Preparation method of full-cyclodextrin polyrotaxane and molecular tube

Abstract

The invention provides a full-cyclodextrin polyrotaxane, a molecular tube and a preparation method of the full-cyclodextrin polyrotaxane and the molecular tube. The preparation method comprises the following steps: carrying out inclusion complexation on a polymer shaft chain of which the chain end is connected with a maleimide group and cavities of a plurality of cyclodextrins, carrying out Diels-Alder reaction on a carbon-carbon double bond on maleimide and a diene in substituted or unsubstituted anthracene alcohol or anthracene ether by taking substituted or unsubstituted anthracene alcohol or anthracene ether as an end-capping reagent to generate a # imgabs0 # structure, and connecting the # imgabs0 # structure to the chain tail end; the cyclodextrin can be effectively prevented from falling off from a macromolecular axial chain, and the cyclodextrin is subjected to'end capping ', so that the cyclodextrin polyrotaxane is obtained. And a retro Diels-Alder reaction can be further carried out by utilizing microwave radiation, so that the cyclodextrin molecular tube is obtained. Compared with a traditional method, the method has the advantages of clear product structure, simplicity and convenience in operation, high yield, high reaction speed, mild conditions, high controllability, high repeatability, greenness, environmental friendliness and the like.

Description

Technical Field

[0001] The invention relates to the field of supramolecular polymers, and in particular to a full-cyclodextrin polyrotaxane and a molecular tube, and a preparation method and application thereof. Technical Background

[0002] Cyclodextrin polyrotaxane is a structurally stable internally locked supramolecular polymer formed by multiple cyclodextrin molecules passing through a polymer chain under the action of hydrophobic force, and introducing large-sized "capping" molecules at both ends of the chain to restrict the cyclodextrin from falling off. The unique molecular composition and topological structure of cyclodextrin polyrotaxane have brought about a wide range of applications. For example, the numerous hydroxyl groups on cyclodextrin provide abundant reaction sites, making it a good carrier for drugs, genes or diagnostic systems; for example, cyclodextrin molecules have the ability to migrate freely on the chain, and the "pulley" gel formed with cyclodextrin as the cross-linking site can greatly improve the tensile properties of the material, and has been successfully used in battery adhesives, strain sensors, etc.

[0003] However, the preparation of cyclodextrin polyrotaxanes usually involves complicated steps, harsh conditions, and low yields. This is because in the preparation of cyclodextrin polyrotaxanes, the introduction of large-sized end-capping groups at both ends of the chain and the dissociation of cyclodextrin from the chain are simultaneous and competing processes. In order to improve the yield, the measures taken usually take into account both improving the efficiency of the end-capping reaction and inhibiting the dissociation of cyclodextrin. The latter requires that the end-capping reaction is preferably carried out in an aqueous phase, because the hydrophobic force in the aqueous environment will ensure the inclusion of the hydrophobic cavity of cyclodextrin with the hydrophobic polymer chain, which can effectively inhibit the dissociation. Among the currently reported methods for preparing cyclodextrin polyrotaxanes, most of the end-capping reactions are carried out in organic solvents, which have significant disadvantages, such as the lack of hydrophobic force, and the easy dissociation of cyclodextrin from the polymer chain, resulting in a low end-capping reaction yield (such as the document "The molecular necklace: arotaxane containing many threaded α-cyclodextrins." (Harada, A., et al. (1992). Nature 356 (6367): 325-327) and Chinese patent document CN 103102492 A). In addition, a small number of preparation methods choose to carry out the end-capping reaction in the aqueous phase, such as using the CuAAC reaction, which requires the preparation of metal ion complexes and an anaerobic environment, and the operation is more cumbersome, the conditions are high, the preliminary preparation is more complicated, and promotion has a certain degree of difficulty (Chinese patent document CN101775146 A). Therefore, it is very important and urgent to find a method for preparing cyclodextrin polyrotaxanes that is simple to operate, mild in conditions, and has a high yield.

[0004] Cyclodextrin molecular tubes are polymers with tubular structures formed by cross-linking multiple cyclodextrin molecules in sequence. It maintains the hydrophobic cavity of cyclodextrin and can form inclusion complexes with a variety of guest molecules; it also maintains the good water solubility of cyclodextrin, and the inclusion complexes formed with guest molecules also have good water solubility, so it has a wide range of application prospects. The preparation of cyclodextrin molecular tubes usually starts with the obtained cyclodextrin polyrotaxane. First, the adjacent cyclodextrins on the same polymer axis chain are cross-linked within the chain, and then the end groups at both ends of the chain are removed to allow the polymer chain to fall freely from the cyclodextrin cavity. Finally, a hollow tubular cross-linked cyclodextrin product is obtained, which is the cyclodextrin molecular tube. The reported methods for obtaining cyclodextrin molecular tubes through cyclodextrin polyrotaxanes have similar synthetic pathways, most of which involve the formation and cleavage of ester bonds, which require the introduction of high temperature and an external strong alkaline environment. The conditions are not mild, nor are they environmentally friendly and economical. The synthetic reaction urgently needs innovation. Summary of the invention

[0005] The purpose of the present invention is to solve the common problems faced in the existing preparation methods of cyclodextrin polyrotaxanes and cyclodextrin molecular tubes, and to provide a preparation method of cyclodextrin polyrotaxanes and cyclodextrin molecular tubes with universality, ease of operation, scalability and high yield, while taking into account green chemistry.

[0006] The specific technical solutions of the present invention are as follows:

[0007] A full cyclodextrin polyrotaxane having a cyclodextrin cavity and a polymer axis chain, wherein one or both ends of the polymer axis chain have a capping group:

[0008] Wherein, R1, R2, and R3 are the same or different, R2 and R3 represent one or more same or different substituents at any position of the benzene ring, R1, R2, and R3 can be H at the same time, or at least one of the groups is a hydrophilic substituent, and the rest are selected from H, halogen groups, C1-C10 alkyl groups, C1-C10 alkoxy groups, C1-C10 carboxyl groups, hydroxyl groups, amino groups, nitro groups, C1-C10 haloalkyl groups, α, β, γ-cyclodextrin groups, and sodium trisulfonate pyrene groups.

