Biologically active protic (2-hydroxyethyl)ammonium ionic liquids. Liquid aspirin

Full text of DOI:10.1007/s11172-012-0172-9

Russian Chemical Bulletin, International Edition, Vol. 61, No. 6, pp. 1260—1261, June, 2012
1260
Letters to the Editor
Biologically active protic (2ꢀhydroxyethyl)ammonium ionic liquids.
Liquid aspirin
S. N. Adamovich, R. G. Mirskov, A. N. Mirskova, and M. G. Voronkov
A. E. Favorsky Irkutsk Institute of Chemistry, Siberian Branch of the Russian Academy of Sciences,
1 ul. Favorskogo, 664033 Irkutsk, Russian Federation.
Eꢀmail: mir@irioch.irk.ru
In recent years, avalancheꢀlike growth of publications
takes place in the field of chemistry and application of
ionic liquids (ILs), which is the most important part of
green chemistry1—15. However, biological properties of ILs
are still to be investigated16. Protonated Nꢀ(2ꢀhydroxyꢀ
ethyl)ꢀcontaining amines, which comprise cations of bioꢀ
genic amines and anions of bioactive organic acids, are
promising biologically and pharmacologically active comꢀ
pounds. A typical example of this type of ILs is the reꢀ
cently described Nꢀ(2ꢀhydroxyethyl)ammoniumformate
[HOCH2CH2NH3+]•[HCOO–] with a freezing point of
–82 C. However, it was recommended only as a solvent
for inorganic salts and polymers17.
In the present work, reactions of tris(2ꢀhydroxyethyl)ꢀ,
bis(2ꢀhydroxyethyl)ꢀ, N,Nꢀbis(2ꢀhydroxyethyl)ꢀ Nꢀmethꢀ
ylꢀ, and Nꢀ(2ꢀhydroxyethyl)ꢀN,Nꢀdimethylamines with
Oꢀacetylsalicylic acid (ASA, aspirin) were investigated,
and novel ionic liquids 1—4 were obtained, which are liquid
waterꢀsoluble derivatives of aspirin, suitable for intraveꢀ
nous injection and exhibiting antiꢀinflammation activity.
Salts 1—4 were synthesized as viscous colorless or pale
yellow liquids in up to 99% yields from Nꢀ(2ꢀhydrꢀ
oxyethyl)amines and ASA taken in equimolar ratio at
50—70 C in methanol. In contrast to aspirin, salts 1—4
n = 3 (1); R = H, n = 2 (2); R = Me, n = 2 (3); R = Me, n = 1 (4)
are waterꢀ and physiological salineꢀsoluble, nonꢀtoxic
(intraꢀperitoneal LD50 of compounds 1—4 for albino
mice 2000 mg kg–1 in comparison to LD50 of ASA
1430 mg kg–1).
In hemocoagulation studies compounds 1 and 4 were
found to show highest activity. Being injected in blood
plasma in concentration 5•10–3 g mL–1 they strongly
inhibited fibrin clot formation. Antiꢀinflammation activity
of salts 1 and 4 was studied on the rabbit model of rheuꢀ
matoid arthritis with the intraꢀarticular injection of the
antigen. Solutions of 1 and 4 (1.5 mL, 10% in saline, 3 inꢀ
jections) were injected into the affected knee joints. This
resulted in fever reduction, and ESR and protein fractions
returned to normal values. Primary histological examination
showed dramatic reduction of inflammation. It should be
noted that activity of compound 1 was higher than that of 4.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 6, pp. 1246—1247, June, 2012.
1066ꢀ5285/12/6106ꢀ1260 © 2012 Springer Science+Business Media, Inc.

Russ.Chem.Bull., Int.Ed., Vol. 61, No. 6, June, 2012
1261
Protic (2ꢀhydroxyethyl)ammonium ionic liquids
IRꢀspectra were recorded on a Varian 3100FTꢀIR75 specꢀ
trophotometer. NMR spectra (CD3OD) were recorded on
a DPXꢀ400 spectrometer (1H, 400.13 MHz; 13C, 101.62 MHz;
15N, 40.53 MHz) with hexamethyldisiloxane (HMDS) as an inꢀ
ternal standard. Alkanolamines were purified by triple distillaꢀ
tion, and ASA — by double recrystallization from hot water.
Tris(2ꢀhydroxyethyl)ammonium salicylate (1). Solution of
1.49 g (0.01 mol) of triethanolamine in 10 mL of methanol was
added dropwise to the solution of 1.8 g (0.01 mol) of ASA in
10 mL of methanol, and the mixture was stirred for 1 h under
reflux. Then the solvent was removed under vacuum. The resiꢀ
due was washed with ether and dried under vacuum over P2O5.
Yield 3.28 g (99%), colorless transparent oil. 1H NMR, :
7.28—6.77 (m, 4 H, C6H4); 5.28 (br.s, 3 H, OH); 3.85 (t, 6 H,
OCH2); 3.33 (t, 6 H, NCH2); 2.00 (s, 3 H, CH3COO). 13С NMR,
: 175.14 (COOH); 172.29 (CH3COO); 162.76—117.44 (C6H4);
59.09 (OCH2); 56.95 (NCH2), 19.90 (CH3COO). 15N NMR,
: –338.8 (referenced to CH3NO3). IR, /cm–1: 1626, 1590 (C=O),
2400—2550 (N+H); 3353 (OH). Found (%): C, 54.99; H, 7.33;
N, 4.37. C15H23O7N. Calculated (%): C, 54.70; H, 7.03; N, 4.25.
Bis(2ꢀhydroxyethyl)ammonium salicylate (2) was obtained
from ASA and diethanolamine using the same procedure as for
H, 6.82; N, 5.14. C13H19O5N. Calculated (%): C, 57.98; H, 7.11;
N, 5.20.
This work was financially supported by Presidium of
Russian Academy of Sciences (Program No. 21 "Fundaꢀ
mental sciences — for medicine").
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1
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: 7.32—6.70 (m, 4 H, C6H4); 5.31 (br.s, 2 H, OH); 3.88 (t, 4 H,
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(CH3COO). 15N NMR, : –341.2. IR, /cm–1: 1627, 1590
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the same procedure as for compound 1, yield 90%, oil. 1H NMR,
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OCH2); 3.32 (t, 2 H, NCH2); 2.88 (s, 6 H, NCH3); 2.01 (s, 3 H,
CH3COO). 13С NMR, : 175.94 (COOH); 162.49 (CH3COO);
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(CH3COO). 15N NMR, : –346.1. IR, /cm–1: 1628, 1591
(C=O); 2400—2520 (N+H); 3378 (OH). Found (%): C, 58.28;
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Received November 14, 2011