A polyrotaxane and a method for preparing the same

Abstract

The present invention relates to the field of polymers, and in particular to a polyrotaxane and a preparation method thereof. The present invention provides a preparation method for a polyrotaxane, comprising the following steps: reacting cyclodextrin and multi-arm polyethylene glycol containing functional groups at the ends to obtain a pseudo-polyrotaxane under a protective gas atmosphere; and performing an end-capping reaction on the pseudo-polyrotaxane to obtain a polyrotaxane. The preparation method provided by the present invention uses multi-arm polyethylene glycol containing functional groups at the ends to prepare a pseudo-polyrotaxane with a natural end-capping at one end, and then uses a dendritic macromolecular compound to perform an end-capping reaction on the pseudo-polyrotaxane in an aqueous phase through a one-pot method. The end-capping is efficient and safe, the raw materials are commercialized, the cost is low, and the manufacture of green polyrotaxane is realized. Experiments show that when four-arm polyethylene glycol is used to prepare polyrotaxane, the polyrotaxane yield per 10g of four-arm polyethylene glycol reaches 86g, while the polyrotaxane yield per 10g of traditional carboxyl-terminated polyethylene glycol in the comparative example is only 67g.

Description

Technical Field

[0001] The invention relates to the field of polymers, in particular to a polyrotaxane and a preparation method thereof. Background Art

[0002] Polyrotaxanes are a type of host-guest interlocked supramolecular system containing multiple cyclic molecules and capped by bulky groups. If the two ends of the polymer are not capped, the cyclic molecules can freely enter and exit the polymer chain, which is called a pseudopolyrotaxane. There are many types of polymer molecular chains (guests) in polyrotaxanes, such as polyglycols (polyethylene glycol, polypropylene glycol), polyolefins (polypropylene), polyethers (polymethyl vinyl ether) and conjugated polymers (polyvinylbenzene, polymethylene alkali). Common cyclic molecules as the main body include: cyclodextrin (CD), crown ethers and calixarene. Cyclodextrin is a macrocyclic compound with a truncated cone structure formed by glucose units connected end to end through glycosidic bonds. The outer wall of the cone is hydrophilic and the inner wall of the cone is hydrophobic. In recent years, cyclodextrin has become the most widely used main molecule of polyrotaxane due to its natural raw materials, relatively cheap price, non-toxicity and good biocompatibility.

[0003] Harada et al. (WO01 / 83566 and Macromolecules 1993, 26, 5698-5703) used α-CD and PEG with amino groups at the end to prepare a pseudopolyrotaxane of white precipitate in water for the first time, separated the pseudopolyrotaxane from the aqueous solution, and obtained a polyrotaxane based on α-CD and PEG by end-capping with 2,4-dinitrofluorobenzene in dimethylformamide (DMF) solution after drying. However, the process of -OH at both ends of PEG being replaced with -NH2 is cumbersome, resulting in high price, which limits the scope of application from the cost perspective. In addition, the end-capping agent 2,4-dinitrofluorobenzene is very toxic and expensive. There are major defects in terms of cost, safety and environment.

[0004] Patents by Yang Bo et al. of Kunming University of Science and Technology (CN105906816A) use aqueous iodinated cyclodextrin and amino-terminated polyether as pseudo-polyrotaxanes, and DCC condensation reagents to condense folic acid for end-capping. Patents by Jiang Yi et al. of Shanghai Jiaotong University (CN101343368) use linear polymers (PEG, PPG, etc.) with amino, carboxyl, thiol, hydroxyl, aldehyde or hydrazide groups at the ends as axes, cyclodextrin, crown ether, cucurbituril as rings, and

[0005] The benzene ring, naphthalene ring and carbon 60 are dehydrated by azeotropic dehydration with toluene or anhydrous magnesium sulfate to achieve dynamic chemical bond end-capping of bulky end groups. This type of end-capping structure is reversible. In the patent of Wan Huishi of Shanghai Jiaotong University (CN101139405), the polyamine monomer and cyclodextrin are compounded in water by the method of "first compound and then polymerize", and then Michael addition reagent is added for addition polymerization to obtain a hyperbranched polyrotaxane based on cyclodextrin. The patent of Wu Yan of the National Center for Nanoscience and Technology (CN101768279A) uses amino-terminated PEG and α-cyclodextrin to prepare pseudo-polyrotaxane and benzyloxycarbonyl-L-phenylalanine succinimide in dry DMSO for end-capping.

