A kind of temperature-sensitive cyclodextrin and preparation method thereof

Abstract

The present invention belongs to the field of intelligent responsive materials, and relates to a thermosensitive cyclodextrin and a preparation method thereof. Functionalized amino acids are grafted onto natural cyclodextrin or modified cyclodextrin, and the reaction temperature, reaction time and reactant concentration are controlled to prepare thermosensitive natural cyclodextrin and modified cyclodextrin with different lower critical solution temperatures (LCST). The preparation process of the present invention is simple and feasible, and the preparation efficiency is high. The prepared thermosensitive cyclodextrin exhibits excellent temperature responsiveness. Such materials will have important application value in drug delivery, intelligent biomaterials, separation and purification, etc.

Description

Technical Field

[0001] The invention belongs to the field of intelligent response materials, and specifically relates to a temperature-sensitive cyclodextrin and a preparation method thereof. Background Art

[0002] Smart responsive materials are a new type of functional materials that can sense external stimuli (such as heat, force, light, etc.) and respond with specific responses. They have attracted widespread attention in recent decades. Temperature-sensitive smart materials are one of the most widely studied smart materials because they are easy to control temperature changes and are therefore used in various fields. So far, the most commonly explored material among temperature-sensitive smart materials is thermosensitive polymers represented by poly (N-isopropylacrylamide) (PNIPAAm). This type of thermosensitive polymer usually has hydrophilic and hydrophobic groups on its main chain. Due to the changes in hydrophilic and hydrophobic interactions, there is a lower critical solution temperature (LCST) in aqueous solution. When the temperature reaches above the LCST, the solubility of the polymer in the solvent drops sharply. This property makes it widely used in various fields such as chemistry and biomedicine. However, since most of them are high-molecular polymers, they usually have a carbon chain structure. The main chain structure of carbon-carbon bonds often does not have good biocompatibility, and the polymer monomer raw materials usually have certain biological toxicity, which limits the development of this type of material.

[0003] Natural cyclodextrin (CD) is a supramolecular functional material with good biocompatibility and environmental friendliness, abundant sources, low price, and can also be derivatized to obtain modified cyclodextrin materials. The structure of natural amino acids obtained by functionalization has both hydrophilic amide bonds and hydrophobic isopropyl groups. We obtained a thermosensitive supramolecular material by grafting functionalized amino acids on the hydroxyl groups of cyclodextrin to make it thermosensitive. The LCST of thermosensitive cyclodextrin can be controlled by adjusting the reaction temperature, reaction time and reactant concentration. This thermosensitive supramolecular material can not only retain the original function of cyclodextrin, but also is non-toxic and harmless, has good biocompatibility, and can achieve more uses through thermosensitivity. Summary of the invention

[0004] In order to overcome the above defects, the present invention grafts functionalized amino acids onto the hydroxyl groups of natural cyclodextrin and modified cyclodextrin through a simple and feasible scheme, designs thermosensitive natural cyclodextrin and modified cyclodextrin supramolecular materials with good temperature responsiveness and environmental friendliness, and can prepare thermosensitive supramolecular materials with different LCST by controlling the reaction temperature, reaction time and reactant concentration.

[0005] In order to achieve the above object, the present invention provides a temperature-sensitive cyclodextrin represented by Formula 1:

[0006] Formula 1

[0007]

[0008] Wherein, in Formula 1, x is a positive integer, y is a positive integer, and x+y is 6, 7 or 8;

[0009] R1 is selected from or n1 is selected from 0, 1 or 2;

[0010] R2 is selected from one of the following structures:

[0011]

[0012] or

[0013] * indicates the binding site with the adjacent atom.

[0014] The present invention provides a method for preparing a thermosensitive cyclodextrin, which comprises:

[0015] Using a first solvent to dissolve the cyclodextrin compound shown in Formula 2 to obtain a first solution;

[0016] Using a second solvent to dissolve the functionalized amino acid as shown in Formula 3, and adding an activator, reacting at 20-60° C. for 0.5-10 hours to obtain a second solution; the molar ratio of the functionalized amino acid to the activator is 1:2 to 1:5;

[0017] The first solution and the second solution are mixed, and reacted at 10-100° C. for 12-48 hours under nitrogen protection to obtain a third solution;

[0018] The third solution is dialyzed using a third solvent for 12-48 hours to obtain a thermosensitive cyclodextrin;

[0019] Among them, formula 2

[0020]

[0021] In Formula 2, R1 is selected from or or n is selected from 5, 6 or 7; n1 is selected from 0, 1 or 2;

[0022] Formula 3

[0023]

[0024] In Formula 3, R2 is selected from one of the following structures:

[0025]

[0026] * indicates the binding site with the adjacent atom.

