WO1998038222A2

WO1998038222A2 - Cyclodextrin modifications with molecular channels, method for the production and use thereof

Info

Publication number: WO1998038222A2
Application number: PCT/DE1998/000566
Authority: WO
Inventors: Gerhard Wenz; Marc Steinbrunn
Original assignee: Universität Karlsruhe (Th)
Priority date: 1997-02-27
Filing date: 1998-02-26
Publication date: 1998-09-03
Also published as: AU6820198A; DE19808063A1; WO1998038222A3

Abstract

The invention relates to a method and a novel modification of cyclodextrins. Said cyclodextrins crystallize with linear aliphatic guest molecules, e.g. pentane, as an inclusion compound. X-ray images reveal that the guest molecules can be expelled from the crystal while structure is maintained, thereby resulting in a remaining crystal with molecular canals. Said crystal modification has a considerably higher guest molecule absorption capacity than the previously known cyclodextrin crystal structure. Especially inorganic molecules such as aliphatic and aromatic hydrocarbons or fluoridized and chloridized hydrocarbons, which fit better into the cylclodextrin cavity by virtue of their dimensions, can be expected to be absorbed even better than iodine.

Description

Cyclodextrin modifications with molecular channels, processes for their production and their use

The invention relates to the production and use of a new modification of α-, β- and γ-cyclodextrins, the crystals of which have a structure permeated by molecular channels, and tubular polymers of these modifications.

The possibility and the need to control molecular processes has led to a large number of works with the aim of creating new channel-shaped structures. S. Iijima described the synthesis of carbon tubes with inner diameters between 2 and 7 nm in 1991 [4]. The synthesis was similar to the synthesis of fullerenes [5], the tubes consist of several layers of carbon, comparable to several cylinders placed one on top of the other. In 1992 Kresge et al. the synthesis of honeycomb-like channel structures by calcination of aluminum silicates in the presence of cetyltrimethylammonium chloride [6]. The ammonium salt acts as a template to direct the aluminum silicate into the honeycomb structure and is removed during the subsequent tempering of the sample. Gadiri et al. 1995 the synthesis of peptide nanotubes based on a cyclic octa- peptide [7, 8]. The oligopeptides methylated on nitrogen accumulate in solution one above the other and form long channels, which have alternating hydrophilic and hydrophobic segments with a length of 10 nm each in their interior. Nesearch has also already been undertaken to synthesize tubular structures based on cyclodextrins. For example, Harada et al. a polymeric tube based on polyethylene glycol included in α-cyclodextrin. After the polymer ends had been blocked with blocking groups, the cyclodextrins thus threaded were crosslinked along the polymer chain by reaction with epichlorohydrin [9]. After hydrolysis of the Soerr groups and gel permeation chromatography in sodium hydroxide solution, they came to a soluble cyclodextrin tube. Due to the complex chromatographic step, this method cannot be transferred to the production of larger quantities. About the solid properties of the connection, especially the conformation of the Cyclodextrin rings to each other, nothing is known. A similar approach was taken by coupling propynyl-substituted cyclodextrin rings that had previously been threaded onto a polyamine chain [10].

Here too, the separation of the tubular polymer is very complex. As described, the need to achieve higher transport and absorption capacities of cyclodextrin crystals by creating channel-shaped molecular structures has led to many attempts, but none of them have been convincing. A large number of publications exist that deal with the structure of monomeric inclusion compounds of the individual cyclodextrins [11, 12]. The expulsion of the guest molecules from the crystalline host structure has so far hardly been investigated. A trivial example of expelling a guest molecule from α-cyclodextrin is drying. Because α-cyclodextrin forms two crystal modifications from an aqueous solution, which differ in that one or two water molecules are built into the inside of the ring, while four or five water molecules are attached to the outside of the cyclodextrin ring [13, 14]. In solution, α-cyclodextrin is present as round toms with Cö symmetry (see Fig la). The carbon and hydrogen atoms of all anhydroglucose units are identical, like the simple 1 H - and 13 C-

Show NMR spectra. In contrast, as shown in Figure lb, this symmetry is broken in the crystalline solid, resulting in the very complicated 13 C-CP-MAS

Spectrum of crystalline a-cyclodextrin results [18]. The bridge bond to the stored water is formed on the one hand by the OH-6 group of the anhydroglucose unit 1, which is slightly turned inside the torus, and on the other hand by the OH-6 group of the strongly twisted glucose unit 5 with the oxygen atom of the included crystal water [13] . As a result, the anhydroglucose unit 6 is twisted so that the OH-2 and OH-3 groups are on the narrow side of the torus. Both crystals are present in the herringbone structure with a stoichiometric composition of a-cyclodextrin * 6 H2O [14].