[0006] In the patent (CN103102492A) of Lin Ligang of Tianjin Polytechnic University, it is believed that the amino-terminated PEG is expensive, and the traditional capping agent 2,4-dinitrofluoride is a controlled product, highly toxic and expensive. The method comprises mixing toluenesulfonated polyethylene glycol (PEG-OTs) with cyclodextrin (CD) molecules at both ends of polyethylene glycol (PEG) to obtain the inclusion process of the pseudopolyrotaxane formed by the chain toluenesulfonated polyethylene glycol passing through the cavities of multiple cyclodextrin molecules; and capping the pseudopolyrotaxane with a phenol derivative (such as 3,5-dimethylphenol) to obtain the capping process of the polyrotaxane with dehydrogenated 3,5-dimethylphenol as the capping agent capping the two ends. The toluenesulfonylation yield of PEG is 90%, the yield of pseudopolyrotaxane is 92%, and the capping yield is 39%.

[0007] Professor Kohzo Ito of the University of Tokyo (Macromolecules, 2005.38(17), 7524-7527) obtained HOOC-PEG-COOH by oxidizing polyethylene glycol to carboxyl groups at both ends, and then prepared pseudo-polyrotaxane with α-cyclodextrin in water phase and dehydrated. The carboxyl groups were condensed with adamantane amine in dimethylformamide (DMF) solution to achieve high-efficiency polyrotaxane preparation. Technical routes such as Figure 1 As shown, Figure 1It is a schematic diagram of the method of Kohzo Ito. Based on this technology, Japan Advanced Soft Co., Ltd. has applied for several related patents for the preparation of polyrotaxanes for specific industrial processing (CN103403031A, CN103221431A, CN104662066A, CN102046662A, CN104204035A, CN101784568A). This is the most mature technology for industrialization, and related products have been put on the market. However, this technology has the following problems: 1. The end-capping reaction is carried out in DMF solution. The strong solubility of DMF will cause cyclodextrin to fall off from the polyethylene glycol axis and reduce the inclusion rate; 2. The end-capping reaction requires anhydrous conditions, while the previous step reaction is a water solvent, which makes industrial processing difficult and energy-consuming; 3. The double-sided end-capping leads to a low total end-capping rate, and the end-capping efficiency is the square of the single-sided end-capping rate. For example, even if the single-side efficiency is as high as 95%, the overall end-capping efficiency is only 90%; 4. Amantadine is easily oxidized and becomes ineffective, and the commercially available product is mainly amantadine hydrochloride, which makes the handling complicated.

[0008] Zhejiang University Gao Chao et al. patent (CN101775146A) cyclodextrin and terminal alkyne linear polymer (PEG, PPG, PEG-PPG, PCL, etc.) generate a suspension in aqueous phase, and use monoazide-substituted-β-cyclodextrin click reaction to end-cap to obtain full cyclodextrin polyrotaxane. This method realizes the one-pot preparation of cyclodextrin polyrotaxane in aqueous phase. However, monoazide-substituted-β-cyclodextrin is currently not produced on a large scale and is expensive, which limits its application. Azide compounds are explosive and pose great safety risks. Figure 2 As shown, Figure 2 Schematic diagram of the method used by Gao Chao's research group.

[0009] Some studies have also noted that the multi-arm molecular axis can still be threaded with cyclodextrin. Multi-arm molecules can be Figure 3 As shown in the figure, glycerol, pentaerythritol or dipentaerythritol are used as the core of the multi-arm grafted with polyethylene glycol (research paper Jiao, H., SH Goh, and S. Valiyaveettil, Inclusion Complexes of Multiarm Poly (ethylene glycol) with Cyclodextrins. Macromolecules, 2002. 35 (5): p. 1980-1983.) The open ends of the multi-arms in this study are not capped. Figure 3 As shown, Figure 3 Schematic diagram of the molecular structure of multi-arm polyethylene glycol.

[0010] In the literature (Sabadini, E. and T. Cosgrove, Inclusion Complex Formed between Star-Poly (ethylene glycol) and Cyclodextrins. Langmuir, 2003. 19 (23): p. 9680-9683.), star-shaped 13-arm molecules can form pseudopolyrotaxanes with α-cyclodextrin and γ-cyclodextrin, such as Figure 4 As shown, Figure 4 Schematic diagram of the structure of a multi-arm pseudopolyrotaxane.