[0027] Optionally, the activator is selected from one of N,N-carbonyldiimidazole, dicyclohexylcarbodiimide or carbodiimide.

[0028] Optionally, the first solvent is selected from one of N,N-dimethylformamide, N,N-dimethylacetamide or dimethyl sulfoxide; the second solvent is selected from one of N,N-dimethylformamide, N,N-dimethylacetamide or dimethyl sulfoxide; the third solvent is selected from one of methanol, ethanol, acetone, acetonitrile or diethyl ether.

[0029] Optionally, the functionalized amino acid is prepared by the following steps: using deionized water to dissolve the amino acid and sodium hydroxide, after dissolution, a fourth solution is obtained; the molar ratio of the amino acid to sodium hydroxide is 1:1 to 1:5; under ice bath conditions, an amino acid modifier is added dropwise to the fourth solution, and sodium hydroxide solution is added dropwise to adjust the pH of the solution to alkaline, and then reacted at 10-60°C for 2-12h to obtain a reaction product solution; the molar ratio of the amino acid to the amino acid modifier is 1:2 to 1:5; concentrated HCl is added to the reaction product solution for acidification, solids are precipitated, and functionalized amino acids are obtained.

[0030] Optionally, the amino acid is selected from one of tryptophan, lysine, phenylalanine, methionine, threonine, valine, leucine, isoleucine, cysteine, serine, glycine, tyrosine, aspartic acid, asparagine, glutamic acid, glutamine, alanine, arginine or histidine.

[0031] Optionally, the amino acid modifier is selected from one of isobutyryl chloride, isobutyric acid or isobutyric anhydride.

[0032] Optionally, when R1 is or The cyclodextrin compound is prepared by the following steps: adding mono-6-p-methylbenzenesulfonyl cyclodextrin and a nitrogen-containing heterocycle with a terminal olefin group to N,N-dimethylformamide, reacting at 50-150° C. for 20-40 hours to obtain a nitrogen-containing heterocycle-derivatized cyclodextrin; wherein the nitrogen-containing heterocycle includes imidazole or pyridine, and the molar ratio of the mono-6-p-methylbenzenesulfonyl cyclodextrin to the nitrogen-containing heterocycle with a terminal olefin group is 1:2 to 1:5.

[0033] Optionally, the nitrogen-containing heterocycle with a terminal alkenyl group is selected from one of butyl imidazole, allyl imidazole, vinyl imidazole, butyl pyridine, allyl pyridine or vinyl pyridine.

[0034] Optionally, the mono-6-p-toluenesulfonyl cyclodextrin is selected from mono-6-p-toluenesulfonyl-α-cyclodextrin, mono-6-p-toluenesulfonyl-β-cyclodextrin or mono-6-p-toluenesulfonyl-γ-cyclodextrin.

[0035] Compared with the prior art, the thermosensitive natural cyclodextrin and thermosensitive modified cyclodextrin prepared by the present invention have excellent temperature response performance, and can be widely used in various fields due to their good biocompatibility and environmental friendliness. BRIEF DESCRIPTION OF THE DRAWINGS

[0036] Figure 1 Schematic diagram of the preparation method of the thermosensitive cyclodextrin of the present invention;

[0037] Figure 2 This is a transmittance-temperature diagram of the temperature-sensitive natural cyclodextrin obtained in Example 1 of the present invention;

[0038] Figure 3 The transmittance-temperature diagram of the temperature-sensitive modified cyclodextrin obtained in Example 2 of the present invention. DETAILED DESCRIPTION

[0039] A method for preparing a thermosensitive cyclodextrin Figure 1 As shown, the steps are as follows:

[0040] 1) Add natural cyclodextrin or modified cyclodextrin to N,N-dimethylformamide, with 2-10 mL of N,N-dimethylformamide required per gram of the cyclodextrin, and stir at 20-60° C. until dissolved.

[0041] Wherein, the natural cyclodextrin includes one of α-cyclodextrin, β-cyclodextrin and γ-cyclodextrin.