[0009] The hydrophilic substituent may be selected from: C1-C10 alkyl, C1-C10 acyl, sulfonic acid, hydrophilic polymer group substituted by one or more hydroxyl, amino, carboxyl, sulfonic acid groups, and the hydrophilic polymer is selected from polyacrylic acid, polyethylene glycol, polyvinyl alcohol, polyacrylamide, polyvinyl pyrrolidone, and polybetaine. Preferably, R1 represents H or alkyl substituted by sulfonic acid or α, β, γ-cyclodextrin, and R2 and R3 are the same or different and represent H or polyethylene glycol.

[0010] Preferably, the polymer axis chain is selected from polyethylene glycol, polypropylene glycol, polytetrahydrofuran, polypropylene oxide, polyisobutylene, polymethyl vinyl ether, polyethylene succinate, polybutylene succinate, polycaprolactone, polyethylene glycol block polypropylene glycol or polyethylene glycol block polycaprolactone, and the number of repeating units of the polymer axis chain is an integer of 20-400, preferably an integer of 33-165.

[0011] The cyclodextrin described in the present invention is selected from α-cyclodextrin, β-cyclodextrin or γ-cyclodextrin.

[0012] Another object of the present invention is to provide a full-cyclodextrin polyrotaxane molecular tube, which is prepared using the full-cyclodextrin polyrotaxane described in the present invention.

[0013] Another object of the present invention is to provide a method for preparing the all-cyclodextrin polyrotaxane of the present invention, wherein a polymer axis chain having a maleimide group connected to the chain end is complexed with the cavity of multiple cyclodextrins, and then a substituted or unsubstituted anthracene alcohol / anthracene ether is prepared. As a capping agent, the carbon-carbon double bond on maleimide undergoes a Diels-Alder reaction with the diene in substituted or unsubstituted anthracene alcohol / anthracene ether.

[0014] The chain ends of the all-cyclodextrin polyrotaxane prepared by the present invention The structure can effectively prevent the cyclodextrin on the chain from falling off and achieve "end-capping" of cyclodextrin.

[0015] The preparation method of the all-cyclodextrin polyrotaxane is:

[0016] Add a polymer axis chain with maleimide at the end to the cyclodextrin aqueous solution in a reactor, stir for 8-20 hours to form a pseudopolyrotaxane suspension; directly add substituted or unsubstituted anthracene alcohol / anthracene ether to the pseudopolyrotaxane suspension, stir at 25-45°C, and react for 12-60 hours to obtain a full cyclodextrin polyrotaxane.

[0017] Specifically, add 1 equivalent of a polymer axis chain with maleimide at the end to a 10-50 equivalent cyclodextrin aqueous solution in a reactor, stir for 8-20 hours to form a pseudo-polyrotaxane suspension; directly add 5-10 equivalents of substituted or unsubstituted anthracene alcohol / anthracene ether to the pseudo-polyrotaxane suspension, stir and react at 25-45°C for 12-60 hours, and centrifuge to obtain a crude product of a full cyclodextrin polyrotaxane. The crude product is dissolved in DMSO, precipitated in water and alcohol in turn, washed repeatedly, and dried to obtain a full cyclodextrin polyrotaxane. (The reaction product can be further centrifuged, dissolved, precipitated, washed repeatedly, and dried)

[0018] A preferred example of the present invention is: add 1 equivalent of a polymer axis chain with maleimide at the end to a saturated concentration of cyclodextrin in an aqueous solution in a reactor, stir for 48 hours to form a pseudo-polyrotaxane suspension; directly add 8-10 equivalents of a large-sized capping agent with anthracene alcohol groups to the suspension, stir and react at 40°C for 12-60 hours, separate and precipitate by centrifugation, dissolve with DMSO, precipitate with water and methanol in turn, wash repeatedly, and obtain a full cyclodextrin polyrotaxane after drying.

[0019] The polymer axis chain with maleimide groups connected to the chain ends can be purchased commercially or prepared by the following method:

[0020] One equivalent of a polymer shaft chain with an amine group at the chain end is dissolved in anhydrous dichloromethane or anhydrous DMF solvent, and 2-4 equivalents of 3-maleimidopropionic acid, 2-4 equivalents of 1-hydroxybenzotriazole (HOBt) and 2-4 equivalents of 1-ethyl-(3-dimethylaminopropyl)carbodiimide (EDC) are added thereto, and the reaction is stirred at room temperature for 24-48 hours. After the reaction is completed, the organic phase is washed with water, and the product is separated by a silica gel column to obtain a polymer shaft chain with a maleimide group at the chain end.

[0021] Another object of the present invention is to provide a method for preparing a full cyclodextrin polyrotaxane molecular tube: cross-linking cyclodextrin by conventional methods, for example, using a cross-linking agent (epichlorohydrin) under alkaline conditions (using an extremely strong base such as sodium hydroxide or potassium hydroxide) to cross-link adjacent cyclodextrin molecules on the same polymer axis chain in the cyclodextrin polyrotaxane, and then cross-linking the chain ends. The structure breaks down by retro Diels-Alder reaction, the end-capping agent leaves, and the polymer chain falls off from the cavity of cyclodextrin, forming a hollow tubular cross-linked cyclodextrin molecule.

[0022] Preferably, the cyclodextrin polyrotaxane chain ends are cross-linked with the intra-chain cyclodextrin by microwave method. The structure undergoes a retro Diels-Alder reaction. The microwave conditions are 700-1200 W microwave irradiation for 10-20 minutes.

[0023] A specific preparation method of the present invention is as follows: dissolving the full cyclodextrin polyrotaxane of the present invention in an organic solution, using epichlorohydrin as a cross-linking agent, adding sodium hydroxide and stirring for reaction, then pouring into water to terminate the reaction, subjecting the product obtained after dialysis to microwave radiation at 700 W for 20 minutes, cooling, and repeating the operation several times to obtain a full cyclodextrin molecular tube.