[0011] There are also studies (He, L., et al., Inclusion Complexation between Comblike PEOGrafted Polymers and α-Cyclodextrin. Macromolecules, 2005. 38 (8): p. 3351-3355.) that use polymerization to achieve comb-like multi-arm molecules, and the comb-tooth structure can still form pseudopolyrotaxanes with cyclodextrin. Figure 5 As shown, Figure 5 Schematic diagram of the comb-type multi-arm pseudopolyrotaxane structure.

[0012] The research on multi-arms only noticed that multi-arm structures such as star-shaped and comb-shaped structures can still form pseudopolyrotaxanes with cyclodextrin and have unique properties, but none of the above structures were end-capped. Summary of the invention

[0013] In view of this, the technical problem to be solved by the present invention is to provide a polyrotaxane and a preparation method thereof. The method provided by the present invention has high efficiency, safety and low cost in capping quasi-polyrotaxane.

[0014] The present invention provides a method for preparing a polyrotaxane, comprising the following steps:

[0015] Under a protective gas atmosphere, cyclodextrin and multi-arm polyethylene glycol containing functional groups at the ends are reacted to obtain a pseudo-polyrotaxane; and the pseudo-polyrotaxane is subjected to an end-capping reaction to obtain a polyrotaxane.

[0016] The present invention has no special limitation on the protective gas, which can be a common protective gas used by those skilled in the art, such as at least one of nitrogen, argon or helium. The present invention has no special limitation on the cyclodextrin, which can be a common cyclodextrin used by those skilled in the art, such as α-cyclodextrin.

[0017] The inventors of the present application creatively discovered that using multi-arm polyethylene glycol to replace traditional linear polyethylene glycol, reacting it with cyclodextrin to obtain a pseudo-polyrotaxane, and then end-capping the obtained pseudo-polyrotaxane is efficient, safe and low-cost. Any arm of the multi-arm structure of the multi-arm polyethylene glycol described in the present invention can be regarded as a molecular axis with one end capped. Traditional linear polyrotaxane molecular axes require end capping at both ends at the same time, which has a high failure rate, while the multi-arm structure end capping only requires one end capping to achieve the goal, which greatly improves the efficiency. At the same time, some arms of the multi-arm structure can also be used to increase hydrophilicity, so that the prepared polyrotaxane molecules have better dispersibility. Therefore, the use of multi-arm molecular axes and multi-arm dendritic molecular end-capping structures can improve the end-capping efficiency from two perspectives. Figure 6 As shown, Figure 6 This is a schematic diagram of a multi-arm polyethylene glycol polyrotaxane. The multi-arm polyethylene glycol only needs to be capped at one end, while the other polyethylene glycol arms at the other end naturally form a cap. This method greatly improves the capping efficiency.

[0018] The multi-arm polyethylene glycol of the present invention is a multi-arm polyethylene glycol having a functional group at the end. In certain embodiments of the present invention, the multi-arm polyethylene glycol is selected from at least one of two-arm polyethylene glycol, three-arm polyethylene glycol, four-arm polyethylene glycol, five-arm polyethylene glycol or six-arm polyethylene glycol. In certain embodiments of the present invention, the functional group is an olefin group, an alkyne group or a thiol group.

[0019] In certain embodiments of the present invention, the structure of the multi-arm polyethylene glycol is: Aj-(PEG-Ab) g ; wherein Aj is any one of substituted or unsubstituted C2-C6 alkyl, substituted or unsubstituted C6-C10 aryl; Ab is an olefin group, an alkyne group or a thiol group; g is an integer selected from 2 to 6. In one embodiment, the olefin group is selected from allyl, isobutylene, acrylate, methacrylate, maleic acid monoester or itaconate; the alkyne group is selected from propargyl; the thiol group is selected from 3-mercaptopropionate, thioglycolate, 4-mercaptobutyrate, 5-mercaptovalerate or 4-mercaptobutyramidine.

