CN111944158B - Cyclodextrin hyperbranched derivative and preparation method thereof - Google Patents
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Abstract
The invention discloses a cyclodextrin hyperbranched derivative and a preparation method thereof, wherein cyclodextrin is taken as an initial raw material, and glycidol is subjected to ring opening under an alkaline condition to obtain cyclodextrin grafted hyperbranched polyglycerol; then, reacting the cyclodextrin grafted hyperbranched polyglycerol with epoxy chloropropane to obtain cyclodextrin grafted hyperbranched polyglycerol glycidyl ether; and finally, grafting an epoxy group on a hyperbranched polyglycerol glycidyl ether molecule by using molecular open-ring cyclodextrin with primary amine or secondary amine groups to obtain the cyclodextrin hyperbranched derivative. Epoxy groups are modified on cyclodextrin hyperbranched polyglycerol, and then amino ring-opening epoxy groups on micromolecule amine are utilized to modify the micromolecule amine, so that the cationic property of amino is retained, and meanwhile, epoxy ring-opening generates hydroxyl, and the hydrophilicity of the final cyclodextrin hyperbranched derivative is ensured.
Description
Technical Field
The invention relates to a cyclodextrin derivative and a preparation method thereof, in particular to a cyclodextrin hyperbranched derivative and a preparation method thereof.
Background
Cyclodextrin (CD) is a generic term for cyclic oligosaccharides formed by cyclization of 6 or more glucopyranose molecules through α -1, 4-glycosidic linkages, and can be produced by the action of cyclodextrin glycosyltransferase on starch. Most common are alpha-CD, beta-CD and gamma-CD, which consist of 6, 7 and 8 glucopyranose units, respectively. Cyclodextrins are widely used in the fields of food, medicine, agriculture, cosmetics, etc. due to their unique truncated cone structure with hydrophilic and hydrophobic outer parts and the property of forming inclusion compounds with specific molecules.
The CD has strong hydrogen bonding among molecules, so that the water solubility of the cyclodextrin and the insufficient inclusion ability of the cyclodextrin to guest molecules are limited. Greatly limiting its commercial application. In addition, the unmodified cyclodextrin is relatively single in performance, and needs to be modified and derived, so that a more diversified application scene can be met. Therefore, by carrying out structural modification on active hydroxyl groups of the cyclodextrin, the obtained cyclodextrin derivative has more diversified properties, which is very important for the commercial application of the cyclodextrin.
The document discloses that hyperbranched polyglycerol is grafted onto beta-cyclodextrin, small-molecule amine modification is carried out on terminal hydroxyl of the beta-cyclodextrin, C18 alkyl chain is introduced as a hydrophobic unit through host-guest action, and amphiphilic polycation vesicles can be formed in an aqueous solution after the hyperbranched polyglycerol is assembled. The small molecule amine at the tail end of the hyperbranched structure can effectively load DNA, the transfection efficiency of the hyperbranched structure under serum conditions is higher than that of PEI25K, and the cytotoxicity is obviously reduced. The cavity structure of the vesicle can realize the encapsulation of the hydrophilic anticancer drug DOX, the in-vitro drug release behavior can be adjusted by changing the external pH value, and the synergistic effect of the two drugs can finally achieve the effect of combined treatment. On one hand, the beta-cyclodextrin derivative constructed by the method has relatively limited hyperbranched degree, so that the number of hydroxyl values capable of being linked by small molecular amine is limited; on the other hand, the beta-cyclodextrin hyperbranched polyglycerol and the small-molecule amine are linked through a urethane bond, each link of the small-molecule amine consumes one hydroxyl group, and the small-molecule amine also consumes one amino group. This necessarily results in a loss of cationic character and insufficient hydrophilicity of the β -cyclodextrin derivative, especially under high pH conditions.
Disclosure of Invention
The invention aims to overcome at least one defect of the prior art and provides a cyclodextrin hyperbranched derivative and a preparation method thereof.
The technical scheme adopted by the invention is as follows:
in a first aspect of the present invention, there is provided:
a cyclodextrin hyperbranched derivative has a structural general formula shown as formula I:
wherein R is a group having a primary or secondary amine group; n is 6, 7 or 8.
