WO2020140326A1 - 一种松香基小分子水凝胶剂及其应用 - Google Patents

一种松香基小分子水凝胶剂及其应用 Download PDF

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WO2020140326A1
WO2020140326A1 PCT/CN2019/077616 CN2019077616W WO2020140326A1 WO 2020140326 A1 WO2020140326 A1 WO 2020140326A1 CN 2019077616 W CN2019077616 W CN 2019077616W WO 2020140326 A1 WO2020140326 A1 WO 2020140326A1
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dimethyl
gel
oxide
emulsion
hydrogel
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宋冰蕾
闫婷婷
王丹萍
崔正刚
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Jiangnan University
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Priority claimed from CN201910007376.8A external-priority patent/CN109627191B/zh
Priority claimed from CN201910063397.1A external-priority patent/CN109772226B/zh
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Priority to US16/832,034 priority Critical patent/US11352317B2/en
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Definitions

  • the invention relates to a rosin-based small molecule hydrogel and its application, which belongs to the fields of supramolecular chemistry, surfactant science and rosin chemical utilization.
  • a hydrogel is a spatial network structure formed by colloidal particles under certain conditions, which is composed of a large amount of water.
  • hydrogels are widely present in nature and people's daily lives, and have important applications in the fields of drug sustained release, tissue engineering, and biological simulation.
  • supramolecular chemistry supramolecular hydrogels formed by small molecules through intermolecular forces (hydrophobic interaction, ionic interaction, hydrogen bonding, host-guest interaction, or ⁇ - ⁇ interaction, etc.) have attracted widespread attention.
  • the core of constructing supramolecular hydrogels is the structure of small molecule hydrogels.
  • Supramolecular hydrogels have a wide range of uses in the field of life sciences. Therefore, the design and synthesis of small molecule hydrogels using natural products as the main raw materials can help construct environmentally friendly and biocompatible supramolecular hydrogels system. Rosin is a kind of abundant and renewable forest resources. Products or deep-processed products using rosin as raw materials have been widely used in various fields of industry and life such as rubber, ink, paint, pesticide, medicine, food, electronics, etc. Nevertheless, so far, there has been no report about rosin-based supramolecular hydrogel systems. If the rosin-based supramolecular hydrogel system can be obtained, the application range of the natural product rosin and the research scope of the supramolecular hydrogel will be greatly expanded.
  • the gel emulsion refers to an emulsion system composed of a dispersed phase (inner phase) and a continuous phase (outer phase) in the presence of a certain stabilizer and having a jelly-like appearance. Due to its special structure and properties, gel emulsions are widely used in food, cosmetics, materials, drug delivery and other fields. The type and concentration of stabilizer have an important influence on the stability of gel emulsion. Surfactants are the most commonly used stabilizers. In the oil-water system, the surfactant molecules are aligned at the oil-water interface, which reduces the interface energy and promotes the formation of gel emulsion.
  • the amount of the surfactant is extremely large, usually 5-30% of the continuous phase. At the same time, it can be formed only after the volume fraction of the dispersed phase is greater than 74%. These factors severely restrict the practical application of gel emulsions.
  • Small molecular hydrogels self-assemble to form fiber network structures through weak molecular interactions such as hydrogen bonding, ⁇ - ⁇ stacking, van der Waals forces, static electricity, and host-guest interactions, which can cause solvents to lose fluidity. If the small molecule gelling agent is used as a new type of stabilizer, the gel emulsion system will be different from the traditional gel emulsion system.
  • the continuous phase appears in a gel state, the dispersed phase is physically wrapped in the gel network, this type of gel emulsion system is not subject to the limit of the continuous phase must be greater than 74%, The range of the volume fraction of the dispersed phase in the emulsion can be greatly widened.
  • not all small molecule hydrogels can stabilize gel emulsions.
  • the aggregation structure formed by the small molecule hydrogel should be able to resist the erosion of the organic oil phase, and at the same time have the effect of reducing the interfacial tension. Therefore, how to design and synthesize new small-molecule hydrogels that meet the requirements to prepare new gel emulsion systems is currently the focus and difficulty of colloidal chemistry.
  • the present invention introduces rosin acid into the structure of a small molecule hydrogel agent to obtain a rosin-based supramolecular hydrogel system with good biocompatibility, good degradability and meeting the requirements of green chemistry, which greatly expands the natural
  • the application scope of the product rosin and the research scope of supramolecular hydrogel Since the main part of rosin acid is a tricyclic diterpene-type rigid hydrophobic group with a stable spatial configuration, it is introduced into the molecular structure of a small molecule hydrogel agent to obtain a hydrogel with extremely high gel efficiency system.