[0020] The multi-arm polyethylene glycol of the present invention can be produced by using glycerol or benzyltriol, pentaerythritol or benzyltriol, xylitol, sorbitol as initiators for the ring-opening polymerization of propylene oxide to produce corresponding 3-arm, 4-arm, 5-arm and 6-arm polyethylene glycols, and will not significantly affect the production cost of polyethylene glycol. In one embodiment, the multi-arm polyethylene glycol is selected from any one of the compounds of the structures described in formula (a) to formula (f);

[0021]

[0022]

[0023] In formula (a) to formula (f), PEG is the same or different -(CH2CH2O) m -, m is an integer from 10 to 450, preferably an integer from 10 to 150; in one embodiment, m is an integer from 10 to 100; in one embodiment, m is an integer from 50 to 100; in another embodiment, m is an integer from 56 to 75; x is 1 or 2; y is an integer from 1 to 4; z is 1; and q is 1.

[0024] In one embodiment, the multi-arm polyethylene glycol is selected from the compound of the structure of formula (a), wherein PEG is the same -(CH2CH2O) m -, m is 56; x is 1 or 2.

[0025] In one embodiment, the multi-arm polyethylene glycol is selected from the compound of the structure of formula (b), wherein PEG is the same -(CH2CH2O) m -, m is 75; y is an integer from 1 to 4; z is 1; q is 1.

[0026] In one embodiment, the multi-arm polyethylene glycol is selected from the compound of the structure of formula (e), wherein PEG is the same -(CH2CH2O) m -, m is 75.

[0027] In the present invention, under a protective gas atmosphere, cyclodextrin and the multi-arm polyethylene glycol are reacted to obtain a pseudo-polyrotaxane; and the pseudo-polyrotaxane is subjected to an end-capping reaction to obtain a polyrotaxane.

[0028] The present invention first reacts cyclodextrin and the multi-arm polyethylene glycol under a protective gas atmosphere to obtain a pseudopolyrotaxane. Specifically, the present invention reacts cyclodextrin and the multi-arm polyethylene glycol under a protective gas atmosphere in water with stirring to obtain a pseudopolyrotaxane. In one embodiment, the reaction is carried out at room temperature for 20 hours to 40 hours, preferably 24 hours. In one embodiment, the room temperature is 20°C to 30°C.

[0029] After obtaining the pseudopolyrotaxane, the present invention performs an end-capping reaction on the pseudopolyrotaxane to obtain a polyrotaxane. Specifically, the present invention adds an end-capping agent to the pseudopolyrotaxane to perform an end-capping reaction to obtain a polyrotaxane. In certain embodiments of the present invention, an end-capping agent is added to the pseudopolyrotaxane and an end-capping reaction is performed by light to obtain a polyrotaxane. The end-capping reaction of the present invention adopts an efficient thiol-olefin / alkyne click reaction; the thiol-olefin / alkyne click reaction can be initiated by light or an initiator. The preparation reaction and the end-capping reaction of the pseudopolyrotaxane of the present invention are both carried out in the aqueous phase, and the reaction does not undergo an intermediate separation process, so that a one-pot method can be used to efficiently prepare cyclodextrin polyrotaxanes.

[0030] In certain embodiments of the present invention, the pseudopolyrotaxane is capped with a dendrimer compound; the dendrimer compound is preferably selected from at least one of polypropyleneimine (PPI) or polyamide-amine (PAMAM) currently produced on an industrial scale. Considering the molecular physical size requirements and atom economy of the capping group, it is preferably selected from at least one of the second to fourth generation polypropyleneimine (PPI) or the first to third generation polyamide-amine (PAMAM).

[0031] The present invention can use a thiolated dendritic macromolecular compound as a capping agent to carry out a capping reaction between a multi-arm polyethylene glycol with a terminal olefin or terminal alkyne and the thiolated dendritic macromolecular compound; or use a dendritic macromolecular compound with a terminal olefin or terminal alkyne as a capping agent to react a thiolated multi-arm polyethylene glycol with a dendritic macromolecular compound with a terminal olefin or terminal alkyne. Commercially available PPI and PAMAM are used as raw materials and directly reacted with allyl bromide or allyl chloride to obtain terminal olefin or terminal alkyne dendritic molecules. Commercially available PPI and PAMAM are used as raw materials and reacted with 3-mercaptopropionic acid or thioglycolic acid or 4-mercaptobutyric acid or 5-mercaptopentanoic acid under the action of toluene reflux and water separation to obtain thiol-modified PAMAM and PPI, such as Figure 7 , 8 As shown, Figure 7 is a schematic diagram of the structure of thiolated PAMAM; Figure 8 The schematic diagram of the structure of thiolated PPI is shown in Figure 2. When Traut's reagent (2-iminothiolane) is used, it can be directly reacted in an aqueous solution at pH 7.0 to 9.5 and a temperature of 25 to 37°C to obtain a dendrimer connected with 4-mercaptobutyramidine.