In some examples, R is selected from-NHCH2CH2NH2，-NHCH2CH2NHCH2CH2NH2，-NHCH2CH2N(CH2CH2NH2)2，-NH(CH2CH2NH)2CH2CH2NH2，-NH(CH2CH2NH)3CH2CH2NH2or-NH (CH)2CH2NH)4CH2CH2NH2。
In a second aspect of the present invention, there is provided:
a preparation method of a cyclodextrin hyperbranched derivative comprises the following steps:
s1) taking cyclodextrin as an initial raw material, and opening the cyclic glycidol under an alkaline condition to obtain cyclodextrin grafted hyperbranched polyglycerol;
s2) reacting the cyclodextrin grafted hyperbranched polyglycerol with epichlorohydrin to obtain cyclodextrin grafted hyperbranched polyglycerol glycidyl ether;
s3) grafting epoxy groups on the hyperbranched polyglycerol glycidyl ether molecules by using molecular open-ring cyclodextrin with primary amine or secondary amine groups to obtain the cyclodextrin hyperbranched derivative.
In some examples, the molecule having a primary or secondary amine group is a C2-C20 diamine, polyamine, or oligomeric ethylene diamine.
In some examples, the molecule having a primary or secondary amine group is a diamine or polyamine of C2 to C10.
In some examples, the molecule having a primary or secondary amine group is ethylenediamine, diethylenetriamine, tris (2-aminoethyl) amine, triethylenetetramine, tetraethylenepentamine, or pentaethylenehexamine.
In some examples, the specific process for preparing cyclodextrin grafted hyperbranched polyglycerol includes:
s11) weighing cyclodextrin, dissolving the cyclodextrin in a solvent, slowly dripping glycidol at 40-60 ℃ under the condition that strong base is used as a catalyst, and then heating to 60-100 ℃ to continue reacting for 12-24 hours;
s12) adding deionized water into the system after the reaction is finished to terminate the reaction and dilute the crude product, dialyzing, purifying and drying to obtain the cyclodextrin grafted hyperbranched polyglycerol.
In some examples, the solvent is selected from N, N-dimethylformamide, N-dimethylacetamide, N-diethylformamide, or N-methylpyrrolidone.
In some examples, the strong base is selected from potassium metal (K) with 18-crown-6 or potassium hydride (KH) with 18-crown-6.
In some examples, the ratio of cyclodextrin: potassium or potassium hydride: 18-crown-6: the molar charge ratio of glycidol is 1: (5-10): (5-10): (20 to 2000).
In some examples, the specific process for preparing cyclodextrin grafted hyperbranched polyglycerol glycidyl ether comprises:
s21) weighing cyclodextrin grafted hyperbranched polyglycerol, dispersing the cyclodextrin grafted hyperbranched polyglycerol in a solvent, adding solid base and a catalyst tetrabutylammonium bromide, and gradually dropwise adding epoxy chloropropane at 10-15 ℃;
s22), heating to 25-30 ℃, reacting for 12-24 h, adding deionized water, standing for layering,
and removing the solvent from the upper oil phase to obtain the cyclodextrin grafted hyperbranched polyglycerol glycidyl ether.
In some examples, the solvent for preparing the cyclodextrin grafted hyperbranched polyglycerol glycidyl ether is selected from tetrahydrofuran, ethylene glycol dimethyl ether, ethylene glycol diethyl ether or dioxane; the solid alkali is selected from solid sodium hydroxide or solid potassium hydroxide.
In some examples, the operation of step 3) includes:
s31) dissolving molecules with primary amine or secondary amine groups in a solvent, slowly dripping a THF (tetrahydrofuran) solution of cyclodextrin grafted hyperbranched polyglycerol glycidyl ether into the molecular solution with the primary amine or secondary amine groups under a reflux condition, and finishing dripping within 6-12 h;
preferably, the solvent is selected from ethanol, isopropanol, n-propanol or tert-butanol;
s32) continuing to react for 6-12 h after the dripping is finished, and dialyzing and purifying with deionized water to obtain the cyclodextrin hyperbranched derivative.