  • the present invention uses dehydroabietic acid, the main component of disproportionated rosin, as a raw material, and after a series of reactions, obtains a small molecule hydrogel 6-dehydroabietylamide-N,N-dimethyl- that meets the requirements of green chemistry. Hexylamine oxide (R-6-OA). Further, the present invention uses this molecule as a building block to prepare a supramolecular hydrogel system, which lays a foundation for the application research of rosin in supramolecular hydrogels.
  • 6-dehydroabietylamino-N,N-dimethyl-hexylamine oxide of the present invention can be used as a stabilizer to prepare a type of O/W gel emulsion.
  • 6-Dehydroabietylamide-N,N-dimethyl-hexylamine oxide reduces the interfacial tension of oil and water, while the three-dimensional network structure formed in the continuous phase prevents the aggregation of droplets.
  • the range of the volume fraction of the dispersed phase is extremely wide and can be adjusted arbitrarily between 1% and 98% (v/v), breaking the conclusion that the volume of the dispersed phase of the conventional gel emulsion must be greater than 74%.
  • most of the oil phase can form a stable gel emulsion, which greatly expands the application range of the gel emulsion.
  • the first object of the present invention is to provide a compound whose structural formula is formula (1):
  • the second object of the present invention is to provide a method for preparing the compound, including: synthesizing 6-dehydroabietylamino-N,N-dimethyl-hexyl from dehydroabietic acid, the main component of disproportionated rosin, as a raw material Amine oxide.
  • the synthetic route of the compound (6-dehydroabietylamino-N,N-dimethyl-hexylamine oxide) is as follows:
  • the compound synthesis step includes:
  • Synthesis of Compound 2 A certain amount of 1,6-hexanediamine and dichloromethane were added to the three-necked flask. Under full stirring, when the temperature dropped to -20°C, the methylene chloride solution of Compound 1 was slowly added dropwise, and the reaction was continued for 3 h after the addition was completed. After the reaction was completed, water was added to the mixture and extracted with dichloromethane. The organic layer was washed with water 5-6 times, and then the organic layer was dried over anhydrous sodium sulfate, and the remaining solvent in the extract was removed by distillation under reduced pressure. A yellow viscous liquid containing Compound 2 was obtained.
  • the third object of the present invention is to provide a supramolecular hydrogel including the use of the 6-dehydroabietylamino-N,N-dimethyl-hexylamine oxide of the present invention as a gel factor.
  • the supramolecular hydrogel is formed by contacting 6-dehydroabietylamino-N,N-dimethyl-hexylamine oxide with water.
  • the supramolecular hydrogel is formed at a temperature below 40°C.
  • the concentration range of 6-dehydroabietylamino-N,N-dimethyl-hexylamine oxide in the supramolecular hydrogel is 3 mmol ⁇ L -1 -1000 mmol ⁇ L -1 .
  • the third object of the present invention is to provide a sustained-release material comprising the 6-dehydroabietylamino-N,N-dimethyl-hexylamine oxide of the present invention and a substance requiring sustained-release.
  • the substance requiring sustained release is a functional factor, including: drugs, nutritional factors, and the like.
  • the sustained-release material is to disperse the substance to be sustained-released in water, and then form the gel skeleton using 6-dehydroabietylamide-N,N-dimethyl-hexylamine oxide Hydrogels.
  • the fourth object of the present invention is to provide a medical wound dressing using the 6-dehydroabietylamide-N,N-dimethyl-hexylamine oxide of the present invention as a gel skeleton to form a hydrogel, hydrogel It contains anti-inflammatory or antibacterial ingredients.
  • the fifth object of the present invention is to provide a water and soil humectant, which includes the use of 6-dehydroabietylamino-N,N-dimethyl-hexylamine oxide of the present invention.
  • the water and soil moisturizer can absorb a large amount of water and slowly release it, which has the effect of moisturizing and drought resistance.
  • the sixth object of the present invention is to provide a hydrogel facial mask, using the 6-dehydroabietic acid-N,N-dimethyl-hexylamine oxide of the present invention as the main gel skeleton to form a hydrogel.
  • one or more of collagen, hyaluronic acid, arbutin, nicotinamide and other substances are also injected into the mask.
  • the seventh object of the present invention is to provide a cell culture method, which includes using the 6-dehydroabietylamino-N,N-dimethyl-hexylamine oxide of the present invention as a gel skeleton to form a hydrogel, as The growth of cells provides a three-dimensional environment.
