The β-cyclodextrin cationic derivatives containing residues of some pharmacologically important acids

Article abstract of DOI:10.1134/S1070363210090161

The cationic derivatives of β-cyclodextrin containing residues of covalently bound pharmacologically important acids were obtained by alkylation of nucleophilic reagents with 6-halo-6-deoxy-β-cyclodextrin.

Full text of DOI:10.1134/S1070363210090161

ISSN 1070-3632, Russian Journal of General Chemistry, 2010, Vol. 80, No. 9, pp. 1812–1818. © Pleiades Publishing, Ltd., 2010.
Original Russian Text © M.K. Grachev, A.A. Charaev, G.I. Kurochkina, L.K. Vasyanina, V.N. Shmelev, E.E. Nifant’ev, 2010, published in Zhurnal Obshchei
Khimii, 2010, Vol. 80, No. 9, pp. 1494–1500.
The β-Cyclodextrin Cationic Derivatives Containing Residues
of Some Pharmacologically Important Acids
M. K. Grachev, A. A. Charaev, G. I. Kurochkina,
L. K. Vasyanina, V. N. Shmelev, and E. E. Nifant’ev
Moscow State Pedagogical University, Nesvizhskii per. 3, Moscow, 119021 Russia
e-mail: chemdept@mtu-net.ru
Received October 1, 2009
Abstract―The cationic derivatives of β-cyclodextrin containing residues of covalently bound pharmacol-
ogically important acids were obtained by alkylation of nucleophilic reagents with 6-halo-6-deoxy-β-cyclodextrin.
DOI: 10.1134/S1070363210090161
Among the numerous β-cyclodextrin compounds,
its cationic derivatives with increased water solubility
and other practically important properties inherent to
alkylammonium (“charged”) amphiphilic cyclodextrins
attract special attention [1]. For the preparation of
appropriate cationic derivatives the respective deriva-
tives of 6-azido-6-dezoxy derivatives of cyclodextrins
were often used, whose treating with triphenyl-
phosphine in aqueous ammonia gave ammonium
derivatives [2]. However, this method is suitable for
primary alkylammonium cyclodextrin derivatives.
Previously we have shown to be promising the direct
synthesis of cationic derivatives by alkylation of a
suitable amine by either cyclodextrin per-6-deoxy-per-
6-bromo- [3] or deoxy-derivatives bearing a smaller
number of bromine atoms [4]. In the latter case, the
difficulty lies in the fact that although the preparation
of per-6-deoxy-6-halocyclodextrins can be reached
well using Reiden [5] or Vilsmeier–Haack [6] re-
agents, the synthesis of cyclodextrins containing fewer
halogen atoms requires another approach, for example,
the application of tosyl and silyl derivatives [7]. It is
important that, in contrast to the classical alkylation of
amines by alkyl halides, the hydrophobic cavity of
cyclodextrin exerts a specific (supramolecular) in-
fluence on the course of the alkylation [4] and an indi-
vidual approach to the development of the methods for
the alkylation by 6-halodeoxycyclodextrins is required.
important acids: 1-(4-isobutylphenyl)propionic acid
(IV, H-Y) (the pharmaceutical in “Ibuprofen” drug),
acetylsalicylic acid (V, H-W) (medicinal drug
“Aspirin”), benzoic acid (VI, H-Z) and p-amino-
benzoic acid (VII), on the basis of cyclodextrin 6-halo
derivatives. Previously we have obtained conjugates
with some of these compounds, that is, the covalently
bound residues of acids (IV) and (V) to the
cyclodextrin skeleton [8], and showed their potential
for further pharmacological studies [9]. In continuation
of this trend is of interest to join the drug residue to the
cationic fragment of the cyclodextrin core using so-
called spacers (legs or hands), among which were
selected 1,2-N,N-dimethylaminoethanol (VIII) and
1,3-N,N-dimethylaminopropanol (IX). It is assumed
that by changing length (n) and the nature of the legs a
better embedding of the drug carrier in the lipid matrix
can be achieved and can facilitate the overcoming the
biological barriers [10]. Note also that the benefits of
our proposed direction of synthesis is the lack of
necessity to protect the secondary hydroxy groups and
the subsequent removing the protection, so that the
broad part cyclodextrin skeleton remains free for the
inclusion of various guests, for example of those
possessing other pharmacological action, that extends
medical application of the studied structures.
For the synthesis of halo-derivatives I–III, we used
different approaches: per-6-bromo-per-6-deoxy-β-cyclo-
dextrin (I) was obtained using Vilsmeier–Haack reagent
[6], tetra-6-bromo-tetra-6-deoxy-β-cyclo-dextrin (II) was
prepared through β-cyclodextrin silyl derivative [7],
In this paper, we set a target to examine the
preparation of cationic derivatives of cyclodextrins I–
III containing residues of some pharmacologically
1812

THE β-CYCLODEXTRIN CATIONIC DERIVATIVES
1813
and tri-6-iodine-tri-6-deoxy-β-cyclo-dextrin (III) was
obtained using the β-cyclodextrin tosyl derivative (see
Experimental).
