Novel polyrotaxane and method for producing the same

Abstract

To provide a novel polyrotaxane.SOLUTION: A polyrotaxane represented by formula (1), wherein n is 10 to 800, x is 5 to 400, A is a group larger than an inner diameter of cyclodextrin, and X is an ether bond, an ester bond, an amide bond, or a carbamate bond, and at least one unit shown in the image below represents a cyclodextrin modified with -L2-Z, or a cyclodextrin modified with -L1-Y and -L2-Z, wherein L1 and L2 are each independently a linker, Y is a sulfo group or a sulfate group, and Z is a radical reactive group.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a novel polyrotaxane and a method for producing the same. [Background technology]

[0002] Polyrotaxanes are molecular assemblies consisting of multiple cyclodextrins and a linear axial molecule that passes through them. Both ends of the axial molecule have groups that are bulkier than the inner diameter of the cyclodextrins, and are generally designed to prevent the cyclodextrins from slipping out of the axial molecule and becoming separated.

[0003] The main cyclodextrins used are α-cyclodextrin (a cyclic hexamer of glucose), β-cyclodextrin (a cyclic heptamer of glucose), and γ-cyclodextrin (a cyclic octamer of glucose). Each cyclodextrin is capable of free movement with the axial molecule threaded through it, and has attracted attention for its unique structure, mechanical properties, and physical properties (molecular mobility). Furthermore, studies have been conducted to introduce various functional groups by utilizing the hydroxyl groups on the glucose of cyclodextrin (e.g., Patent Documents 1 to 5). The use of polyrotaxanes in various applications, such as floor coatings, coating films, nail resins, dental products, sensors, and cell culture substrates, has been investigated. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] Japanese Patent Application Laid-Open No. 2011-127012 [Patent Document 2] Japanese Patent Application Laid-Open No. 2010-42415 [Patent Document 3] Japanese Patent Application Publication No. 2017-226601 [Patent Document 4] Japanese Patent Application Publication No. 2019-85330 [Patent Document 5] Japanese Patent Publication No. 2022-135159 Summary of the Invention [Problem to be solved by the invention]

[0005] However, no polyrotaxane capable of radical polymerization under aqueous conditions has been known to date. Polyrotaxanes with novel physical and chemical properties are expected to be useful in new applications and broaden the range of practical applications of polyrotaxanes. Therefore, an object of the present invention is to provide a novel polyrotaxane. [Means for solving the problem]

[0006] The present invention provides, for example, the following inventions. [1] A polyrotaxane represented by formula (1). [ka] [In the formula, n is 10 to 800, x is 5 to 400, A is a group larger than the inner diameter of cyclodextrin, and X is an ether bond, an ester bond, an amide bond, or a carbamate bond, each [ka] are independently an unsubstituted cyclodextrin or a cyclodextrin in which at least one hydroxyl group is -L 1 -Y, -L 2 -Z, or both, At least one [ka] But -L 1 -Y modified cyclodextrin or -L 1 -Y and -L 2 -Z modified cyclodextrin, At least one [ka] But -L 2 -Z modified cyclodextrin or -L 1 -Y and -L 2 -Z modified cyclodextrin, L 1 and L 2 are each independently a linker, Y is a sulfo group or a sulfate group, and Z is a radical reactive group. [2] The polyrotaxane according to [1], wherein the radical reactive group comprises an acryloyl group, a methacryloyl group, an optionally substituted allyl group, an optionally substituted vinyl group, an optionally substituted maleimide group, an optionally substituted vinyloxycarbonyl group, or an aryl group substituted with at least one group selected from the group consisting of an allyl group, a vinyl group, a maleimide group, and a vinyloxycarbonyl group. [3] The polyrotaxane according to [1] or [2], wherein Y is a sulfo group. [4] The polyrotaxane according to any one of [1] to [3], wherein the cyclodextrin is α-cyclodextrin. [5] The polyrotaxane according to any one of [1] to [4], wherein the threading number of cyclodextrins is 5 to 400. [6] The polyrotaxane according to any one of [1] to [5], wherein the average number of radical reactive groups modified per cyclodextrin molecule is 0.002 to 5.5. [7] The polyrotaxane according to any one of [1] to [6], wherein the average number of sulfo or sulfate groups modified per cyclodextrin molecule is 0.1 to 10. [8] A composition containing the polyrotaxane according to any one of [1] to [7]. [9] The composition according to [8], further comprising water.

[10] The composition according to [9], which is a hydrogel.