  • the invention also provides the application of the 6-dehydroabietylamino-N,N-dimethyl-hexylamine oxide in the fields of drug sustained release, tissue engineering, cell culture, sewage treatment and daily chemicals.
  • the eighth object of the present invention is to provide an O/W-type gel emulsion whose stabilizer includes 6-dehydroabietic acid-N,N-dimethyl-hexyl oxidation Amine (R-6-OA), its molecular structure is as follows:
  • the concentration range of 6-dehydroabietylamide-N,N-dimethyl-hexylamine oxide in the gel emulsion is 0.22%-80% of the mass of the continuous phase, and the volume fraction of the dispersed phase In 1%-98%.
  • the O/W gel emulsion system is composed of an aqueous phase, an oil phase, and a rosin-based amine oxide surfactant.
  • the preparation of the O/W-type gel emulsion can be formed by a homogenizer or by hand shaking; specifically, it can be oxidation of 6-dehydroabietylamide-N,N-dimethyl-hexyl
  • the amine is dissolved in water, then added to the oil phase, and prepared by the homogenization method or the hand shaking method.
  • the oil phase may be an aliphatic hydrocarbon mineral oil, triglyceride, or edible oil; specifically, the preparation method of the O/W-type gel emulsion is to combine 6-dehydroabietylamide-N, After dissolving N-dimethyl-hexylamine oxide in water and heating it to completely dissolve, add the corresponding proportion of oil phase. After homogenization, the oil and water phases are fully mixed to form an emulsion. After cooling, a gel emulsion is obtained.
  • the ninth object of the present invention is to provide the application of the gel emulsion.
  • the application includes use in the fields of food, cosmetics, materials, drug delivery, and the like.
  • the application in the food field can imitate the texture characteristics of saturated fatty acids and design low-fat foods; as a delivery system for functional factors, embedding probiotics, flavor substances, and the like.
  • the gel emulsion can be used as a fat substitute, which can effectively reduce the content of saturated fatty acids and increase the content of polyunsaturated fatty acids, essential amino acids, minerals, etc.
  • 6-dehydroabietylamide-N,N-dimethyl-hexylamine oxide as the continuous phase and sunflower oil as the dispersed phase to prepare the gel emulsion, it can be used as a substitute for lard and reduce fresh meat Saturated fatty acid content in products.
  • the application in the cosmetics field specifically includes: adding moisturizing ingredients to the gel emulsion to prepare a smearable mask to improve the water-locking function without greasy feeling; adding active substances to the internal phase through The release of the two-phase interface delays the release rate of the active ingredient, prolongs the action time of the active ingredient, and achieves the effects of controlled release and delayed release.
  • the application in the field of materials is for the synthesis of porous materials.
  • the application in the field of drug delivery specifically includes: embedding drug molecules in a gel emulsion system to improve the stability of drug molecules while achieving the goal of slow release of drug molecules.
  • the tenth object of the present invention is to provide a method for transporting oil products.
  • the method is: adding 6-dehydroabietylamino-N,N-dimethyl-hexylamine oxide to the oil as a stabilizer to obtain a solid state Or semi-solid oil products for easy transportation.
  • the oil transportation method further includes external stimulation to break the milk after transportation.
  • the external stimulus includes adding an external stimulus responder, such as methanol, ethanol and other alcoholic substances, to destroy the gel of 6-dehydroabietyl-N,N-dimethyl-hexylamine oxide in the continuous phase
  • an external stimulus responder such as methanol, ethanol and other alcoholic substances
  • the addition of alcohol reduces the stability of the adsorption film formed by the 6-dehydroabietylamide-N,N-dimethyl-hexylamine oxide molecule at the oil-water interface, thereby demulsifying the emulsion.
  • the external stimulus may also be heating, such as heating to above 40°C.
  • the gel state of the continuous phase is first destroyed to make the gel emulsion into a fluid emulsion. Continued heating will intensify the Brownian motion of the liquid beads, causing the flocculation and coalescence of the liquid beads, thereby breaking the gel emulsion.
  • the eleventh object of the present invention is to provide a method for synthesizing a porous material.
  • the method is: after adding a crosslinking agent and an initiator to an aqueous phase, the 6-dehydroabietylamide-N , N-dimethyl-hexylamine oxide emulsion, add a reducing agent to the prepared emulsion. After stirring well, transfer the emulsion to the mold to cool down to form a gel emulsion and then solidify. Wash the cured monolith off the gel emulsion and vacuum dry.