[0024] A specific example of the present invention is a method for preparing a full cyclodextrin molecular tube: dissolve a full cyclodextrin polyrotaxane (wherein the cyclodextrin is 1 equivalent) and 5-10 equivalents of epichlorohydrin in a reactor with DMSO, add sodium hydroxide thereto, stir and react for 12-18 hours, pour into an appropriate amount of water to terminate the reaction, neutralize with dilute hydrochloric acid and dialyze for 24-48 hours. The product obtained by dialysis is irradiated with 700W microwaves for 20 minutes, cooled for 5 minutes, and the operation is repeated 5 times. Dissolve with DMSO, precipitate with acetone and ethanol in turn, wash repeatedly, and dry to obtain a full cyclodextrin molecular tube.

[0025] Another object of the present invention is to provide the use of the all-cyclodextrin polyrotaxane or all-cyclodextrin polyrotaxane molecular tube in the preparation of drug delivery vectors, gene delivery vectors, diagnostic and therapeutic system vectors, elastomer cross-linked materials, molecular device materials, molecular transmission materials, molecular recognition materials, biomembrane transmission simulation materials or supramolecular chemical materials.

[0026] The present invention utilizes the Diels-Alder reaction between the carbon-carbon double bond of maleimide in the aqueous phase and the diene structure of anthracene alcohol as the end-capping reaction to generate a The structure is modified by introducing a large-sized end-capping group to hinder the detachment of cyclodextrin, thereby obtaining a fully cyclodextrin polyrotaxane. This preparation method has obvious advantages over the traditional preparation methods reported:

[0027] (1) The method can be carried out by directly adding the material into the suspension of pseudopolyrotaxane, and the operation is simple and convenient.

[0028] (2) The aqueous environment ensures the hydrophobic effect, avoids the dissociation of cyclodextrin, and ensures high yield. The yields of β- and γ-cyclodextrin polyrotaxanes are increased from less than 10% and 5% in the prior art to 16% and 55%, respectively.

[0029] (3) The cyclodextrin dissolved in the reaction system can further catalyze the reaction, and the reaction speed is very fast.

[0030] (4) The reaction conditions are very mild, simple, easy to operate, highly controllable, and highly repeatable, making it easy to promote.

[0031] (5) Anthracene alcohol can be coupled to other functional groups at the same time as the end-capping, including protein molecules, fluorescent groups and drug molecules. The prepared all-cyclodextrin polyrotaxane is directly functional and has potential wide application value in the fields of drug delivery, gene delivery, preparation of diagnostic and therapeutic system carriers, elastomer cross-linking, preparation of molecular devices and supramolecular chemistry.

[0032] (6) The present invention also utilizes the retro Diels-Alder reaction under microwave irradiation to make the chain end The structure was destroyed, and as a method for dissociating the end groups of the cyclodextrin polyrotaxane and removing the polymer chain, a full cyclodextrin molecular tube was obtained.

[0033] The preparation of cyclodextrin molecular tubes by dissociating the chain end capping groups by microwave radiation is simpler to operate, faster, more chemically efficient, green and environmentally friendly than the traditional alkaline hydrolysis reaction. The obtained full cyclodextrin molecular tubes have potential application value in host-guest chemistry, biomedicine and other fields. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] Figure 1 The α-cyclodextrin polyrotaxane synthesized by using 9-anthryl alcohol as a capping agent in Example 4 of the present invention in DMSO-d6 1 HNMR spectrum.

[0035] Figure 2 This is the 2DNOESY graph of the α-cyclodextrin polyrotaxane synthesized in Example 4 of the present invention using 9-anthryl alcohol as a capping agent in DMSO-d6.

[0036] Figure 3 This is the 2DDOSY graph of the α-cyclodextrin polyrotaxane synthesized in Example 4 of the present invention using 9-anthryl alcohol as a capping agent in DMSO-d6.

[0037] Figure 4 The β-cyclodextrin polyrotaxane synthesized by using 9-anthryl alcohol as a capping agent in Example 8 of the present invention in DMSO-d6 1 HNMR spectrum.

[0038] Figure 5 This is the 2DNOESY graph of the β-cyclodextrin polyrotaxane synthesized in Example 8 of the present invention using 9-anthryl alcohol as a capping agent in DMSO-d6.

[0039] Figure 6 This is the 2DDOSY graph of the β-cyclodextrin polyrotaxane synthesized in Example 8 of the present invention using 9-anthryl alcohol as a capping agent in DMSO-d6.

[0040] Figure 7 The γ-cyclodextrin polyrotaxane synthesized by using 9-anthryl alcohol as a capping agent in Example 12 of the present invention in DMSO-d6 1 HNMR spectrum.

[0041] Figure 8 This is the 2D NOESY graph of the γ-cyclodextrin polyrotaxane synthesized in Example 12 of the present invention using 9-anthryl alcohol as a capping agent in DMSO-d6.

[0042] Fig. 9 This is the 2DDOSY graph of the γ-cyclodextrin polyrotaxane synthesized in Example 12 of the present invention using 9-anthryl alcohol as a capping agent in DMSO-d6.

[0043] Fig.10 Embodiment 13 of the present invention utilizes β-cyclodextrin polyrotaxane synthesized as a capping agent in DMSO-d6 1 H NMR spectra.

[0044] Fig.11 Embodiment 14 of the present invention utilizes β-cyclodextrin polyrotaxane synthesized as a capping agent in DMSO-d6 1 H NMR spectra.

[0045] Fig.12 Embodiment 15 of the present invention utilizes γ-cyclodextrin polyrotaxane synthesized as a capping agent in DMSO-d6 1 H NMR spectra.

[0046] Fig.13 Embodiment 16 of the present invention utilizes β-cyclodextrin polyrotaxane synthesized as a capping agent in DMSO-d6 1 H NMR spectra.

[0047] Fig.14 Embodiment 17 of the present invention utilizes γ-cyclodextrin polyrotaxane synthesized as a capping agent in DMSO-d6 1 H NMR spectra.

[0048] Fig.15 The α-cyclodextrin molecular tube synthesized in Example 18 of the present invention is in DMSO-d6 1 H NMR spectra.

[0049] Fig.16 These are the GPC data of the α-cyclodextrin polyrotaxane synthesized in Example 4 of the present invention (curve a) and the GPC data of the α-cyclodextrin molecular tube synthesized in Example 18 (curve b).