[11] A method for producing a polyrotaxane represented by formula (1), [ka] [In the formula, n is 10 to 800, x is 5 to 400, A is a group larger than the inner diameter of cyclodextrin, and X is an ether bond, an ester bond, an amide bond, or a carbamate bond, each [ka] are independently an unsubstituted cyclodextrin or a cyclodextrin in which at least one hydroxyl group is -L 1 -Y, -L 2 -Z, or both, At least one [ka] But -L 1 -Y modified cyclodextrin or -L 1 -Y and -L 2 -Z modified cyclodextrin, At least one [ka] But -L 2 -Z modified cyclodextrin or -L 1 -Y and -L 2 -Z modified cyclodextrin, L 1 and L 2 are each independently a linker, Y is a sulfo group or a sulfate group, and Z is a radical reactive group. A production method comprising the step of reacting a polyrotaxane represented by formula (3) with a sulfo group-introducing agent or a sulfate group-introducing agent in dimethyl sulfoxide in the presence of an alkali metal hydroxide to obtain a polyrotaxane represented by formula (2). [ka] [In the formula, n, x, A, and X are as defined above, each [ka] are independently an unsubstituted cyclodextrin or -L 1 -Y modified cyclodextrin, L 1 and Y is as defined above, At least one [ka] But -L 1 -Y modified cyclodextrin, L 1 and Y is as defined above.] [ka] [In the formula, n, x, A, and X are as defined above, each [ka] is an unsubstituted cyclodextrin.

[12] A step of dissolving the polyrotaxane represented by formula (2) in dimethyl sulfoxide and dehydrating the resulting solution; The method according to

[11] , further comprising the step of reacting the dehydrated solution with a base and a radical-reactive group-introducing agent to obtain a polyrotaxane represented by formula (1).

[13] The production method according to

[12] , wherein the sulfo group introducing agent is 1,3-propane sultone. [Effects of the Invention]

[0007] According to the present invention, a novel polyrotaxane capable of undergoing a radical reaction under aqueous conditions can be provided. The polyrotaxane according to the present invention has high water solubility and therefore does not require an organic solvent when used. [Brief explanation of the drawings]

[0008] [Figure 1] 1H-NMR spectrum of SPE-PRX obtained in step 1. a, b, and c indicate the peaks of propylene protons derived from 1,3-propane sultone, and d indicates the peak of the anomeric proton of glucose. [Figure 2] 1H-NMR spectrum of SPE-PRX-MA obtained in step 3. a, b, and c indicate the peaks of propylene protons derived from 1,3-propane sultone, d indicates the peak of the anomeric proton of glucose, and h, i, and j indicate the peaks of the exomethylene proton and methyl proton of the methacryloyl group. [Figure 3] These are the H-NMR spectra of SPE-PRX-MA synthesized by steps 2 and 3, respectively, and the powder obtained by one-step synthesis. The powder obtained by one-step synthesis exhibited a different peak from SPE-PRX-MA in the region of 3.6 ppm to 4.7 ppm, where the peaks of the PEG chain and cyclodextrin overlap. DETAILED DESCRIPTION OF THE INVENTION

[0009] Each embodiment of the present invention will be described in detail below.

[0010] A first embodiment of the present invention is a polyrotaxane represented by formula (1). [ka] In formula (1), n ​​is 10 to 800, x is 5 to 400, A is a group larger than the inner diameter of cyclodextrin, and X is an ether bond, an ester bond, an amide bond, or a carbamate bond. [ka] are independently an unsubstituted cyclodextrin or a cyclodextrin in which at least one hydroxyl group is -L 1 -Y, -L 2-Z, or both, and at least one [ka] But -L 1 -Y modified cyclodextrin or -L 1 -Y and -L 2 -Z-modified cyclodextrin, [ka] But -L 2 -Z modified cyclodextrin or -L 1 -Y and -L 2 -Z modified cyclodextrin, L 1 and L 2 are each independently a linker, Y is a sulfo group or a sulfate group, and Z is a radical reactive group.

[0011] In formula (1), each cyclodextrin is threaded by an axial molecule represented by formula (1'). The axial molecule has a polyethylene glycol moiety in the center of the molecule and -XA at ​​both ends. The orientation of each cyclodextrin may be the same or different. For convenience, the cyclodextrins are expressed in the same orientation in formula (1), but this does not limit the orientation of the cyclodextrins. [ka]

[0012] In formula (1'), n / 2 represents the number of repeating oxyethylene units in the polyethylene glycol moiety, and n may be 10 to 800. When n is 10 to 800, n / 2 is 5 to 400. n is preferably 400 to 800. The larger n is, the longer the axis molecule becomes, and more cyclodextrins can be threaded through it. The number of threading cyclodextrins can be set independently of the length of the axis molecule. When the number of threading cyclodextrins is set to be small for an axis molecule of a certain length, the cyclodextrins in the polyrotaxane become sparse, and each cyclodextrin can move more easily in the longitudinal direction of the axis molecule.

[0013] In formula (1'), A is a group larger than the inner diameter of the cyclodextrin used, and serves to cap the cyclodextrin so that it does not slip off the axial molecule. A may be, for example, a three-dimensionally bulky alicyclic hydrocarbon group such as a cyclohexyl group or an adamantyl group, or an aromatic hydrocarbon group (aryl group) such as a phenyl group, a naphthyl group, or a biphenyl group, or a heteroaryl group such as a pyridinyl group or a thiophenyl group. These groups may be optionally substituted. Examples of the substituent include halogen atoms (e.g., fluorine atoms, chlorine atoms, bromine atoms, iodine atoms), alkyl groups (e.g., C 1-6 alkyl groups), alkenyl groups (e.g., C 2-6 alkenyl groups), alkynyl groups (e.g., C 2-6 alkynyl groups), alkoxy groups (e.g., C 1-6 alkoxy group), cyano group, nitro group, hydroxyl group, sulfo group, and carboxy group.