A completely empty structure of the cyclodextrin host crystal could not be achieved or described in any of the experiments described. However, this is absolutely necessary in order to provide a system that is capable of molar molecules, such as active ingredients, fragrances or pollutants, and release them elsewhere.

The object of this invention is to enable the production of a completely empty channel structure of the cyclodextrin host crystal in a simple manner and thereby to expand the field of application of these compounds.

This object is achieved according to the invention in that a method is made available with which such an empty molecular channel system is created in a sufficiently large amount. This takes place, starting from a channel-like inclusion compound of cyclodextrin and a suitable guest molecule, by removing the guest molecule, for example by thermally expelling the guest molecule, while maintaining the present structure. This creates a crystalline structure with high absorption capacity that is traversed by molecular channels. For example, in the case of iodine, the absorption capacity can be increased fourfold compared to normal cyclodextrins.

These cyclodextrin channel structures are also able to absorb additional guest molecules. This can be an advantage if the included molecules are to be transported across phase boundaries, for example. Due to the solubility of cyclodextrins in polar media, especially in water, is compared to other absorbents, such as. B. activated carbon and zeolites, an advantage can be expected if, for example, cyclodextrins are used in a liquid / liquid extraction, the cyclodextrin then being able to be recovered from the aqueous phase. Another advantage is the biodegradability of cyclodextrins, so that disposal here could be done, for example, by composting. An application for this new modification of cyclodextrin can be seen, for example, as an alternative to classic adsorbents such as activated carbon or zeolites in the purification of gases. The adsorption capacity of conventional microporous materials, such as activated carbon, which has a pore diameter between 400 and 2000 pm, or various metal phosphates and zeolites with pore diameters between 1000 and 1200 pm [1, 2, 3] can be attributed to their large surface area. Most of the The cavities inside the material are available on the surface.

Since the cyclodextrin channels allow the guest molecules to escape just as slowly, they can also be used to control molecular transport processes. Controlling molecular transport processes is understood to mean the selective complexation and the directed transport of guest molecules in the interior of the host channel and their metered and controlled release of the included molecules. This can be, for example, the transportation of pharmaceuticals or fragrances or the use as a depot for these pharmaceuticals or fragrances. A special application of this channel structure could, for example, be the creation of an iodine depot preparation that can be used to treat thyroid dysfunction. Further possible applications can be seen through the use of these channel structures in the implementation in suspensions (e.g. alcohols). This solid structure should be expected to be more reactive than native cyclodextrin in this area. Further applications can result from the incorporation of highly reactive guest molecules into this channel structure. This clathrate could then, under exclusion of water, gradually make the stored molecules available under appropriate conditions for a reaction. In this way, for example, a phase transfer reaction can take place or be catalyzed. Furthermore, these tubular crystal structures can be used to produce tubular cyclodextrin polymers.

For this purpose, the cyclodextrin guest compounds are first produced and then linked to one another by polymerization with difunctional reagents, such as epichlorohydrin, bisepoxides, diisocyanate. The corresponding guest molecule is then removed either thermally or by ultrafiltration. Polymers produced in this way have significant advantages over existing polymers (20). These are in detail - no high-molecular fractions form, which lead to gelation with previously known polymers (20). - Polymers produced in this way are readily soluble. Crosslinking reactions, for example with other bifunctional reagents such as epichlorohydrin, can be carried out more quickly and easily.

- The production is cheaper, since the expulsion processes for the guest molecule are considerably simplified. - The complexation ability against large guest molecules, such as. Anthracene, is considerably improved compared to known, conventionally cross-linked cyanodextrins.

- The polymers have, compared to known cyclodextrin polymers, a significantly increased specific surface area and therefore have a significantly improved absorption behavior.

