Cyclodextrin and some its derivatives inclusion compounds with "ibuprofen" remedy substrate

Article abstract of DOI:10.1134/S1070363209060231

The practical pathways are proposed for the synthesis of cyclodextrins and some of their derivatives inclusion compounds with the "Ibuprofen" remedy substrate. The effect of the cavity size, nature of the solvent and character and number of substituents a

Full text of DOI:10.1134/S1070363209060231

ISSN 1070-3632, Russian Journal of General Chemistry, 2009, Vol. 79, No. 6, pp. 1167–1170. © Pleiades Publishing, Ltd., 2009.
Original Russian Text © I.A. Senyushkina, G.I. Kurochkina, M.K. Grachev, V.A. Grinberg, T.A. Batalova, E.E. Nifant’ev, 2009, published in Zhurnal
Obhchei Khimii, 2009, Vol. 79, No. 6, pp. 995–998.
Cyclodextrin and Some Its Derivatives Inclusion Compounds
with “Ibuprofen” Remedy Substrate
I. A. Senyushkinaa, G. I. Kurochkinaa, M. K. Gracheva, V. A. Grinbergb,
T. A. Batalovac, and E. E. Nifant’eva
a Moscow Pedagogical State University, Nesvizhskii per. 3, Moscow, 119021 Russia
e-mail: chemdept@mtu-net.ru
b Frumkin Institute of Physical Chemistry and Electrochemistry, Russian Academy of Sciences, Moscow, Russia
e-mail: Vitgreen@mail.ru
c Amur State Medical Academy, Blagoveshchensk, Russia
e-mail: Batalova_ta@mail.ru
Received October 16, 2008
Abstract—The practical pathways are proposed for the synthesis of cyclodextrins and some of their derivatives
inclusion compounds with the “Ibuprofen” remedy substrate. The effect of the cavity size, nature of the solvent
and character and number of substituents at the cyclodextrin carcass on the possibility of isolation of the
inclusion compounds that are of pharmacological significance, are elucidated.
DOI: 10.1134/S1070363209060231
The cyclodextrin complexes with various com-
pounds (the inclusion compounds of guest–host type)
are of great significance e.g., for the study of
metabolism of some biologically important compounds
and for targeted delivery of medicine means (e.g., see
reviews [1]). However, preparation of the complexes
in mach is tentative because it is based on the different
experimental approaches [2] and in a great extent
depends on the nature of the cyclodextrin (its internal
cavity size, substituents, or absence of the latter),
choice of the solvent, and particular procedure. Earlier
we have proposed a method for the preparation of the
β-cyclodextrin and its silyl and phosphorus-containing
derivatives inclusion compounds with the “Ibuprofen”
remedy substrate, 1-(4-isobutylphenyl)propanoic acid I
and its synthetic precursors [3]. We have found that the
solvent and the cyclodextrin nature affect considerably
the stoichiometry of the formed complexes and the
possibility of their isolation. Accounting for the
pharmacological significance of such inclusion
compounds, in this work we continued the study of the
dependence of their preparation on the nature of free
cyclodextrins α-(II, n = 6), β-(III, n = 7) and γ-(IV,
n = 8) that differ considerably by the internal cavity
size (0.176, 0.346 and 0.510 nm3, respectively) and
solubility in water (145, 18.5 and 232 g l–1,
respectively) [4]. In addition, we studied a possibility
of formation of the inclusion compounds by the β-
cyclodextrin derivatives bearing functional groups in
the С6 positions of the cyclodextrin carcass glycoside
fragments at various degree of substitution (n): acetyl
(V, n = 2; VI, n = 4), tosyl (VII, n = 2; VIII, n = 4)
and silyl (IX, n = 4; X, n = 7). Besides, we studied the
β-cyclodextrin derivative XI possessing 7 acetyl
groups in С2, С3 positions of the glycoside fragments.
In the first step of the study, we explored formation
of inclusion compounds of acid I with unsubstituted
cyclodextrins II–IV by the method of join
precipitation of the complex from a hot (70°С) water
solution of cyclodextrin and the acid at slow cooling to
20°С. The precipitate formed was washed and dried in
a vacuum. Individuality of the complex was confirmed
by TLC and its composition was revealed on the basis
of the data of 1Н NMR spectroscopy by the
comparison of intensity of the signals of methyl
protons of the sec-butyl fragment of the acid I and the
protons of the cyclodextrin frame (see Experimental).
We found that under these conditions α-cyclodextrin II
does not form inclusion compounds while β-
cyclodextrins III and γ-cyclodextrins IV do form
inclusion complexes XII and XIII respectively, of 1:1
1167

1168
SENYUSHKINA et al.