In some examples, the cyclodextrin is selected from alpha-cyclodextrin, beta-cyclodextrin, or gamma-cyclodextrin.
In a third aspect of the present invention, there is provided:
use of a cyclodextrin hyperbranched derivative as described in the first or second aspect of the invention for the preparation of a pharmaceutical carrier.
The invention has the beneficial effects that:
according to the cyclodextrin hyperbranched derivative provided by the invention, an epoxy group is firstly modified on cyclodextrin hyperbranched polyglycerol, and then small molecule amine modification is carried out through an amino ring-opening epoxy group on the small molecule amine, so that the cationic property of the amino group is reserved, and meanwhile, hydroxyl is generated through epoxy ring opening, so that the hydrophilicity of the final cyclodextrin hyperbranched derivative is ensured.
According to the cyclodextrin hyperbranched derivative provided by the invention, potassium or potassium hydride and crown ether are used as catalysts to catalyze hydroxyl ring-opening glycidol of cyclodextrin to prepare cyclodextrin grafted hyperbranched polyglycerol. The feeding of the glycidol can be flexibly adjusted, and the cyclodextrin grafted hyperbranched polyglycerol of different polymers can be prepared according to different use requirements.
Drawings
FIG. 1 is the nuclear magnetic hydrogen spectrum of the product of example 1.
Detailed Description
In order that the invention may be more fully understood, reference will now be made to the following description. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. As used herein, the term "and/or" includes any and all combinations of one or more of the associated listed items.
The technical scheme of the invention is further explained by combining the embodiment.
Example 1
The cyclodextrin derivative and the preparation method thereof comprise the following steps:
(1) beta-cyclodextrin (4.0g,3.53mmol) and 18-crown-6 (6.6g,25.0mmol) were accurately weighed out under inert gas protection, dissolved in 150mL DMF, and then KH (1.12g,28.0mmol) was added and stirring continued to react well with the hydroxyl groups of cyclodextrin. Glycidol (15.0g,202.6mmol) dissolved in 100mL DMF was slowly added dropwise to the above solution by warming to 50 ℃ over about 24 h. The temperature is controlled to be 80 ℃, and the reaction is continued for 16 h. After the temperature of the system is reduced to room temperature, adding a small amount of water to terminate the reaction, directly dialyzing the water (MWCO:1000), and freeze-drying to obtain 17.1g of beta-cyclodextrin grafted hyperbranched polyglycerol;
(2) and (3) dispersing the beta-cyclodextrin grafted hyperbranched polyglycerol obtained in the last step into 200mL of THF, adding solid NaOH (13.3g and 0.33mol) and a catalyst tetrabutylammonium bromide (1.1g and 3.4mmol), gradually dropwise adding epoxy chloropropane (30.4g and 0.33mol) at 10 ℃, and finishing dropping for 6 hours. After the dropwise addition, heating to 25 ℃ to react for 16h, adding 500mL of deionized water, standing for layering, taking the upper oil phase, and removing the solvent to obtain 26.8g of beta-cyclodextrin grafted hyperbranched polyglycerol glycidyl ether;
(3) tris (2-aminoethyl) amine (98.0g,0.67mol) was weighed into 500mL of ethanol and heated to reflux. And (3) dissolving the beta-cyclodextrin grafted hyperbranched polyglycerol glycidyl ether obtained in the last step in 500mL of THF, slowly dropwise adding the solution into an ethanol solution of tris (2-aminoethyl) amine, and finishing dropping for 9 hours. After 9h under reflux, the reaction was purified by dialysis against deionized water and lyophilized to give 50.9g of a cyclodextrin derivative of formula I, wherein n is 7 and R is-NHCH2CH2N(CH2CH2NH2)2The nuclear magnetic hydrogen spectrum is shown in figure 1.