  • 6-dehydroabietylamino-N,N-dimethyl-hexylamine oxide stabilized gel emulsion can be arbitrarily adjusted in volume ratio of oil to water
  • the porous material prepared by using hexylamine oxide stabilized gel emulsion as a template can arbitrarily adjust the pore size.
  • a twelfth object of the present invention is to provide a functional factor delivery system, which includes preparing an O/W gel emulsion using 6-dehydroabietylamide-N,N-dimethyl-hexylamine oxide, the functional factor Embed in gel emulsion.
  • the functional factors include but are not limited to: probiotics, flavor substances, nutrients, drugs, and the like.
  • the rosin derivative dehydroabietic acid can be obtained through simple synthetic steps to obtain the rosin-based small molecule 6-dehydroabietic acid-N,N-dimethyl-hexylamine oxide meeting the requirements of "green chemistry".
  • 6-Dehydroabietylamide-N,N-dimethyl-hexylamine oxide can form a left-handed spiral fiber structure with a cross-sectional diameter of about 10nm through molecular self-assembly. It can gel water at room temperature and its critical gel The concentration is only 0.176%.
  • each gelling agent molecule can fix 13,889 water molecules, which has extremely high gelation efficiency.
  • This small molecule hydrogel is derived from the natural product rosin and has mild and non-toxic properties. It has important applications in the fields of drug sustained release, tissue engineering, cell culture, sewage treatment, and daily chemicals.
  • the 6-dehydroabietylamide-N,N-dimethyl-hexylamine oxide of the present invention can be used to prepare O/W gel emulsion products, and has the advantages of simple process, good emulsion stability, environmental friendliness and economy, etc. .
  • the amount of surfactant 6-dehydroabietyl amine oxide required for this type of O/W gel emulsion is much lower than that of traditional surfactants , The minimum is only 0.22% of the quality of the continuous phase.
  • the volume fraction of the dispersed phase can be adjusted arbitrarily between 1%-98% (v/v), breaking the conclusion that the volume ratio of the continuous phase in the traditional gel emulsion must be greater than 74%, greatly expanding the types and types of gel emulsions. Range of application.
  • Using the rosin-based surfactant 6-dehydroabietylamide-N,N-dimethyl-hexylamine oxide in the present invention as a stabilizer most of the oil can form a stable gel emulsion. It can be seen that the present invention has broad application prospects and important application value.
  • Figure 1 shows the molecular structure of 6-dehydroabietylamino-N,N-dimethyl-hexylamine oxide.
  • Figure 2 shows the molecular structure of 2-dehydroabietylamino-N,N-dimethyl-ethylamine oxide.
  • Figure 3 shows the molecular structure of 3-dehydroabietyl-N,N-dimethyl-propylamine oxide.
  • Fig. 4 is a hydrogen nuclear magnetic resonance spectrum of 6-dehydroabietylamino-N,N-dimethyl-hexylamine oxide.
  • Figure 5 is a photo of the appearance of a gel formed by 6-dehydroabietylamino-N,N-dimethyl-hexylamine oxide (concentrations from left to right are 4 mmol ⁇ L -1 , 10 mmol ⁇ L -1 , 15 mmol ⁇ L -1 , 20 mmol ⁇ L -1 , 25 mmol ⁇ L -1 ).
  • Fig. 6 is a dynamic shear diagram of a gel formed by 6 mmol of dehydroabietylamino-N,N-dimethyl-hexylamine oxide at 5 mmol ⁇ L -1 (G is the storage modulus, solid symbol; G′′ is Loss modulus, open symbol).
  • Figure 7 is a 5 mmol ⁇ L -1 2-dehydroabietylamino-N,N-dimethyl-ethylamine oxide aqueous solution (solid symbol) and 3-dehydroabietylamino-N,N-dimethyl -Steady-state shear diagram of aqueous propylamine oxide solution (open symbol).
  • Fig. 8 is an in-situ cryo-transmission electron micrograph of a 5 mmol ⁇ L -1 6-dehydroabietylamino-N,N-dimethyl-hexylamine oxide gel.
  • Fig. 9 is a circular dichroism spectrum of 6mmol - L -1 6-dehydroabietylamino-N,N-dimethyl-hexylamine oxide gel.
  • Fig. 10 is the release curve of R-6-OA embedded rhodamine B at 20 mmol ⁇ L -1 at 37°C.