(I) and iodo-derivatives (III) with amino derivatives X
and XII at 80°C for 6 hours with the yield of the
product XVI–XVIII of 76–81%. At the shorter
reaction duration (3 h) a significant amount of the non-
reacted cyclodextrin halo derivative remains in the
reaction mass. The longer exposure of the reaction
mixture to 80°C does not lead to a substantial increase
in conversion. Therefore, further syntheses of
compounds XIX–XVIII we carried out at a higher
temperature (135°C) and at the reaction duration 39 h.
Under these conditions the alkylation by the
cyclodextrin derivatives I–III of the amino derivatives
X–XV proceeds with an average degree m = 2
(compounds XIX–XXVIII). Longer heating at this
temperature does not lead to a significant increase in
the degree of alkylation.
Nucleophilic reagents X–XV for the alkylation,
containing terminal dimethylamino group and the
residues of drugs IV–VI we obtained through pro-
cessing aminoalcohol VIII or IX with the correspond-
ing acid chloride in benzene in the presence of sodium
hydrogen carbonate. Compounds X–XV were isolated
1
in the individual state and characterized by H NMR
spectroscopic data, TLC, and elemental analysis.
(HO)7−m
( X)m
Me2N−(CH2)n−Y(W,Z)
X−XV
(OH
OH)7
I−III
X−
+
I, X = Br, m = 7; II, X = Br, m = 4; III, X = I, m = 3; X,
n = 2, Y; XI, n = 2, W; XII, n = 2, Z; XIII, n = 3, Y; XIV,
n = 3, W; XV, n = 3, Z.
(X
N−(CH2)n−Y(W,Z)
)
p
(HO)7−(m+p)
Me2
m
I−III + X−XV
The central point of the investigation is selecting
the conditions for the alkylation of the terminal amino
group of compound X–XV or acid VII by the
cyclodextrin halo derivative I–III. The reaction was
carried out in DMF (in other solvents the halo
derivatives I–III are poorly soluble) at 135°C (80°C),
using a large excess of amine X–XV. The product of
alkylation was precipitated by adding diethyl ether,
washed with acetone, dried in a vacuum1 and its
OH
OH
XVI, X = Br, n = 2, m = 1, p = 6, Y; XVII, X = Br, n = 3,
m = 1, p = 6, Y; XVIII, X = I, n = 3, m = 1, p = 2, Y; XIX,
X = Br, n = 2, m = 2, p = 5, Y; XX, X = Br, n = 3, m = 2,
p = 5, Y; XXI, X = Br, n = 2, m = 2, p = 5, W; XXII, X =
Br, n = 3, m = 2, p = 5, W; XXIII, X = Br, n = 2, m = 2,
p = 2, Y; XXIV, X = Br, n = 3, m = 2, p = 2, Y; XXV, X =
Br, n = 2, m = 2, p = 2, W; XXVI, X = Br, n = 3, m = 2,
p = 2, W; XXVII, X = Br, n = 2, m = 2, p = 2, Z; XXVIII,
X = Br, n = = 3, m = 2, p = 2, Z.
1
individuality was analyzed by methods of H NMR
spectroscopy, TLC, and elemental analysis.
CH2CH(CH3)2;
Y, OC(O)CH(CH3)
Processing amino acids VII with per- (I) and
tetrabromo- (II) cyclodextrin derivatives also resulted
in the degree of alkylation m = 2, with the formation of
the corresponding ammonium derivatives XXIX and
XXX.
Z, OC(O)
;
.
W, OC(O)
AcO
The average degree of alkylation (m) was estimated
from the data of H NMR spectroscopy by comparing
Br−
1
+
(Br
(HO)7−(p+2)
COOH
N
H2
integral intensities of the signals of cyclodextrin
skeleton protons at 3.22–3.90 ppm with the integral
intensity of N-methyl protons at 2.81 ppm. It turned
out that the average degree of alkylation m = 1 is
reached only in the reaction of β-cyclodextrin bromo-
)
p
2
VII
I, II
OH
OH
1
XXIX, XXX
Another possibility of amine alkylation by per-6-bromo-per-6-
deoxy-β-cyclodextrin was described in the literature, but for
simpler amines and under the other conditions [11].
XXIX, p = 5; XXX, p = 2.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 80 No. 9 2010

1814
GRACHEV et al.
