JPH0625307A - Method for producing α-cyclodextrin inclusion compound endcapped with guest polymer and cyclodextrin inclusion compound endcapped with guest polymer - Google Patents

Abstract

(57) [Summary] [Objective] An inclusion compound of cyclodextrin endcapped with a guest polymer is provided. [Constitution] α-cyclodextrin and poly (ethylene glycol) bisamine are allowed to undergo an inclusion reaction, and the obtained inclusion compound is allowed to react with 2,4-dinitrophenylfluoride to obtain an end-capped α-cyclodextrin. The inclusion compound is prepared. [Effect] By endcapping a clathrate compound of a high molecular compound such as polyethylene glycol and α-cyclodextrin at both ends of the guest polymer, effects such as modification of the high molecular compound and impartation of crosslinkability can be obtained. Be expected.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel type of inclusion compound of cyclodextrin, and more particularly to an inclusion compound of a guest polymer end-capped α-cyclodextrin. Further, the present invention provides
The present invention relates to a method for producing an inclusion compound of cyclodextrin endcapped with a guest polymer.

[0002]

2. Description of the Related Art With the recent increase in recognition of the importance of specific non-covalent intermolecular interactions in biological systems, the chemistry of noncovalent assemblies, that is, supramolecular chemistry. (Supramolecular chemistry)
Interest in is getting higher. Supramolecular complexes treated in supramolecular chemistry are two or more molecules that approach each other non-covalently to form one complex and organize different functions of each molecule. It should be called a kind of complex molecule that can also express new functions that could not be exhibited.

As one of such supramolecules, a non-covalently integrated rotor and an axis (ax) are included in one molecule.
is) and a rotaxane-type complex having a structure in which the shaft is end-capped so that the rotor cannot be detached from the shaft is known. Recently,
"Rotator" of methylated β-cyclodextrin
A rotaxane as a molecule was synthesized (“John S. Manka
and David S. Lawrence, J. Am. Chem. Soc., 1990, 11
2, 2440 "and" Taka Venkata S. Rao and David S. L
awrence, J. Am. Chem. Soc., 1990, 112, 3614 ").

Such rotaxanes are those in which one or two methylated β-cyclodextrin molecules as "rotor" molecules enclose one "axis" molecule.

[0005]

DISCLOSURE OF THE INVENTION Problems to be Solved by the Invention In view of the possibility of expressing a specific function of supramolecules as described above, the present inventors have found that many cyclodextrin molecules as “rotor” molecules are If a rotaxane is prepared in which "axis" molecules are included and both ends of the "axis" molecules are blocked, there are many "rotor" molecules per "axis" molecule, and both species are present. Due to the peculiarity of these molecules forming a kind of complex molecule that cannot be released from each other, we think that they will open up the prospects for the development of new functions and organization, and we have been eager to provide the above-mentioned rotaxanes. I did a research.

[0006]

DISCLOSURE OF THE INVENTION The present inventors have found that α-cyclodextrin forms a crystalline inclusion compound (inclusion complex) with polyethylene glycol in a high yield (Patent application No. 2-34252). This clathrate compound is the first to have a polymer compound as a guest molecule. The polyethylene glycol molecule is considered to be included in the tunnel formed by a large number of α-cyclodextrins as host molecules.

Therefore, the present inventors first considered to chemically modify both ends of the polyethylene glycol chain as a guest polymer of the inclusion compound of polyethylene glycol and α-cyclodextrin with bulky blocking groups. ,
As a result of intensive studies, the present invention has been completed.

That is, according to the present invention, a polyethylene glycol molecule is included in a skewered manner in the α-cyclodextrin molecule forming the inclusion lattice, and the α-cyclodextrin molecule is desorbed from the polyethylene glycol molecule. There is provided an inclusion compound of α-cyclodextrin in which a guest polymer is end-capped, wherein both ends of the polyethylene glycol molecule are chemically modified with a blocking group that is sufficiently bulky to prevent separation.