[0050] Fig.17 The β-cyclodextrin molecular tube synthesized in Example 19 of the present invention is in DMSO-d6 1 H NMR spectra.

[0051] Fig.18 These are the GPC data of the β-cyclodextrin polyrotaxane synthesized in Example 8 of the present invention (curve a) and the GPC data of the β-cyclodextrin molecular tube synthesized in Example 19 (curve b).

[0052] Fig.19 The γ-cyclodextrin molecular tube synthesized in Example 20 of the present invention in DMSO-d6 1 H NMR spectra.

[0053] Fig. 20 These are the GPC data of the γ-cyclodextrin polyrotaxane synthesized in Example 12 of the present invention (curve a) and the GPC data of the γ-cyclodextrin molecular tube synthesized in Example 20 (curve b). DETAILED DESCRIPTION

[0054] The synthesis principle is to use substituted or unsubstituted anthracene alcohol or anthracene ether as a capping agent, which directly reacts with the maleimide at the end of the polymer axis chain in the pseudopolyrotaxane in the aqueous phase to produce a Diels-Alder reaction. structure, thereby obtaining a full cyclodextrin polyrotaxane; after intrachain crosslinking of the cyclodextrin molecules on the same axis chain in the aforementioned cyclodextrin polyrotaxane, a retro Diels-Alder reaction is performed under microwave irradiation conditions to make The structure breaks, dissociates the end-capping groups from the polymer axis chain, and thus obtains a full cyclodextrin molecular tube.

[0055] The following examples are provided to further illustrate the present invention, but are not intended to limit the scope of the present invention.

[0056] Embodiment 1:

[0057] At room temperature, 2.20g of α-cyclodextrin (2.25mmol) was dissolved in water, and 200μL of an aqueous solution containing 115mg of polyethylene glycol chain with maleimide at the end (polyethylene glycol segment molecular weight of 2000g / mol, containing 0.1mmol of maleimide) was added thereto. The reaction system was stirred for 48 hours to form a pseudopolyrotaxane suspension. 166.6mg of 9-anthracene alcohol (0.8mmol) was added thereto, and the reaction was stirred at 40°C for 12 hours. The precipitate was collected by centrifugation, dissolved in DMSO, precipitated with water and methanol in turn, washed repeatedly, and dried to obtain a white powder, i.e., α-cyclodextrin polyrotaxane, with a yield of 75.5%.

[0058] Embodiment 2:

[0059] The same reaction steps as in Example 1 were adopted, the reaction time was 24 hours, and the yield was 85.1%.

[0060] Embodiment 3:

[0061] The same reaction steps as in Example 1 were adopted, the reaction time was 48 hours, and the yield was 92.4%.

[0062] Embodiment 4:

[0063] The same reaction steps as in Example 1 were adopted, the reaction time was 60 hours, and the yield was 92.9%.

[0064] Figure 1The α-cyclodextrin polyrotaxane synthesized in this example is in DMSO-d6 1 H NMR spectrum showed obvious α-cyclodextrin, polyethylene glycol and Characteristic peaks of the structure. According to NMR integral calculation, each polyethylene glycol (polyethylene glycol segment molecular weight is 2000 g / mol) axis chain has 12 α-cyclodextrin molecules, and the α-cyclodextrin coverage is 57%.

[0065] Figure 2 This is the 2D NOESY image of the α-cyclodextrin polyrotaxane synthesized in this example in DMSO-d6. The figure shows that C(3)H (3.65ppm) and C(5)H (3.55ppm) on α-cyclodextrin and methylene hydrogen (3.51ppm) in polyethylene glycol show strong cross signals, indicating that α-cyclodextrin and polyethylene glycol self-assemble to form an inclusion complex through hydrophobic force, and the inclusion complex is stably retained by the end-capping reaction.

[0066] Figure 3 This is a 2D DOSY image of the α-cyclodextrin polyrotaxane synthesized in this example in DMSO-d6. The image shows α-cyclodextrin, polyethylene glycol axis chain and two ends. The structures showed the same diffusion coefficient, indicating that α-cyclodextrin passed through the polyethylene glycol axis chain and was fixed on the axis by the end-capping groups at both ends. The three formed a stable whole, proving the successful synthesis of α-cyclodextrin polyrotaxane.

[0067] Embodiment 5:

[0068] At room temperature, 1.93g of β-cyclodextrin (1.70mmol) was dissolved in water, and 200μL of methanol solution containing 115mg of polypropylene glycol chain with maleimide at the end (polypropylene glycol chain segment molecular weight is 2000g / mol, containing 0.1mmol maleimide) was added thereto. The reaction system was stirred for 48 hours to form a pseudopolyrotaxane suspension. 166.6mg of 9-anthracene alcohol (0.8mmol) was added thereto, and the reaction was stirred at 40°C for 12 hours. The precipitate was collected by centrifugation, dissolved in DMSO, precipitated with water and methanol in turn, washed repeatedly, and dried to obtain a white powder, namely β-cyclodextrin polyrotaxane, with a yield of 5.1%.

[0069] Embodiment 6:

[0070] The same reaction steps as in Example 5 were adopted, the reaction time was 24 hours, and the yield was 7.8%.

[0071] Embodiment 7:

[0072] The same reaction steps as in Example 5 were adopted, the reaction time was 48 hours, and the yield was 15.5%.

[0073] Embodiment 8:

[0074] The same reaction steps as in Example 5 were adopted, the reaction time was 60 hours, and the yield was 15.9%.

[0075] Figure 4 The β-cyclodextrin polyrotaxane synthesized in this example is in DMSO-d6 1 H NMR diagram. The structure shows obvious β-cyclodextrin, polypropylene glycol and Characteristic peaks of the structure. According to NMR integral calculation, there are 13 β-cyclodextrin molecules on each polypropylene glycol (polypropylene glycol chain segment molecular weight is 2000 g / mol) axis chain, and the coverage rate of β-cyclodextrin is 78%.