Example 2
The cyclodextrin derivative and the preparation method thereof comprise the following steps:
(1) beta-cyclodextrin (4.0g,3.53mmol) and 18-crown-6 (6.6g,25.0mmol) were accurately weighed out under inert gas protection, dissolved in 150mL DMF, and then KH (1.12g,28.0mmol) was added and stirring continued to react well with the hydroxyl groups of cyclodextrin. Glycidol (30.0g,405.2mmol) dissolved in 100mL DMF was slowly added dropwise to the above solution by warming to 50 ℃ over about 24 h. The temperature is controlled to be 80 ℃, and the reaction is continued for 16 h. After the temperature of the system is reduced to room temperature, adding a small amount of water to terminate the reaction, directly dialyzing the water (MWCO:1000), and freeze-drying to obtain 32.3g of beta-cyclodextrin grafted hyperbranched polyglycerol;
(2) and (2) dispersing the beta-cyclodextrin grafted hyperbranched polyglycerol obtained in the last step into 300mL of THF, adding solid NaOH (19.7g and 0.49mol) and a catalyst tetrabutylammonium bromide (1.7g and 5.1mmol), gradually dropwise adding epoxy chloropropane (45.1g and 0.49mol) at 10 ℃, and finishing dropping for 6 hours. After the dropwise addition, heating to 25 ℃ to react for 16h, adding 750mL of deionized water, standing for layering, taking the upper oil phase, and removing the solvent to obtain 53.2g of beta-cyclodextrin grafted hyperbranched polyglycerol glycidyl ether;
(3) tris (2-aminoethyl) amine (140.3g,0.96mol) was weighed into 1000mL of ethanol and heated to reflux. And (3) dissolving the beta-cyclodextrin grafted hyperbranched polyglycerol glycidyl ether obtained in the last step in 1000mL of THF, slowly dropwise adding the solution into an ethanol solution of tris (2-aminoethyl) amine, and finishing dropping for 9 hours. After 9h under reflux, the reaction was purified by dialysis against deionized water and lyophilized to give 99.3g of a cyclodextrin derivative of formula I, wherein n is 7 and R is-NHCH2CH2N(CH2CH2NH2)2。
Example 3
The cyclodextrin derivative and the preparation method thereof comprise the following steps:
(1) alpha-cyclodextrin (3.43g,3.03mmol) and 18-crown-6 (6.6g,25.0mmol) were accurately weighed out under inert gas protection, dissolved in 150mL DMF, and then KH (1.12g,28.0mmol) was added and stirring continued to react well with the hydroxyl groups of cyclodextrin. Glycidol (15.0g,202.6mmol) dissolved in 100mL DMF was slowly added dropwise to the above solution by warming to 50 ℃ over about 24 h. The temperature is controlled to be 80 ℃, and the reaction is continued for 16 h. After the temperature of the system is reduced to room temperature, adding a small amount of water to terminate the reaction, directly dialyzing the water (MWCO:1000), and freeze-drying to obtain 16.5g of beta-cyclodextrin grafted hyperbranched polyglycerol;
(2) and (3) dispersing the alpha-cyclodextrin grafted hyperbranched polyglycerol obtained in the last step into 200mL of THF, adding solid NaOH (13.3g and 0.33mol) and a catalyst tetrabutylammonium bromide (1.1g and 3.4mmol), gradually dropwise adding epoxy chloropropane (30.4g and 0.33mol) at 10 ℃, and finishing dropping for 6 hours. After the dropwise addition, heating to 25 ℃ to react for 16h, adding 500mL of deionized water, standing for layering, taking the upper oil phase, and removing the solvent to obtain 24.2g of alpha-cyclodextrin grafted hyperbranched polyglycerol glycidyl ether;
(3) tris (2-aminoethyl) amine (98.0g,0.67mol) was weighed into 500mL of ethanol and heated to reflux. And (3) dissolving the alpha-cyclodextrin grafted hyperbranched polyglycerol glycidyl ether obtained in the last step in 500mL of THF, slowly dropwise adding the solution into an ethanol solution of tri (2-aminoethyl) amine, and finishing dropping for 9 hours. After 9h under reflux, the reaction was purified by dialysis against deionized water and lyophilized to give 47.2g of a cyclodextrin derivative of formula I, wherein n is 6 and R is NHCH2CH2N(CH2CH2NH2)2。
Example 4
The cyclodextrin derivative and the preparation method thereof comprise the following steps:
the procedures (1) and (2) are the same as those in example 1.
