N 7.90.
The resulting mixture was kept for 20 min at room tem-
perature, then for 30 min at 45°C. After cooling to 0°C,
16.08 g (0.42 mol) of NaOH and 150 g of crushed ice
were poured into the mixture and stirred for 10 min. The
organic layer was separated and poured onto a mixture of
15 mL of CHCl3, 2.79 g (0.02 mol) of glycine ethyl ester
hydrochloride and 4.05 g (0.04 mol) of triethylamine. The
resulting mixture was kept for 10 h at room temperature,
then washed with water (3×15 mL), dried with Na2SO4,
and the solvent was distilled off in vacuum at 20–30°С.
4-Amino-N-[(4-methoxy-6-methyl-5,6,7,8-tetra-
hydro[1,3]dioxolo[4,5-g]isoquinolin-9-yl)methyl]-
benzamide (8b). First, 4-nitrobenzamide was obtained
from 2.50 g (10 mmol) of amine 7 and 2.15 g (11 mmol)
of 4-nitrobenzoyl chloride as described above. 4-Nitro-
benzamide was added without further purification to a
boiling mixture of 5.6 g of finely ground iron, 5 mL of
glacial CH3COOH and 100 mLof EtOH. The mixture was
boiled for 2–3 h (TLC control), then filtered. The slurry
was treated with hot EtOH (3×30 mL), and the solvent
was distilled off in vacuum at 70–80°С. Yield 2.95 g
1
Yield 4.7 g (61%), mp 136–137°C (EtOAc). Н NMR
spectrum, δ, ppm: 1.11 t (3Н, СH3СН2, J = 7.1 Hz), 2.32 s
(3Н, NСН3), 2.47‒2.49 m (2Н, H8), 3.00 t (2Н, Н5, J =
5.9 Hz), 3.30 s (2Н, Н7), 3.73 s (2Н, СH2NH), 3.94‒4.01 m
(5Н, ОСН3, СH2СН3), 6.03 s (2Н, Н2), 8.13 s (1H, NH).
Found, %: C 49.80; H 5.30; N 6.90; S 8.02. С16H22N2O7S.
Calculated, %: C 49.73; H 5.74; N 7.25; S 8.30.
tert-Butyl 4-[(6-methyl-4-methoxy-5,6,7,8-tetra-
hydro[1,3]dioxolo[4,5-g]isoquinolin-9-yl)sulfanyl]-
piperazin-1-ylcarboxylate (9b) was prepared similarly
from cotarnine 3 hydrochloride and tert-butyl piperazin-
1-ylcarboxylate. Yield 59%, mp 186–188°С (cyclohex-
ane). 1Н NMR spectrum, δ, ppm: 1.39 s (9Н, СН3), 2.31 s
(2Н, NСН3), 2.46‒2.48 m (2Н, H8), 2.48 s (2Н, Н5),
2.95‒3.30 m (8Н, СН2, piperazin-1-yl), 3.38 s (2Н, Н7),
4.02 s (3Н, ОСН3), 6.07 s (1Н, Н2). Found, %: C 53.40;
H 6.82; N 9.25; S 6.83. С21H31N3O7S. Calculated, %: C
53.72; H 6.65; N 8.95; S 6.83.
1
(80%), mp 219–221°C (EtOH). Н NMR spectrum, δ,
ppm: 2.31 s (3Н, NCH3), 2.46‒2.48 m (2Н, Н8), 2.69 t
(2Н, Н7, J = 6.0 Hz), 3.30 s (2Н, Н5), 3.89 s (3Н, ОСН3),
4.32 s (2Н, СH2NН), 5.55 br. s (2Н, NH2), 5.94 s (2Н,
Н2), 6.50–6.53 m (2Н, Н3',5), 7.56–7.60 m (2Н, Н2',6'),
7.99 br. s (1H, NH). Found, %: C 65.22; H 6.01; N 11.00.
C20H23N3O4. Calculated, %: C 65.03; H 6.28; N 11.37.