In the inclusion compound of α-cyclodextrin in which the guest polymer of the present invention is end-capped, the bulky blocking group is preferably a 2,4-dinitrophenylamino group.

Further, according to the present invention, a cyclodextrin and an ether bond-containing polymer compound are allowed to undergo an inclusion reaction, and both polymer ends of the ether bond-containing polymer compound are bound to the cyclodextrin molecule by the ether bond. There is also provided a method for producing an inclusion compound of cyclodextrin in which a guest polymer is end-capped, which is characterized in that it is chemically modified with a blocking group that is sufficiently bulky so that it cannot be removed from the molecule of the contained polymer compound.

In a specific embodiment of the method for producing an inclusion compound of cyclodextrin endcapped with a guest polymer according to the present invention, the cyclodextrin is α-cyclodextrin, and the ether bond-containing polymer is Poly (ethylene glycol) bisamine is preferable, and at both ends of the polymer, for example,
If the chemical modification is performed with the 2,4-dinitrophenylamino group as the bulky blocking group by reacting with 2,4-dinitrophenylfluoride, the guest polymer endcapped α-cyclodextrin An inclusion compound is prepared.

Further, the present inventors have found that β-cyclodextrin and γ-cyclodextrin form an inclusion compound with polypropylene glycol in the same manner as described above (Japanese Patent Application No. 2-116861). These inclusion compounds also chemically modify both polymer terminals of polypropylene glycol, which is a guest molecule of the inclusion compound, with bulky blocking groups, as in the case of the above-described inclusion compound of α-cyclodextrin and polyethylene glycol. be able to.

In the present specification, the term "polyethylene glycol", "polypropylene glycol" and the like mean that both ends of these molecules are modified.

As another example of the above bulky blocking group, for example, instead of the "2,4-dinitrophenyl group" of the above "2,4-dinitrophenylamino group", the following "chemical formula 1" A trityl group represented by the chemical formula, a dansyl group represented by the chemical formula of “Chemical Formula 2” below,
A bulky group such as a 2,4,6-trinitrophenyl group may be used.

[0015]

[Chemical 1]

[0016]

[Chemical 2]

An inclusion compound of α-cyclodextrin (α-CD) and polyethylene glycol [PEG, eg, poly (ethylene glycol) bisamine (PEG-BA) with both molecular terminals modified, and β or γ.
-The method for producing an inclusion compound of cyclodextrin (β- or γ-CD) and polypropylene glycol (PPG) will be described in more detail.

With respect to 1 mol of α-, β- or γ-CD,
Both are stirred and mixed in an aqueous medium so that the alkylene glycol unit (unit) of PEG or PPG is 2 mol or more, and the reaction is performed, for example, at around room temperature for 10 seconds to 1 hour. It is not preferable to use PEG or PPG in an unnecessarily large amount because of high cost. In particular, when PPG is used, it may be in a dispersed state, so it is preferable to perform ultrasonic stirring. The precipitate formed is solid-liquid separated from the reaction mixture. As a method for this solid-liquid separation, filtration, centrifugation, membrane separation using an ultrafiltration membrane, etc. are generally used.

Next, as a typical method for chemically modifying both ends of the guest polymer with a blocking group, α-CD and PEG-BA are used.
An example of the case of reacting the clathrate compound of 2 with 2,4-dinitrophenyl fluoride [2,4-dinitrofluorobenzene (DNFB)] will be described.

For example, DNFB is added to a solution of the above-mentioned clathrate compound dissolved in a solvent such as dimethylformamide, and the mixture is stirred, for example, at around room temperature for 10 hours to 1 day. The reaction mixture is poured into a large amount of a solvent such as ether, and the formed precipitate is washed with a solvent such as ether or dimethylformamide to remove unreacted raw materials and by-products. Further, the washed product may be dissolved in dimethyl sulfoxide, poured into water and washed with water to further raise the purity. For further purification, for example, a method such as column chromatography may be used.