(3) Triethylene tetramine (98.0g,0.67mol) was weighed into 500mL of ethanol and heated under reflux. And (3) dissolving 26.8g of beta-cyclodextrin grafted hyperbranched polyglycerol glycidyl ether in 500mL of THF, slowly dropwise adding the solution into an ethanol solution of triethylene tetramine, and finishing dropwise adding for 9 hours. After 9h under reflux, the reaction was purified by dialysis against deionized water and lyophilized to give 48.1g of a cyclodextrin derivative of formula I, wherein n is 7 and R is NH (CH)2CH2NH)2CH2CH2NH2。
Comparative example 1
The other cyclodextrin derivative and the preparation method thereof of the comparative example comprise the following steps:
the procedures (1) and (2) are the same as those in example 1.
(3) Beta-cyclodextrin grafted hyperbranched polyglycerol glycidyl ether (1.0g) was dissolved in 10mL of DMF, and then a solution of carbonyldiimidazole (CDI, 3.1g) previously dissolved in 10mL of DMF was added dropwise to the above solution, stirred at room temperature for 2 hours, poured into anhydrous ether for precipitation, and after centrifugation, the precipitate was collected and dissolved in 15mL of DMF. After 1mL of triethylamine was added to the mixture, the mixture was added dropwise to a solution of tris (2-aminoethyl) amine (2.8g) dissolved in 5mL of DMF, and the reaction was stirred at room temperature for 24 hours. Dialyzing and purifying deionized water, and freeze-drying to obtain the cyclodextrin derivative for comparison.
Experimental data:
solubility of the hyperbranched derivatives of Cyclodextrin in the examples
| Cyclodextrin derivatives | Solubility in deionized water (pH 7.0) | Solubility in deionized water (pH 11.0) |
| Example 1 | >0.1g/mL | ～10mg/mL |
| Example 2 | >0.1g/mL | ～10mg/mL |
| Example 3 | >0.1g/mL | ～10mg/mL |
| Example 4 | >0.1g/mL | ～10mg/mL |
| Comparative example 1 | >0.1g/mL | <0.1mg/mL |
Note: the test temperature was 25 ℃.
The technical features of the embodiments described above may be arbitrarily combined, and for the sake of brevity, all possible combinations of the technical features in the embodiments described above are not described, but should be considered as being within the scope of the present specification as long as there is no contradiction between the combinations of the technical features.
The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present invention should be subject to the appended claims.
Claims (13)
1. A cyclodextrin hyperbranched derivative has a structural general formula shown as formula I:
wherein R is a group having a primary or secondary amine group; n is 6, 7 or 8.
2. A preparation method of a cyclodextrin hyperbranched derivative comprises the following steps:
s1) taking cyclodextrin as an initial raw material, and opening the cyclic glycidol under an alkaline condition to obtain cyclodextrin grafted hyperbranched polyglycerol;
s2) reacting the cyclodextrin grafted hyperbranched polyglycerol with epichlorohydrin to obtain cyclodextrin grafted hyperbranched polyglycerol glycidyl ether;
s3) grafting epoxy groups on the hyperbranched polyglycerol glycidyl ether molecules by using molecular open-ring cyclodextrin with primary amine or secondary amine groups to obtain the cyclodextrin hyperbranched derivative.
3. The cyclodextrin hyperbranched derivative of claim 2, wherein: the molecule with primary amine or secondary amine groups is diamine, polyamine or oligomeric ethylene diamine with C2-C20.
4. The cyclodextrin hyperbranched derivative of claim 2, wherein: the molecule with primary amine or secondary amine groups is diamine or polyamine with C2-C10.
5. The cyclodextrin hyperbranched derivative of claim 2, wherein: the molecule having a primary or secondary amine group is selected from ethylenediamine, diethylenetriamine, tris (2-aminoethyl) amine, triethylenetetramine, tetraethylenepentamine or pentaethylenehexamine.