Analyzing the results, we have to note that under
2-N,N-Dimethylaminoethyl 1-(4-isobutylphenyl)-
propionate (X). To a solution of 5.00 g of acid
chloride IV in 10 ml of benzene was added dropwise at
stirring 2.00 g of amino derivative VIII in 25 ml of
benzene. The stirring was continued at 20ºС for 3 h,
30 ml of benzene was added and the stirring was
continued at 20ºС for 24 h. To the reaction mixture
was added 10 ml of saturated solution of NaHCO3, the
mixture was stirred, then the benzene layer was
separated, dried over СaCl2, the solvent was then
removed and the residue was maintained at 60ºС for 5
h in a vacuum (1 mm Hg). Yield of compound X2 5.20
these conditions of synthesis of compounds XIX–
XXX the found average degree of alkylation (m = 2)
corresponds to the maximum, despite the presence of a
large excess of amine. Use of iodine derivative III
instead of bromo compound did not lead to a higher
degree of alkylation. Apparently, this is a result of the
complex competitive, including supramolecular, inter-
acttions of the solvent (DMF), reagents, reaction
products with the cyclodextrin cavity. For example, it
was also noted in [11] that the alkylation of amines by
per-6-bromo-per-6-deoxycyclodextrin in DMF medium
is incomplete.
1
g (84%), Rf 0.45 (B). The Н NMR spectrum (DMSO-
d6), δ, ppm (J, Hz): 0.84 d [6H, HC(CH3)2, 3JHH 6.4],
1.36 d [3H, (O)CCHCH3, 3JHH 7.0], 1.73–1.86 m (1H,
CH2CH), 2.07 s [6H, N(CH3)2], 2.34–2.43 m (4H;
C6H4CH2 , NCH2), 3.72 q [1H, (O)CCHCH3, 3JHH 7.1],
4.07 t (2H, CH2O, 3JHH 5.6), 7.09 d (2H, C6HorthoCH2,
3JHH 7.8), 7.18 d (2H, C6HmetaCH2, 3JHH 8.0). Found, %:
C 74.02; H 9.56. C17H27NO2. Calculated, %: C 73.61;
H 9.81.
Thus, we investigated new possibilities of alkyla-
tion of nucleophilic reagents bearing terminal dimethyl-
amino group by 6-halo-6-deoxy-β-cyclodextrin, and on
this basis proposed practical ways of synthesis of β-
cyclodextrin cationic derivatives of different struc-
tures, containing residues of covalently bound pharma-
cologically important acids that are interesting for
biomedical research in various aspects.
2-N,N-Dimethylaminoethyl acetylsalicylate (XI)
was synthesized by analogy to compound X from
5.00 g of acid chloride V and 2.24 g of amino
derivative VIII. Yield of compound XI 5.26 g (83%),
EXPERIMENTAL
All experiments were carried out in anhydrous
solvents purified by standard methods.
1H NMR spectra were recorded on a spectrometer
JNM-ECX400 (400 MHz), external reference TMS.
1
Rf 0.57 (B). The Н NMR spectrum (DMSO-d6), δ,
ppm (J, Hz): 2.16 s [6H, N(CH3)2], 2.26 s [3H,
3
C(O)CH3], 2.54 t (2H, NCH2, JHH 6.0), 4.27 t (2H,
3
3
For thin layer chromatography aluminum plates
were used with fixed layer of silica gel (Silufol UV-
254), eluents methanol–chloroform 3:1 (A), benzene–
dioxane 3:1 (B), benzene–dioxane–water 1:10:1 (C).
CH2O, JHH 5.8), 7.19 d [1H, C6HorthoC(O), JHH 7.8],
3
7.37 t [1H, C6HparaC(O), JHH 6.4], 7.62 t [1H,
3
C6HmetaC(O), JHH 6.8], 7.91 d [1H, C6HorthoOC(O),
3JHH 6.4]. Found, %: C 61.81; H 7.13. C13H17NO4.
Calculated, %: C 62.14; H 6.82.
We used β-cyclodextrin from “Wacker” (USA)
subjected to thorough dehydration.
2-N,N-Dimethylaminoethyl benzoate (XII) was
synthesized by analogy to compound X from 5.00 g of
acid chloride VI and 3.17 g of amino derivative VIII.
Yield of compound XII 5.75 g (84%), Rf 0.49 (B). The
1Н NMR spectrum (DMSO-d6), δ, ppm (J, Hz): 2.10 s
[6H, N(CH3)2], 2.30 t (2H, NCH2, 3JHH 6.9), 4.29 t (2H,
Tri-6-iodo-tri-6-deoxy-β-cyclodextrin (III). To a
solution of 0.51 g of tri-6-О-tosyl-tri-6-deoxy-β-
cyclodextrin [7] in 15 ml of DMF was added at stirring
0.32 g of potassium iodide, and the mixture was
maintained at 55ºС for 48 h. The reaction mixture was
evaporated to syrupy state and poured at stirring in
50 ml of acetone. The precipitate formed was
separated, washed with water (2×5 ml), stirred, and
ground with 4 ml of chloroform. The solvent was
removed, and the residue was dried at 60ºС for 3 h in a
vacuum (1 mm Hg). Yield of compound III 0.34 g
3
3
CH2O, JHH 6.5), 7.50 t [2H, C6HmetaC(O), JHH 7.4],
3
7.65 t [1H, C6HparaC(O), JHH 6.4], 7.95 d [2H,
3
C6HorthoC(O), JHH 7.4]. Found, %: C 68.07; H 8.03.