Instead of the above 2,4-dinitrophenyl fluoride, for example, trityl bromide, dansyl chloride, 2,4,6-trinitrophenyl fluoride and the like can be used.

[0022]

[Function] After a high molecular compound such as polyethylene glycol or polypropylene glycol is used as a guest molecule and cyclodextrin is included as a host molecule in a skewered form, both polymer terminals of the high molecular compound are chemically treated with a bulky blocking group. When modified and blocked, such a bulky blocking group prevents the cyclodextrin molecule as a host molecule from being detached from the chain of the polymer compound, and the inclusion compound is bound to the host molecule even when contact is made with heating or a solvent. It is not detached to the guest molecule.

The inclusion compound of cyclodextrin endcapped with the guest polymer of the present invention is
It is the first synthetic supramolecule in the form of a large number of "rotor" molecules enclosed in a single "axis" molecule. Since the molecular structure is similar to abacus, the present inventors named it “molecular abacus”.

FIG. 1 is a model representation of the molecular structure of the inclusion compound of α-cyclodextrin endcapped with polyethylene glycol of the present invention. It can be seen that the inclusion of 1 unit of α-cyclodextrin to 2 units of ethylene glycol is included.
If the polyethylene glycol chain has a planar zigzag, the length of ethylene glycol 2 units is 7.0 angstroms, which is in good agreement with the cavity depth of α-cyclodextrin of 7.1 angstroms. β
-Or γ-CD and the inclusion compound of PPG is similar, β- or γ-C to 2 units of propylene glycol
It is a D1 unit. The arrangement of α-cyclodextrins is assumed to be head-head or tail-tail.

[0025]

EXAMPLES The present invention will now be described in more detail with reference to examples, but the present invention is not limited to the examples.

Example 1 [Preparation of inclusion compound of α-cyclodextrin endcapped with polyethylene glycol molecule] Poly (ethylene glycol) bisamine (average molecular weight: 34
8 ml of a 15 wt% aqueous solution of 50) was added to 100 ml of a saturated aqueous solution of α-cyclodextrin, and the mixture was stirred at room temperature for 30 minutes. The obtained suspension was filtered and washed with water to separate the inclusion compound precipitate, and then dried.

This clathrate compound was put into dimethylformamide, 100 mole times of 2,4-dinitrofluorobenzene was added to poly (ethylene glycol) bisamine, and the mixture was stirred at room temperature overnight. The reaction mixture obtained was poured into a large amount of ether.

The precipitate obtained is filtered, washed three times with ether to remove unreacted 2,4-dinitrofluorobenzene and then with dimethylformamide, free α-cyclodextrin, poly (ethylene glycol). The bisamine and the by-produced dinitrophenyl derivative were removed.

The residue was dissolved in dimethyl sulfoxide and put into water. Next, the obtained suspension was filtered and washed with water to remove unreacted α-cyclodextrin, poly (ethylene glycol) bisamine and by-produced water-soluble dinitrophenyl derivative.

The product obtained is collected, washed with ether,
It was then dried. The yield was 60%. Finally, using dimethyl sulfoxide as a solvent, this product was subjected to column chromatography using Sephadex G-50 (Sephadex G-50, manufactured by Pharmacia) as a packing material for purification. The product thus purified is free of free α-cyclodextrin, poly (ethylene glycol) bisamine and dinitrophenyl derivatives,
It was of high purity.

[Solubility of Inclusion Compound] Each component such as α-cyclodextrin, poly (ethylene glycol) bisamine, and bis (2,4-dinitrophenyl) -polyethylene glycol, and α-cyclodextrin and poly ( The product obtained in this example was insoluble in water and dimethylformamide, whereas the inclusion compound with (ethylene glycol) bisamine was water-soluble.

This product was soluble in dimethyl sulfoxide and 0.1N caustic soda. In the case of caustic soda, the hydroxyl group of α-cyclodextrin (pK
a = 12) may be ionized and solubilized in an aqueous medium. A solution of the product dissolved in caustic soda was added to 0.
Upon neutralization with 1N hydrochloric acid, a precipitate immediately formed. The above phenomenon was reversible.

