New Method of Synthesis of Biologically Active Get(aryl)chalcogenylacetates of Tris(2-hydroxyethyl)ammonium

Article abstract of DOI:10.1134/S1070363218100353

Physiologically and pharmacologically active het(aryl)chalcogenylacetates of tris(2-hydroxyethyl)ammonium of pharmacopeial purity have been synthesized by the reaction of het(aryl)chalcogenylacetic acids with sodium (potassium) hydroxide and triethanolami

Full text of DOI:10.1134/S1070363218100353

ISSN 1070-3632, Russian Journal of General Chemistry, 2018, Vol. 88, No. 10, pp. 2227–2229. © Pleiades Publishing, Ltd., 2018.
Original Russian Text © S.N. Adamovich, Е.N. Oborina, I.А. Ushakov, А.N. Mirskova, 2018, published in Zhurnal Obshchei Khimii, 2018, Vol. 88, No. 10,
pp. 1743–1745.
LETTERS
TO THE EDITOR
New Method of Synthesis of Biologically Active
Get(aryl)chalcogenylacetates of Tris(2-hydroxyethyl)ammonium
S. N. Adamovicha*, Е. N. Oborinaa, I. А. Ushakovb, and А. N. Mirskovaa
a A.E. Favorskii Irkutsk Institute of Chemistry, Siberian Branch, Russian Academy of Sciences,
ul. Favorskogo 1, Irkutsk, 664033 Russia
*e-mail: mir@irioch.irk.ru
b Irkutsk National Research Technical University, Irkutsk, Russia
Received May 24, 2018
Abstract―Physiologically and pharmacologically active het(aryl)chalcogenylacetates of tris(2-hydroxyethyl)ammo-
nium of pharmacopeial purity have been synthesized by the reaction of het(aryl)chalcogenylacetic acids with sodium
(potassium) hydroxide and triethanolamine hydrochloride by one-pot method in quantitative yield (up to 99.8%).
Keywords: het(aryl)chalcogenylacetates of tris(2-hydroxyethyl)ammonium, triethanolamine hydrochloride,
crezacine
DOI: 10.1134/S1070363218100353
Earlier we obtained a series of aryl(oxy)(sulfanyl)-
(sulfonyl)acetates of tris(2-hydroxyethyl)ammonium
ArXCH2COO–·HN(CH2CH2OH)3 (1) (Х = O, S, SO2)
[1–4]. By the methods of IR and NMR spectroscopy,
X-ray and elemental analysis the atrane, more
specifically, protatrane structure of these compounds
was determined [1].
stimulator and adaptogen of wide spectrum of action
under the name crezacine [2].
It must be noted that all so far obtained compounds
of series 1, including crezacine, were synthesized by
the reaction of the corresponding aryloxy or arylsul-
fanylacetic acids with tris(2-hydroxyethyl)amine. The
yields of the products were high (75–90%) but their
purity was low [6, 7]. Crezacine of purity sufficient for
use in medicine [8] can be obtained only by complex
multistep procedure, but the yields decrease to 55–
65%. The main reason of low purity of crezacine is a
difficult method of purification of triethanolamine
(TEA), which is a viscous, hygroscopic, highly boiling
liquid. The problem is that even pure triethanolamine
prepared by a vacuum fractional distillation contains
impurities formed during high-temperature distillation.
When storing triethanolamine even in closed vessel in
the absence of light the coloration is strengthened [9].
H
H
O
O
H
H
−
.
O
O(O)CCH2XAr
N
+
1
It is assumed that the unique structure of com-
pounds 1 is responsible for the high physiological
activity. Thus, the ability to accelerate many times the
growth and development of microorganisms, plants and
animals make them effective biostimulators [2]. Besides,
they demonstrate antitrombotic, antisclerotic, immuno-
tropic, anticancer, antometastatic activity [2, 3, 5]. As
a consequence, compounds 1 can be used for working
out new synthetic biostimulators for agriculture, bio-
technology and microbiology, and advanced drugs. For
example, 2-methylphenyloxyacetate of tris(2-hydroxy-
ethylammonium is known as a permitted for use
The goal of this work was to work out an efficient
method for preparation of crezacine and its analogs of
pharmacopeia purity. This goal is achieved by the use
of triethanolamine hydrochloride and potassium or
sodium salts of get(aryl)chalcogenylacetic acids formed
in situ. The reaction was performed by one-pot method
in boiling methanol and ethanol during 3–4 h. The
yield and purity of the target reaction products 2–10
reach 99.8% (Scheme 1).
2227