[0042] 2) Add functionalized amino acid to N,N-dimethylformamide, 2-10 mL of N,N-dimethylformamide per gram of the functionalized amino acid, stir at 20-60° C. until dissolved, add activator to the solution, the molar ratio of the functionalized amino acid to the activator per gram is 0.5:1-1:5, and react at 20-60° C. for 0.5-10 h.

[0043] Wherein, the activator includes one of N,N-carbonyldiimidazole, dicyclohexylcarbodiimide, and carbodiimide. The solvent includes one of methanol, ethanol, acetone, acetonitrile, and ether.

[0044] 3) adding the solution obtained in 2) to the cyclodextrin solution obtained in 1), wherein the molar ratio of the isobutyrylated amino acid to cyclodextrin is 0.5:1-10:1, and reacting at 10-100° C. for 12-48 hours under nitrogen protection.

[0045] 4) After the reaction is completed, cool to room temperature and dialyze with a solvent for 12-48 hours. In practical applications, impurities in the solution can be removed by dialysis. After the dialysis is completed, the dialysis solvent is rotary evaporated and vacuum dried at 30-60° C. for 12-48 hours to obtain a thermosensitive natural cyclodextrin or a thermosensitive modified cyclodextrin.

[0046] The functionalized amino acid in step 2) is prepared by the following steps:

[0047] Add amino acid and sodium hydroxide to deionized water (the sodium hydroxide added here can improve the solubility of amino acid in water and adjust the pH of the solution), the molar ratio of amino acid to sodium hydroxide is 1:1-1:5, and stir for 0.5-5h after complete dissolution. Add amino acid modifier to the solution under ice bath conditions, the molar ratio of amino acid to amino acid modifier is 0.5:1-1:5, and adjust the pH to alkaline with sodium hydroxide solution at the same time. After the addition is complete, react at 10-60°C for 2-12h. After the reaction is completed, add 5-50mL concentrated HCl to acidify, solid precipitates, continue stirring for 0.5-15h, filter and vacuum dry to obtain functionalized amino acid.

[0048] The amino acid is one of tryptophan, lysine, phenylalanine, methionine, threonine, valine, leucine, isoleucine, cysteine, serine, glycine, tyrosine, aspartic acid, asparagine, glutamic acid, glutamine, alanine, arginine, and histidine. The amino acid modifier is one of isobutyryl chloride, isobutyric acid, and isobutyric anhydride.

[0049] The modified cyclodextrin in step 1) is prepared by the following steps:

[0050] Mono-6-p-methylbenzenesulfonyl cyclodextrin and a nitrogen-containing heterocycle with a terminal olefin group are added to N,N-dimethylformamide, wherein the nitrogen-containing heterocycle includes imidazole or pyridine, and the molar ratio of the mono-6-p-methylbenzenesulfonyl cyclodextrin and the nitrogen-containing heterocycle with a terminal olefin group is 1:2-1:5, and the reaction is carried out at 50-150°C for 20-40h to obtain a nitrogen-containing heterocycle-derivatized cyclodextrin.

[0051] The nitrogen-containing heterocyclic ring with terminal alkenyl groups is one of butyl imidazole, allyl imidazole, vinyl imidazole, butyl pyridine, allyl pyridine and vinyl pyridine. The mono-6-p-toluenesulfonyl cyclodextrin is one of mono-6-p-toluenesulfonyl-α-cyclodextrin, mono-6-p-toluenesulfonyl-β-cyclodextrin and mono-6-p-toluenesulfonyl-γ-cyclodextrin.

[0052] The technical solution of the present invention is further described in detail below with multiple embodiments. The specific embodiments described are only used to explain the present invention and are not intended to limit the present invention.

[0053] Example 1

[0054] Dissolve 5g L-valine (Valine, abbreviated as Val) and 1.72g sodium hydroxide in 200mL deionized water. After complete dissolution, stir for 0.5h. Add 2g isobutyryl chloride dropwise under ice bath conditions, and adjust the pH to alkaline with sodium hydroxide solution at the same time. After the addition is complete, react at 50℃ for 2h. After the reaction is completed, cool to room temperature, add 5mL concentrated HCl, solid precipitates, continue stirring for 2h, and filter. Dry in vacuo at 50℃ to obtain white powder Val-IBAm with isobutyramide (IBAm) structure.