C11H15NO2. Calculated, %: C 68.37; H 7.82.
3-N,N-Dimethylaminopropyl 1-(4-isobutylphenyl)-
propionate (XIII) was synthesized by analogy to
compound X from 5.00 g of acid chloride IV and
2.30 g of amino derivative IX. Yield of compound
XIII 5.54 g (85%), Rf 0.40 (B). The 1Н NMR spectrum
1
(71%), mp 192–194ºС (decomp.), Rf 0.65 (А). The Н
NMR spectrum, DMSO-d6, δ, ppm: 3.08–3.96 m (42Н;
С2Н–С5Н, С6Н2), 4.79–5.20 m (11Н; С6ОН, С1Н),
5.62–6.20 m (14Н; С2ОН, С3ОН). Found, %: C 34.12;
H 4.95. C42H67I3O32. Calculated, %: C 34.44; H 4.61.
2
Compounds X–XV are viscous light yellow oily liquids.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 80 No. 9 2010

THE β-CYCLODEXTRIN CATIONIC DERIVATIVES
1815
(DMSO-d6), δ, ppm (J, Hz): 0.89 d [6H, HC(CH3)2,
3JHH 6.5], 1.48 d [3H, (O)CCHCH3, 3JHH 7.1], 1.64–
1.91 m (3H; CH2CH, CH2CH2CH2), 2.08–2.32 m [8H;
N(CH3)2, NCH2], 2.44 d (2H, C6H4CH2, 3JHH 7.1), 3.67
q [1H, (O)CCHCH3, 3JHH 7.1], 4.12 t (2H, CH2O, 3JHH
5.7), 7.08 d (2H, C6HorthoCH2, 3JHH 7.9), 7.20 d (2H,
C6HmetaCH2, 3JHH 7.9). Found, %: C 74.53; H 6.86.
C18H29NO2. Calculated, %: C 74.18; H 7.03.
CHCH2), 3.32 s [6Н, N(СН3)2], 3.47–4.16 m [45Н;
С2Н–С5Н, С6Н2, (O)CCHCH3, CH2O], 4.82–5.00 br.s
(7Н, С1Н), 5.62–6.08 m (14Н; С2ОН, С3ОН), 7.08–
7.43 m (4Н, CHarom). Found, %: C 38.54; H 4.68.
C59H90Br7NO30. Calculated, %: C 38.25; H 4.90.
Mono-6-({3-О-[1-(4-isobutylphenyl)propanoyl]-
propyleneoxy-1-yl}dimethylammonium bromide)hexa-
6-bromo-hepta-6-deoxy-β-cyclodextrin (XVII) was
synthesized by analogy to compound XVI from 0.20 g
of the cyclodextrin halo derivative (I) and 0.55 g of the
nucleophilic reagent XIII. Yield of compound XVII
0.19 g (81%), mp 179–180ºС (decomp.), Rf 0.73 (C).
3-N,N-dimethylaminopropyl acetylsalicylate (XIV)
was synthesized by analogy to compound X from
5.00 g of acid chloride V and 2.60 g of amino
derivative IX. Yield of compound (XIV) 5.65 g (85%),
1
1
The Н NMR spectrum (DMSO-d6), δ, ppm (J, Hz):
Rf 0.51 (B). The Н NMR spectrum (DMSO-d6), δ,
0.84 d [6Н, СН(СН3)2, 3JHH 6.5], 1.38 d [3Н, (O)
CCHCH3, 3JHH 7.1], 1.71–2.15 m [3Н; СН2СН2СН2,
СН(СН3)2], 2.73–2.87 m (4Н; NСН2, CHCH2), 3.36 s
[6Н, N(СН3)2], 3.39–3.95 m [43Н; С2Н–С5Н, С6Н2,
(O)CCHCH3], 4.05 t (2Н, CH2O, 3JHH 6.0), 4.78–5.40
m (21Н; С1Н, С2ОН, С3ОН), 7.10 d (2H, C6HorthoCH2,
3JHH8.2), 7.19 d (2H, C6HmetaCH2, 3JHH 8.0). Found, %:
C 38.23; H 5.19. C60H92Br7NO30. Calculated, %: C
38.61; H 4.97.
ppm (J, Hz): 1.81 m (2H, CH2CH2CH2), 2.16 s [6H,
N(CH3)2], 2.28 s [3H, C(O)CH3], 2.35 t (2H, NCH2,
3
3JHH 7.1), 4.25 t (2H, CH2O, JHH 6.5), 7.23 d [1H,
C6HorthoC(O), 3JHH 8.1], 7.40 t [1H, C6HparaC(O), 3JHH
7.6], 7.67 t [1H, C6HorthoOC(O), 3JHH 7.7], 7.94 d [1H,
3
C6HmetaC(O), JHH 7.8]. Found, %: C 62.99; H 7.50.