[0076] Figure 5 This is a 2D NOESY graph of the β-cyclodextrin polyrotaxane synthesized in this example in DMSO-d6. The graph shows that C(3)H (3.65ppm) and C(5)H (3.55ppm) on β-cyclodextrin and methyl hydrogen (1.04ppm) in polypropylene glycol exhibit strong cross signals, indicating that β-cyclodextrin and polypropylene glycol self-assemble to form an inclusion complex through hydrophobic force, and the inclusion complex is stably retained by the end-capping reaction.

[0077] Figure 6 This is a 2D DOSY image of the β-cyclodextrin polyrotaxane synthesized in this example in DMSO-d6. The image shows the β-cyclodextrin, the polypropylene glycol axis chain and the two ends. The structures showed the same diffusion coefficient, indicating that β-cyclodextrin passed through the polypropylene glycol axis chain and was fixed on the axis by the end-capping groups at both ends. The three formed a stable whole, proving the successful synthesis of β-cyclodextrin polyrotaxane.

[0078] Embodiment 9:

[0079] At room temperature, 2.20g of γ-cyclodextrin (1.70mmol) was dissolved in water, and 200μL of DMF solution containing 199mg of polypropylene glycol chain with 8 maleimide groups introduced at both ends (4 maleimides were introduced at one end, the molecular weight of the polypropylene glycol chain segment was 2000g / mol, and it contained 0.4mmol maleimide) was added thereto. The reaction system was stirred for 48 hours to form a pseudopolyrotaxane suspension. 666.4mg of 9-anthracene alcohol (3.2mmol) was added thereto, and the reaction was stirred at 40°C for 24 hours. The precipitate was collected by centrifugation, dissolved with DMSO, precipitated with water and methanol in turn, washed repeatedly, and dried to obtain a white powder, i.e., γ-cyclodextrin polyrotaxane, with a yield of 13.6%.

[0080] Preparation of polypropylene glycol axis chain with 4 maleimide groups introduced at one end and 8 maleimide groups introduced at both ends: 200 mg of polypropylene glycol axis chain with amino groups at the chain end (polypropylene glycol segment molecular weight is 2000 g / mol) was dissolved in 20 mL of anhydrous dichloromethane solvent, and 193 mg of second-generation polylysine molecules were added thereto. (0.24mmol, directly purchased), 32mg 1-hydroxybenzotriazole (0.24mmol, HOBt) and 46mg 1-ethyl-(3-dimethylaminopropyl) carbonyl diimide (0.24mmol, EDC), stirring reaction 24 hours at room temperature. Subsequently, wash organic phase with water, separate and obtain product with silica gel column. Product is dissolved in 10mL anhydrous dichloromethane, drip 5mL trifluoroacetic acid, stirring reaction 2 hours, and desolvation is removed by underpressure distillation subsequently. Product is dissolved with 20mL anhydrous dichloromethane again, 162mg 3-maleimido propionic acid (0.96mmol), 130mg 1-hydroxybenzotriazole (0.96mmol, HOBt) and 184mg 1-ethyl-(3-dimethylaminopropyl) carbonyl diimide (0.96mmol, EDC) are added thereto, stirring reaction 40 hours at room temperature. After the reaction is completed, the organic phase is washed with water, and the product is separated by a silica gel column to obtain a polypropylene glycol axis chain with 4 maleimide groups introduced at one end and 8 maleimide groups introduced at both ends.

[0081] Example 10: The same reaction steps as in Example 9 were adopted, the reaction time was 48 hours, and the yield was 45.9%.

[0082] Example 11: The same reaction steps as in Example 9 were adopted, the reaction time was 60 hours, and the yield was 54.6%.

[0083] Example 12: The same reaction steps as in Example 9 were adopted, the reaction time was 72 hours, and the yield was 55.2%.

[0084] Figure 7 The γ-cyclodextrin polyrotaxane synthesized in this example is in DMSO-d6 1 H NMR spectrum. The results showed that γ-cyclodextrin, polypropylene glycol and Characteristic peaks of the structure. According to NMR integral calculation, there are 8 γ-cyclodextrin molecules on each polypropylene glycol (polypropylene glycol chain segment molecular weight is 2000 g / mol) axis chain, and the coverage of γ-cyclodextrin is 51%.

[0085] Figure 8This is a 2D NOESY graph of the γ-cyclodextrin polyrotaxane synthesized in this example in DMSO-d6. The graph shows that C(3)H (3.65ppm) and C(5)H (3.55ppm) on γ-cyclodextrin and methyl hydrogen (1.04ppm) in polypropylene glycol exhibit strong cross signals, indicating that γ-cyclodextrin and polypropylene glycol self-assemble to form an inclusion complex through hydrophobic force, and the inclusion complex is stably retained by the end-capping reaction.

[0086] Fig. 9 This is a 2D DOSY image of the γ-cyclodextrin polyrotaxane synthesized in this example in DMSO-d6. The image shows the γ-cyclodextrin, the polypropylene glycol axis chain and the two ends. The structures showed the same diffusion coefficient, indicating that γ-cyclodextrin passed through the polypropylene glycol axis chain and was fixed on the axis by the end-capping groups at both ends. The three formed a stable whole, proving the successful synthesis of γ-cyclodextrin polyrotaxane.

[0087] Embodiment 13:

[0088] At room temperature, 1.93 g of β-cyclodextrin (1.70 mmol) was dissolved in water, and 200 μL of a methanol solution containing 115 mg of polypropylene glycol chains with maleimide ends (polypropylene glycol chain molecular weight of 2000 g / mol, containing 0.1 mmol of maleimide) was added. The reaction system was stirred for 48 hours to form a pseudopolyrotaxane suspension. 293 mg of (0.8mmol), stirred and reacted at 40℃ for 48 hours, centrifuged and collected the precipitate, dissolved in DMSO, precipitated with water and methanol in turn, washed repeatedly, and dried to obtain a white powder, namely β-cyclodextrin polyrotaxane, with a yield of 10.8%.

[0089] Preparation: 416 mg of 9-anthryl alcohol (2 mmol) was dissolved in 10 mL of anhydrous tetrahydrofuran, 120 mg of sodium hydride was added thereto in an ice bath, and after the reaction was smooth, it was transferred to an oil bath and refluxed at 65° C. for 2 hours. After cooling to room temperature, 218 mg (1.6 mmol) of 1,4-butanesulfonic acid lactone dissolved in 2 mL of anhydrous tetrahydrofuran was added thereto, and it was transferred to an oil bath again and refluxed at 65° C. for 3 hours. After the reaction was completed, it was precipitated with acetone and washed to obtain the product.