[0032] In one embodiment, when the functional group of the multi-arm polyethylene glycol containing a functional group at the end is an olefin group or an alkyne group, the dendrimer compound is selected from a dendrimer compound having a thiol group; or, when the functional group of the multi-arm polyethylene glycol containing a functional group at the end is a thiol group, the dendrimer compound is selected from a dendrimer compound having an olefin group or an alkyne group.

[0033] In certain embodiments of the present invention, the capping reaction is carried out at a pH of 1 to 10, preferably at a pH of 5.5 to 7.5. PAMAM and PPI, as dendritic amine compounds, have strong alkalinity, which will cause the cyclodextrin in the pseudorotaxane to fall off the main axis, and at the same time cause the thiol group to become a sulfur anion, inhibiting the light-induced reaction. Therefore, the thiolated PAMAM and PPI capping agents need to be dissolved in a small amount of water before adding to the reaction aqueous solution and adjusted to a pH of 1 to 10 with an inorganic acid or an organic acid, preferably a 10% mass concentration aqueous solution with a pH adjusted to 5.5 to 7.5 with hydrochloric acid; the inorganic acid is selected from at least one of hydrochloric acid, sulfuric acid, and phosphoric acid; the organic acid is selected from at least one of acetic acid and fluoroacetic acid.

[0034] The present invention also provides a polyrotaxane prepared by the preparation method.

[0035] The present invention provides a method for preparing a polyrotaxane, comprising the following steps: reacting cyclodextrin and multi-arm polyethylene glycol containing functional groups at the end to obtain a pseudo-polyrotaxane under a protective gas atmosphere; and performing an end-capping reaction on the pseudo-polyrotaxane to obtain a polyrotaxane. At present, the yield of cyclodextrin polyrotaxane is low, and it is difficult to synthesize a large number of products, resulting in high prices and limiting large-scale applications. The fundamental reason is that the efficiency of the pseudo-polyrotaxane is low during the end-capping process. The preparation method provided by the present invention uses multi-arm polyethylene glycol to prepare a pseudo-polyrotaxane with a natural end-capping at one end, and then uses a dendritic macromolecular compound to perform an end-capping reaction on the pseudo-polyrotaxane in an aqueous phase through a one-pot method. The end-capping efficiency is high and safe, the raw materials are commercialized, the cost is low, and the manufacture of green polyrotaxane is realized. Experiments show that when four-arm polyethylene glycol is used to prepare polyrotaxane, the polyrotaxane yield per 10g of four-arm polyethylene glycol reaches 86g, while the polyrotaxane yield per 10g of traditional carboxyl-terminated polyethylene glycol in the comparative example is only 67g. BRIEF DESCRIPTION OF THE DRAWINGS

[0036] Figure 1 Schematic diagram of Kohzo Ito's method;

[0037] Figure 2 This is a schematic diagram of the method used by Gao Chao's research group;

[0038] Figure 3 It is a schematic diagram of the molecular structure of multi-arm polyethylene glycol;

[0039] Figure 4 Schematic diagram of the structure of a multi-arm pseudopolyrotaxane;

[0040] Figure 5 Schematic diagram of the comb-type multi-arm pseudopolyrotaxane structure;

[0041] Figure 6 Schematic diagram of multi-arm polyethylene glycol polyrotaxane;

[0042] Figure 7 is a schematic diagram of the structure of thiolated PAMAM;

[0043] Figure 8 Schematic diagram of the structure of thiolated PPI. DETAILED DESCRIPTION

[0044] The present invention discloses a polyrotaxane and a method for preparing the same. A person skilled in the art may refer to the contents of this invention and appropriately improve the process parameters to achieve the same. It should be particularly noted that all similar substitutions and modifications are obvious to a person skilled in the art and are considered to be included in the present invention. The methods and applications of the present invention have been described through preferred embodiments, and relevant personnel can obviously modify or appropriately change and combine the methods and applications of this invention without departing from the content, spirit and scope of the present invention to achieve and apply the technology of the present invention.