C14H19NO4. Calculated, %: C 63.38; H 7.22.
3-N,N-dimethylaminopropyl benzoate (XV) was
synthesized by analogy to compound X from 5.00 g of
acid chloride VI and 3.67 g of amino derivative IX.
Yield of compound XV 6.17 g (84%), Rf 0.57 (B). The
1Н NMR spectrum (DMSO-d6), δ, ppm (J, Hz): 1.83 m
(2H, CH2CH2CH2), 2.12 s [6H, N(CH3)2], 2.32 t (2H,
Mono-6-({3-О-[1-(4-isobutylphenyl)propanoyl]-
propyleneoxy-1-yl}dimethylammonium iodide)di-6-
iodo-tri-6-deoxy-β-cyclodextrin (XVIII) was syn-
thesized by analogy to compound XVI, from 0.20 g of
the cyclodextrin halo derivative III and 0.27 g of the
nucleophilic reagent XIII. Yield of compound (XVIII)
0.18 g (77%), mp 195–197ºС (decomp.), Rf 0.60 (C).
3
3
NCH2, JHH 7.0), 4.28 t (2H, CH2O, JHH 6.5), 7.52 t
[2H, C6HmetaC(O), 3JHH 7.5], 7.64 t [1H, C6HparaC(O),
3JHH 6.4], 7.95 d (2H, C6HorthoC(O), 3JHH 7.6). Found,
%: C 69.13; H 8.46. C12H17NO2. Calculated, %: C
69.54; H 8.27.
1
The Н NMR spectrum (DMSO-d6), δ, ppm (J, Hz):
3
0.83 d [6Н, СН(СН3)2, JHH 6.5], 1.37 d [3Н,
3
(O)CСНСН3, JHH 6.9], 2.03–2.28
m
[3Н;
Mono-6-({3-О-[1-(4-isobutylphenyl)propanoyl]-
ethyleneoxy-1-yl}dimethylammonium bromide)hexa-
6-bromohepta-6-deoxy-β-cyclodextrin (XVI). To a
solution of 0.20 g of cyclodextrin halo derivative I in
3 ml of DMF was added 1.50 g of nucleophilic reagent
X, and the mixture was maintained at 80ºС for 6 h. To
the reaction mixture was added 5 ml of acetone, the
mixture was stirred, then filtered, the precipitate was
washed with diethyl ether (2×3 ml), and the solvent
was removed in a vacuum. The residue was dried at
50ºС for 5 h in a vacuum (1 mm Hg). Yield of
compound XVI 0.18 g (76%), mp 184–186ºС
(decomp.)3, Rf 0.79 (C). The 1Н NMR spectrum
(DMSO-d6), δ, ppm (J, Hz): 0.84 d [6Н, СН(СН3)2,
3JHH 6.6], 1.37 d [3Н, (O)CCHCH3, 3JHH 7.2], 1.72–
1.88 m [1Н, CH(СН3)2], 2.70–2.76 m (4Н; NСН2,
СН2СН2СН2, СН(СН3)2,], 2.60–2.88 m (4Н; NСН2,
CHCH2), 3.32 s [6Н, N(СН3)2], 3.39–3.80 m [43Н;
С2Н–С5Н, С6Н2, (O)CСНСН3, CH2O], 4.12–4.21 m
(2Н, CH2O), 4.45–4.62 br.s (4Н, С6ОН), 4.70–4.85 m
(7Н, С1Н), 5.63–6.95 br.s (14Н; С2ОН, С3ОН), 7.10 d
(2H, C6HorthoCH2, 3JHH 7.7), 7.44 d (2H, C6HmetaCH2,
3JHH 7.9). Found, %: C 40.67; H 5.79. C60H96I3NO34.
Calculated, %: C 41.04; H 5.51.
Bis-6-({2-О-[1-(4-isobutylphenyl)propanoyl]ethyl-
eneoxy-1-yl}dimethylammonium bromide)penta-6-
bromohepta-6-deoxy-β-cyclodextrin (XIX). To a
solution of 0.20 g of cyclodextrin halo derivative I in
3 ml of DMF was added 0.53 g of nucleophilic reagent
X and the mixture was maintained at 135ºС for 39 h.
To the reaction mixture was added 5 ml of acetone, the
mixture was stirred, then filtered, the precipitate was
washed with diethyl ether (2×3 ml) and the solvent
was removed in a vacuum. The residue was dried at
3
Compounds XVI–XXX are light-brown solid amorphous
substances.