  • FIG. 11 is a laser confocal micrograph of the cultured L929 cells.
  • Fig. 12 is a graph showing the relationship between the surface tension ⁇ of 6-dehydroabietylamino-N,N-dimethyl-hexylamine oxide and the concentration C.
  • Figure 13 is a photograph of the appearance of dodecane/hydrogel emulsion at different oil-water ratios stabilized by 20 mmol ⁇ L -1 6-dehydroabietic acid amine oxide (from left to right, the volume ratio of dodecane/water is 9:1) 8:2, 7:3, 6:4, 5:5, 4:6, 3:7, 2:8, 1:9).
  • Compound 1 was reacted with N,N-dimethylethylenediamine and N,N-dimethylpropanediamine respectively, and then subjected to H 2 O 2 oxidation and column chromatography to obtain two kinds of contrasts 2-de Hydroabietylamide-N,N-dimethyl-ethylamine oxide and 3-dehydroabieticamide-N,N-dimethyl-propylamine oxide are white powdery solids after drying.
  • Photograph of the appearance of the gel formed from 6-dehydroabietylamino-N,N-dimethyl-hexylamine oxide in Figure 5 (from left to right concentrations are 4 mmol ⁇ L -1 , 10 mmol ⁇ L -1 , 15 mmol ⁇ L -1 ,20 mmol ⁇ L -1 ,25 mmol ⁇ L -1 ) It can be seen that when the concentration of 6-dehydroabietyl-N,N-dimethyl-hexylamine oxide is greater than 4 mmol ⁇ L -1 It can support its own gravity, has the characteristics of not flowing upside down, and the formed gel has good viscoelasticity.
  • Example 8 Viscoelasticity measurement of hydrogel formed by 6-dehydroabietylamino-N,N-dimethyl-hexylamine oxide
  • the gel of 6-dehydroabietylamino-N,N-dimethyl-hexylamine oxide with a concentration of 5 mmol ⁇ L -1 was first heated to 45°C and then cooled to 25°C, waiting for the test sample to completely gel The rheological properties were tested at 25°C. Before dynamic scanning, stress scanning is performed to determine the linear viscoelastic area of the test sample. The samples are all tested in the linear viscoelastic area.
  • Example 9 Comparison of viscosity of aqueous solutions of 2-dehydroabietylamino-N,N-dimethyl-ethylamine oxide and 3-dehydroabietylamino-N,N-dimethyl-propylamine oxide Elasticity measurement
  • Example 10 6-Dehydroabietylamino-N,N-dimethyl-hexylamine oxide to construct a gel system microscopic morphology measurement
  • Cryoplunge TM3 a low-temperature sample preparation device with a controlled environment, was used for sample preparation, and the ambient temperature was controlled at 25°C. Adjust the relative humidity in the device cavity to greater than 90%, use a pipette to transfer about 5 ⁇ L of sample to the surface of the microgrid, and tap the sample through the filter paper on both sides of Cp3 to absorb the droplets on the surface of the microgrid to obtain extremely thin A layer of liquid film. The sample was then quickly inserted into liquid nitrogen-cooled liquid ethane. The frozen sample was transferred to a liquid nitrogen-cooled sample rod and transferred to a transmission electron microscope for observation. The operating voltage was 120 kV.
  • the morphology is a relatively rigid nanofiber with a cross-sectional diameter of about 10 nm and a length of more than 2 ⁇ m.
  • 6-Dehydroabietylamide-N,N-dimethyl-hexylamine oxide hydrogel also showed extremely strong stability. The reason is that 6-dehydroabietylamino-N,N-dimethyl-hexylamine oxide molecules form a left-handed spiral fiber structure with a diameter of about 10 nm through molecular self-assembly. The fibers are intertwined to form a three-dimensional network structure, and then the water molecules are fixed by capillary action and surface tension, and then a stable hydrogel is formed.
  • Example 11 Measurement of the circular dichroism spectrum of 6 mmol ⁇ L -1 6-dehydroabietylamino-N,N-dimethyl-hexylamine oxide formed gel
  • the measurement was carried out on a circular dichroism spectrometer model MOS-450. In the wavelength range of 300-180nm every 0.1nm interval recording. Gel samples were measured with a 0.1 mm quartz sample cell. It can be seen from the circular dichroism spectrum of the 5mmol ⁇ L -1 6-dehydroabietylamino-N,N-dimethyl-hexylamine oxide gel in Figure 9 that the gel sample showed a strong
  • the CD signal shows a positive absorption peak in the wavelength range of 190-212nm and a negative absorption peak in the wavelength range of 212-300nm, which shows that the nanofibers formed in the system are a left-handed spiral chiral aggregation structure.