[0014] C 1-6 The alkyl group is an alkyl group having 1 to 6 carbon atoms, and examples thereof include a methyl group, an ethyl group, a 1-propyl group, a 2-propyl group, a 1-butyl group, a 2-butyl group, a tert-butyl group, a 1-pentyl group, a 2-pentyl group, a neopentyl group, a 1-hexyl group, a 2-hexyl group, and a 3-hexyl group.

[0015] C 2-6The alkenyl group is an alkenyl group having 1 to 6 carbon atoms, and examples thereof include an ethenyl group (vinyl group), an allyl group, an isopropenyl group, a 1-butenyl group, a 2-butenyl group, a 1-pentenyl group, a 2-pentenyl group, a 1-hexenyl group, a 2-hexenyl group, and a 3-hexenyl group.

[0016] C 2-6 The alkynyl group is an alkyl group having 1 to 6 carbon atoms, and examples thereof include an ethynyl group (propargyl group), a 1-propynyl group, a 2-propynyl group, a 1-butynyl group, a 2-butynyl group, a 1-pentynyl group, a 2-pentynyl group, a 1-hexynyl group, a 2-hexynyl group, and a 3-hexynyl group.

[0017] C 1-6 An alkoxy group is a group in which an alkyl group having 1 to 6 carbon atoms is bonded to an oxygen atom (oxy group), and examples thereof include a methoxy group, an ethoxy group, a 1-propoxy group, a 2-propoxy group, a 1-butoxy group, a 2-butoxy group, a tert-butoxy group, a 1-pentoxy group, a 2-pentoxy group, a neopentyloxy group, a 1-hexyloxy group, a 2-hexyloxy group, and a 3-hexyloxy group.

[0018] X is a linker and can be a reaction site for bonding the polyethylene glycol moiety to A. X may be, for example, an ether bond, an ester bond (-C(=O)-O-, -OC(=O)-), an amide bond (-C(=O)-NH-, -NH-C(=O)-), or a carbamate bond (-NH-C(=O)-O-, -OC(=O)-NH-). X can be set depending on the application of the polyrotaxane. For example, if X is a biodegradable bond, the polyrotaxane can be decomposed by cleaving A as needed to decompose the axial molecule. Alternatively, a bond that is difficult to decompose in the environment of use may be used as X.

[0019] In equation (1), each [ka] are independently an unsubstituted cyclodextrin or a cyclodextrin in which at least one hydroxyl group is -L 1 -Y, -L 2 -Z, or both, and L 1 and L 2 are each independently a linker, Y is a sulfo group or a sulfate group, and Z is a radical-reactive group. In a preferred embodiment, the cyclodextrin is an optionally substituted α-cyclodextrin.

[0020] The polyrotaxane according to this embodiment has at least one [ka] But -L 1 -Y modified cyclodextrin or -L 1 -Y and -L 2 -Z-modified cyclodextrin, [ka] But -L 2 -Z modified cyclodextrin or -L 1 -Y and -L 2 The polyrotaxane according to this embodiment has at least one sulfo group or sulfate group and at least one radical reactive group, and these groups may be present on the same cyclodextrin or on different cyclodextrins.

[0021] L 1 and L 2 are each independently a linker, for example, an alkylene group (e.g., C 1-6alkylene group), an ether bond, an ester bond (-C(=O)-O-, -OC(=O)-), an amide bond (-C(=O)-NH-, -NH-C(=O)-), a carbamate bond (-NH-C(=O)-O-, -OC(=O)-NH-), or any combination thereof.

[0022] C 1-6 The alkylene group is an alkylene group having 1 to 6 carbon atoms, and examples thereof include a methylene group, a 1,1-ethylene group, a 1,2-ethylene group, a 1,2-propylene group, a 1,3-propylene group, a 1,2-butylene group, a 1,3-butylene group, a 1,4-butylene group, a 1,2-pentylene group, a 1,3-pentylene group, a 1,4-pentylene group, a 1,5-pentylene group, a 1,2-hexylene group, a 1,3-hexylene group, a 1,4-hexylene group, a 1,5-hexylene group, and a 1,6-hexylene group.

[0023] In certain embodiments, Y is a sulfo group (-SO3H) or a sulfate group (-OSO3H), preferably a sulfo group.

[0024] The radical reactive group Z is not particularly limited as long as it is a group capable of reacting with a radical. Examples of the radical reactive group include an acryloyl group, a methacryloyl group, an optionally substituted allyl group, an optionally substituted vinyl group, an optionally substituted maleimide group, an optionally substituted vinyloxycarbonyl group, or an aryl group substituted with at least one group selected from the group consisting of an allyl group, a vinyl group, a maleimide group, and a vinyloxycarbonyl group. The allyl group, the vinyl group, the maleimide group, and the vinyloxycarbonyl group may be optionally substituted. Examples of the substituent include a halogen atom (e.g., a fluorine atom, a chlorine atom, a bromine atom, an iodine atom), an alkyl group (e.g., a C 1-6 alkyl groups), alkenyl groups (e.g., C 2-6 alkenyl groups), alkynyl groups (e.g., C 2-6 alkynyl groups), alkoxy groups (e.g., C 1-6Examples of radical reactive groups include an alkoxy group, a cyano group, a nitro group, a hydroxyl group, a sulfo group, and a carboxy group. The radical reactive group can bond with other molecules (for example, the polyrotaxane according to this embodiment) through a radical reaction to form a complex such as a dimer or trimer. When the polyrotaxane has two or more radical reactive groups, a molecular network can also be formed by bonding multiple polyrotaxanes to each other.