The use of such cyclodextrin polymers can be seen in the use of such polymers as absorbents in the purification of gases or liquids. Furthermore, their use as a carrier base for active pharmaceutical ingredients or fragrances is conceivable. Such polymers can also be immobilized on stationary phases and used for chromatographic separation.

Examples

Basic representation of channel structures in α-, ß- and γ-cyclodextrin crystals.

In principle, the proposed method is based on the incorporation of linear guest molecules, the linear arrangement of the cyclodextrin molecules caused by this procedure and the final removal of the guest molecules from the cyclodextrin crystal or polymer.

Pentane, hexane, heptane and octane - hereinafter also referred to as guest - can be used as guest molecules. In principle, however, longer-chain aliphatic hydrocarbons and other long-chain compounds such as esters, ethers, alcohols, cycloaliphatics, aromatics, unsaturated aliphatics, bridged aliphatics or norbornene can also be used.

Example 1: Inclusion compounds α-cyclodextrin-pentane and α-cyclodextrin-octane

7 g (7.2 mmol) of α-cyclodextrin are dissolved in 50 ml of water in a 100 ml one-necked flask and then covered with 5 ml of pentane / octane. The mixture is shaken for five minutes and left at room temperature for four days. A crystalline precipitate is formed. The precipitate is filtered off and washed with 30 ml of water. For drying, the substance is placed in the desiccator over P ₂ 0 ₅ (without vacuum). White crystals. Yield: α-cyclodextrm »pentane: 6.4 g (90% of theory) α-cyclodextrin» octane: 6.2 g (87% of theory) α-cyclodextrin »pentane NMR-NMR (DMSO-d ₆ ): δ / ppm: 0.89 (t, 3.3 H, Hb, c), 1.28 (m, 3.3 H, Ha), 3.27-3.50

(m, 12 H, H-2.4), 3.63-3.84 (m, 24 H, H-3, -5, -6) 4.53 (t, 6 H, OH-6), 4.83 (m, 6 H, St. ), 5.47 (m, 6 H, OH-3), 5.55 (m, 6 H, OH-2). IR (KBr pellet) v / cm-1: 3280 (OH), 2935 (C-H), 1647, 1350, 1155-950 (C-O),

849. WAXS: 2Θ = 6.52w, 7.36m, 11.05w, 12.60m, 15.99w, 19.52s, 20.66w,

20.66w, 22.09w, 26.76w, 43.10w ° X-ray structure analysis was carried out on a single crystal (Prof. Klüfers Univ. Karlsruhe). This resulted in a triclinic unit cell with a = 1.3666 nm, b = 1.3732 nm, c = 1.5502 nm and α = 91.43 °, ß = 92.98 °, γ = l 19.49 °. This unit cell is characteristic of a columnar packing of the cyclodextrin rings.

α-Cyclodextrin «octane: Η NMR (DMSO-d ₆ ): δ / ppm: 0.89 (t, 8.9 H, Hb, c), 1.28 (m, 4.3 H, Ha), 3.27-3.50

(m, 12 H, H-2.4), 3.63-3.84 (m, 24 H, H-3, -5, -6) 4.53 (6, 6 H,

OH-6) 4.83 (m, 6 H, H-1), 5.47 (m, 6 H, OH-3), 5.47 (m, 6 H,

OH-2).

WAXS: 2Θ = 5.05m, 5.25m, 7.36m, 11.08s, 12.02w, 12.60m, 14.45w,

15.97w, 17.13s, 19.57s, 20.66w, 22.65w ° (see fig. L). Expelling the guest molecule:

The crystals of α-cyclodextrin »pentane are crushed in a mortar and tempered for 2 days at 80 ° C in a vacuum drying cabinet (10 torr). The 'H-NMR spectrum of the product showed a residual pentane content of 19 mol% based on α-

Cyclodextrin. The WAXS (see Figure 1.) shows that the columnar structure is preserved during the annealing.

Absorption of iodine

300 mg of the tempered α-cyclodextrin »pentane sample was placed in a small crystallizing dish in a wide-mouth screw cap vessel (500 mL) with iodine crystals at room temperature. The atmosphere was saturated with iodine vapor. After 2 days, the cyclodextrin sample was colored dark purple. A comparison sample with native α-cyclodextrin only turned yellow.

