CN109675491B - Method for preparing microvesicle based on non-covalent complex of myristic acid and imidazole derivatives - Google Patents
Method for preparing microvesicle based on non-covalent complex of myristic acid and imidazole derivatives Download PDFInfo
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Abstract
The invention relates to a method for preparing microvesicles based on a non-covalent complex of myristic acid and imidazole derivatives, which sequentially comprises the following steps: (1) preparing a non-covalent complex of myristic acid and an imidazole compound; (2) recrystallizing and purifying the crude product of the non-covalent complex of myristic acid and imidazole compound; (3) preparing microvesicles from a non-covalent complex of myristic acid and an imidazole compound; the method has the advantages of easily available raw materials, low cost, simple preparation method and simple and convenient operation, and the prepared product has a stable micro-bubble structure, obvious maltese cross shape can be represented by a polarizing microscope and has better fluidity; the vesicle system prepared by the method has good stability and high vesicle concentration, can be used in various aspects such as cell biomembrane simulation, drug delivery, drug slow release, micro-nano reactors, preparation of nano materials and the like, and has wide application prospect.
Description
Technical Field
The invention belongs to the field of soft matter surfactant ordered aggregate materials, and particularly relates to a method for preparing a microvesicle based on a non-covalent complex of myristic acid and imidazole derivatives.
Background
Molecular ordered aggregate structures are widely found in nature, and for example, cell membranes of animals and plants, double helix DNA in life, bacteria, viruses and the like belong to ordered molecular aggregates. Ordered molecular aggregates can be constructed by ordered aggregation of surfactants, and it is found that various micelle ordered aggregates such as spherical micelles, rod-shaped micelles, lamellar micelles and columnar micelles can be formed according to the proportion of the surfactants and various solvents, and various lyotropic liquid crystal aggregate structures can be formed by the structure expansion, wherein various flexible vermicular micelles, bilayer, multilayer and other vesicle ordered aggregates can also be formed (Wang, L.; Dong, S.; Hao, J. Curr Opin Colloid Interface Sci 2018,35: 81-90; Whitesides, G. M.; Mathias, J. P.; Seto, C. T., Science 1991, 254:1312 1319.). These ordered aggregates are generally the spontaneous formation of ordered structures by surfactants through some hydrophobic and hydrophilic interactions, hydrogen bonding, and the like. The formation of ordered aggregates requires, on the one hand, that the molecules have sufficient hydrophilicity, for example, the head group is an ionic structure or a polyol structure, such as dodecanol, etc., and only one hydroxyl group tends to have insufficient order and to be difficult to form ordered aggregates. On the other hand, the hydrophilicity and hydrophobicity are also proper, generally, the layering is easy to happen if the carbon chain is too long, and the self-assembly is difficult to happen if the carbon chain is too short. In addition to hydrophilicity and hydrophobicity, non-covalent interactions such as electrostatic, pi-pi stacking, hydrogen bonding, and dipoles also contribute to the building of aggregates. The ordered aggregates have a nano structure in at least one dimension, so the ordered aggregates can be used as a microreactor and the like to prepare various nano materials. The construction and application of ordered aggregates are receiving more and more attention in various fields such as biology, nanometer materials, energy science, information materials and the like and the aspect of high and new technology application.