[0045] The synthesis principle of the present invention is:

[0046] 1. Multi-arm polyethylene glycol is selected instead of linear polyethylene glycol, and stirred with cyclodextrin in aqueous solution to form pseudopolyrotaxane.

[0047] 2. Using water-soluble thiolated dendritic macromolecules PAMAM or PPI as end-capping agents, a "click" reaction is directly performed with olefins or alkynes at the ends of the pseudopolyrotaxane molecular axis chains in the aqueous phase to prepare cyclodextrin polyrotaxanes.

[0048] The present invention will be further described below in conjunction with embodiments:

[0049] Example 1

[0050] Under the protection of nitrogen, a mixture of 10 g of a four-arm polyethylene glycol axis chain containing allyl groups at the end (the molecular weight of the polyethylene glycol initiated by pentaerythritol is about 10k, and the olefinic bonds are about 4 mmol) and 120 g of α-cyclodextrin (123 mmol) was dissolved in 2 L of deionized water, and stirred at room temperature for 24 hours until the solution became a viscous slurry, and stirring was maintained to form a pseudopolyrotaxane suspension;

[0051] 6.2 g of thiolated PAMAM (generation 1, molecular weight about 1400, containing 4.4 mol of -SH) was dispersed uniformly with 100 mL of deionized water by stirring, and then acidified to pH=6 with hydrochloric acid to obtain a thiolated PAMAM aqueous solution, at which time the solution was dissolved and clear.

[0052] The thiolated PAMAM aqueous solution was added to the pseudopolyrotaxane suspension, and the solution was irradiated with ultraviolet light at a wavelength of 365 nm and stirred for 24 hours. The mixture was centrifuged at room temperature to collect the precipitate, which was dissolved in dimethyl sulfoxide (DMSO) and precipitated in water, and repeated twice. The product was repeatedly washed with hot water at 50°C and vacuum dried at 60°C to an off-white powder. The yield was 86g / 10g of four-arm polyethylene glycol.

[0053] Example 2

[0054] Under the protection of nitrogen, a mixture of 10 g of a three-arm polyethylene glycol axis chain containing an allyl group at the end (the molecular weight of the glycerol-initiated polyethylene glycol is about 10k, and the olefinic bonds are about 3 mmol) and 120 g of α-cyclodextrin (123 mmol) was dissolved in 2 L of deionized water, and stirred at room temperature for 24 hours until the solution became a viscous slurry, and stirring was maintained to form a pseudopolyrotaxane suspension;

[0055] 4.6 g of thiolated PAMAM (generation 1, molecular weight about 1400, containing 3.3 mol of -SH) was dispersed uniformly with 100 mL of deionized water by stirring, and then acidified to pH=6 with hydrochloric acid to obtain a thiolated PAMAM aqueous solution, at which time the solution was dissolved and clear.

[0056] The thiolated PAMAM aqueous solution was added to the pseudopolyrotaxane suspension, and the solution was irradiated with ultraviolet light at a wavelength of 365 nm and stirred for 24 hours. The mixture was centrifuged at room temperature to collect the precipitate, which was dissolved in dimethyl sulfoxide (DMSO) and precipitated in water, and the process was repeated twice. The product was repeatedly washed with hot water at 50°C and vacuum dried at 60°C to an off-white powder. The yield was 81 g / 10 g of three-arm polyethylene glycol.

[0057] Example 3

[0058] Under the protection of nitrogen, a mixture of 10 g of a three-arm polyethylene glycol axis chain containing an allyl group at the end (the molecular weight of pyrogallol is about 10k, about 3 mmol of olefinic bonds) and 120 g of α-cyclodextrin (123 mmol) was dissolved in 2 L of deionized water, and stirred at room temperature for 24 hours until the solution became a viscous slurry, and stirring was maintained to form a pseudopolyrotaxane suspension;

[0059] 4.6 g of thiolated PAMAM (generation 1, molecular weight about 1400, containing 4.4 mol-SH) was dispersed uniformly with 100 mL of deionized water by stirring, and then acidified to pH=6 with hydrochloric acid to obtain a thiolated PAMAM aqueous solution, at which time the solution was dissolved and clear.