[0025] The number of cyclodextrins threading through the axis molecule is 5 to 400, and may be 20 to 300. The number of cyclodextrins threading through the axis molecule is preferably 50 to 200.

[0026] The average number of sulfo or sulfate groups modified per cyclodextrin molecule is preferably 0.1 to 10, more preferably 1.0 to 6.0, and even more preferably 3.0 to 5.0. When the average number of sulfo or sulfate groups modified per cyclodextrin molecule is 3 or more, water solubility is further improved. The "average number of sulfo or sulfate groups modified per cyclodextrin molecule" can be calculated as the value obtained by dividing the number of sulfo or sulfate groups in the polyrotaxane by the number of cyclodextrins. The "average number of sulfo or sulfate groups modified per cyclodextrin molecule" is 1 It may be calculated based on the integral values ​​of the peaks characteristic of the sulfo group or sulfate group and cyclodextrin in the H NMR spectrum.

[0027] The average number of radical reactive groups modified per cyclodextrin molecule is preferably 0.002 to 5.5, more preferably 0.04 to 5.5. The "average number of radical reactive groups modified per cyclodextrin molecule" can be calculated as the value obtained by dividing the number of radical reactive groups in the polyrotaxane by the number of cyclodextrins. The "average number of radical reactive groups modified per cyclodextrin molecule" is 1 It may be calculated based on the integral values ​​of the peaks characteristic of the radical reactive group and cyclodextrin in the H NMR spectrum.

[0028] The second embodiment of the present invention is a composition containing the polyrotaxane according to the first embodiment. The composition may contain a solvent and any additives in addition to the polyrotaxane.

[0029] The solvent may be any solvent capable of dissolving or dispersing polyrotaxane, such as water or an organic solvent. Examples of the organic solvent include dimethyl sulfoxide. The composition according to this embodiment contains the polyrotaxane at a concentration of 1 to 100 mass%, 5 to 95 mass%, 10 to 90 mass%, 15 to 85 mass%, 20 to 80 mass%, 25 to 75 mass%, 30 to 70 mass%, or 35 to 65 mass%, based on the total mass of the composition.

[0030] The optional additives may be any commonly used component depending on the intended use. Examples of additives include inorganic salts (e.g., sodium chloride, magnesium chloride), solubilizers, radical initiators, colorants, thickeners, sensitizers, excipients, stabilizers, plasticizers, pH adjusters, osmotic pressure adjusters, chelating agents, enzymes, amino acids, proteins, and polysaccharides. The composition according to this embodiment may contain a polyrotaxane and physiological saline. The composition according to this embodiment may contain the additives at a concentration of 0.1 to 20% by mass, 0.5 to 18% by mass, 1 to 15% by mass, 1.5 to 13% by mass, 20 to 80% by mass, 25 to 75% by mass, 30 to 70% by mass, or 35 to 65% by mass, based on the total mass of the composition.

[0031] The composition according to this embodiment may be a hydrogel.

[0032] The third embodiment of the present invention is a method for producing the polyrotaxane according to the first embodiment. The method for producing the polyrotaxane according to this embodiment includes a step (step 1) of reacting the polyrotaxane represented by formula (3) with a sulfo group-introducing agent in dimethyl sulfoxide in the presence of an alkali metal hydroxide to obtain the polyrotaxane represented by formula (2).

[0033] The polyrotaxane represented by formula (3) is the same as the polyrotaxane represented by formula (1), except that the cyclodextrin is unsubstituted. The polyrotaxane represented by formula (2) is the same as the polyrotaxane represented by formula (1), except that the hydroxyl groups on some of the cyclodextrins are -L 1 Apart from being modified with -Y, it is the same as the polyrotaxane represented by formula (1). That is, the axial molecules of the polyrotaxanes represented by formulas (2) and (3) are identical to each other, have a polyethylene glycol moiety in the center of the molecule, and are capped at both ends with -XA. [ka] [In the formula, n, x, A, and X are the same as defined in formula (1), each [ka] is an unsubstituted cyclodextrin. [ka] [In the formula, n, x, A, and X are the same as defined in formula (1), each [ka] are independently an unsubstituted cyclodextrin or -L 1 -Y modified cyclodextrin, L 1 and Y are defined as in formula (1), At least one [ka] But -L 1 -Y modified cyclodextrin, L 1 and Y is defined as in formula (1).

[0034] [Polyrotaxane represented by formula (3)] The polyrotaxane represented by formula (3) can be produced by a method well known to those skilled in the art, and may be a commercially available polyrotaxane.