The vesicle is one of ordered aggregates, and the cell biomembrane is generally a similar vesicle double-layer ordered aggregate structure, so that the vesicle is widely applied to the aspects of simulating the cell biomembrane, delivering drugs, releasing drugs slowly, preparing micro-nano reactors, various nano materials or structures and the like. Structurally, vesicles are generally spherical or near-spherical single-compartment or multi-compartment ordered aggregates constructed from closed surfactant bilayers. With regard to the preparation of vesicles, researchers and researchers have researched and simulated the structure of biological vesicles and inspired from the tissue structure, morphology and function of biological vesicles, and have developed and reported many methods and approaches for preparing ordered aggregates of microvesicle structures, such as self-assembly vesicle method, ultrasonic oscillation method, reverse evaporation method, ethanol or ether injection method, and the like. The preparation of vesicles by surfactant self-assembly is the simplest method, and the preparation of vesicle aggregates by a single surfactant or a surfactant compound system is one of the most extensive methods. Songweiming et al (Korea Xueya, Songweiming et al. journal of man-hours, 2014, 28: 12-17.) successfully prepared spontaneously forming vesicle system by compounding anionic and cationic surfactants (SDS/CTAB), adjusting concentration, temperature, solvent, pH value and other factors, and obtaining the most stable vesicle preparation conditions by changing and adjusting the above conditions. The ether or ethanol injection method is that amphiphilic substance or surfactant is prepared into ether or ether solution, and then the ether or ether solution is injected into water to remove organic solvent to prepare vesicle aggregate. Some surfactants or amphiphilic substances cannot spontaneously form vesicle structures, and can form vesicle aggregates by using an ultrasonic method. In addition, the Bola type amphiphilic compound surfactant has the characteristic that both ends are hydrophilic groups, and is easier to form monomolecular layer vesicles in water. The structure is similar to the structure of a biological membrane, can be used for regulating and controlling the stability of a double-layer lipid membrane, and can also be used for constructing an electric ion channel connecting the inside and the outside of the double-layer lipid membrane.
The vesicle has wide application, for example, the structure of the vesicle generally has a nano-sized and micro-sized ordered structure, and the vesicle can be used for preparing nano-sized or micro-sized materials. YaoSongnian et al (YaoSongnian. report of physical chemistry 1994, 10: 950-. The structure of the vesicle is very similar to that of the biological membrane, so that the vesicle is one of the best systems for simulating a biological system and the biological membrane, is beneficial to exploring the mysteries of the biological membrane and developing the bionic high and new technology in the aspect. Wang Huiyun et al (report of Wang Huiyun Jining medical college, 2013, 36: 9-13.) explore the changes of the granularity, potential, encapsulation rate, the release rate of the vesicle under different pH values and the fluorescence intensity of the vesicle after being cultivated in bovine serum by taking Tween-20, cholesterol hemisuccinate and the like as materials to construct the vesicle for developing a novel drug delivery system. The pH sensitive lipoid vesicle containing the Gemini surfactant is found to have uniform system distribution, high encapsulation efficiency and quick drug release in an acidic environment. The gemini surfactant vesicles can be used for targeted delivery of drugs to certain pathological tissues, and can be developed into an ideal novel drug delivery system.
With the continuous development of industrial technology and research and development, people develop vesicle preparation technology, and develop some vesicle preparation methods and processes gradually. In recent years, methods for constructing vesicles by using ionic liquids have appeared, for example, Wang et al (H. Wang, B. Tan, J. Wang; Z, Li.; S, Zhang, Langmuir, 2014, 30: 3975-. However, the use of imidazole ionic liquids also has certain limitations and complexities, for example, the preparation procedures of ionic liquids are often complicated, special technicians are generally required for operation, the cost is high, and the use of toxic solvents and the like limits the further development of industrialization. Based on this, there is a need to find a simple and feasible method for preparing vesicle aggregate material with low cost, which is suitable for industrial production application.
Disclosure of Invention
The invention aims to provide a method for preparing microvesicles based on a non-covalent complex of myristic acid and imidazole derivatives, aiming at the problems that the existing preparation method for preparing microvesicle ordered aggregates has expensive preparation instruments and materials, high cost and complicated preparation procedures, and the prepared microvesicle ordered aggregates have poor stability and are easily damaged in the using process.