Example 2:

Inclusion compound ß-cyclodextrin »methylcyclohexane

2.0 g (2.47 mmol) of β-cyclodextrin are dissolved in 150 ml of water in a 250 ml flask. This solution is mixed with methylcyclohexane. The solution is then shaken and left to stand at room temperature for four days. The white precipitate is filtered off and washed with 30 ml of water. The product is dried over P ₂ O ₅ in a desiccator. White dust.

Yield: ß-cyclodextrin »methylcyclohexane 1.3 g (60% of theory)

WAXS: 2Θ = 11.6s, 17.1m, 18.0s, 20.8m (see Figure 2) Example 3:

Inclusion compound γ-cyclodextrin * octane

24 g (8.5 mmol) γ-cyclodextrin are dissolved in 150 ml water. Representation analogous to the inclusion compound α-cyclodextrin. White dust. Yield: γ-cyclodextrin »octane: 23 g (95% of theory)

Η NMR (DMSO-d ₆ ): δ / ppm: 0.89 (t, 14.7 H, Hb, c), 1.28 (m, 7.2 H, Ha), 3.27-

3.50 (m, 16 H, H-2.4), 3.63-3.84 (m, 32 H, H-3, -5, -6) 4.53 (t,

8 H, OH6), 4.83 (m, 8 H, Hl), 5.63-5.81 (m, 16 H, 3.2). IR (KBr pellet) v / cm ^"1 : 3280 (OH), 2940 (CH), 1647, 1349, 1157-953 (CO),

489.

WAXS: 2Θ = 5.3m, 7.5s, 14.2m, 14.9m, 15.7m, 16.7m (see Fig. 3)

Expulsion of the guest molecule: The crystals of γ-cyclodextrin «octane are crushed in a mortar and lg tempered for 2 days at 80 ° C in a vacuum drying cabinet (10 torr). The Η-NMR spectrum of the product showed a residual pentane content of 1.6 mol% based on α-cyclodextrin.

Example 4:

Tubular cyclodextrin polymer

30 g (0.8 mmol) of α-cyclodextrin are dissolved in 20 ml of 10% NaOH in a 100 ml one-necked flask. 10 ml of octane are added to the solution and shaken. A white precipitate forms. The mixture is left overnight at room temperature. 13 g (1.2 mmol) are removed from the dried substance and suspended in 3 ml of 10% NaOH. 8 ml (0.1 mol) epichlorohydrin are added to the suspension at 30 ° C. within 5 hours. The mixture is then stirred at 30 ° C. for a further hour. The result is a clear solution. Excess epichlorohydrin will separated with a separatory funnel. The aqueous phase is neutralized with acetic acid and ultrafiltered against an ultrafiltration membrane (Hoechst High Chem, UF-PES-4H, 4000 Da cutoff) with water. The solution is then freeze-dried. The product is a white foam. Yield: 3.4g

Thin layer chromatography, Si-60, eluent: water / n-butanol / ethanol 6/5/4 v / v / v: R _F : = 0 - 0.18. Sample contains no monomeric α-cyclodextrin (R _F = 0.7). Η NMR (DMSO-d ₆ ): δ / ppm: 2.92 (t, Hc), 3.72-3.81 (m, 12 H, H-2, -4), 3.84-4.35 (m, 21 H, H-5 , -6, -3, Ha, -b), 5.00-5.22 (m, 6 H, OH-6), 5.38-5.84 (m, 6 H, Hl.l), 5.84-6.08 (m, 12 H, OH-2.3) identical to the spectrum of the tubular polymer (22).

Gel permeation chromatography (Suprema-100, Polymer Standards Service, Mainz, eluent water / acetonitrile / acetic acid 80/20 / 0.02, calibration with Pullulan standards) Molar mass: M _w = 10,000 g / mol.

Inclusion of AI ₃ :

A 0.8 10 ^"4 M solution of KI ₃ in water is prepared and the tubular polymer dissolved in it at 0.4 g / L. The UV spectrum (see Fig. 5) shows one compared to that of an equally concentrated solution of α-cyclodextrin significant increase in intensity, a shift of the absorption maximum to longer wavelengths (from 353 nm to 360 nm) and an additional shoulder at 430 nm. This UV spectrum is similar to that of the KI ₃ complex of the tubular polymer from (22).