[0035] In the polyrotaxane represented by formula (3), the number average molecular weight M of the polyethylene glycol moiety n may be 500 to 50,000, and is preferably 20,000 to 35,000.

[0036] The polyrotaxane represented by formula (3) can be produced, for example, by mixing polyethylene glycol of a desired average molecular weight with cyclodextrin, threading the mixture through the desired number of cyclodextrins, and then bonding an A group to the terminal hydroxyl group of the polyethylene glycol. A method for bonding an A group to the terminal hydroxyl group may be a reaction using a capping reagent such as an acylating agent or isocyanate, which is suitable for the structure of the desired linker X. For example, when X in formula (3) is an ether bond, AT is used as the capping reagent. 1 (In the formula, T 1 is a leaving group.) can be used. When X in formula (3) is an ester bond, AT can be used as a capping reagent. 2 (In the formula, T 2 is a carboxy group, or an acid halide (halocarbonyl group). When X in formula (3) is a carbamate bond, AT can be used as a capping reagent. 3 (In the formula, T 3 is an isocyanate group.

[0037] In another embodiment, the polyrotaxane represented by formula (3) may have a carboxyl group at the end of the axial molecule instead of a hydroxyl group. Such a polyrotaxane can be produced, for example, by oxidizing the terminal hydroxyl group of polyethylene glycol having a desired average molecular weight to a carboxyl group, mixing with cyclodextrin, threading the desired number of cyclodextrins, and then bonding an A group to the terminal carboxyl group of the polyethylene glycol. The terminal hydroxyl group may be oxidized after the polyethylene glycol has threaded through the cyclodextrin. To bond an A group to the terminal carboxyl group, a reaction using a capping reagent such as an alcohol or amine may be used, depending on the structure of the desired linker X. For example, when X in formula (3) is an ester bond, AT may be used as the capping reagent. 4 (In the formula, T 4 is a hydroxyl group.) can be used. When X in formula (3) is an amide bond, AT 5 (In the formula, T 5 is an amino group.) can be used.

[0038] In yet another embodiment, the polyrotaxane represented by formula (3) may have an amino group at the end of the axis molecule instead of a hydroxyl group. Such a polyrotaxane can be produced, for example, by mixing polyoxyethylenediamine of a desired average molecular weight with cyclodextrin, threading the mixture through a desired number of cyclodextrins, and then bonding an A group to the terminal amino group. For example, when X in formula (3) is an amide bond or a carbamate bond, AT is used as a capping reagent. 6 (In the formula, T 6 is a carboxy group or an acid halide (halocarbonyl group). When X in formula (3) is a carbamate bond, AT can be used as a capping reagent. 7 (In the formula, T 7 is a halocarbonyloxy group.

[0039] [Process 1] Step 1 is a step of reacting a polyrotaxane represented by formula (3) with a sulfo group-introducing agent or a sulfate group-introducing agent in dimethyl sulfoxide in the presence of an alkali metal hydroxide to obtain a polyrotaxane represented by formula (2).

[0040] Examples of alkali metal hydroxides include lithium hydroxide, sodium hydroxide, potassium hydroxide, and cesium hydroxide. A preferred alkali metal hydroxide is sodium hydroxide. The amount of alkali metal hydroxide used may be 1 to 100 equivalents, and preferably 20 to 60 equivalents, based on the amount of cyclodextrin contained in the polyrotaxane represented by formula (3).

[0041] The sulfo group introducing agent may be any compound capable of introducing a sulfo group into a hydroxyl group. 1 -Y (wherein Y is a sulfo group, and L 1 is a linker, and T is a group capable of reacting with a hydroxyl group. 1 is, for example, an alkylene group (e.g., C 1-6 The sulfo group-introducing agent may be an alkylene group), an ether bond, an ester bond (-C(=O)-O-, -OC(=O)-), an amide bond (-C(=O)-NH-, -NH-C(=O)-), a carbamate bond (-NH-C(=O)-O-, -OC(=O)-NH-), or any combination thereof. Examples of the sulfo group-introducing agent include sultones such as 1,3-propane sultone, and salts such as sodium 2-bromoethanesulfonate and sodium 3-bromopropanesulfonate. A preferred sulfo group-introducing agent is 1,3-propane sultone. The amount of the sulfo group-introducing agent used may be 0.1 to 15 equivalents, and preferably 0.5 to 10 equivalents, based on the amount of the cyclodextrin moiety contained in the polyrotaxane represented by formula (3).

[0042] The sulfate group introducing agent may be any compound capable of introducing a sulfate group into a hydroxyl group (sulfate esterification). 1 -Y (wherein Y is a sulfate group, and L 1is a linker, and T is a group capable of reacting with a hydroxyl group. 1 is, for example, an alkylene group (e.g., C 1-6 The bond may be an alkylene group, an ether bond, an ester bond (-C(=O)-O-, -OC(=O)-), an amide bond (-C(=O)-NH-, -NH-C(=O)-), a carbamate bond (-NH-C(=O)-O-, -OC(=O)-NH-), or any combination thereof. Examples of sulfate group-introducing agents include sulfuric acid, sulfamic acid, and SO₃·Lewis base complexes. Specific examples of SO₃·Lewis base complexes include SO₃·trimethylamine, SO₃·triethylamine, SO₃·pyridine (SO₃·py), SO₃·N,N-dimethylaniline, SO₃·N,N-dimethylformamide (SO₃·DMF), and SO₃·dioxane. Other sulfate group-introducing agents that can be used include phenyl sulfate, trifluoroethyl sulfate, trichloroethyl sulfate, neopentyl sulfate, isobutyl sulfate, and fluorosulfate. When using these sulfates, a compound protected with a phenyl group or the like is produced, so it is preferable to further include a deprotection step. The amount of the sulfate group-introducing agent used may be 0.1 to 15 equivalents, and preferably 0.5 to 10 equivalents, based on the amount of cyclodextrin contained in the polyrotaxane represented by formula (3).