The invention discloses a method for preparing microvesicles based on a non-covalent complex of myristic acid and imidazole derivatives, which sequentially comprises the following steps:
(1) preparation of non-covalent complexes of myristic acid and imidazole Compounds
Weighing a proper amount of myristic acid, dissolving in a proper amount of absolute ethyl alcohol, placing in an ice water bath, stirring and protecting with nitrogen; slowly dripping a proper amount of imidazole compound into a container, slowly dripping an ethanol solution of myristic acid into the imidazole compound under the conditions of stirring and nitrogen protection, and stirring and reacting for 18-56 hours under nitrogen atmosphere; after the reaction is finished, cooling, and removing the solvent by rotary evaporation with a rotary evaporator under vacuum to obtain a crude product of the non-covalent complex of the myristic acid and the imidazole compound; the mass ratio of the myristic acid to the imidazole compound is 1: 1.2-2;
(2) recrystallizing and purifying crude myristic acid and imidazole compound non-covalent complex
Dissolving the prepared crude myristic acid and imidazole compound non-covalent complex in a proper amount of acetone under the heating condition, then adding a proper amount of organic solvent acetonitrile, slowly cooling the solution mixture at room temperature, standing for 2-6 hours, separating out a crystallization product, and filtering under reduced pressure; recrystallizing for 2-5 times by the same method to obtain refined product of non-covalent complex of white myristic acid and imidazole compound; drying the refined product in a vacuum drying oven at 30-80 deg.C for 12-56 hr;
(3) preparation of microvesicles from non-covalent complex elaborations of myristic acid and imidazole compounds
Preparing a myristic acid and imidazole compound non-covalent complex competitive product and water into a series of mixtures with the mass fractions of 0.5%, 0.6%, 0.7%, … … 9.8.8%, 9.9% and 10%, and sealing; and (3) respectively stirring and centrifuging the series of mixtures by using a vortex mixer and a high-speed centrifuge in sequence, repeating stirring and centrifuging for 3-8 times according to the viscosity of a sample to fully mix the mixtures into a homogeneous system, and placing the prepared homogeneous system mixture in a thermostat at 20-30 ℃ for 1-8 weeks to obtain series of micro-capsule products with the mass concentrations of 0.5%, 0.6%, 0.7% … … 9.8.8%, 9.9% and 10% respectively.
The product prepared by the invention has a micro-bubble structure, is obviously represented by a polarizing microscope, and has a maltese cross shape and good fluidity.
When the homogeneous system mixture of 5-10% by mass of the non-covalent complex of myristic acid and imidazole compound and water is prepared in step (3), the sample has high viscosity, so that the material can be heated until the material can flow sufficiently, and then stirring and centrifuging operations are performed, so that the product fluidity is enhanced, and the homogeneous system is formed more quickly.
The imidazole compound is N-methylimidazole, or the carbon atom on the imidazole ring is connected with C1-C12And imidazole derivatives of organic groups such as alkyl groups, halogenated hydrocarbon groups, hydroxyl groups, and carboxyl groups. Of course, other imidazole derivatives may be used to prepare the non-covalent complexes of the invention.
The solvent used for recrystallization in the step (2) of the invention can be dissolved by using organic solvents such as ethanol, toluene, dichloromethane, trichloromethane and the like instead of acetone; the recrystallization may be carried out using a mixed solution of acetonitrile and acetone, a mixed solution of ethanol and acetonitrile, or an organic solvent such as tetrahydrofuran, instead of acetonitrile. It is of course also possible to use mixed solutions of organic solvents and acetonitrile, as long as recrystallization of the noncovalent compounds of the invention is achieved.
The concentration of the vesicle aggregate solution is prepared and constructed in the step (3), and the composite aqueous solution with the mass concentration of 0.5-10% can form a microvesicle aggregate structure. The subsequent centrifugation and blending operations can adopt different equipment according to conditions, as long as the centrifugation and blending effects can be achieved. The standing time after uniform mixing can be indefinite from 1 day to 1 year, and can be optimized according to specific production and preparation conditions, and the longer the standing time is, the better the stability of the obtained vesicle system is.
The method prepares the myristic acid and imidazole compound non-covalent compound through a series of physical and chemical processes, then purifies the prepared non-covalent compound through methods such as recrystallization and the like, then prepares aqueous solutions with different concentrations by the non-covalent compound, and prepares the micro-vesicle ordered aggregate through processes such as uniform mixing, centrifugation, constant temperature placement and the like. The micro-vesicle system with an ordered structure can be simply prepared by the method. The prepared product can be seen to have certain birefringence through the polarizer. The polarizing microscope further characterizes the polarizing performance, can obviously observe a specific Maltese cross polarizing structure and shows better fluidity under the polarizer. The prepared vesicle system has good stability and high vesicle concentration, and can be used in various aspects such as cell biomembrane simulation, drug delivery, drug slow release, micro-nano reactor, preparation of nano materials and the like.