[0090] Fig.10 The β-cyclodextrin polyrotaxane synthesized in this example is in DMSO-d6 1 H NMR graph. The graph shows obvious characteristic peaks of β-cyclodextrin, polypropylene glycol and terminal structure. According to NMR integral calculation, there are 8 β-cyclodextrin molecules on each polypropylene glycol (polypropylene glycol chain segment molecular weight is 2000g / mol) axis chain.

[0091] Embodiment 14:

[0092] At room temperature, 1.93 g of β-cyclodextrin (1.70 mmol) was dissolved in water, and 200 μL of a methanol solution containing 115 mg of polypropylene glycol chains with maleimide ends (polypropylene glycol chain molecular weight of 2000 g / mol, containing 0.1 mmol of maleimide) was added thereto. The reaction system was stirred for 48 hours to form a pseudopolyrotaxane suspension. 732 mg of (0.8mmol), stirred at 40℃ for 48 hours, centrifuged to collect the precipitate, dissolved in DMSO, precipitated with water and methanol, washed repeatedly, and dried to obtain a white powder, namely β-cyclodextrin polyrotaxane, with a yield of 8.2%.

[0093] The preparation is divided into three steps:

[0094] ① Dissolve 208 mg of 9-anthrol (1 mmol) in 5 mL of anhydrous tetrahydrofuran, add 400 mg of sodium hydride in an ice bath, transfer to room temperature after the reaction is slow, and continue to react for 1 hour. Then add 1.05 g (4 mmol) of 1,4-di(bromomethyl)benzene dissolved in 10 mL of anhydrous tetrahydrofuran, transfer to an oil bath, and reflux at 70 ° C overnight. After the reaction is completed, pour a large amount of ice water to quench, extract with dichloromethane, and separate the product through a silica gel column. 313 mg of the above product (0.8 mmol) was further dissolved in 5 mL of anhydrous DMF, 130 mg of sodium azide (2 mmol) was added, and the mixture was refluxed at 60°C overnight. After the reaction was completed, deionized water was added, and the mixture was extracted with ethyl acetate. The solvent was removed by distillation under reduced pressure to obtain the product.

[0095] ② Dissolve 524 mg of 8-hydroxy-1,3,6-pyrene trisulfonic acid trisodium salt (1 mmol) and 48 mg of sodium hydroxide (1.2 mmol) in 20 mL of DMSO solution, add 143 mg of propargyl bromide (1.2 mmol), and reflux at 60 ° C overnight. After the reaction is completed, precipitate with isopropanol and wash several times to obtain the product

[0096] ③ Take 85 mg of the product of step ① (0.24 mmol) and 112 mg of the product of step ② (0.2 mmol) and dissolve them in a mixed solution of 3.2 mL DMF and 0.8 mL deionized water. Add 34.7 mg of pentamethyldiethylenetriamine (0.2 mmol, PMDETA) and 10 mg of copper sulfate pentahydrate (0.04 mmol). Then, the reaction system is protected by argon, 106 mg of sodium ascorbate (0.6 mmol) is added, and the reaction is carried out at 60 ° C for 48 hours. After the reaction is completed, precipitate with isopropanol and wash several times to obtain the product

[0097] Fig.11 The β-cyclodextrin polyrotaxane synthesized in this example is in DMSO-d6 1 H NMR graph. The results show obvious characteristic peaks of β-cyclodextrin, polypropylene glycol and terminal large-sized molecular structure. According to NMR integral calculation, there are 9 β-cyclodextrin molecules on each polypropylene glycol (polypropylene glycol chain segment molecular weight is 2000g / mol) axis chain.

[0098] Embodiment 15:

[0099] At room temperature, 2.20 g of γ-cyclodextrin (1.70 mmol) was dissolved in water, and 200 μL of a methanol solution containing 115 mg of a maleimide-terminated polypropylene glycol chain (polypropylene glycol chain segment molecular weight of 2000 g / mol, containing 0.1 mmol of maleimide) was added thereto. The reaction system was stirred for 48 hours to form a pseudopolyrotaxane suspension. 732 mg of (0.8mmol), stirred at 40℃ for 48 hours, centrifuged to collect the precipitate, dissolved in DMSO, precipitated with water and methanol, washed repeatedly, and dried to obtain a white powder, i.e., γ-cyclodextrin polyrotaxane, with a yield of 5.8%.

[0100] Fig.12 The γ-cyclodextrin polyrotaxane synthesized in this example is in DMSO-d6 1 H NMR graph. The results show obvious characteristic peaks of γ-cyclodextrin, polypropylene glycol and terminal large-sized molecular structure. According to NMR integral calculation, there are 5 γ-cyclodextrin molecules strung on each polypropylene glycol (polypropylene glycol chain segment molecular weight is 2000g / mol) axis chain.

[0101] Embodiment 16:

[0102] At room temperature, 1.93 g of β-cyclodextrin (1.70 mmol) was dissolved in water, and 200 μL of a methanol solution containing 115 mg of a maleimide-terminated polypropylene glycol chain (polypropylene glycol chain segment molecular weight of 2000 g / mol, containing 0.1 mmol of maleimide) was added thereto. The reaction system was stirred for 48 hours to form a pseudopolyrotaxane suspension. 1124 mg of (0.8mmol), stirred and reacted at 40℃ for 48 hours, centrifuged and collected the precipitate, dissolved in DMSO, precipitated with water and methanol in turn, washed repeatedly, and dried to obtain a white powder, namely β-cyclodextrin polyrotaxane, with a yield of 8.8%.