2228
ADAMOVICH et al.
Scheme 1.
+
−
.
.
Ar−X−CH2COONa(K) + HCl N(CH2CH2OH)3
Ar−X−CH2COO HN(CH2CH2OH)3
−NaCl (KCl)
Ar = Ph (2), 2-ClC6H4 (3), 4-ClC6H4 (4), 2-HOC6H4 (5), 2-NO2C6H4 (6), 2-MeC6H4 (7), indol-3-yl (8), 1-benzylindol-3-yl
(9); X = O (2, 5, 6), S (3, 8), SO2 (4, 9), Se (10).
The novelty of the method is that instead of viscous
hygroscopic difficultly purified triethanolamine we use
solid, chemically stable easily purified by crystal-
lization triethanolamine hydrochloride, and instead of
free acids their Na(K)-salts prepared directly in the
process of the synthesis of compounds 2–10. Note that
so far no such irreversible reactions of ionic exchange
were known for triethanolamine hydrochloride.
5.6 Hz). 13С NMR spectrum (D2O), δС, ppm: 180.15
(С=О), 114.11–132.17 (С6Н4), 57.18 (ОСН2 ), 54.23
(SО2CH2), 52.99 (NCН2).
2-Hydroxyphenyloxyacetate of tris(2-hydroxyethyl)-
ammonium (5). Yield 99.7%, mp 130°C, purity
99.7%. IR spectrum, ν, cm–1: 1597 (С=О), 2210–2805
1
br (N+Н), 3315 (ОН). Н NMR spectrum (D2O), δ,
ppm: 7.46–7.22 m (4Н, С6Н4), 3.57 t (6Н, ОСН2, J =
5.6 Hz), 3.35 s (2Н, ОCН2), 3.08 t (6Н, NСН2, J =
5.6 Hz). 13С NMR spectrum (D2O), δС, ppm: 179.18
(С=О), 113.13–129.18 (С6Н4), 56.19 (ОСН2), 53.13
(ОCH2), 52.09 (NCН2).
General procedure for the synthesis of get(aryl)-
chalcogenylacetates of tris(2-hydroxyethyl)ammo-
nium (2–10). A mixture of 0.01 mol of get(aryl)-
chalogenylacetic acid and 0.01 mol of NaOH or KОН
in 30 ml of methanol or ethanol was stirred at reflux
for 1 h, then 0.01 mol of triethanolamine hydro-
chloride was added. The mixture was stirred for
another 2–3 h, then cooled to 5–10°С. The precipitate
of NaCl or KCl was filtered off, the solvent was
distilled off to obtain a solid product in the yield and
purity of 99.7–99.8%.
2-Nitrophenyloxyacetate of tris(2-hydroxyethyl)-
ammonium (6). Yield 99.7%, mp 133°C, purity
99.7%. IR spectrum, ν, cm–1: 1601 (С=О), 2200–2800
1
br (N+Н), 3310 (ОН). Н NMR spectrum (D2O), δ,
ppm: 7.71–7.11 m (4Н, С6Н4), 3.50 t (6Н, ОСН2, J =
5.6 Hz), 3.30 s (2Н, ОCН2), 3.00 t (6Н, NСН2, J =
5.6 Hz). 13С NMR spectrum (D2O), δС, ppm: 181.20
(С=О), 118.13–131.18 (С6Н4), 55.20 (ОСН2), 53.23
(ОCH2), 53.00 (NCН2).
Phenyloxyacetate of tris(2-hydroxyethyl)ammo-
nium (2). Yield 99.7%, mp 70–71°C, purity 99.7%. IR
spectrum, ν, cm–1: 1591 (С=О), 2200–2800 br (N+Н),
1
3308 (ОН). Н NMR spectrum (D2O), δ, ppm: 7.70–
2-Methylphenyloxyacetate of tris(2-hydroxyethyl)-
ammonium (7). Yield 99.8%, mp 81°C, purity 99.8%.
IR spectrum, ν, cm–1: 1598 (С=О), 2215–2809 br
7.10 m (5Н, Ph), 3.65 t (6Н, ОСН2, J = 5.6 Hz), 3.35 s
(2Н, ОCН2), 3.19 t (6Н, NСН2, J = 5.6 Hz). 13С NMR
spectrum (D2O), δС, ppm: 180.27 (С=О), 111.00–
125.05 (Ph), 56.37 (ОСН2), 53.11 (OCH2), 52.92 (NCН2).
1
(N+Н), 3310 (ОН). Н NMR spectrum (D2O), δ, ppm:
7.77–7.11 m (4Н, С6Н4), 3.57 t (6Н, ОСН2, J =
5.6 Hz), 3.33 s (2Н, ОCН2), 3.09 t (6Н, NСН2, J =
5.6 Hz), 1.80 s (3Н, Ме). 13С NMR spectrum (D2O),
δС, ppm: 181.17 (С=О), 112.11–122.15 (С6Н4), 56.07
(ОСН2), 53.11 (OCH2), 52.92 (NCН2), 23.20 (Ме).
2-Chlorophenylsulfanylacetate of tris(2-hydroxyl-
ethyl)amonium (3). Yield 99.7%, mp 90–91°C, purity
99.7%. IR spectrum, ν, cm–1: 1598 (С=О), 2210–2820
1
br (N+Н), 3310 (ОН). Н NMR spectrum (D2O), δ,
ppm: 7.77–7.12 m (4Н, С6Н4), 3.71 t (6Н, ОСН2, J =
5.6 Hz), 3.45 s (2Н, SCН2), 3.21 t (6Н, NСН2, J =
5.6 Hz). 13С NMR spectrum (D2O), δС, ppm: 179.17
(С=О), 110.10–131.15 (С6Н4), 57.27 (ОСН2), 53.00
(SCH2), 52.72 (NCН2).
1Н-Indol-3-ylsulfanylacetate of tris(2-hydroxy-
ethyl)ammonium (8). Yield 99.8%, mp 92–93°С,
purity 99.8%. IR spectrum, ν, cm–1: 1591 (С=О), 2200–
1
2800 br (N+Н), 3308 (ОН). Н NMR spectrum (D2O),
δ, ppm: 7.70–7.12 m (5Н, Ind), 3.77 t (6Н, ОСН2, J =
5.6 Hz), 3.37 s (2Н, SCН2), 3.19 t (6Н, NСН2, J =
5.6 Hz). 13С NMR spectrum (D2O), δС, ppm: 177.27
(С=О), 138.96–105.88 (Ind), 57.37 (ОСН2), 57.11
(SCH2), 50.91 (NCН2). Found, %: С 54.01; Н 6.77; N
7.80; S 9.09. С16Н24О5N2S. Calculated, %: С 53.91; Н
6.78; N 7.86; S 8.99.
4-Chlorophenylsulfonylacetate of tris(2-hydroxyl-
ethyl)ammonium (4). Yield 99.8%, mp 121°C, purity
99.8%. IR spectrum, ν, cm–1: 1602 (С=О), 2220–2830
1
br (N+Н), 3330 (ОН). Н NMR spectrum (D2O), δ,
ppm: 7.65–7.20 m (4Н, С6Н4), 3.68 t (6Н, ОСН2, J =
5.6 Hz), 3.55 s (2Н, SО2CН2), 3.18 t (6Н, NСН2, J =
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 88 No. 10 2018