The method of the invention has the following advantages:
(1) the method for preparing the microvesicles based on the non-covalent complex of the myristic acid and the imidazole derivatives is novel, simple in process, low in cost, easy to operate and simple and convenient to prepare, the used raw materials are basically easily available reagent materials, common and cheap reagents can be used for preparing microvesicle products, and the method is convenient for industrial production and popularization.
(2) The invention uses a non-covalent complex constructed by myristic acid and imidazole derivatives to prepare microvesicles, and has novel method and materials. Compared with common surfactants used for constructing vesicles, such as common surfactants, ionic liquid surfactants, Gemini surfactants and the like, the non-covalent compound avoids an organic chemical reaction process, greatly improves or reduces the preparation temperature, purification, the use amount of organic solvents and the like, and is simple in preparation process.
(3) The preparation of the micro-vesicle system is simple, and the prepared micro-vesicle has adjustable concentration and good stability. The microvesicle system can be prepared by simple proportioning of the non-covalent complex and solvents such as water, the mass concentration is adjustable, a series of microvesicles with different concentrations such as 0.5%, 0.6%, 0.7%, … … 9.7.7%, 9.8%,9.9%, 10.0% and the like can be prepared, the structural parameters such as the concentration, the size and the like of the microvesicles can be adjusted, the obtained vesicle ordered aggregate has stable structure and wide range, the microvesicle concentration is high, and the microvesicle ordered aggregate can be used in various fields such as biology, medicine, materials and the like.
The method for preparing the microvesicle by using the non-covalent complex of the myristic acid and the imidazole derivatives has the advantages of easily available raw materials, low cost, simple method and simple and convenient operation, and can be used for preparing the vesicle aggregate material with good stability and high vesicle concentration. At present, the preparation of the microvesicle by using the non-covalent complex of myristic acid and imidazole derivatives is not reported in research and development and application at home and abroad, and has better application prospect.
Drawings
FIG. 1 shows a Maltese cross structure of the microvesicle system prepared in example 1 of the present invention under a polarizing microscope;
FIG. 2 shows an appearance picture without a polarizer (left) and a birefringence picture with a polarizer (right) of the micro-bubble system prepared in example 1 of the present invention;
FIG. 3 is a photograph showing the vesicle fluidity of the microvesicle system prepared in example 2 of the present invention under a polarization microscope.
Detailed Description
Example 1
The method for preparing the microvesicles based on the non-covalent complex of myristic acid and imidazole derivatives of the embodiment sequentially comprises the following steps:
(1) preparation of non-covalent myristic acid and N-methylimidazole complex
Weighing 14.02g of myristic acid, dissolving in a proper amount of absolute ethyl alcohol, placing in an ice-water bath, stirring and protecting with nitrogen, slowly dropwise adding 8.21g of N-methylimidazole compound into a 500mL round-bottom flask, slowly dropwise adding an ethanol solution of myristic acid under the conditions of stirring and protecting with nitrogen, and stirring and reacting for 24 hours under a nitrogen atmosphere; after the reaction is finished, cooling, and removing the solvent by rotary evaporation with a rotary evaporator under vacuum to obtain a myristic acid and N-methylimidazole non-covalent complex crude product;
(2) recrystallization purification of non-covalent complex of myristic acid and N-methylimidazole
Dissolving the prepared myristic acid and N-methylimidazole compound crude product in a proper amount of acetone under a heating condition, then adding 200ml of acetonitrile, placing the solution mixture at room temperature for slowly cooling, standing for 4 hours, crystallizing the solution to separate out a crystal product, and filtering under reduced pressure; recrystallizing for 3 times by the same method to obtain a refined product of the non-covalent complex of the white myristic acid and the N-methylimidazole, and drying the refined product in a vacuum drying oven at 60 ℃ for 36 hours for later use;
(3) preparation of microvesicles from a complex of myristic acid and N-methylimidazole with non-covalent complexation
Preparing a myristic acid and N-methylimidazole non-covalent complex competitive product and water into mixtures with mass concentrations of 2%, 3% and 4% respectively in a test tube with a plug, mixing and sealing; and (3) stirring and centrifuging the three groups of mixtures by using a vortex mixer and a high-speed centrifuge, repeating the stirring and centrifuging for 5 times to obtain homogeneous systems of the myristic acid and N-methylimidazole non-covalent complex competitive products and water with the mass concentrations of 2%, 3% and 4%, respectively, and placing the three groups of homogeneous systems in a thermostat at the temperature of 20-25 ℃ for 1 week to obtain stable micro-capsule products with the mass concentrations of 2%, 3% and 4%, respectively. Figure 1 shows the maltese cross structure of the 4% by mass microvesicle system prepared in this example. Fig. 2 is an appearance picture without polarizer (left) and a birefringence picture with polarizer (right) of the microvesicle system with a mass concentration of 4%.
