Biologically active ionic liquids. New analogs of acetylcholine

Full text of DOI:10.1007/s11172-012-0311-3

Russian Chemical Bulletin, International Edition, Vol. 61, No. 11, pp. 2192—2193, November, 2012
2192
Biologically active ionic liquids. New analogs of acetylcholine
S. N. Adamovich, A. N. Mirskova, R. G. Mirskov, 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
Acetylcholine, an endogenous neurotransmitter, perꢀ
methyl (6)2—4), we synthesized new analogs of acetylcholꢀ
ine with potential biological activity. The products obꢀ
tained contain either protonated cations and the Cl– anꢀ
ion (ionic liquids 7—11, m.p. 75—100 C) or alkylated
cations and the I– anion (salts 12—16, m.p. 160—193 C)
(Scheme 1).
forms one of the most vital functions in a living organism
by promoting neuromuscular transmission from its brain
and central nervous system to effector organs. This comꢀ
pound has ionic liquid structure and is commonly used as
the chloride (MeCOOCH2CH2N+Me3)•Cl–, which is
the first representative of soꢀcalled cholinomimetics.
The drugs of this group include succinic (succinylcholꢀ
ine, Quelicin) and carbamic acid esters (carbacholine).1
Another group of drugs that block cholinergic transmission
is constituted by cholinolytics containing aryl substituꢀ
ents in the ester group. They include [2ꢀ(2ꢀhydroxyꢀ
2,2ꢀdiphenylacetoxy)ethyl]trimethylammonium iodide
[Ph2C(OH)COOCH2CH2N+Me3]•I– (metacin), spasꢀ
molytin, arpenal, and thiphen.1
The structures of compounds 2—16 were confirmed using
1H and 13C NMR spectroscopy, IR spectroscopy, and elemental
analysis. IR spectra were recorded on a Varian 3100 FTꢀIR75
spectrophotometer. 1H and 13C NMR spectra were recorded on
a DPX 400 spectrometer (400.13 (1H) and 101.62 MHz (13C)) in
CDCl3 with HMDS as the internal standard. The starting arylꢀ
heteroacetic acids were prepared as described earlier.2—4
2ꢀMethylphenoxyacetyl chloride (2). Thionyl chloride (1.31 g,
0.011 mol) was added to a stirred solution of 2ꢀmethylphenoxyꢀ
acetic acid (1.66 g, 0.01 mol) in benzene (15 mL). The reaction
mixture was heated at 80 C for 3 h until SO2 ceased to evolve.
The solvent was removed and the residue was dried in vacuo.
Yield 2.51 g (79%), a colorless powder soluble in diethyl ether
and benzene, m.p. 135 C. 1H NMR, : 7.09—6.71 (m, 4 H,
C6H4); 4.63 (s, 2 H, OCH2); 2.20 (s, 3 H, Me). 13C NMR,
In the present work, starting from (2ꢀhydroxyethyl)ꢀ
dimethylamine (1) and various acyl chlorides RC(O)Cl
(R = 2ꢀmethylphenoxymethyl (2), 4ꢀchlorophenylsulꢀ
fanylmethyl (3), 4ꢀchlorophenylsulfonylmethyl (4), indolꢀ
3ꢀylsulfanylmethyl (5), and 1ꢀbenzylindolꢀ3ꢀylsulfanylꢀ
Scheme 1
i. H2O, 10% NaOH.
R =
(2, 7, 12),
(3, 8, 13),
(6, 11, 16)
(4, 9, 14),
(5, 10, 15),
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 11, pp. 2175—2176, November, 2012.
1066ꢀ5285/12/6111ꢀ2192 © 2012 Springer Science+Business Media, Inc.

New analogs of acetylcholine
Russ.Chem.Bull., Int.Ed., Vol. 61, No. 11, November, 2012 2193
: 170.90 (C=O); 154.38—111.86 (C6H4); 64.55 (OCH2); 14.52
(Me). IR, /cm–1: 1760 (C=O). Found (%): C, 58.64; H, 4.70;
Cl, 19.49. C9H9ClO2. Calculated (%): C, 58.55; H, 4.91; Cl, 19.20.
Acid chlorides 3—6 were obtained from appropriate acids as
described for compound 2.
4ꢀChlorophenylsulfanylacetyl chloride (3). Yield 71%, colorꢀ
less liquid, b.p. 113—115 C (1 mmHg). 1H NMR, : 7.19—6.67
(m, 4 H, C6H4); 3.70 (s, 2 H, SCH2). 13C NMR, : 175.12 (C=O);
156.07—111.75 (C6H4); 49.50 (SCH2). IR, /cm–1: 1780 (C=O).
Found (%): S, 14.25; Cl, 32.20. C8H6Cl2OS. Calculated (%):
S, 14.50; Cl, 32.06.