[0043] The amount of dimethyl sulfoxide used may be 50 to 2000 equivalents, and preferably 200 to 1400 equivalents, based on the amount of cyclodextrin contained in the polyrotaxane represented by formula (3).

[0044] The reaction temperature in step 1 may be 20 to 60°C, and is preferably 20 to 35°C.

[0045] The polyrotaxane represented by formula (2) obtained in step 1 can be purified by methods well known to those skilled in the art. For example, after the reaction in step 1, the reaction solution is dialyzed and further washed with water (e.g., MilliQ water), thereby purifying the polyrotaxane represented by formula (2). The purified polyrotaxane is preferably dehydrated by freeze-drying. The resulting polyrotaxane represented by formula (2) has increased water solubility due to the introduction of sulfo or sulfate groups.

[0046] [Steps 2 and 3] The method for producing a polyrotaxane according to this embodiment may further include a step (step 2) of dissolving a polyrotaxane represented by formula (2) in dimethyl sulfoxide and dehydrating the resulting solution, and a step (step 3) of reacting the dehydrated solution with a base and a radical-reactive group-introducing agent to obtain a polyrotaxane represented by formula (1).

[0047] Step 2 is a step of dehydrating a solution obtained by dissolving a polyrotaxane represented by formula (2) in dimethyl sulfoxide. A desiccant is added to the dimethyl sulfoxide solution of the polyrotaxane represented by formula (2) and mixed thoroughly, after which the desiccant may be filtered or the supernatant may be used. Examples of desiccant include anhydrous sodium sulfate, anhydrous magnesium sulfate, calcium chloride, and calcium sulfate. It is more preferable to dehydrate the dimethyl sulfoxide before use or to use a grade of dimethyl sulfoxide with a low water content. By performing Step 2, the efficiency of introducing radical reactive groups in Step 3 is further improved.

[0048] Step 3 is a step in which the solution dehydrated in step 2 is reacted with a base and a radical-reactive group-introducing agent to obtain a polyrotaxane represented by formula (1).

[0049] The base may be any compound having sufficient basicity to allow the hydroxyl groups on the cyclodextrin to react with the radical-reactive group-introducing agent. The base is preferably an organic base. Examples of organic bases include tertiary amines such as triethylamine and N,N-diisopropylethylamine, nitrogen-containing aromatic compounds such as pyridine and 2,6-lutidine, and cyclic amines such as DABCO (1,4-diazabicyclo[2.2.2]octane), quinuclidine, DBU (1,8-diazabicyclo[5.4.0]undec-7-ene), and DBN (1,5-diazabicyclo[4.3.0]non-5-ene). The amount of the base used may be 1 to 24 equivalents, preferably 4 to 12 equivalents, based on the amount of cyclodextrin contained in the polyrotaxane represented by formula (2).

[0050] The radical reactive group introducing agent may be a compound having a group capable of reacting with a hydroxyl group and a group having radical reactivity. 2 -Z, where Z is a radical reactive group, and L 2 is a linker, and T is a group capable of reacting with a hydroxyl group. 2 is, for example, an alkylene group (e.g., C 1-6 The radical reactive group may be an alkylene group), an ether bond, an ester bond (-C(=O)-O-, -OC(=O)-), an amide bond (-C(=O)-NH-, -NH-C(=O)-), a carbamate bond (-NH-C(=O)-O-, -OC(=O)-NH-), or any combination thereof. The radical reactive group can be introduced into the cyclodextrin of the polyrotaxane by forming an organic bond through the reaction of a group capable of reacting with a hydroxyl group with a hydroxyl group on the cyclodextrin.

[0051] Examples of the radical reactive group Z include an acryloyl group, a methacryloyl group, an optionally substituted allyl group, an optionally substituted vinyl group, an optionally substituted maleimide group, an optionally substituted vinyloxycarbonyl group, or an aryl group substituted with at least one group selected from the group consisting of an allyl group, a vinyl group, a maleimide group, and a vinyloxycarbonyl group. The allyl group, the vinyl group, the maleimide group, and the vinyloxycarbonyl group may be optionally substituted. Examples of the substituent include a halogen atom (e.g., a fluorine atom, a chlorine atom, a bromine atom, an iodine atom), an alkyl group (e.g., a C 1-6 alkyl groups), alkenyl groups (e.g., C 2-6 alkenyl groups), alkynyl groups (e.g., C 2-6 alkynyl groups), alkoxy groups (e.g., C 1-6 alkoxy group), cyano group, nitro group, hydroxyl group, sulfo group, and carboxy group. [Example]