Example 2
(1) Preparation of non-covalent myristic acid and 4-methylimidazole complex
Weighing 19.06g of myristic acid, dissolving in a proper amount of absolute ethyl alcohol, placing in an ice-water bath, stirring and protecting with nitrogen; slowly dripping 10.25g of 4-methylimidazole compound into a 500mL round-bottom flask, slowly dripping an ethanol solution of myristic acid under the conditions of stirring and nitrogen protection, and stirring and reacting for 18 hours under a nitrogen atmosphere; after the reaction is finished, cooling, and removing the solvent by rotary evaporation with a rotary evaporator under vacuum to obtain a myristic acid and 4-methylimidazole non-covalent complex crude product;
(2) recrystallization purification of non-covalent complex of myristic acid and 4-methylimidazole
Dissolving the prepared myristic acid and 4-methylimidazole non-covalent complex crude product in a proper amount of acetone under a heating condition, then adding 300ml of organic solvent acetonitrile, placing the solution mixture at room temperature, slowly cooling, standing for 3 hours, precipitating a crystallization product, and filtering under reduced pressure; recrystallizing for 2 times by the same method to obtain a refined product of the non-covalent complex of the white myristic acid and the 4-methylimidazole, and drying for 24 hours in a vacuum drying oven at 70 ℃ for later use;
(3) preparation of microvesicles with a non-covalent complex of white myristic acid and 4-methylimidazole
Preparing a series of mixtures with the mass concentrations of 1%, 2%, 3% and 5% respectively by using refined myristic acid and 4-methylimidazole non-covalent compound and water in a test tube with a plug, mixing and sealing the mixtures, stirring the mixtures by using a magnetic stirrer, and placing the uniformly mixed homogeneous system in a thermostat at 25 ℃ for 2 weeks to obtain stable micro-bubble products with the mass concentrations of 1%, 2%, 3% and 5%. Fig. 3 shows the maltese cross structure of the 3% by mass microvesicle system prepared in this example and a vesicle fluidity picture thereof under a polarization microscope.
Example 3
(1) Preparation of non-covalent complex of myristic acid and 5-chloro-1-methylimidazole
Weighing 15.20g of myristic acid, dissolving the myristic acid in a proper amount of absolute ethyl alcohol, placing the myristic acid in an ice-water bath, stirring and protecting with nitrogen, slowly dropwise adding 16.22g of 5-chloro-1-methylimidazole compound into a 500mL round-bottom flask, slowly dropwise adding an ethanol solution of myristic acid under the conditions of stirring and protecting with nitrogen, and stirring and reacting for 36 hours under a nitrogen atmosphere; after the reaction is finished, cooling, and removing the solvent by rotary evaporation with a rotary evaporator under vacuum to obtain a crude product of the myristic acid and the 5-chloro-1-methylimidazole non-covalent complex;
(2) recrystallization purification of non-covalent complex of myristic acid and 5-chloro-1-methylimidazole
Dissolving the prepared crude myristic acid and 5-chloro-1-methylimidazole non-covalent complex in a proper amount of acetone under a heating condition, then adding 100ml of acetonitrile, slowly cooling, standing for 2 hours, separating out a crystal product from the solution, filtering under reduced pressure, recrystallizing for 4 times by the same method to obtain a refined myristic acid and 5-chloro-1-methylimidazole non-covalent complex, and drying for 56 hours in a vacuum drying oven at the temperature of 80 ℃ for later use;
(3) preparation of microvesicles with a non-covalent complex of myristic acid and 5-chloro-1-methylimidazole
According to certain mass concentration, myristic acid, 5-chloro-1-methylimidazole non-covalent compound and water are prepared into a series of mixtures with the mass concentration of 0.5%, 1%, 3% and 6% in a volumetric flask, a magnetic stirrer is used for stirring to prepare a homogeneous system, and the uniformly mixed homogeneous system is placed in a 30 ℃ thermostat for 4 weeks to prepare stable micro-bubble products with the mass concentration of 0.5%, 1%, 3% and 6%.