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1816
GRACHEV et al.
50ºС for 5 h in a vacuum (1 mm Hg). Yield of
compound XIX 0.20 g (75%), mp 158–160ºС
(decomp.), Rf 0.70 (C). The 1Н NMR spectrum
(DMSO-d6), δ, ppm (J, Hz): 0.86 d [12Н, СН(СН3)2,
3JHH 6.9], 1.45 d [6Н, (O)CCHCH3, 3JHH 7.4], 1.70–
1.89 m [2Н, СН(СН3)2], 2.65–2.80 m (8Н; NСН2,
CHCH2), 3.29 s [12Н, N(СН3)2], 3.37–4.21 m [48Н;
С2Н–С5Н, С6Н2, (O)CCHCH3, CH2O], 4.78–5.11 br.s
(7Н, С1Н), 5.53–6.02 m (14Н; С2ОН, С3ОН), 7.06–
7.28 m (8Н, CHarom). Found, %: C 43.15; H 5.22.
C76H117Br7NO32. Calculated, %: C 42.85; H 5.54.
СН2СН2СН2), 2.29 s [6H, C(O)CH3], 2.73–2.87 m
(4H, NCH2), 3.13–3.85 m [54Н; С2Н–С5Н, С6Н2,
N(СН3)2], 4.38–4.45 m (4H, CH2O), 4.86–5.29 m (7Н,
С1Н), 5.61–6.03 br.s (14Н; С2ОН, С3ОН), 6.89–7.95
m (8H, CHarom). Found, %: C 40.23; H 4.51.
C70H101Br7N2O36. Calculated, %: C 39.92; H 4.83.
Bis-6-({2-О-[1-(4-isobutylphenyl)propanoyl]ethyl-
eneoxy-1-yl}dimethylammonium bromide)di-6-bro-
motetra-6-deoxy-β-cyclodextrin (XXIII) was syn-
thesized by analogy to compound XIX from 0.20 g of
the cyclodextrin halo derivative II and 0.28 g of
nucleophilic reagent X. Yield of compound XXIII
0.21 g (75%), mp 173–175ºС (decomp.), Rf 0.71 (C).
Bis-6-({3-О-[1-(4-isobutylphenyl)propanoyl]pro-
pyleneoxy-1-yl}dimethylammonium bromide)-
penta-6-bromohepta-6-deoxy-β-cyclodextrin (XX)
was synthesized by analogy to compound XIX from
0.20 g of the cyclodextrin halo derivative I and 0.55 g
of nucleophilic reagent XIII. Yield of compound XX
0.21 g (76%), mp 155–157ºС (decomp.), Rf 0.58 (C).
1
The Н NMR spectrum (DMSO-d6), δ, ppm (J, Hz):
3
0.81 d [12Н, СН(СН3)2, JHH 6.8], 1.38 d [6Н, (O)
CСНСН3, 3JHH 7.0], 1.68–1.79 m (2Н, СНСН2), 2.38 d
3
3
(4Н, CHCH2, JHH 6.5) 2.67 t (4Н, NСН2, JHH 6.8),
2.96 s [12Н, N(СН3)2], 3.37–3.70 m (46Н; С2Н–С5Н,
С6Н2, CH2O), 3.76 q [2H, (O)CCHCH3, JHH 7.2],
3
1
The Н NMR spectrum (DMSO-d6), δ, ppm (J, Hz):
4.35–4.51 br.s (3Н, С6ОН), 4.78–5.11 br.s (7Н, С1Н),
5.53–6.02 br.s (14Н; С2ОН, С3ОН), 7.08 d (4H,
3
0.87 d [12Н, СН(СН3)2, JHH 7.2], 1.42 d [6Н,
3
(O)CCHCH3, JHH 7.3], 1.70–2.17
m
[6Н;
3
3
C6HorthoCH2, JHH 7.9), 7.19 d (4H, C6HmetaCH2, JHH
8.1). Found, %: C 47.24; H 6.02. C76H120Br4N2O35.
Calculated, %: C 46.99; H 6.28.
СН2СН2СН2, СН(СН3)2], 2.70–2.86 m (8Н; NСН2,
CHCH2), 3.21 s [12Н, N(СН3)2], 3.35–3.91 m [44Н;
С2Н–С5Н, С6Н2, (O)CCHCH3], 4.09 t (4Н, CH2O, 3JHH
6.4), 4.73–5.48 m (21Н; С1Н, С2ОН, С3ОН), 7.11 d
(4H, C6HorthoCH2, 3JHH 7.3), 7.20 d (4H, C6HmetaCH2,
3JHH 7.5). Found, %: C 43.89; H 5.47. C78H121Br7·
N2O32. Calculated, %: C 43.41; H 5.65.