Example 5:

Absorption of benzene through the empty channel structures of the ß- and γ-cyclodextrin

Approx. 1 g each of the crystalline channel structures of the β- and γ-cyclodextrin and of the β- and γ-cyclodextrin previously dried in vacuo at 130 ° C. are placed in a sealed container with 5 ml of benzene in the presence of a drying agent (Blaugel). The four samples are only in contact with benzene through the gas phase. In order to determine the benzene content in the channel-shaped samples and to compare it with that of the native cyclodextrins, DSC measurements are carried out after five days. As in Example 1, the amount of heat required to remove the benzene is determined. Figure 7 shows that the expulsion of the guest molecules begins at about 50 ° C and continues up to a temperature of 160 ° C. The comparison of the integrated signals shows that the absorption capacity of the β-cyclodextrin can be increased four to five times. The signals between 220 and 235 ° C are not due to the expulsion of the guest, but are characteristic of ß-cyclodextrin. By GC-MS

(Gas chromatograph with mass spectrometer as a detector) it was demonstrated that the expelled guest molecules are actually benzene.

References:

1. Davies R.M., Saldarriaga C, Montes C, Garces J. and Crowder C, Nature 331 (1988), pp 698-699.

2. Dessau R. M., Schlenker J.L. and Higgins J.B. "Zeolites 10 (1990) pp. 522-524.

3. Esterman M., McCusker L.B., Merrouche A. and Kessler H., Nature 352 (1991), pp. 320-328.

4. Iijima S., Nature 354 (1991), pp. 56-58.

5. Kroto H.W., Heath J.R., O'Brien S.C., Curl R.F. and Smalley R.E., Nature 318 (1985), pp. 162-163.

6. Kresge T.C., Leonowicz M.E., Roth W.J., Vartuli J.C. and Beck J.S., Nature 359 (1992), pp. 710-712.

7. Gadiri M.R., Kobayashi K., Granja J.R., Chadha R.K. and McRee D.E., Angew. Chem. 107 (1995) No. 1, pp. 76-78.

8. Gadiri, J.R. Granja, R.M. Milligan, McRee D.E. and Khazanovicch N., Nature 366 (1993), pp. 324-327. 9. Harada, J. Li and M. Kamachi, Nature 364 (1993), pp. 516-518.

10. Steinbrunn, diploma thesis, synthesis of a tubular polymer from cyclodextrin,

Mainz 1993. l l.Saenger and B. Pullman (ed), Enviromental Effects on Molecular Strucure and Properties, D. Reidel Publishing Company, Dortrecht Holland 1976, pp. 265-305. 12.Saenger, Structural Aspects of Cyclodextrins and their Inclusion Complexes, in: Inclusion Compounds 2 (JL Atwood, JED Davies and DD MacNicol, ed.), Acad. Press, London 1984, pp. 231-259. 13.Manor and W. Saenger, J. Am. Chem. Soc. 96 (1974) No. 11, pp. 3630-9. 14. Lindner and W. Saenger, Acta Cryst. 38 (1982), pp. 203-10. j. A. Ripmeester, 15th Inclusion Phenom. 4 (1986), pp. 129-34. lό.Cramer and FM Henglein, Chem. Ber. 90 (1957), pp. 2561-71. 17. Harada and M. Kamachi, Macromolecules 23 (1990), pp. 2821-2823. lδ.Ding, T. Steiner, W. Saenger, Acta Cryst. B47 (1991), pp. 731-738. 19.A. Ripmeester, J. Inclusion Phenom. 4 (1986), pp. 129-134.

20.E. Renard, A. Deratani, G. Violet and B. Sebille et al Eur. Polym. j. (1997) Vol. 33, No. 1, pp 49-57 21.R.K. McMullan, W. Saenger, j. Favos, D. Mootz; Carbohydr. Res. (1973), 31, 37-46 22. Harada, A .; Li, j .; Kamachi, M .; Nature (1993) 364, 516-518

HETZBLATT (RULE 26) Drawings and figures:

The figures show:

FIG. 1 shows the X-ray diffractograms (WAXS) of a) native α-cyclodextrin, b) α-cyclodextrin-pentane c)) α-cyclodextrin-pentane after annealing 2d at 80 ° C

FIG. 2 shows X-ray diffractograms (WAXS) of native β-cyclodextrin

FIG. 3 shows X-ray diffractograms (WAXS) of β-cyclodextrin-methylcyclohexane

FIG. 4 shows the X-ray diffractogram (WAXS) of native γ-cyclodextrin,

Figure 5 shows the X-ray diffractogram (WAXS) of γ-cyclodextrin octane

Figure 6 shows the NMR-NMR spectrum of the tubular polymer in DMSO-d ₆

Figure 7 shows the UV spectra of a 0.8 10 ^"4 M aqueous solution of KI ₃ A) without addition B) with 0.4 g / L α-cyclodextrin, C) with 0.4g / L tubular polymer.