O
H3C
C
C6
OH
OH
CH
HO
OH
HO
OR
n
_
_
OR
OH
7
7 n
6 n
n
n
C3
OH
C2
CH2
OH
6
OH
OH
OH
OAc
7
OH
n
7
7
CH
CH3
H3C
V_X
I
II_IV
XI
XVI, XVII
II: n = 6; III: n = 7; IV: n = 8; V: n = 2, R = Ac; VI: n = 4, R = Ac; VII: n = 2, R = n-S(O)2C6H4Me; VIII: n = 4, R = n-
S(O)2C6H4Me; IX: n = 4, R = SiMe2-t-Bu; X: n = 7, R = SiMe2-t-Bu; XVI: n = 3, R = SiMe2-t-Bu; XVII: n = 6, R = SiMe2-t-Bu.
composition, in 67 and 57% yield. Tacking into
account good solubility of α-cyclodextrin in water, we
carried out similar experiments taking water in a half
amount, but in this case also we did not register
formation of the α-cyclodextrin compex with the acid I1.
Cyclodextrins II–IV are well enough soluble in
DMSO and DMFA, therefore we attempted to obtain
individual complexes using these solvents. However,
we failed to register formation of respective complexes
under these conditions also.
O
H3C
C
HO
OH
OR
_
OR
6
OH
n
7 n
CH
CH2
OH
OH
OH
6
m
CH
H3C
CH3
XII_XV
XVIII
I
XII: n = m = 7, R = H; XIII: n = m = 8, R = H; XIV: n = 4, m = 7, R = SiMe2-t-Bu; XV: n = m = 7, R = SiMe2-t-Bu.
1
Among other cyclodextrin derivatives V–X, the
acetyl derivatives V, VI and XI only turn to be soluble
in water, but attempted interaction of compounds V,
VI and XI with acid I by the same procedure did not
lead to formation of inclusion compounds. Taking into
account a high enough solubility of derivatives V–X in
organic solvents (in distinct to the parent cyclodextrins
II–IV), we attempted to obtain and isolate the
inclusion compounds using as a solvent either DMFA,
DMSO, dioxane, acetone, or hexane (see Experi-
mental). We found that silyl derivatives IX, X form
respective inclusion compounds XIV, XV with acid I
in DMFA and dioxane (in water they are insoluble).
By comparison of integral intensities in the Н NMR
spectra of the signals of aromatic protons of the acid I
with that of the signals of tert-butyltdimethylsilyl
group protons and cyclodextrin frame of compounds
IX and X we established that the complexes XIV and
XV are of guest–host 1:1 composition.
Thus, indroduction of bulky t-butyl groups to the β-
cyclodextrin molecule promotes formation of stable
inclusion comppounds. Taking this into account, for
the increase of “inclusing” power of α-cyclodextrin we
prepared two its derivatives, XVI and XVII, that bear
respectively 3 and 6 silyl residues in С6 positions of
glucoside fragments. These compounds were tested on
the complex formation with acid I, with the same
solvents and under the same conditions as were used
for the synthesis and isolation of the complexes of β-
cyclodextrin silyl derivatives IX and X. We found that
1
Here and thereafter is noteworthy that it is possible that in
solution exist labile inclusion complexes in equilibrium with the
parent compounds, but in this work we consider a possibility of
isolation of individual complexes.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 79 No. 6 2009

CYCLODEXTRIN AND SOME ITS DERIVATIVES
1169
the α-cyclodextrin derivative XVI with 3 silyl groups
do not form inclusion compounds under these
conditions while the derivative XVII bearing 6 silyl
groups form inclusion compound XVIII of 1:1
composition that could be isolated, but only when
either DMFA, or dioxane, or acetone were used as a
solvent.
Found, %: С 48.12; Н 6.75. С55Н88О37. Calculated, %:
С 49.25; Н 6.61.
Inclusion compound of γ-cyclodextrin with 1-(4-
isobutylphenyl)propanoic acid (XIII). To a solution
of 0.20 g of γ-cyclodextrin IV in 4 ml of water at 70°С
was added at stirring 0.06 g of acid I. The reaction
mixture was left for cooling to room temperature, 20 h
later the precipitate dropped was filtered off, washed
with acetone (2×5 ml ) and dried in a vacuum (1 mm Hg)
for 4 h at 50°С. Yield 0.13 g (57%), mp 247–249°С
(decomp.), Rf 0.83 (А). The 1H NMR spectrum
(DMSO-d6), δ, ppm, γ-cyclodextrin IV: 3.35–3.64 m
(48Н; С2Н–С5Н, С6Н2), 4.39–4.69 br.s (8Н, С6ОН),
4.81–5.09 m (8Н, С1Н), 5.56–6.06 br.s (16Н; С2ОН,
С3ОН); acid I: 0.79–1.00 m [6Н, (СН3)2], 1.30–1.48 m
(3Н, СН3), 1.74–1.92 m [1Н, СН(СН3)2], 2.36–2.46 m
(2Н, СН2), 3.63–3.80 m (1Н, СН), 7.05–7.29 m (4Н,
СНarom), 12.40 s [1Н, С(О)ОН]. Found, %: С 47.91; Н
6.68. С61Н98О42. Calculated, %: С 48.73; Н 6.57.