[0103] The preparation is divided into two steps:

[0104] ① Dissolve 208 mg of 9-anthryl alcohol (1 mmol) in 5 mL of anhydrous tetrahydrofuran, add 400 mg of sodium hydride in an ice bath, transfer to room temperature after the reaction is slow, and continue to react for 1 hour. Then add 120 mg (1 mmol) of propargyl bromide, transfer to an oil bath, and reflux at 65°C for 2 hours. After the reaction is completed, pour a large amount of ice water to quench, extract with dichloromethane, and separate through a silica gel column to obtain the product

[0105] ② Take 98.4 mg of the product of step ① (0.4 mmol) and 232 mg of mono(6-azido-6-deoxy)β-cyclodextrin (0.2 mmol) and dissolve them in 5 mL of DMF solution. Add 34.7 mg of pentamethyldiethylenetriamine (0.2 mmol, PMDETA) and 10 mg of copper sulfate pentahydrate (0.04 mmol). Then, the reaction system is protected by argon, and 106 mg of sodium ascorbate (0.6 mmol) is added to react at 60°C for 48 hours. After the reaction is completed, precipitate with acetone and wash several times to obtain the product.

[0106] Fig.13 The β-cyclodextrin polyrotaxane synthesized in this example is in DMSO-d6 1 H NMR graph. The results show obvious characteristic peaks of β-cyclodextrin, polypropylene glycol and terminal large-sized molecular structure. According to NMR integral calculation, there are 5 β-cyclodextrin molecules on each polypropylene glycol (polypropylene glycol chain segment molecular weight is 2000g / mol) axis chain.

[0107] Embodiment 17:

[0108] At room temperature, 2.20 g of γ-cyclodextrin (1.70 mmol) was dissolved in water, and 200 μL of a methanol solution containing 115 mg of a maleimide-terminated polypropylene glycol chain (polypropylene glycol chain segment molecular weight of 2000 g / mol, containing 0.1 mmol of maleimide) was added thereto. The reaction system was stirred for 48 hours to form a pseudopolyrotaxane suspension. 1124 mg of (0.8mmol), stirred and reacted at 40℃ for 48 hours, centrifuged and collected the precipitate, dissolved in DMSO, precipitated with water and methanol in turn, washed repeatedly, and dried to obtain a white powder, i.e., γ-cyclodextrin polyrotaxane, with a yield of 6.9%.

[0109] Fig.14 The γ-cyclodextrin polyrotaxane synthesized in this example is in DMSO-d6 1 H NMR graph. The results show obvious characteristic peaks of γ-cyclodextrin, polypropylene glycol and terminal large-sized molecular structure. According to NMR integral calculation, there are 4 γ-cyclodextrin molecules on each polypropylene glycol (polypropylene glycol chain segment molecular weight is 2000g / mol) axis chain.

[0110] Embodiment 18:

[0111] At room temperature, 100 mg of the α-cyclodextrin polyrotaxane synthesized in Example 4 (containing 0.09 mmol of α-cyclodextrin), 35 μL of epichlorohydrin (0.5 mmol) and 120 mg of sodium hydroxide (3.0 mmol) were dissolved in 10 mL of DMSO solution. After stirring for 18 hours, the reaction was stopped by pouring into 10 mL of water and adjusted to neutral with dilute hydrochloric acid. Dialyze with deionized water for 24 hours, remove insoluble matter by centrifugation, and freeze-dry the clarified filtrate to obtain a white solid. The solid was subjected to microwave irradiation for 20 minutes at 700 W power, then the irradiation was stopped, cooled for 5 minutes, and this step was repeated 5 times. Finally, it was dissolved with DMSO, precipitated with acetone and ether in turn, washed repeatedly, and dried to obtain α-cyclodextrin molecular tubes with a yield of 80.2%.

[0112] Fig.15 The α-cyclodextrin molecular tube synthesized in this example is in DMSO-d6 1 H NMR spectrum. The results showed the characteristic peaks of cross-linked α-cyclodextrin, while polyethylene glycol and The characteristic peaks of the structure disappeared, indicating that the polyethylene glycol axis chain successfully dissociated from the cavity of α-cyclodextrin.

[0113] Fig.16The GPC data of the α-cyclodextrin polyrotaxane synthesized in Example 4 (curve a) and the GPC data of the α-cyclodextrin molecular tube synthesized in this example (curve b). As shown in the figure, the two curves show a unimodal distribution, indicating that the synthesized α-cyclodextrin polyrotaxane and α-cyclodextrin molecular tube have stable structures and good uniformity. At the same time, the peak positions of the two curves are very close, indicating that the α-cyclodextrin molecular tube synthesized based on the α-cyclodextrin polyrotaxane has a similar hydrodynamic volume to the α-cyclodextrin polyrotaxane, that is, the cross-linking of α-cyclodextrin in the polyrotaxane is concentrated in the polyrotaxane molecule, and the cross-linking does not change the linear arrangement of the cyclodextrin molecules in the polyrotaxane. After the chain axis is dissociated, the α-cyclodextrin molecular tube with a hollow tubular structure is obtained.

[0114] Embodiment 19:

[0115] At room temperature, 100 mg of the β-cyclodextrin polyrotaxane synthesized in Example 8 (containing 0.07 mmol of β-cyclodextrin), 31 μL of epichlorohydrin (0.4 mmol) and 120 mg of sodium hydroxide (3.0 mmol) were dissolved in 10 mL of DMSO solution. Subsequently, the same reaction steps as in Example 18 were taken to obtain β-cyclodextrin molecular tubes with a yield of 85.3%.

[0116] Fig.17 The β-cyclodextrin molecular tube synthesized in this example is in DMSO-d6 1 H NMR spectrum. The results show the characteristic peaks of cross-linked β-cyclodextrin, while polypropylene glycol and The characteristic peaks of the structure disappeared, indicating that the polypropylene glycol axis chain successfully dissociated from the cavity of β-cyclodextrin.

[0117] Fig.18 It is the GPC data of the β-cyclodextrin polyrotaxane synthesized in Example 8 (curve a) and the GPC data of the β-cyclodextrin molecular tube synthesized in this example (curve b). As shown in the figure, the two curves show a unimodal distribution, indicating that the synthesized β-cyclodextrin polyrotaxane and the β-cyclodextrin molecular tube have stable structures and good uniformity. At the same time, the peak positions of the two curves are very close, indicating that the β-cyclodextrin molecular tube synthesized based on the β-cyclodextrin polyrotaxane has a similar hydrodynamic volume to the β-cyclodextrin polyrotaxane, that is, the cross-linking of β-cyclodextrin in the polyrotaxane is concentrated in the polyrotaxane molecule, and the cross-linking does not change the linear arrangement of the cyclodextrin molecules in the polyrotaxane. After the chain axis is dissociated, a β-cyclodextrin molecular tube with a hollow tubular structure is obtained.