[0060] The thiolated PAMAM aqueous solution was added to the pseudopolyrotaxane suspension, and the solution was irradiated with ultraviolet light at a wavelength of 365 nm and stirred for 24 hours. The mixture was centrifuged at room temperature to collect the precipitate, which was dissolved in dimethyl sulfoxide (DMSO) and precipitated in water, and the process was repeated twice. The product was repeatedly washed with hot water at 50°C and vacuum dried at 60°C to an off-white powder. The yield was 82 g / 10 g of three-arm polyethylene glycol.

[0061] Example 4

[0062] Under the protection of nitrogen, a mixture of 10 g of a four-arm polyethylene glycol axis chain containing allyl groups at the end (the molecular weight of the polyethylene glycol initiated by pentaerythritol is about 10k, and the olefinic bonds are about 4 mmol) and 120 g of α-cyclodextrin (123 mmol) was dissolved in 2 L of deionized water, and stirred at room temperature for 24 hours until the solution became a viscous slurry, and stirring was maintained to form a pseudopolyrotaxane suspension;

[0063] 3.8 g of thiolated PPI (generation 2, molecular weight of about 850, containing 4.4 mol of -SH) was dispersed uniformly with 100 mL of deionized water by stirring, and then acidified to pH = 6 with hydrochloric acid to obtain a thiolated PPI aqueous solution, at which time the solution was dissolved and clear.

[0064] The above thiolated PPI aqueous solution was added to the above pseudopolyrotaxane suspension, and the solution was irradiated with ultraviolet light at a wavelength of 365 nm and stirred for 24 hours. The mixture was centrifuged at room temperature to collect the precipitate, which was dissolved in dimethyl sulfoxide (DMSO) and precipitated in water, and repeated twice. The product was repeatedly washed with hot water at 50°C and vacuum dried at 60°C to an off-white powder, with a yield of 80g / 10g four-arm polyethylene glycol.

[0065] Example 5

[0066] Under the protection of nitrogen, a mixture of 10 g of a four-arm polyethylene glycol axis chain containing 3-mercaptopropionate at the end (the molecular weight of the pentaerythritol-initiated polyethylene glycol is about 10k, about 4 mmol of mercapto groups) and 120 g of α-cyclodextrin (123 mmol) was dissolved in 2 L of deionized water, and stirred at room temperature for 24 hours until the solution became a viscous slurry, and stirring was maintained to form a pseudopolyrotaxane suspension;

[0067] 3.8 g of allylated PPI (generation 2, molecular weight of about 850, containing 4.4 mol of -C=CH2) was dispersed uniformly with 100 mL of deionized water by stirring, and then acidified to pH=6 with hydrochloric acid to obtain an allylated PPI aqueous solution, at which time the solution was dissolved and clear.

[0068] The allylated PPI aqueous solution was added to the pseudopolyrotaxane suspension, and the solution was irradiated with ultraviolet light at a wavelength of 365 nm and stirred for 24 hours. The mixture was centrifuged at room temperature to collect the precipitate, which was dissolved in dimethyl sulfoxide (DMSO) and precipitated in water, and repeated twice. The product was repeatedly washed with hot water at 50°C and vacuum dried at 60°C to an off-white powder, with a yield of 75g / 10g four-arm polyethylene glycol.

[0069] Comparative Example 1

[0070] Under nitrogen protection, a mixture of 10 g of double-end COOH-modified polyethylene glycol (HOOC-PEG-COOH molecular weight of about 2k) and 120 g of α-cyclodextrin (123 mmol) was dissolved in 2 L of deionized water and stirred at room temperature for 24 hours until the solution became a viscous slurry, and a white solid pseudopolyrotaxane was obtained by suction filtration. The pseudopolyrotaxane was vacuum dried below 40°C to obtain 100 g of pseudopolyrotaxane.