Example 4
(1) Preparation of non-covalent complex of myristic acid and 1-methyl-5-aminomethyl imidazole
Weighing 12.01g of myristic acid, dissolving in a proper amount of absolute ethyl alcohol, placing in an ice-water bath, stirring and protecting with nitrogen, slowly dropwise adding 15.52g of 1-methyl-5-aminomethyl imidazole into a 500mL round-bottom flask, slowly dropwise adding an ethanol solution of myristic acid under the conditions of stirring and protecting with nitrogen, stirring and reacting for 28 hours under a nitrogen atmosphere, cooling after the reaction is finished, and removing the solvent by rotary evaporation with a rotary evaporator under vacuum to obtain a crude complex of myristic acid and 1-methyl-5-aminomethyl imidazole non-covalent complex.
(2) Recrystallization purification of non-covalent complex of myristic acid and 1-methyl-5-aminomethyl imidazole
Dissolving the prepared myristic acid and 1-methyl-5-aminomethyl imidazole non-covalent complex crude product in a proper amount of acetone under the heating condition, then adding 400ml of organic solvent acetonitrile, placing the solution mixture at room temperature for slow cooling, standing for 6 hours, separating out a crystalline product, filtering under reduced pressure, recrystallizing for 4 times by the same method to obtain white myristic acid and 1-methyl-5-aminomethyl imidazole non-covalent complex crude product, and placing the white myristic acid and 1-methyl-5-aminomethyl imidazole non-covalent complex crude product in a vacuum drying oven at 50 ℃ for drying for 48 hours for later use.
(3) Preparation of microvesicles with a non-covalent complex of myristic acid and 1-methyl-5-aminomethylimidazole
Preparing a series of mixtures with the mass concentrations of 1.5%, 2.5% and 3.5% respectively by myristic acid, 1-methyl-5-aminomethyl imidazole non-covalent compound and water in a test tube with a plug, mixing and sealing the mixtures, respectively stirring and uniformly mixing the mixtures by using a vortex mixer, and placing the uniformly mixed homogeneous system in a constant temperature box at the room temperature of 25 ℃ for 3 weeks to obtain stable micro-capsule products with the mass concentrations of 1.5%, 2.5% and 3.5%.
Example 5
(1) Preparation of non-covalent complex of myristic acid and 1-propylimidazole
Weighing 15.22g of myristic acid, dissolving the myristic acid in an appropriate amount of acetone solution, placing the myristic acid in an ice-water bath, stirring and protecting with nitrogen, slowly dropwise adding 16.25g of 1-propylimidazole compound into a 500mL round-bottom flask, slowly dropwise adding the myristic acid in the acetone solution under the conditions of stirring and protecting with nitrogen, and stirring and reacting for 39 hours under nitrogen atmosphere; after the reaction is finished, cooling, and removing the solvent by rotary evaporation with a rotary evaporator under vacuum to obtain a myristic acid and 1-propylimidazole non-covalent complex crude product;
(2) recrystallization purification of non-covalent complex of myristic acid and 1-propylimidazole
Dissolving the prepared crude myristic acid and 1-propylimidazole non-covalent compound in a proper amount of acetone under a heating condition, then adding 100ml of organic solvent acetonitrile, placing the solution mixture in an ice water bath for cooling, standing for 2 hours, separating out a crystalline product, filtering under reduced pressure, recrystallizing for 4 times by using the same method to obtain a refined myristic acid and 1-propylimidazole non-covalent compound, and drying for 48 hours in a vacuum drying oven at the temperature of 80 ℃ for later use;
(3) preparation of microvesicles using complexes
Preparing a series of mixtures with the mass concentrations of 1%, 2%, 3% and 5% respectively by myristic acid, 1-propylimidazole non-covalent compound and water in a conical flask, mixing and sealing the mixtures, stirring the mixtures by using a magnetic stirrer to prepare a homogeneous system, and placing the uniformly mixed product in a thermostat at 25 ℃ for 6 weeks to prepare stable micro-bubble products with the mass concentrations of 1%, 2%, 3% and 5%.