[0055] Weigh 1g of β-CD into a 25mL round-bottom flask and dissolve it with 2mL of N,N-dimethylformamide. Weigh 0.2g of Val-IBAm into a 25mL round-bottom flask and dissolve it with 2mL of N,N-dimethylformamide. Add 0.5g of N,N-carbonyldiimidazole under an ice bath, add the activated Val-IBAm to β-CD, and react at 20℃ for 12h under nitrogen protection. After the reaction, dialyze with ethanol for 3 days. After the dialysis, evaporate the ethanol and dry it under vacuum at 50℃ to obtain β-CD-Val-IBAm.

[0056] The present invention also tests the transmittance-temperature variation of β-CD-Val-IBAm. 10 mg, 20 mg, and 30 mg of β-CD-Val-IBAm are weighed and dissolved in 1 mL of deionized water. The transmittance-temperature variation of β-CD-Val-IBAm is measured using a T6 New Century UV-Vis spectrophotometer with an MP-5H heating circulation tank. The results are as follows: Figure 1 The LCST of β-CD-Val-IBAm at concentrations of 20 mg / mL and 30 mg / mL are 45°C and 52°C, respectively.

[0057] Example 2

[0058] Dissolve 2g L-Val and 0.5g sodium hydroxide in 100mL deionized water. Stir for 0.5h after complete dissolution. Add 1g isobutyryl chloride dropwise under ice bath conditions, and adjust the pH to alkaline with sodium hydroxide solution at the same time. After the addition is complete, react at 30℃ for 5h. After the reaction is completed, cool to room temperature, add 2mL concentrated HCl, solid precipitates, continue stirring for 5h, and filter. Dry under vacuum at 50℃ to obtain white powder Val-IBAm.

[0059] 5 g of mono-6-p-toluenesulfonyl-β-cyclodextrin, 20 mL of N,N-dimethylformamide and 2 mL of 1-allylimidazole were added to a 100 mL three-necked flask in sequence, and stirred at 50°C for 12 h. Acetonitrile was added to precipitate a large amount of solid, which was filtered to obtain mono-6-(1-allylimidazole)-β-cyclodextrin (AI-β-CD).

[0060] Weigh 1g of mono-6-(1-allylimidazole)-β-cyclodextrin and dissolve it in 4mL of N,N-dimethylformamide in a 25mL round-bottom flask. Weigh 0.5g of Val-IBAm and dissolve it in 4mL of N,N-dimethylformamide in a 25ml round-bottom flask. Slowly add 0.5g of N,N-carbonyldiimidazole in an ice bath. Add the activated Val-IBAm to AI-β-CD and react at 30℃ for 48h under nitrogen protection. After the reaction, cool to room temperature and dialyze with ethanol for 3 days. After the dialysis, evaporate the ethanol and dry it in a vacuum at 50℃ to obtain AI-β-CD-Val-IBAm.

[0061] The present invention also tests the transmittance-temperature variation of AI-β-CD-Val-IBAm. 10 mg, 20 mg, and 30 mg of AI-β-CD-Val-IBAm are weighed and dissolved in 1 mL of deionized water. The transmittance-temperature variation of AI-β-CD-Val-IBAm is measured using a T6 New Century UV-Vis spectrophotometer with an MP-5H heating circulation tank. The results are as follows: Figure 2 The LCST of AI-β-CD-Val-IBAm at concentrations of 20 mg / mL and 30 mg / mL were 46°C and 51°C, respectively.

[0062] In summary, combined with the above multiple embodiments, it can be seen that the thermosensitive natural cyclodextrin and thermosensitive modified cyclodextrin prepared by the present invention have excellent temperature response performance and will be widely used in various fields due to their good biocompatibility and environmental friendliness.

[0063] It should be understood that although this specification is described according to implementation methods, not every implementation method contains only one independent technical solution. This narrative method of the specification is only for the sake of clarity. Those skilled in the art should regard the specification as a whole. The technical solutions in each embodiment can also be appropriately combined to form other implementation methods that can be understood by those skilled in the art.

[0064] The series of detailed descriptions listed above are only specific descriptions of feasible implementation methods of the present invention. They are not intended to limit the scope of protection of the present invention. Any equivalent implementation methods or changes that do not deviate from the technical spirit of the present invention should be included in the scope of protection of the present invention.