3.77 (t, 2 H, OCH2); 3.45 (s, 2 H, SCH2); 3.27 (t, 2 H, NCH2);
2.88 (s, 6 H, N+Me2). 13C NMR, : 177.79 (C=O); 138.00—104.95
(Ph, Ind); 58.16 (OCH2); 54.58 (NCH2); 44.00 (SCH2); 42.15
(N+Me2). IR, /cm–1: 1756 (C=O); 2510—2785 (N+H).
Trimethyl[2ꢀ(2ꢀmethylphenoxyacetoxy)ethyl]ammonium iodꢀ
ide (12). A suspension of compound 7 in water was alkalified
with 10% NaOH to pH 9 (NaCl remained dissolved). The preꢀ
cipitate that formed was filtered off, repeatedly washed with
water, dissolved in acetone, and dried with Na2SO4. Then MeI
(1.55 g, 0.011 mol) was added and the reaction mixture was
stirred at 20 C for 18 h. The precipitate that formed was filtered
off, washed with acetone, and dried in vacuo. Yield 78%, a powꢀ
der soluble in EtOH and water, m.p. 180—181 C. 1H NMR,
: 7.12—6.77 (m, 4 H, C6H4); 4.43 (s, 2 H, OCH2COO); 3.90 (t, 2 H,
OCH2); 3.39 (t, 2 H, NCH2); 2.89 (s, 9 H, N+Me3); 2.20 (s, 3 H,
Me). 13C NMR, : 175.91 (C=O); 149.30—111.11 (C6H4); 65.31
(OCH2COO); 58.20 (OCH2); 55.58 (NCH2); 53.15 (N+Me3);
14.39 (CH3C6H4). IR, /cm–1: 1760 (C=O). Found (%): C, 44.63;
H, 5.58; N, 3.59. C14H22INO3. Calculated (%): C, 44.34;
H, 5.84; N, 3.69.
4ꢀChlorophenylsulfonylacetyl chloride (4). Yield 90%, powder,
1
m.p. 75—76 C. H NMR, : 7.21—6.66 (m, 4 H, C6H4); 4.44
(s, 2 H, SO2CH2). 13C NMR, : 177.00 (C=O); 160.07—111.11
(C6H4); 64.00 (SO2CH2). IR, /cm–1: 1135 ( (SO2)); 1362
s
(as(SO2)); 1777 (C=O). Found (%): S, 12.70; Cl, 28.25.
C8H6Cl2O3S. Calculated (%): S, 12.66; Cl, 28.01.
Indolꢀ3ꢀylsulfanylacetyl chloride (5). Yield 76%, pink powꢀ
der, m.p. 69—70 C. 1H NMR, : 7.77—7.10 (m, 5 H, Ind); 3.45
(s, 2 H, SCH2). 13C NMR, : 176.11 (C=O); 137.18—104.35
(Ind); 44.79 (SCH2). IR, /cm–1: 1778 (C=O).
Iodides 13—16 were obtained from MeI and appropriate
chlorides 8—11 as described for compound 12.
[2ꢀ(4ꢀChlorophenylsulfanylacetoxy)ethyl]trimethylammonium
iodide (13). Yield 77%, powder, m.p. 160—163 C. 1H NMR,
1ꢀBenzylindolꢀ3ꢀylsulfanylacetyl chloride (6). Yield 85%,
powder, m.p. 72 C. 1H NMR, : 7.75—6.91 (m, 10 H, Ph, Ind);
5.22 (s, 2 H, PhCH2); 3.41 (s, 2 H, SCH2). 13C NMR, : 177.01
(C=O); 138.08—105.55 (Ph, Ind); 46.90 (SCH2). IR, /cm–1
1780 (C=O).
:
: 7.42—6.70 (m, 4 H, C6H4); 3.18 (s, 2 H, SCH2); 3.78 (t, 2 H,
OCH2); 3.29 (t, 2 H, NCH2); 2.87 (s, 9 H, N+Me3). IR, /cm–1
:
Dimethyl[2ꢀ(2ꢀmethylphenoxyacetoxy)ethyl]ammonium chlorꢀ
ide (7). Solutions of compounds 2 (1.84 g, 0.01 mol) and 1 (0.89 g,
0.01 mol) in diethyl ether were mixed and stirred at 35 C for 3 h.
The precipitate that formed was filtered off, washed with diethyl
ether, and dried in vacuo. Yield 1.99 g (72 %), a colorless powder
soluble in water and EtOH, m.p. 100—104 C. 1H NMR,
: 7.19—6.74 (m, 4 H, C6H4); 4.45 (s, 2 H, OCH2COO); 3.82
(t, 2 H, OCH2); 3.21 (t, 2 H, NCH2); 2.85 (s, 6 H, N+Me2); 2.19
(s, 6 H, Me). 13C NMR, : 177.90 (C=O); 150.30—111.10
(C6H4); 66.37 (OCH2COO); 58.16 (OCH2); 54.58 (NCH2);
42.15 (N+Me2); 14.52 (CH3C6H4). IR, /cm–1: 1757 (C=O);
2475—2690 (N+H). Found (%): C, 57.30; H, 7.08; Cl, 13.19.
C13H20ClNO3. Calculated (%): C, 57.03; H, 7.36; Cl, 12.95.