NEW METHOD OF SYNTHESIS OF BIOLOGICALLY ACTIVE
1-Benzindol-3-ylsulfonylacetate of tris(2-hydro- ACKNOWLEDGMENTS
2229
xyethyl)ammonium (9). Yield 99.7%, mp 93°С,
This work was performed with the use of
equipment of the Baikal analytical center for Joint Use
of Siberian Branch of Russian Academy of Sciences.
purity 99.7%. IR spectrum, ν, cm–1: 1607 (С=О), 2200–
1
2800 br (N+Н), 3300 (ОН). Н NMR spectrum (D2O),
δ, ppm: 7.98–7.23 m (10Н, С8Н5N, С6Н5), 5.44 br. s
(2Н, СН2Ph), 4.06 br. s (2Н, SО2СН2), 3.83 t (6Н,
ОСН2, J = 5.6 Hz), 3.32 t (6Н, NСН2, J = 5.6 Hz). 13С
NMR spectrum (D2O), δС, ppm: 166.45 (С=О),
135.52–110.15 (С8Н5N, С6Н5), 63.16 (SО2СН2), 54.80
(ОСН2), 54.73 (NСН2), 49.43 (СН2Ph). Found, %: С
57.90; Н 6.11; N 5.95. С23Н30N2О5S. Calculated, %: С
57.67; Н 6.26; N 5.85.
CONFLICT OF INTERESTS
No conflict of interests was declared by the authors.
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on a Bruker DPX-400 spectrometer [400.13 (1H),
101.62 MHz (13С)], internal reference HMDS. IR
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RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 88 No. 10 2018