Bis-6-({3-О-[1-(4-isobutylphenyl)propanoyl]-
propyleneoxy-1-yl}dimethylammonium bromide)-di-
6-bromotetra-6-deoxy-β-cyclodextrin (XXIV) was
synthesized by analogy to compound (XIX) from
0.20 g of the cyclodextrin halo derivative II and 0.30 g
of nucleophilic reagent XIII. Yield of compound
XXIV 0.22 g (76%), mp 162–164ºС (decomp.), Rf
Bis-6-{[2-О-acetylsalicyl)ethyleneoxy-1-yl]dimethyl-
ammonium bromide}-penta-6-bromohepta-6-
deoxy-β-cyclodextrin (XXI) was synthesized by
analogy to compound XIX from 0.20 g of the
cyclodextrin halo derivative I and 0.22 g of nucleo-
philic reagent XI. Yield of compound XXI 0.19 g
1
0.63 (C). The Н NMR spectrum (DMSO-d6), δ, ppm
(J, Hz): 0.80 d [12Н, СН(СН3)2, 3JHH 6.9], 1.39 d [6Н,
3
(O)CCHCH3, JHH 7.3], 1.69–1.81
m
(4Н,
1
(73%), mp 152–154ºС (decomp.), Rf 0.69 (C). The Н
СН2СН2СН2), 1.83–2.04 m (2Н, СНСН2), 2.37 d (4Н,
CHCH2, 3JHH 6.8), 2.69 t (4Н, NСН2, 3JHH 7.3), 2.97 s
[12Н, N(СН3)2], 3.25–3.68 m (42Н; С2Н–С5Н, С6Н2),
3.72 q [2H, (O)CСНСН3, 3JHH 6.7], 3.95–4.15 m (4H,
CH2O) 4.37–4.52 br.s (3Н, С6ОН), 4.76–5.09 br.s (7Н,
С1Н), 5.55–6.08 br.s (14Н; С2ОН, С3ОН), 7.10 d (4H,
C6HorthoCH2, 3JHH 8.1), 7.18 d (4H, C6HmetaCH2, 3JHH
7.7). Found, %: C 47.82; H 6.04. C78H124Br4N2O35.
Calculated, %: C 47.57; H 6.35.
NMR spectrum (DMSO-d6), δ, ppm: 2.25 s [6H,
C(O)CH3], 2.56–2.67 m (4H, NCH2), 3.09 s [12Н,
N(СН3)2], 3.21–3.96 m (46 Н; С2Н–С5Н, С6Н2,
CH2O), 4.82–5.21 m (7Н; С1Н), 5.62–6.08 br.s (14Н;
С2ОН, С3ОН), 6.54–7.68 m (8H, CHarom). Found, %:
C 39.56; H 4.52. C68H97Br7N2O36. Calculated, %: C
39.31; H 4.71.
Bis-6-{[3-О-(acetylsalicyl)propyleneoxy-1-yl]di-
methylammonium bromide}-penta-6-bromohepta-
6-deoxy-β-cyclodextrin (XXII) was synthesized by
analogy to compound XIX from 0.20 g of the
cyclodextrin halo derivative I and 0.51 g of nucleo-
philic reagent XIV. Yield of compound XXII 0.21 g
Bis-6-{[2-О-(acetylsalisyl)ethyleneoxy-1-yl]di-
methylammonium bromide}-di-6-bromotetra-6-de-
oxy-β-cyclodextrin (XXV) was synthesized by
analogy to compound XIX from 0.20 g of the
cyclodextrin halo derivative II and 0.25 g of
nucleophilic reagent XI. Yield of compound XXV
0.21 g (75%), mp 148–150ºС (decomp.), Rf 0.76 (C).
1
(78%), mp 167–169ºС (decomp.), Rf 0.65 (C). The Н
NMR spectrum (DMSO-d6), δ, ppm: 2.06–2.14 m (4Н,
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 80 No. 9 2010

THE β-CYCLODEXTRIN CATIONIC DERIVATIVES
1817
1
The Н NMR spectrum (DMSO-d6), δ, ppm: 2.26 s
7.4). Found, %: C 44.38; H 5.32. C66H100Br4N2O35.
Calculated, %: C 44.01; H 5.60.
[6H, C(O)CH3], 2.60–2.69 m (4H, NCH2), 3.10 s
[12Н, N(СН3)2], 3.26–3.89 m (46Н; С2Н–С5Н, С6Н2,
CH2O), 4.35–4.48 br.s (3Н, С6ОН), 4.73–5.15 br.s
(7Н, С1Н), 5.50–6.01 br.s (14Н; С2ОН, С3ОН), 6.43–
7.68 m (8H, CHarom). Found, %: C 42.95; H 5.72.
C68H100Br4N2O39. Calculated, %: C 43.23; H 5.34.