[0071] 100g of the above-mentioned pseudopolyrotaxane (equivalent to 0.11mmol terminal COOH), 0.16g of adamantane amine (MW=151, 1.1mmol), 0.48g of BOP (1.1mmol) and 0.19mL of EDIPA (1.2mmol) were dissolved in 100mL of dry DMF to obtain a slurry mixture. The slurry mixture was kept at 4°C overnight with slow stirring. The precipitate was separated by centrifugation, dissolved in DMSO, precipitated in water, and repeated twice. The product was repeatedly washed with hot water at 50°C and vacuum dried at 60°C to an off-white powder. The yield was 67g / 10g of carboxyl-terminated polyethylene glycol

[0072] Comparative Example 2

[0073] Under the protection of nitrogen, a mixture of 1g of double-terminal azidized polyethylene glycol (N3-PEG-N3, molecular weight of about 20k) and 12g of α-cyclodextrin (12mmol) was dissolved in 200L of deionized water and stirred at room temperature for 24 hours until the solution became a viscous slurry. 0.5g of mono-6-azid cyclodextrin, 0.2g of CuSO4, 0.15mL of pentamethyldiethylenetriamine and 0.34g of sodium ascorbate were added thereto in sequence, stirred slowly, and reacted at room temperature in the dark for 24 hours. The mixture was centrifuged at room temperature to collect the precipitate, which was dissolved in dimethyl sulfoxide (DMSO), precipitated in water, and repeated twice. The product was repeatedly washed with hot water at 50°C and vacuum dried at 60°C to an off-white powder, with a yield of 7.6g / 1g polyethylene glycol.

[0074] The yield of Examples 1 to 5 is about 75 to 86 g per 10 g of polyethylene glycol axial molecules, which is higher than 67 g per 10 g of carboxyl-terminated polyethylene glycol in Comparative Example 1, which indicates that the method of capping only one side is more efficient. In addition, the capping group also has a dual active group, and the reaction efficiency of the capping group is also higher.

[0075] The yield of Comparative Example 2 can reach 7.6g per 1g of polyethylene glycol. This is because the reaction uses the copper-catalyzed azide-terminal alkyne cycloaddition reaction (CuAAC) with extremely high reaction efficiency, which means that even if both ends are capped, a high yield can be achieved. However, this method uses high-cost azidocyclodextrin molecular raw materials, and there are safety risks in large-scale mass production. Comparative Example 2 achieves a yield close to that of the embodiment at a higher cost and greater safety risk, which also shows that the embodiment has great advantages.

[0076] The above description is only a preferred specific implementation manner of the present invention, but the protection scope of the present invention is not limited thereto. Any technician familiar with the technical field can make equivalent replacements or changes according to the technical scheme and inventive concept of the present invention within the technical scope disclosed by the present invention, which should be covered by the protection scope of the present invention.

Claims

1. A method for preparing a polyrotaxane, characterized in that: The following steps are involved: Under a protective gas atmosphere, cyclodextrin and multi-arm polyethylene glycol containing functional groups at the ends are reacted to obtain a pseudo-polyrotaxane; a dendrimer compound is used to cap the pseudo-polyrotaxane to obtain a polyrotaxane; the dendrimer compound is selected from at least one of polypropyleneimine and polyamide-amine; The structure of the multi-arm polyethylene glycol is: Aj-(PEG-Ab) g ; Wherein, Aj is any one of a substituted or unsubstituted C2-C6 alkyl group, or a substituted or unsubstituted C6-C10 aryl group; Ab is an alkene group, an alkyne group or a thiol group; g is an integer selected from 2 to 6.

2. The method according to claim 1, characterized in that: The olefin group is selected from an allyl group, an isobutylene group, an acrylate group, a methacrylate group, a maleic acid monoester group or an itaconate group; The alkynyl group is selected from propargyl; The thiol group is selected from 3-mercaptopropionate, thioglycolate, 4-mercaptobutyrate, 5-mercaptovalerate or 4-mercaptobutyramidine.

3. The method according to claim 2, characterized in that The multi-arm polyethylene glycol is selected from any one of the compounds of formula (a) to formula (f); In formula (a) to formula (f), PEG is the same or different -(CH2CH2O) m -, m is an integer from 10 to 450; x is 1 or 2; y is an integer from 1 to 4; z is 1; and q is 1.

4. The method according to claim 2, characterized in that: When the functional group of the multi-arm polyethylene glycol containing a functional group at the end is an olefin group or an alkyne group, the dendrimer compound is selected from a dendrimer compound having a thiol group; or, When the functional group of the multi-arm polyethylene glycol containing a functional group at the terminal is a thiol group, the dendrimer compound is selected from the dendrimer compounds having an olefin group or an alkyne group.

5. The method according to claim 1, characterized in that: The end-capping reaction is carried out at a pH of 1-10.

6. The polyrotaxane obtained by the method according to any one of claims 1 to 5.

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