[NMR Analysis of Inclusion Compound]
¹ H NMR and ¹³ C NMR spectra show α-cyclodextrin [α-CD] and poly (ethylene glycol)
It was in agreement with a similar spectrum of a mixture containing both components of bisamine [PEG-BA]. However, in the case of the produced clathrate, some broadening of the peak was observed.

Next, the measurement results of ¹ H NMR will be described. ¹ H
_{NMR (DMSO-d 6) (} 270 MHz): 8.87
(s, 2H, ortho H of phenyl), 8.30 (d, 2H, meta H of p
henyl), 7.26 (d, 2H, meta H of phenyl), 5.63 (s, 6Hx
20, O (2) H of α-CD), 5.48 (s, 6Hx20, O (3) H of α-C
D), 4.80 (s, 6Hx20, C (1) H of α-CD), 4.40 (s, 6Hx20,
O (6) H of α-CD), 3.64-3.74 (m, 24Hx20, C (3) H, C (6)
H, and C (5) H of α-CD), 3.51 (s, 4x82, CH ₂ of PEG),
3.24-3.29 (m, 12Hx20, C (2) H and C (4) H of α-CD).

¹ H NMR (D ₂ O + NaOH) (270
MHz): 8.93 (s, 2H, ortho H of phenyl), 8.17
(d, 2H, meta H (1) of phenyl), 7.05 (d, 2H, meta H
(2) of phenyl), 4.74 (d, 6Hx20, C (1) H of α−CD),
3.59-3.75 (m, 24Hxn, C (3) H, C (6) H, and C (5) H of α
−CD), 3.50 (s, 4Hx82, CH ₂ of PEG), 3.19-3.32 (m, 12
Hx20, C (2) H and C (4) H of α-CD).

Next, the measurement results of ¹³ C NMR will be described. ¹³
_{C NMR (DMSO-d 6)} (125.65 MH
z): 101.93 (C (1) of α-CD), 81.69 (C (4) of α-C)
D), 73.33 (C (3) of α-CD), 72.08 (C (2) of α-CD), 71.
53 (C (5) of α-CD), 69.38 (PEG), 59.74 (C (6) of α-C
D).

[Combustion analysis of clathrate compound] Actual value (calculated value for C ₈₄₄ H ₁₄₄₄ N ₆ O ₆₅₁ (H ₂ ) ₃₈ ):
C: 43.77 (44.51), H: 6.82 (6.73), N: 0.38 (0.48).

[Gel Chromatography] Gel chromatography (column: 1.7) of the product by Sephadex G-50 (exclusion limit molecular weight: 30,000) using dimethyl sulfoxide (DMSO) as an eluent.
As a result of (× 70 cm), a single peak appeared near the fraction number corresponding to the porosity of the Sephadex packed bed. In contrast, the product (3 mg), α-
Cyclodextrin (30 mg) and bis (2,4-dinitrophenylamino) -polyethylene glycol (2
Similar gel chromatography of 0 mg) mixture revealed 3 peaks.

FIG. 2 is a diagram showing the latter chromatogram (elution curve). The horizontal axis of this figure represents the fraction number (1 fraction: 1.5 ml), and the vertical axis represents the absorbance of ultraviolet absorption measurement and the optical rotation of optical rotation measurement. In this figure, the solid curve is the one detected by UV absorption measurement (wavelength: 316.5 nm),
The dotted curve is the one detected by optical rotation measurement. The first peak was for the product inclusion compound and was detected by both UV absorption and optical rotation measurements. The second peak detected only by UV absorption measurement is that of bis (2,4-dinitrophenylamino) -polyethylene glycol. The third peak detected only by the optical rotation measurement is
It is that of α-cyclodextrin.