Bis-6-(p-carboxyphenylammonium bromide)penta-
6-bromo-hepta-6-deoxy-β-cyclodextrin (XXIX) was
synthesized by analogy to compound XIX, from
0.20 g of the cyclodextrin halo derivative I and 0.35 g
of nucleophilic reagent VII. Yield of compound XXIX
0.16 g (70%), mp 225–227ºС (decomp.), Rf 0.67(C).
The 1Н NMR spectrum (DMSO-d6), δ, ppm: 3.22–3.88
m (42 Н; С2Н–С5Н, С6Н2), 4.77–5.12 m (7Н, С1Н),
5.50–6.06 br.s (14Н; С2ОН, С3ОН), 6.49–6.51 br.s
(4Н, NH2), 7.56–7.95 m (8H, CHarom), 8.29 s [2Н, C
(O)OH]. Found, %: C 36.68; H 3.88. C56H77Br7N2O32.
Calculated, %: C 36.37; H 4.20.
Bis-6-{[3-О-(acetylsalicyl)propyleneoxy-1-yl]di-
methylammonium bromide}-di-6-bromotetra-6-de-
oxy-β-cyclodextrin (XXVI) was synthesized by
analogy to compound XIX from 0.20 g of the cyclo-
dextrin halo derivative II and 0.27 g of nucleophilic
reagent XIV. Yield of compound XXVI 0.20 g (71%),
1
mp 145–147ºС (decomp.), Rf 0.68 (C). The Н NMR
spectrum (DMSO-d6), δ, ppm (J, Hz): 2.00–2.18 m
(4Н, СН2СН2СН2), 2.27 s [6H, C(O)CH3], 2.68–2.75
m (4H, NCH2), 3.11 s [12Н, N(СН3)2], 3.15–3.87 m
(42 Н; С2Н–С5Н, С6Н2), 4.36 t (4H, CH2O, 3JHH 6.7),
4.42–4.73 br.s (3Н, С6ОН), 4.85–5.27 m (7Н; С1Н),
5.62–6.05 br.s (14Н; С2ОН, С3ОН), 6.73–7.93 m (8H,
CHarom). Found, %: C 43.58; H 5.86. C70H104Br4N2O39.
Calculated, %: C 43.85; H 5.47.
Bis-6-( p-carboxyphenylammonium bromide)di-
6-bromotetra-6-deoxy-β-cyclodextrin (XXX) was
synthesized by analogy to compound XIX from 0.20 g
of the cyclodextrin halo derivative II and 0.40 g of
nucleophilic reagent VII. Yield of compound XXX
0.17 g (72%), mp 184–186ºС (decomp.), Rf 0.45 (C).
The 1Н NMR spectrum (DMSO-d6), δ, ppm: 3.11–4.15
m (42 Н; С2Н–С5Н, С6Н2), 4.35–4.63 br.s (3Н,
С6ОН), 4.75–5.11 m (7Н, С1Н), 5.52–6.05 br.s (14Н;
С2ОН, С3ОН), 6.47–6.54 br.s (4Н, NH2), 7.58–7.96 m
(8H, CHarom), 8.23 s [2Н, C(O)OH]. Found, %: C
40.85; H 4.63. C56H80Br4N2O35. Calculated, %: C
40.50; H 4. 86.
Bis-6-{[2-О-(benzoyl)ethyleneoxy-1-yl]dimethyl-
ammonium bromide}-di-6-bromotetra-6-deoxy-β-
cyclodextrin (XXVII) was synthesized by analogy to
compound XIX from 0.20 g of the cyclodextrin halo
derivative II and 0.20 g of nucleophilic reagent XII.
Yield of compound XXVII 0.19 g (74%), mp 175–
ACKNOWLEDGMENTS
1
177ºС (decomp.), Rf 0.56 (C). The Н NMR spectrum
(DMSO-d6), δ, ppm: 2.37–2.45 m (4H, NCH2), 3.16 s
[12Н, N(СН3)2], 3.25–4.14 m (46Н; С2Н–С5Н, С6Н2,
CH2O), 4.36–4.66 br.s (3Н, С6ОН), 4.92–5.21 m (7Н;
С1Н), 5.63–6.05 br.s (14Н; С2ОН, С3ОН), 7.36–8.10
m (10H, CHarom). Found, %: C 43.39; H 5.17.
C64H96Br4N2O35. Calculated, %: C 43.15; H 5.46.
This work was financially supported by Russian
Foundation for Basic Research (grant no. 08-03-
00374a) and Grant of the President of Russian
Federation for support of leading scientific schools
(project no. NSh-582.2008.3).
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ammonium bromide}-di-6-bromotetra-6-deoxy-β-
cyclodextrin (XXVIII) was synthesized by analogy to
compound XIX from 0.20 g of the cyclodextrin halo
derivative II and 0.21 g of nucleophilic reagent XV.
Yield of compound XXVIII 0.19 g (72%), mp 170–
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