[0052] The present invention will be described below with reference to examples. The abbreviations used in the examples have the meanings well known to those skilled in the art. DABCO: 1,4-diazabicyclo[2.2.2]octane DMSO: dimethyl sulfoxide LAP: Lithium phenyl(2,4,6-trimethylbenzoyl)phosphinate NaOH: Sodium hydroxide PRX: Polyrotaxane SPE-PRX: sulfonated polyrotaxane SPE-PRX-MA: sulfonated methacryloylated polyrotaxane

[0053] (1) Process 1 Polyrotaxane (PRX) represented by the following formula was weighed into Flask A, and dehydrated DMSO was added and stirred at 23°C. Granular sodium hydroxide (NaOH) was ground in a mortar and then weighed into Flask B. The solution in Flask A was transferred to Flask B, and while stirring, 1,3-propane sultone was added and stirred. After stirring for 2 hours at 23°C, the mixture was dialyzed at 23°C for 3 to 5 days, and the resulting product was freeze-dried for 3 to 7 days to obtain SPE-PRX. The amounts of each reagent used are shown in Table 1.

[0054] The polyrotaxane (PRX) used had a number-average molecular weight of axial molecules M n The average number of α-cyclodextrin strands was 52.6, and the number average molecular weight M n is 71200. [ka]

[0055] [Table 1]

[0056] Regarding the obtained SPE-PRX 1 H-NMR was measured. 1 The H-NMR spectrum is shown in Figure 1. The average number of sulfo groups per cyclodextrin molecule was calculated by comparing the integrals of the anomeric protons of the glucose constituting the cyclodextrin with the integrals of the protons of the propylene groups derived from 1,3-propane sultone. 1 The H-NMR measurement conditions are as follows: Device: AVANCE NEO500 (manufactured by Bruker) Frequency: 500MHz Solvent: Deuterium oxide (DO) Analysis software: Topspin 4.0.6

[0057] [Process 2] The SPE-PRX obtained in step 1 was weighed into vial A, and anhydrous DMSO was added to obtain a solution. For the dehydration procedure, anhydrous sodium sulfate was added to this solution and stirred, and then the supernatant was collected and transferred to vial B. The amounts of each reagent used are as shown in Table 2. In Table 2, for runs where the dehydration procedure is marked "No," SPE-PRX was dissolved in anhydrous DMSO, and then step 3 was carried out without dehydrating with anhydrous sodium sulfate.

[0058] [Step 3] DABCO and 2-isocyanatomethacrylate were added to the solution in vial B and stirred. After stirring at 25°C for 24 hours, the mixture was dialyzed at 23°C for 3 days, and the resulting product was freeze-dried for 3 to 7 days to obtain SPE-PRX-MA as a powder. The amounts of each reagent used are shown in Table 2. In Table 2, the SPE-PRX of each run is a sulfonated polyrotaxane derived from the same run number listed in Table 1.

[0059] [Table 2]

[0060] Regarding the obtained SPE-PRX-MA 1 H-NMR was measured. 1 The H-NMR spectrum is shown in Figure 2. The ratio of introduced sulfo groups to methacryloyl groups was calculated by comparing the integrals of the protons of the propylene groups derived from 1,3-propane sultone with those of the exomethylene protons of the methacryloyl groups. The average number of methacryloyl groups per cyclodextrin molecule was calculated by comparing the integrals of the anomeric protons of the glucose constituting the cyclodextrin with those of the exomethylene protons of the methacryloyl groups. 1 The H-NMR measurement conditions are as follows: Device: AVANCE NEO500 (manufactured by Bruker) Frequency: 500MHz Solvent: Deuterium oxide (DO) Analysis software: Topspin 4.0.6

[0061] [Evaluation of radical reactivity] The SPE-PRX-MA (0.15 g) obtained above was weighed into a vial, water was added to a concentration of 10 wt%, and 0.1 wt% of the radical initiator LAP was added and stirred at room temperature for 1 hour. The mixture was then irradiated with ultraviolet light using a UV irradiator to induce a reaction. The UV irradiation conditions were as follows: Equipment: Wafer irradiation machine MUVBA (manufactured by ITEC Systems) Wavelength: 365 nm Irradiation dose: 80 mW / cm 2 Irradiation time: 30s

[0062] Radical reactivity was evaluated by determining whether the composition came out of the vial when the vial was irradiated with ultraviolet light and held upside down for 60 minutes. If SPE-PRX-MA has radical reactivity, the composition will gel (evaluation: ○) and will not come out of the vial. Even if gelation was not observed (evaluation: ×), 1 When H-NMR is measured and the exomethylene proton of the methacryloyl group disappears or the integral value decreases, it is considered that the double bond has been consumed by a radical reaction (i.e., the compound has radical reactivity). As shown in Table 3, gelation of the composition was observed in Runs 2 to 10, and consumption of the double bond was observed in Run 1, which is therefore considered to have radical reactivity. Runs 11 and 12 did not completely dissolve in the solvent and did not gel because the number of sulfate group modifications was low and their water solubility was low.