3-Amino-N-[(4-methoxy-6-methyl-5,6,7,8-tetra-
hydro[1,3]dioxolo[4,5-g]isoquinolin-9-yl)methyl]-
benzamide (8c) was obtained similarly from 2.5 g
(10 mmol) of amine 7 and 2.15 g (11 mmol) of 3-nitro-
benzoyl chloride. The nitro derivative was reduced as
described above. Yield 2.65 g (72%), mp 196–198°C
FUNDUNG
This work was financially supported by the Ministry
of Education and Science of the Russian Federation (grant
no. 4.5821.2017/8.9) in the framework of the Fundamental Sci-
entific Research Program of the StateAcademies of Sciences for
2013–2020 (no. 0710-2019-0044) using the equipment of the
Center for Collective Use of the Southern Federal University.
1
(EtOH). Н NMR spectrum, δ, ppm: 3.02‒3.05 m (3Н,
NCH3), 3.24 t (2Н, Н8, J = 5.9 Hz), 3.62 s (2Н, Н5), 3.96 s
(3Н, ОСН3), 4.03 s (2Н, Н7), 4.30‒4.49 m (4Н, СH2NH,
NH2), 6.05 s (2Н, Н2), 7.35‒7.39 m (1Н, Н5'), 7.49 t (1Н,
Н4', J = 7.8 Hz), 7.68‒7.74 m (2Н, Н2',6'), 8.81 br. s (1Н,
NH). Found, %: C 65.40; H 6.65; N 11.25. C20H23N3O4.
Calculated, %: C 65.03; H 6.28; N 11.37.
CONFLICT OF INTEREST
No conflict of interest was declared by the authors.
REFERENCES
1. Kartsev, V.G., Zubenko, A.A., Morkovnik, A.S., and
Divaeva, L.N., Tetrahedron Lett., 2015, vol. 56, p. 6988.
https://doi.org/10.1016/j.tetlet.2015.10.103
2. Beke, D., Adv. Heterocycl. Chem., 1963, vol. 1,
p. 167.
https://doi.org/10.1016/S0065-2725(08)60525-5
3. Choudhury, S.K., Rout, P., Parida, B.B., Florent, J-C.,
Johannes, L., Phaomei, G., Bertounesque, E., and
Rout, L., Eur. J. Org. Chem., 2017, p. 5275.
https://doi.org/10.1002/ejoc.201700471
Ethyl 2-(6-methyl-4-methoxy-5,6,7,8-tetra-
hydro[1,3]dioxolo[4,5-g]isoquinoline-9-sulfonyl-
amino)acetate (9a). A mixture of 5.15 g (0.02 mol)
of 1,2-dihydrocotarnine 3 hydrochloride and 30 mL of
CHCl3 was cooled to ‒10°C, then 13.98 g (0.12 mol) of
chlorosulfonic acid was added with vigorous stirring.
1 Hereinafter, the numbers with a dash denote the protons of the aryl
substituent.
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NEW STRUCTURAL MODIFICATIONS OF COTARNINE ALKALOID DERIVATIVES
4. Khrustalev, V.N., Krasnov, K.A., and Timofeeva, T.V., Pat. Anti-Cancer Drug Disc., 2009, vol. 4, p. 92.
243
J. Mol. Struct., 2008, vol. 878, p. 40.
https://doi.org/10.1039/10.2174/157489209787002524
20. Krasnov, K.A., Kartsev, V.G., and Yurova, M.N.,
Chem. Nat. Comp., 2001, vol. 37, p. 543.
https://doi.org/10.1016/j.molstruc.2007.07.036
5. Shvartsberg, M.S., Vasilevskii, S.F., Kostrovskii, V.G.,
and Kotlyareskii, I.L., Chem. Heterocycl. Comp., 1972,
vol. 5, p. 797. doi.10.1007/BF00475858
6. Ukhin, L.Yu, Gol’ding, I.R., and Kartsev, V.G.,
Chem. Nat. Compd., 2004, vol. 40, p. 156.
https://doi.org/10.1023/B:CONC.0000033934.74690.21
7. Hope, E. and Robinson, R., J. Chem. Soc. Trans.,
1911, vol. 99, p. 2114.
https://doi.org/10.1039/CT9119902114
8. Maslennikova, G.N. and Lazurevskii, G.V., Doklady
Akad. Nauk SSSR, 1950, vol. 72, p. 305.
9. Maslennikova, G.N. and Lazurevskii, G.V., Doklady
Akad. Nauk SSSR, 1951, vol. 73, p. 1604.