FIG. 8 shows free α-cyclodextrin a) in aqueous solution and b) in the crystal (according to Saenger [12]).

FIG. 9 shows the H-NMR spectrum of a - cyclodextrin - pentane - clathrate in DMSO-d6.

FIG. 10 shows the diffractogram of the inclusion compound of a-cyclodextrin-pentane-clathrate (powder uptake).

FIG. 11 shows a diffractogram of the inclusion compound of cyclodextrin-pentane clathrate after the guest molecule has been driven out (powder uptake). FIG. 12 shows the ¹³ C-CP-MAS NMR spectrum of the inclusion compound of cyclodextrin - pentane - clathrate after the guest molecule has been driven out.

FIG. 13 shows the DSC measurement of the inclusion compound of pentane in cyclodextrin pentane - clathrate, a) first heating cycle, b) second heating cycle

Claims

claims

1.) Cyclodextrin modifications with molecular channels, characterized in that the structure consists of several successive cyclodextrin units.

2.) Cyclodextrin modifications with molecular channels according to claim 1, wherein the cyclodextrins used are α-, ß- and γ - cyclodextrins.

3.) Cyclodextrin modifications with molecular channels according to claim 1 and 2, wherein the cyclodextrin units are tubular.

4.) Cyclodextrin modifications with molecular channels according to claim 1 and 3, wherein the cyclodextrin units are polymer-linked.

5.) Process for the preparation of cyclodextrin modifications with molecular channels, characterized in that first cyclodextrins in solution, preferably aqueous solution, are brought into contact with linear hydrocarbons, these linear hydrocarbons are incorporated as guest molecules and are removed after the crystal formation and thereby channel-like leave molecular structures behind.

6.) Process for the preparation of cyclodextrin modifications with molecular channels according to claims 1-5, wherein the linear hydrocarbons used as the guest molecule are aliphatic, preferably C3 to C8 aliphatics, and also esters, ethers, alcohols, cycloaliphatics, aromatics, unsaturated aliphatics, bridged Are aliphatic or norbornene.

7.) Process for the preparation of cyclodextrin modifications with molecular channels according to claims 1-6, wherein the removal of the guest molecule can be carried out by heating the host-guest compound at temperatures of 100-250 ° C. both under room pressure and under vacuum.

8.) Process for the preparation of cyclodextrin modifications with molecular channels according to claims 1-7, wherein the solvents used are alkanes, cycloalkanes, alcohols, ketones, aromatic hydrocarbons or water.

9.) Process for the preparation of polymeric cyclodextrin modifications with molecular channels according to claim 3 and 4, wherein the polymerization is carried out using bifunctional reagents.

10.) Process for the preparation of polymeric cyclodextrin modifications with molecular channels according to claim 3, 4 and 9, wherein the polymerization is carried out by epichlorohydrin, bisepoxides or diisocyanate or mixtures thereof.

11.) Use of the cyclodextrin modifications according to claims 1-10 as a molecular carrier in the pharmaceutical industry.

12.) Use of the cyclodextrin modifications according to claims 1-10 as a component of galenical preparations.

13.) Use of the cyclodextrin modifications according to claims 1-10 as carriers for phase transfer reactions.

14.) Use of the cyclodextrin modifications according to claims 1-10 as absorbents for removing harmful and / or toxic substances from air, water and soil.

15.) Use of the cyclodextrin modifications according to claims 1-10 for the purification of gases.

16.) Use of the cyclodextrin modifications according to claims 1-10, as absorbents for removing pollutants from the animal or human body. X.) Use of the Cvclodextπnenmodierungen according to claims 1-10 for the manufacture _D olvmerer tubular mixed polymers.

^• SPARE BLADE (RULE 26)