Chlorides 8—11 were obtained from alcohol 1 and appropriꢀ
ate acid chlorides 3—6 as described for compound 7.
1760 (C=O).
[2ꢀ(4ꢀChlorophenylsulfonylacetoxy)ethyl]trimethylammonium
iodide (14). Yield 75%, m.p. 172—174 C. 1H NMR, : 7.42—6.70
(m, 4 H, C6H4); 4.55 (s, 2 H, SO2CH2); 3.80 (t, 2 H, OCH2);
3.32 (t, 2 H, NCH2); 2.87 (s, 9 H, N+Me3). IR, /cm–1: 1185
( (SO2)); 1333 ( (SO2)); 1755 (C=O).
s
as
[2ꢀ(Indolꢀ3ꢀylsulfanylacetoxy)ethyl]trimethylammonium iodꢀ
ide (15). Yield 70%, pink powder, m.p. 190—193 C. 1H NMR,
: 7.80—7.15 (m, 5 H, Ind); 3.73 (t, 2 H, OCH2); 3.40 (s, 2 H,
SCH2); 3.25 (t, 2 H, NCH2); 2.88 (s, 9 H, N+Me3). IR, /cm–1
:
1749 (C=O).
[2ꢀ(1ꢀBenzylindolꢀ3ꢀylsulfanylacetoxy)ethyl]trimethylamꢀ
monium iodide (16). Yield 71%, red powder, m.p. 178—179 C.
1H NMR, : 7.70—7.01 (m, 10 H, Ph, Ind); 3.80 (t, 2 H, OCH2);
3.44 (s, 2 H, SCH2); 3.35 (t, 2 H, NCH2); 2.88 (s, 9 H, N+Me3).
IR, /cm–1: 1741 (C=O).
[2ꢀ(4ꢀChlorophenylsulfanylacetoxy)ethyl]dimethylammonium
chloride (8). Yield 64%, colorless powder, m.p. 98 C. IR, /cm–1
:
1760 (C=O); 2500—2710 (N+H). Found (%): Cl, 22.56; N, 4.38;
S, 10.19. C12H17Cl2NO2S. Calculated (%): Cl, 22.85; N, 4.51;
S, 10.33.
References
1. M. D. Mashkovskii, Lekarstvennye veshchestva [Drugs],
Novaya Volna, Moscow, 2000, 14th ed., Vols 1, 2 (in Russian).
2. A. N. Mirskova, G. G. Levkovskaya, O. P. Kolesnikova, O. M.
Perminova, E. V. Rudyakova, S. N. Adamovich, Russ. Chem.
Bull. (Int. Ed.), 2010, 59, 2236 [Izv. Akad. Nauk, Ser. Khim.,
2010, 2181].
[2ꢀ(4ꢀChlorophenylsulfonylacetoxy)ethyl]dimethylammonium
chloride (9). Yield 51%, m.p. 80—82 C. IR, /cm–1: 1180
( (SO2)); 1330 ( (SO2)); 1740 (C=O); 2450—2680 (N+H).
s
as
Found (%): Cl, 22.56; N, 4.38; S, 10.19. C12H17Cl2NO2S. Calꢀ
culated (%): Cl, 22.85; N, 4.51; S, 10.33.
[2ꢀ(Indolꢀ3ꢀylsulfanylacetoxy)ethyl]dimethylammonium chlorꢀ
ide (10). Yield 52%, a pink hygroscopic powder with no definite
melting point. 1H NMR, : 7.70—7.12 (m, 5 H, Ind); 3.70 (t, 2 H,
OCH2); 3.39 (s, 2 H, SCH2); 3.49 (t, 2 H, NCH2); 2.88 (s, 6 H,
N+Me2). 13C NMR, : 178.19 (C=O); 137.07—105.05 (Ind);
57.46 (OCH2); 55.55 (NCH2); 43.09 (SCH2); 41.19 (N+Me2).
IR, /cm–1: 1749 (C=O); 2505—2800 (N+H).
3. O. P. Kolesnikova, A. N. Mirskova, S. N. Adamovich, O. T.
Kudaeva, R. G. Mirskov, M. G. Voronkov, Byull. Sib. Otd.
Russ. Akad. Med. Nauk [Bulletin of the Siberian Branch of the
Russian Academy of Medical Sciences], 2010, 12 (in Russian).
4. A. N. Mirskova, R. G. Mirskov, S. N. Adamovich, M. G.
Voronkov, Khim. v Interesakh Ustoich. Razvit., 2011, 467
[Chem. Sustain. Dev., 2011, 19 (Engl. Transl.)].
[2ꢀ(1ꢀBenzylindolꢀ3ꢀylsulfanylacetoxy)ethyl]dimethylamꢀ
monium chloride (11). Yield 51%, reddish powder, m.p. 75—79 C.
1H NMR, : 7.76—6.08 (m, 10 H, Ph, Ind); 5.20 (s, 2 H, PhCH2);
Received June 13, 2012;
in revised form November 2, 2012