6. The cyclodextrin hyperbranched derivative of claim 2, wherein: the specific process for preparing the cyclodextrin grafted hyperbranched polyglycerol comprises the following steps:
s11) weighing cyclodextrin, dissolving the cyclodextrin in a solvent, slowly dripping glycidol at 40-60 ℃ under the condition that strong base is used as a catalyst, and then heating to 60-100 ℃ to continue reacting for 12-24 hours;
s12) adding deionized water into the system after the reaction is finished to terminate the reaction and dilute the crude product, dialyzing, purifying and drying to obtain the cyclodextrin grafted hyperbranched polyglycerol.
7. Cyclodextrin hyperbranched derivative according to claim 6, characterized in that: the solvent in the step S11 is selected from N, N-dimethylformamide, N-dimethylacetamide, N-diethylformamide or N-methylpyrrolidone; the strong base is selected from 18-crown-6 collocated with metal potassium or 18-crown-6 collocated with potassium hydride.
8. Cyclodextrin hyperbranched derivative according to claim 7, characterized in that: cyclodextrin: potassium or potassium hydride: 18-crown-6: the molar charge ratio of glycidol is 1: (5-10): (5-10): (20 to 2000).
9. The cyclodextrin hyperbranched derivative of claim 2, wherein: the specific process for preparing the cyclodextrin grafted hyperbranched polyglycerol glycidyl ether comprises the following steps:
s21) weighing cyclodextrin grafted hyperbranched polyglycerol, dispersing the cyclodextrin grafted hyperbranched polyglycerol in a solvent, adding solid base and a catalyst tetrabutylammonium bromide, and gradually dropwise adding epoxy chloropropane at 10-15 ℃;
s22), heating to 25-30 ℃, reacting for 12-24 h, finishing the reaction, adding deionized water, standing for layering, taking the upper oil phase, and removing the solvent to obtain the cyclodextrin grafted hyperbranched polyglycerol glycidyl ether.
10. The cyclodextrin hyperbranched derivative of claim 9, wherein: the solvent for preparing the cyclodextrin grafted hyperbranched polyglycerol glycidyl ether is selected from tetrahydrofuran, ethylene glycol dimethyl ether, ethylene glycol diethyl ether or dioxane; the solid alkali is selected from solid sodium hydroxide or solid potassium hydroxide.
11. The cyclodextrin hyperbranched derivative of claim 2, wherein: the operation of the step 3) comprises the following steps:
s31) dissolving molecules with primary amine or secondary amine groups in a solvent, slowly dripping a THF (tetrahydrofuran) solution of cyclodextrin grafted hyperbranched polyglycerol glycidyl ether into the molecular solution with the primary amine or secondary amine groups under a reflux condition, and finishing dripping within 6-12 h;
s32) continuing to react for 6-12 h after the dripping is finished, and dialyzing and purifying with deionized water to obtain the cyclodextrin hyperbranched derivative.
12. The cyclodextrin hyperbranched derivative of claim 11, wherein: the solvent in the step 31) is selected from ethanol, isopropanol, n-propanol or tert-butanol.
13. The application of the cyclodextrin hyperbranched derivative in the preparation of a drug carrier is characterized in that: the cyclodextrin hyperbranched derivative is as defined in any one of claims 1 to 12.
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| CN115785990B (en) * | 2022-12-22 | 2024-05-17 | 南阳腾远石油工程技术服务有限公司 | Crude oil demulsifier and preparation method thereof |
| CN115960363B (en) * | 2023-03-17 | 2023-05-23 | 山东国邦药业有限公司 | Hyperbranched polyamide-amine beta-cyclodextrin derivative and preparation method thereof |
| CN116375399B (en) * | 2023-03-22 | 2023-10-24 | 河源市源隆新型环保建材有限公司 | Dry-mixed thin-layer anti-cracking plastering mortar and preparation method thereof |
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| CN101139406A (en) * | 2007-10-18 | 2008-03-12 | 上海交通大学 | Method for preparing hyper branched supermolecule main block based on modification cyclodextrin |
| CN109384937A (en) * | 2018-09-30 | 2019-02-26 | 广州医科大学 | The hyperbranched polyglycidyl ether derivative and its preparation method and application of chlorin modification |
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