[0118] Embodiment 20:

[0119] At room temperature, 100 mg of the γ-cyclodextrin polyrotaxane synthesized in Example 12 (containing 0.05 mmol of γ-cyclodextrin), 21 μL of epichlorohydrin (0.3 mmol) and 120 mg of sodium hydroxide (3.0 mmol) were dissolved in 10 mL of DMSO solution. Subsequently, the same reaction steps as in Example 18 were taken to obtain γ-cyclodextrin molecular tubes with a yield of 81.1%.

[0120] Fig.19 The γ-cyclodextrin molecular tube synthesized in this example is in DMSO-d6 1 H NMR spectrum. The results show the characteristic peaks of cross-linked γ-cyclodextrin, while polypropylene glycol and The characteristic peaks of the structure disappeared, indicating that the polypropylene glycol axis chain successfully dissociated from the cavity of γ-cyclodextrin.

[0121] Fig. 20 It is the GPC data of the γ-cyclodextrin polyrotaxane synthesized in Example 12 (curve a) and the GPC data of the γ-cyclodextrin molecular tube synthesized in this example (curve b). As shown in the figure, the two curves show a unimodal distribution, indicating that the synthesized γ-cyclodextrin polyrotaxane and the γ-cyclodextrin molecular tube have stable structures and good uniformity. At the same time, the peak positions of the two curves are very close, indicating that the γ-cyclodextrin molecular tube synthesized based on the γ-cyclodextrin polyrotaxane has a similar hydrodynamic volume to the γ-cyclodextrin polyrotaxane, that is, the cross-linking of the γ-cyclodextrin in the polyrotaxane is concentrated in the polyrotaxane molecule, and the cross-linking does not change the linear arrangement of the cyclodextrin molecules in the polyrotaxane. After the chain axis is dissociated, the γ-cyclodextrin molecular tube with a hollow tubular structure is obtained.

Claims

1. A fully cyclodextrin polyrotaxane having a cyclodextrin cavity and a polymer axis chain, characterized in that One or both ends of the polymer axis chain have a capping group: Wherein, R1, R2, and R3 are the same or different, R2 and R3 represent one or more same or different substituents at any position of the benzene ring, R1, R2, and R3 can be H at the same time, or at least one of the groups is a hydrophilic substituent, and the rest are selected from H, halogen groups, C1-C10 alkyl groups, C1-C10 alkoxy groups, C1-C10 carboxyl groups, hydroxyl groups, amino groups, nitro groups, C1-C10 haloalkyl groups, α, β, γ-cyclodextrin groups, and sodium trisulfonate pyrene groups.

2. The all-cyclodextrin polyrotaxane according to claim 1, characterized in that The hydrophilic substituent is selected from C1-C10 alkyl, C1-C10 acyl, sulfonic acid, and hydrophilic polymer groups substituted by one or more hydroxyl, amino, carboxyl, and sulfonic acid groups, and the hydrophilic polymer group is selected from polyacrylic acid, polyethylene glycol, polyvinyl alcohol, polyacrylamide, polyvinyl pyrrolidone, and polybetaine.

3. The all-cyclodextrin polyrotaxane according to claim 2, characterized in that The R1 represents H, sulfonic acid group or β-cyclodextrin, and R2 and R3 represent H.

4. The all-cyclodextrin polyrotaxane according to claim 1, characterized in that The polymer axis chain is selected from polyethylene glycol, polypropylene glycol, polytetrahydrofuran, polypropylene oxide, polyisobutylene, polymethyl vinyl ether, polyethylene succinate, polybutylene succinate, polycaprolactone, polyethylene glycol block polypropylene glycol or polyethylene glycol block polycaprolactone, and the number of repeating units of the polymer axis chain is an integer of 20-400.

5. The all-cyclodextrin polyrotaxane according to claim 1, characterized in that The cyclodextrin is selected from α-cyclodextrin, β-cyclodextrin or γ-cyclodextrin.

6. A fully cyclodextrin polyrotaxane molecular tube, characterized in that The invention is prepared by using the full cyclodextrin polyrotaxane described in any one of claims 1 to 5.

7. The method for preparing the all-cyclodextrin polyrotaxane according to any one of claims 1 to 5, characterized in that After the polymer axis chain with maleimide group connected to the chain end is complexed with the cavity of multiple cyclodextrins, the substituted or unsubstituted anthracene alcohol / anthracene ether As a capping agent, the carbon-carbon double bond on maleimide undergoes a Diels-Alder reaction with the diene in substituted or unsubstituted anthracene alcohol or anthracene ether.

8. The preparation method according to claim 7, characterized in that: Add a polymer axis chain with maleimide at the end to the cyclodextrin aqueous solution in a reactor, stir for 8-20 hours to form a pseudopolyrotaxane suspension; directly add substituted or unsubstituted anthracene alcohol / anthracene ether to the pseudopolyrotaxane suspension, stir at 25-45°C, and react for 12-60 hours to obtain a full cyclodextrin polyrotaxane.

9. A method for preparing a fully cyclodextrin polyrotaxane molecular tube, characterized in that: The all-cyclodextrin polyrotaxane described in any one of claims 1 to 5 is cross-linked with epichlorohydrin in an alkaline solution, irradiated with 700-1200W microwaves for 10-20 minutes, cooled, and the operation is repeated several times to obtain an all-cyclodextrin molecular tube.

10. Use of the all-cyclodextrin polyrotaxane according to any one of claims 1 to 5 or the all-cyclodextrin polyrotaxane molecular tube according to claim 6 in the preparation of drug delivery vectors, gene delivery vectors, diagnostic and therapeutic system vectors, elastomer cross-linked materials, molecular device materials, molecular transmission materials, molecular recognition materials, biomembrane transmission simulation materials or supramolecular chemical materials.

Images