Claims (5)
1. A method for preparing microvesicles based on a non-covalent complex of myristic acid and imidazole derivatives is characterized by sequentially comprising the following steps:
(1) preparation of non-covalent complexes of myristic acid and imidazole Compounds
Weighing a proper amount of myristic acid, dissolving in a proper amount of absolute ethyl alcohol, placing in an ice water bath, stirring and protecting with nitrogen; slowly dripping a proper amount of imidazole compound into a container, slowly dripping an ethanol solution of myristic acid into the imidazole compound under the conditions of stirring and nitrogen protection, and stirring and reacting for 18-56 hours under nitrogen atmosphere; after the reaction is finished, cooling, and removing the solvent by rotary evaporation with a rotary evaporator under vacuum to obtain a crude product of the non-covalent complex of the myristic acid and the imidazole compound; the mass ratio of the myristic acid to the imidazole compound is 1: 1.2-2;
(2) recrystallizing and purifying crude myristic acid and imidazole compound non-covalent complex
Dissolving the prepared crude myristic acid and imidazole compound non-covalent complex in a proper amount of acetone under the heating condition, then adding a proper amount of organic solvent acetonitrile, slowly cooling the solution mixture at room temperature, standing for 2-6 hours, separating out a crystallization product, and filtering under reduced pressure; recrystallizing for 2-5 times by the same method to obtain refined product of non-covalent complex of white myristic acid and imidazole compound; drying the refined product in a vacuum drying oven at 30-80 deg.C for 12-56 hr;
(3) preparation of microvesicles from non-covalent complex elaborations of myristic acid and imidazole compounds
Preparing a myristic acid and imidazole compound non-covalent complex competitive product and water into a series of mixtures with the mass fractions of 0.5%, 0.6%, 0.7%, … … 9.8.8%, 9.9% and 10%, and sealing; and (3) respectively stirring and centrifuging the series of mixtures by using a vortex mixer and a high-speed centrifuge in sequence, repeating stirring and centrifuging for 3-8 times according to the viscosity of a sample to fully mix the mixtures into a homogeneous system, and placing the prepared homogeneous system mixture in a thermostat at 20-30 ℃ for 1-8 weeks to obtain series of micro-capsule products with the mass concentrations of 0.5%, 0.6%, 0.7% … … 9.8.8%, 9.9% and 10% respectively.
2. The method for preparing microvesicles based on the non-covalent complex of myristic acid and imidazole derivatives according to claim 1, wherein: the prepared product has a micro-bubble structure, is obviously represented by a polarizing microscope, and has a maltese cross shape and good fluidity.
3. The method for preparing microvesicles based on the non-covalent complex of myristic acid and imidazole derivatives according to claim 1, wherein: when the homogeneous system mixture of 5-10% by mass of the non-covalent complex of myristic acid and imidazole compound and water is prepared in the step (3), the materials are heated until the materials can flow sufficiently, and then stirring and centrifugal operation are carried out, so that the product fluidity is enhanced, and the homogeneous system is formed more quickly.
4. The method for preparing microvesicles based on the non-covalent complex of myristic acid and imidazole derivatives according to claim 1, wherein: the imidazole compound is N-methylimidazole, or the carbon atom on the imidazole ring is connected with C1-C12And imidazole derivatives of organic groups such as alkyl groups, halogenated hydrocarbon groups, hydroxyl groups, and carboxyl groups.
5. The method for preparing microvesicles based on the non-covalent complex of myristic acid and imidazole derivatives according to claim 1, wherein: the solvent used for recrystallization in the step (2) can be dissolved by using organic solvents such as ethanol, toluene, dichloromethane, trichloromethane and the like instead of acetone; the recrystallization may be carried out using a mixed solution of acetonitrile and acetone, or an organic solvent such as tetrahydrofuran, instead of acetonitrile.
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| CN110975748A (en) * | 2019-12-27 | 2020-04-10 | 湖北理工学院 | Method for preparing vesicle aggregates based on compounding of imidazole compounds and capric acid |
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