Claims

1. A thermosensitive cyclodextrin, It is characterized in that The temperature-sensitive cyclodextrin is represented by Formula 1: Formula 1 Wherein, in Formula 1, x is a positive integer, y is a positive integer, and x+y is 6, 7 or 8; R1 is selected from n 1 Selected from 0, 1 or 2; R2 is selected from one of the following structures: * indicates the binding site with the adjacent atom.

2. A method for preparing a thermosensitive cyclodextrin, It is characterized in that The method comprises the following steps: Using a first solvent to dissolve the cyclodextrin compound shown in Formula 2 to obtain a first solution; Using a second solvent to dissolve the functionalized amino acid as shown in Formula 3, and adding an activator, reacting at 20-60° C. for 0.5-10 hours to obtain a second solution; the molar ratio of the functionalized amino acid to the activator is 1:2 to 1:5; The first solution and the second solution are mixed, and reacted at 10-100° C. for 12-48 hours under nitrogen protection to obtain a third solution; The third solution is dialyzed using a third solvent for 12-48 hours to obtain a thermosensitive cyclodextrin; Among them, formula 2 In Formula 2, R1 is selected from n is selected from 5, 6 or 7; n 1 Selected from 0, 1 or 2; Formula 3 In Formula 3, R2 is selected from one of the following structures: * indicates the binding site with the adjacent atom.

3. The preparation method according to claim 2, It is characterized in that The activator is selected from one of N,N-carbonyldiimidazole, dicyclohexylcarbodiimide or carbodiimide.

4. The preparation method according to claim 2, It is characterized in that The first solvent is selected from one of N,N-dimethylformamide, N,N-dimethylacetamide or dimethyl sulfoxide; The second solvent is selected from one of N,N-dimethylformamide, N,N-dimethylacetamide or dimethyl sulfoxide; The third solvent is selected from one of methanol, ethanol, acetone, acetonitrile or diethyl ether.

5. The preparation method according to claim 2, It is characterized in that The functionalized amino acid is prepared by the following steps: Dissolving amino acid and sodium hydroxide in deionized water to obtain a fourth solution; the molar ratio of the amino acid to sodium hydroxide is 1:1 to 1:5; Under ice bath conditions, an amino acid modifier is added dropwise to the fourth solution, and a sodium hydroxide solution is added dropwise to adjust the pH of the solution to be alkaline, and the mixture is reacted at 10-60° C. for 2-12 hours to obtain a reaction product solution; wherein the molar ratio of the amino acid to the amino acid modifier is 1:2 to 1:5; Concentrated HCl is added to the reaction product solution for acidification, solid is precipitated, and functionalized amino acid is obtained.

6. The preparation method according to claim 5, It is characterized in that The amino acid is selected from one of tryptophan, lysine, phenylalanine, methionine, threonine, valine, leucine, isoleucine, cysteine, serine, glycine, tyrosine, aspartic acid, asparagine, glutamic acid, glutamine, alanine, arginine or histidine.

7. The preparation method according to claim 5, It is characterized in that The amino acid modifier is selected from one of isobutyryl chloride, isobutyric acid or isobutyric anhydride.

8. The preparation method according to claim 2, It is characterized in that When R1 is When the cyclodextrin compound is prepared by the following steps: Add mono-6-p-methylbenzenesulfonyl cyclodextrin and a nitrogen-containing heterocycle with a terminal olefin group to N,N-dimethylformamide, and react at 50-150° C. for 20-40 hours to obtain a nitrogen-containing heterocycle-derivatized cyclodextrin; wherein the nitrogen-containing heterocycle includes imidazole or pyridine, and the molar ratio of the mono-6-p-methylbenzenesulfonyl cyclodextrin to the nitrogen-containing heterocycle with a terminal olefin group is 1:2 to 1:

5.

9. The preparation method according to claim 8, It is characterized in that The nitrogen-containing heterocycle with a terminal alkenyl group is selected from one of butyl imidazole, allyl imidazole, vinyl imidazole, butyl pyridine, allyl pyridine or vinyl pyridine.

10. The preparation method according to claim 8, It is characterized in that The mono-6-p-toluenesulfonyl cyclodextrin is selected from mono-6-p-toluenesulfonyl-α-cyclodextrin, mono-6-p-toluenesulfonyl-β-cyclodextrin or mono-6-p-toluenesulfonyl-γ-cyclodextrin.

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