10. Krasnov, K.A., Kartsev, V.G., and Vasilevskii, S.F.,
Chem. Nat. Comрd., 2005, vol. 41, p. 446.
https://doi.org/10.1007/s10600-005-0174-z
11. Mohrle, H. and Grimm, B., Arch. Pharm., 1986, vol. 319,
p. 835.
https://doi.org/10.1002/ardp.19863191110
12. Krasnov, K.A. and Kartsev, V.G., Russ. J. Org. Chem.,
2002, vol. 38, p. 457.
https://doi.org/10.1023/A:1014821016904
21. Krasnov, K.A., Kartsev, V.G., and Khrustalev, V.N.,
Heterocycles, 2007, vol. 71, p. 13.
https://doi.org/10.3987/COM-06-10854
22. Krasnov, K.A., Kartsev, V.G., and Khrustalev, V.N.,
Russ. Chem. Bull., 2002, vol. 51, p. 1540.
https://doi.org/10.1023/A:1020983527851
23. Khrustalev, V.N., Krasnov, K.A., and Timofeeva, T.V.,
J. Mol. Struct., 2008, vol. 878, p. 40.
https://doi.org/10.1016/j.molstruc.2007.07.036
24. Wang, H.-Y. and Burns, B.L., WO Patent 2015/54027
A1, 2015.
25. Burns, B.L., Wang, H.-Y., Lin, N.-H., and Blasko, A., WO
Patent 2010051476 A1, 2009.
26. Zubenko, A.A., Kartsev, V.G., Morkovnik, A.S., Divae-
va, L.N., and Suponitsky, K.Yu., Chem. Select., 2016,
vol. 1, p. 2560.
https://doi.org/10.1002/slct.201600727
27. Zubenko, A.A., Divaeva, L.N., Morkovnik, A.S., Kar-
tsev, V.G., Drobin, Y.D., Serbinovskaya, N.M., Feti-
sov, L.N., Bodryakov, A.N., Bodryakova, M.A., and Lya-
shenko, L.A., Russ. J. Bioorg. Chem., 2017, vol. 43,
p. 311.
https://doi.org/10.1023/A:1016354730304
13. Schneider, W. and Mueller, B., Lieb. Ann., 1958, vol. 615,
p. 34.
https://doi.org/10.1002/jlac.19586150106
14. Krasnov, K.A., Kartsev, V.G., and Khrustalev, V.N.,
Chem. Nat. Comp., 2008, vol. 44, p. 48.
https://doi.org/10.1007/s10600-008-0013-0
15. Min, C., Sanchawala, A., and Seidel, D., Org. Lett.,
2014, vol. 16, p. 2756.
https://doi.org/10.1134/S1068162017030189
28. Zubenko, A.A., Kartsev, V.G., Morkovnik, A.S., Divae-
va, L.N., Alexeenko, D.V., Borodkin, G.S., Supo-
nitsky, K.Y., and Klimenko, A.I., Tetrahedron Lett., 2017,
vol. 58, p. 1233.
https://doi.org/10.1021/ol501073f
https://doi.org/10.1016/j.tetlet.2017.02.036
29. Bernhard, H.O. and Snieckus, V., Tetrahedron, 1971,
vol. 27, p. 2091.
16. Bergonzini, G., Schindler, C.S., Wallentin, C.-J.,
Jacobsen, E.N., and Stephenson, C.R.J., Chem. Sci.,
2014, vol. 5, p. 112.
https://doi.org/10.1016/S0040-4020(01)91607-2
30. Janssen, R.H.A.M., Wijkens, P., Krijk, C., Biessels, H.W.A.,
Menichinis, F., and Theuns, H.G., Phytochem., 1990,
vol. 29, p. 3331.
https://doi.org/10.1039/C3SC52265B
17. Wang, T., Schrempp, M., Berndhäuser, A., Schiemann, O.,
and Menche, D., Org. Lett., 2015, vol. 17, p. 3982.
https://doi.org/10.1039/10.1021/acs.orglett.5b01845
18. Burks, H.E., Karki, R.G., Kirby, C.A., Nunez, J., Peukert, S.,
Springer, C., Sun, Y., and Thomsen, N.M.-F., WO Patent,
2015/92634 A1, 2015.
https://doi.org/10.1016/0031-9422(90)80210-8
31. Semonsky, M., Coll. Czech. Chem. Commun., 1951,
vol. 15, p. 1024.
19. Mahmoudian, M. and Rahimi-Moghaddam, P., Recent
https://doi.org/10.1135/cccc19501024
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 90 No. 2 2020