[0063] [Table 3]

[0064] [One-step synthesis] The polyrotaxane (PRX) used in step 1 above was weighed into vial A, and DABCO, granular sodium hydroxide, and dehydrated DMSO were added. Anhydrous sodium sulfate was then added and stirred thoroughly (dehydration operation). The supernatant was then transferred to another vial (vial B), and 1,3-propane sultone and 2-isocyanato methacrylate were added and stirred. After stirring at 25°C for 24 hours, the mixture was dialyzed at 25°C for 3 days, and the resulting product was freeze-dried for 3 to 7 days to obtain a powder. Since the resulting powder was insoluble in water, it was purified using DMSO-d6. 1 H-NMR was measured. Analysis was carried out in the same manner as in step 3. As shown in Figure 3, the composition synthesized in one step was water-insoluble. 1 The peaks corresponding to PEG and cyclodextrin in the HNMR spectrum were different from those of SPE-PRX-MA, indicating that a different composition was produced than that of SPE-PRX-MA. From the above, this manufacturing method is suitable for synthesizing the target product.

Claims

1. A polyrotaxane represented by formula (1): 【Chemistry 1】 [In the formula, n is 10 to 800, x is 5 to 400, A is a group larger than the inner diameter of cyclodextrin, and X is an ether bond, an ester bond, an amide bond, or a carbamate bond, each 【Chemistry 2】 are independently unsubstituted cyclodextrin or a cyclodextrin in which at least one hydroxyl group is -L １ -Y, -L ２ -Z, or both, At least one 【Transformation 3】 But, -L １ -Y modified cyclodextrin or -L １ -Y and -L ２ -Z modified cyclodextrin, At least one 【Chemistry 4】 But, -L ２ -Z modified cyclodextrin or -L １ -Y and -L ２ -Z modified cyclodextrin, L １ and L ２ are each independently a linker, Y is a sulfo group or a sulfate group, and Z is a radical reactive group.

2. 2. The polyrotaxane according to claim 1, wherein the radical reactive group comprises an acryloyl group, a methacryloyl group, an optionally substituted allyl group, an optionally substituted vinyl group, an optionally substituted maleimide group, an optionally substituted vinyloxycarbonyl group, or an aryl group substituted with at least one group selected from the group consisting of an allyl group, a vinyl group, a maleimide group, and a vinyloxycarbonyl group.

3. The polyrotaxane according to claim 1 , wherein Y is a sulfo group.

4. The polyrotaxane according to claim 1, wherein the cyclodextrin is α-cyclodextrin.

5. 2. The polyrotaxane according to claim 1, wherein the threading number of cyclodextrin is 5 to 400.

6. 2. The polyrotaxane according to claim 1, wherein the average number of radical reactive groups per cyclodextrin molecule is 0.002 to 5.

5.

7. 2. The polyrotaxane according to claim 1, wherein the average number of sulfo or sulfate groups modified per cyclodextrin molecule is 0.1 to 10.

8. A composition comprising the polyrotaxane according to any one of claims 1 to 7.

9. The composition of claim 8 further comprising water.

10. The composition of claim 9 which is a hydrogel.

11. A method for producing a polyrotaxane represented by formula (1), 【Transformation 5】 [In the formula, n is 10 to 800, x is 5 to 400, A is a group larger than the inner diameter of cyclodextrin, and X is an ether bond, an ester bond, an amide bond, or a carbamate bond, each 【Transformation 6】 are independently unsubstituted cyclodextrin or a cyclodextrin in which at least one hydroxyl group is -L １ -Y, -L ２ -Z, or both, At least one 【Transformation 7】 But, -L １ -Y modified cyclodextrin or -L １ -Y and -L ２ -Z modified cyclodextrin, At least one 【Transformation 8】 But, -L ２ -Z modified cyclodextrin or -L １ -Y and -L ２ -Z modified cyclodextrin, L １ and L ２ are each independently a linker, Y is a sulfo group or a sulfate group, and Z is a radical reactive group. A production method comprising the step of reacting a polyrotaxane represented by formula (3) with a sulfo group-introducing agent or a sulfate group-introducing agent in dimethyl sulfoxide in the presence of an alkali metal hydroxide to obtain a polyrotaxane represented by formula (2). 【Chemistry 9】 [In the formula, n, x, A, and X are as defined above, each 【Chemistry 10】 are independently an unsubstituted cyclodextrin or -L １ -Y modified cyclodextrin, L １ and Y is as defined above; At least one 【Chemistry 11】 But, -L １ -Y modified cyclodextrin, L １ and Y is as defined above.] 【Chemistry 12】 [In the formula, n, x, A, and X are as defined above, each 【Chemistry 13】 is an unsubstituted cyclodextrin.

12. a step of dissolving the polyrotaxane represented by formula (2) in dimethyl sulfoxide and dehydrating the resulting solution; The method according to claim 11 , further comprising the step of reacting the dehydrated solution with a base and a radical-reactive group-introducing agent to obtain the polyrotaxane represented by formula (1).

13. The method according to claim 12, wherein the sulfo group-introducing agent is 1,3-propane sultone.

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