Thus, the cavity size, nature of solvent, character
and number of substituents at the cyclodextrin carcass
affect considerably the possibility of formation and
isolation of the inclusion complexes with acid I. The
carried out investigation opens practical pathways for
preparation of important in pharmacological aspect
inclusion compounds and new remedies forms based
on the cyclodextrins and some their derivatives and
remedy Ibuprofen.
EXPERIMENTAL
1
The Н NMR spectra were registered on a Bruker
AC-200 instrument at the operating frequency
200.13 MHz, external reference TMS.
Inclusion compound of tetra-[6-О-(tert-butyl)(di-
methyl)silyl]-β-cyclodextrin with 1-(4-isobutyl-
phenyl)propanoic acid (XIV). To a solution of 0.20 g
of the β-cyclodextrin derivative IX in 4 ml of DMFA
was added 0.05 g of acid I and the mixture was stirred
for 24 h at 20°С. The reaction mixture was then poured
to ice water (8 ml ), the precipitate dropped was stirred
and then filtered off, washed with water (2×5 ml) and
dried in a vacuum (1 mm Hg) for 4 h at 50°С. Yield
For thin layer chromatography were used aluminum
plates with fixed silica gel layer (Silufol UV–254).
Eluents: acetonitrile–water–25% aqueous ammonia 6 :
3 : 2 (А), benzene–ethanol 3 : 1 (B).
The α- and β-cyclodextrin acetyl derivatives V, VI
and XI are prepared along the procedure in [5], the
tosyl derivatives VII, VIII as in [6] and the silyl
derivatives IX, XVI and X, XVII as in [7] and [8],
respectively.
1
0.19 g (83%), mp 218–220°С, Rf 0.72 (B). The H
NMR spectrum (DMSO-d6), δ, ppm (J, Hz), β-cyclo-
dextrin derivative IX: –0.14 to 0.30 br.s [24Н, Si(СН3)2],
0.71–1.10 s [36Н, С(СН3)3], 3.34–3.62 m (42Н; C2H–
C5H, C6H2), 3.85–4.06 br.s (3Н, С6ОН), 4.70–4.92 m
(7Н, C1H), 5.60–5.94 br.s (14Н; C2ОН, C3ОН); acid I:
β-Cyclodextrin from “Sigma” was additionally
carefully dried.
Inclusion compound of β-cyclodextrin with 1-(4-
isobutylphenyl)propanoic acid (XII). To a solution
of 0.20 g of β-cyclodextrin III in 4 ml of water at 70°С
was added at stirring 0.07 g of acid I. The reaction
mixture was left for cooling to room temperature, the
precipitate dropped in 20 h was filtered off, washed
with acetone (2×5 ml ) and dried in a vacuum (1 mm
Hg) for 4 h at 50°С. Yield 0.16 g (67%), mp 237–240°С
(decomp.), Rf 0.80 (А). The 1H NMR spectrum
(DMSO-d6), δ, ppm (J, Hz): β-cyclodextrin: 3.29–3.63
m (42Н; С2Н–С5Н, С6Н2), 4.32–4.75 br.s (7Н, С6ОН),
4.66–4.99 m (7Н, С1Н), 5.56–5.89 br.s (14Н; С2ОН,
3
–0.14–0.3 br.s [6Н, (СН3)2], 1.33 d (3Н; СН3, JHCCH
7.0), 1.72–1.90 m [1Н, СН(СН3)2], 2.45 d (2Н; СН2,
3JНССН 7.0), 3.34–3.62 m (1Н, СН), 7.07–7.20 m (4Н,
СНarom), 12.3 s [1Н, С(О)ОН]. Found, %: С 53.66; Н
7.98. С79Н144О37Si4. Calculated, %: С 52.76; Н 8.07.
Inclusion compound of per[6-О-(tert-butyl)(di-
methyl)silyl]-β-cyclodextrin with 1-(4-isobutyl-
phenyl)propanoic acid (XV). а. in DMFA. To a solu-
tion of 0.17 g of β-cyclodextrin derivative X in 4 ml of
DMFA was added 0.04 g of acid I and the mixture was
stirred for 24 h at 20°С. The reaction mixture was
poured to ice water (8 ml) and stirred, and then the
precipitate dropped was filtered off, washed with water
(2×5 ml ) and dried in a vacuum (1 mm Hg) for 4 h at 50°С.