[Average Molecular Weight] The average molecular weight of the clathrate compound examined by ¹ H NMR was 23,200, which suggests that the number of α-cyclodextrin molecules trapped in one polymer chain is about 20. To do. On the other hand, the average molecular weight of the clathrate compound examined by ultraviolet absorption measurement is 26,400,
This value suggests that 23 α-cyclodextrin units are contained in one molecule.

It is considered that polyethylene glycol having bulky substituents such as 3,5-dinitrobenzoic acid ester group and 2,4-dinitrophenyl group at both molecular ends does not form an inclusion compound with α-cyclodextrin. Taken together, it is concluded that in the case of the inclusion compound of this example, 20 to 23 α-cyclodextrin units as beads of the molecular abacus are trapped on one polyethylene glycol chain on average.

According to the powder X-ray diffraction pattern of the clathrate compound of this example, the clathrate compound is crystalline and similar to the powder X-ray diffraction pattern of the clathrate compound of valeric acid or octanol and α-cyclodextrin. However, the powder X-ray diffraction pattern of the inclusion compound of α-cyclodextrin with a smaller molecule such as propionic acid or propanol is different. These results suggest that the clathrate of this example is isomorphic to that of the channel-type structure.

[0043]

INDUSTRIAL APPLICABILITY The inclusion compound of cyclodextrin in which the guest polymer of the present invention is end-capped allows a large number of “rotor” molecules, which are host molecules, to be trapped in one guest molecule, “axis” molecule. The bulky blocking groups at both ends of the molecule prevent the host molecule from leaving. Therefore, a usual clathrate compound is easily desorbed into a guest molecule and a host molecule by heating or contact with a solvent, whereas the clathrate compound of the present invention does not dissociate.

Therefore, it is possible to modify various properties such as thermal stability, orientation, crystallinity and solubility of the guest polymer through inclusion and end capping. Further, by utilizing the hydroxyl group of cyclodextrin, intramolecular cross-linking of the clathrate compound (for example, cross-linking between adjacent cyclodextrin units) or inter-molecular cross-linking is possible, and it is possible to have unique properties, Various possibilities are expected, such as the development of new polymers in which cyclodextrins are arrayed.

[Brief description of drawings]

FIG. 1 is a model view showing the molecular structure of an inclusion compound of α-cyclodextrin endcapped with a polyethylene glycol chain of the present invention.

FIG. 2 is a diagram showing an elution curve obtained by gel chromatography of a mixture of an inclusion compound of the present invention, α-cyclodextrin and bis (2,4-dinitrophenylamino) -polyethylene glycol.

Claims (4)

[Claims] 1. A polyethylene glycol molecule is included in a skewered manner in an α-cyclodextrin molecule constituting an inclusion lattice, and is sufficient to prevent the α-cyclodextrin molecule from being detached from the polyethylene glycol molecule. An inclusion compound of α-cyclodextrin in which a guest polymer is end-capped, wherein both ends of the polyethylene glycol molecule are chemically modified with a bulky blocking group. 2. The inclusion compound of α-cyclodextrin endcapped with a guest polymer according to claim 1, wherein the bulky blocking group is a 2,4-dinitrophenylamino group. . 3. A cyclodextrin and an ether bond-containing polymer compound are subjected to an inclusion reaction, and both molecular ends of the ether bond-containing polymer compound are separated from the molecule of the ether bond-containing polymer compound by the cyclodextrin molecule. A method for producing an inclusion compound of cyclodextrin in which a guest polymer is end-capped, characterized by chemically modifying with a blocking group that is sufficiently bulky so that it cannot be eliminated. 4. The cyclodextrin is α-cyclodextrin, and the ether bond-containing polymer compound is poly (ethylene glycol) bisamine.
The chemical modification is performed with the 2,4-dinitrophenylamino group as the bulky blocking group by reacting both polymer terminals with 2,4-dinitrophenylfluoride. A method for producing an inclusion compound of cyclodextrin endcapped with the guest polymer according to claim 1.