3
С3ОН); acid I: 0.84 d [6Н; (СН3)2, JHCCH 6.4], 1.33 d
3
(3Н; СН3, JНССН 7.0), 1.70–1.95 m [1Н, СН(СН3)2],
3
2.40 d (2Н; СН2, JНССН 6.8), 3.58–3.72 m (1Н, СН),
7.02–7.28 m (4Н, СНarom), 12.2 s [1Н, С(О)ОН].
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SENYUSHKINA et al.
b. In dioxane. The synthesis was carried out like in
the method a from 0.17 g of β-cyclodextrin derivative
X in 4 ml of dioxane and 0.04 g of acid I.
br.s [36Н, Si(СН3)2], 0.65–1.10 br.s [54Н, С(СН3)3],
3.26–3.89 m (36Н; C2H–C5H, C6H2), 4.68–4.90 m
(6Н, C1H), 5.60–5.56 br.s (12Н; C2ОН, C3ОН); acid I:
–0.02 to 0.25 br.s [6Н, (СН3)2], 1.30 d (3Н; СН3,
3JНССН 6.0), 1.70–1.95 m [1Н, СН(СН3)2], 2.38 d (2Н;
Yields: (method а) 0.17 g (89%), (method b) 0.14 g
1
(74%), mp 209–211°С, Rf 0.72 (B). The H NMR
3
СН2, JНССН 7.1), 3.58–3.72 m (1Н, СН), 7.05–7.19 m
spectrum (DMSO-d6), δ, ppm (J, Hz): β-cyclodextrin
derivative (X): –0.1 to 0.2 br.s [42Н, Si(СН3)2], 0.71–
1.10 s [63Н, С(СН3)3], 3.32–3.92 m (42Н; C2H–C5H,
C6H2), 4.70–4.92 m (7Н, C1H), 5.62–6.00 br.s (14Н;
C2ОН, C3ОН); acid I: –0.10 to 0.20 br.s [6Н, (СН3)2],
(4Н, СНarom), 12.30 s [1Н, С(О)ОН]. Found, % : С
56.32; Н 8.58. С85Н162О32Si6. Calculated, % : С 54.75;
Н 8.76.
ACKNOWLEDGMENTS
3
1.32 d (3Н; СН3, JHCCH 7.0), 1.70–1.90 m [1Н,
СН(СН3)2], 2.39 d (2Н; СН2, 3JНССН 7.0), 3.32–3.93 m
(1Н, СН), 7.05–7.20 m (4Н, СНarom), 12.30 s [1Н,
С(О)ОН]. Found, %: С 55.52; Н 8.18. С97Н186О37Si7.
Calculated, %: С 54.41; Н 8.26.
This work was supported financially by Russian
Foundation for Basic Research (grant no. 08–03–
00374a) and the Grant of the President of Russian
Federation for supporting advanced scientific schools
of Russian Federation (grant no. NSh-582.2008.3).
Inclusion compound of per[6-О-(tert-butyl)(di-
methyl)silyl]-α-cyclodextrin with 1-(4-isobutyl-
phenyl)propanoic acid (XVIII). а. in DMFA. To a
solution of 0.20 g of α-cyclodextrin derivative XVII in
2 ml of DMFA was added 0.05 g of acid I and the
mixture was stirred for 24 h at 20°С. The reaction
mixture was then poured to ice water (4 ml), stirred
and the precipitate dropped was filtered off, washed
with water (2×3 ml ) and dried in a vacuum (1 mm Hg)
for 4 h at 50°С.
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b. In dioxane. The synthesis was carried out like in
the method а, from 0.15 g of α-cyclodextrin derivative
XVII in 3 ml of dioxane and 0.04 g of acid I.
c. in acetone. The synthesis was carried out like in
the method а, from 0.20 g of α-cyclodextrin derivative
XVII in 15 ml of acetone and 0.05 g of acid I.
Yield: (method а) 0.15 g (75%), (method b) 0.11 g
(65%), (method c). 0.07 g (41%), mp 242–244°С, Rf
0.65 (B). The H NMR spectrum (DMSO-d6), δ, ppm
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Grachev, M.K., and Nifant’ev, E.E., Zh. Obshch. Khim.,
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1
8. Fügedi, P., Carbohydr. Res., 1989, vol. 192, p. 366.
(J, Hz.): α-cyclodextrin derivative XVII: –0.02–0.25
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 79 No. 6 2009