  • Rhodamine B was embedded in a hydrogel formed by 20 mmol ⁇ L -1 of 6-dehydroabietylamino-N,N-dimethyl-hexylamine oxide, and was subjected to in vitro in a 37°C constant temperature shaking water bath Release experiment. The absorbance of the release solution was measured with an ultraviolet-visible spectrophotometer to obtain an in vitro release curve. It can be seen from FIG. 10 that the release rate of rhodamine B within 5 hours is only 28%, and the release rate of rhodamine B after 40 hours is 76%, and thereafter shows a slower release. It can be seen that the hydrogel formed by 6-dehydroabietylamino-N,N-dimethyl-hexylamine oxide has a good sustained-release ability, and can be used in the field of sustained-release medicine.
  • Example 13 Hydrogel formed by 6-dehydroabietylamino-N,N-dimethyl-hexylamine oxide for cell culture
  • L929 cells were encapsulated in 6-dehydroabietylamide-N,N-dimethyl-hexylamine oxide gel for 3D cell culture.
  • the cell suspension was added in the state of sol to form a cell/hydrogel system within 30 seconds, and further incubated at 37°C for 15 minutes.
  • 2mL of RPMI-1640 medium containing 10% FBS fetal bovine serum and 1% penicillin/streptomycin was gently added to the petri dish, and the cell/hydrogel system was incubated at 37°C in a humidified atmosphere of 5% CO 2 Medium cultivation.
  • the culture medium was changed after 1 hour of cultivation, and then every 12 hours.
  • a certain amount of 6-dehydroabietic acid amine oxide was added to a 22mm (d) ⁇ 52mm (h) glass bottle, the total volume of the glass bottle was 10mL. After adding a certain amount of deionized water, it was heated in a 50°C water bath until the 6-dehydroabietylamide amine oxide was completely dissolved to obtain a transparent solution.
  • the appearance photos of dodecane/hydrogel emulsion with different oil-water ratios stabilized by 6mmol of 6-dehydroabietylaminoamine oxide at 20mmol ⁇ L -1 can be seen that the volume fraction of the oil phase is between 10% and 90% Within the range, stable gel emulsion can be formed, and there is no precipitation of water phase.
  • the dynamic rheological behavior of the system was measured by a rheometer (Discovery DHR-2, TA).
  • the cone angle (ETC) used in the test is 2°
  • the diameter is 40 mm
  • the distance between the cone and the platform is 48 ⁇ m
  • the measurement temperature is 25°C.
  • the microstructure of the gel emulsion was observed with the German Leica TCS SP8 laser confocal microscope. A certain amount of 6-dehydroabietic acid amine oxide aqueous solution was added with 1 ⁇ 10 -3 mol ⁇ L -1 of rhodamine B as an indicator to prepare a gel emulsion.
  • external stimulation can be used to break the milk when needed.
  • the external stimulus may be the addition of external stimuli responders, such as methanol, ethanol and other alcohols, to destroy the gel structure of 6-dehydroabietylamino-N,N-dimethyl-hexylamine oxide in the continuous phase.
  • external stimuli responders such as methanol, ethanol and other alcohols
  • the addition of alcohol reduces the polarity of the stable water of the adsorption film formed by the 6-dehydroabietylamide-N,N-dimethyl-hexylamine oxide molecule at the oil-water interface, thereby demulsifying the emulsion.
  • the external stimulus may also be an increase in temperature.
  • the external stimulus may also be an increase in temperature.
  • the gel emulsion is heated above 40°C, the gel structure of the continuous phase is destroyed, and the gel emulsion becomes a general emulsion. Heating can also cause the Brownian motion of the liquid beads Intensified, causing flocculation and coalescence of the liquid beads, thereby breaking the gel emulsion.
  • the surface hydrophilic porous material prepared with O/W gel emulsion as a template has good biocompatibility and has potential application value in tissue engineering scaffolds.
  • the reducing agent N,N,N,N-tetramethylethylenediamine was added to the emulsion.
  • the emulsion was transferred to a mold (polyethylene container) and cooled to form a gel emulsion, and cured at room temperature for 1 hour.
  • the obtained solid was immersed in propanol for 24 hours and vacuum dried at 60°C to obtain a polymer porous material. .
  • 6-dehydroabietylamino-N,N-dimethyl-hexylamine oxide stabilized gel emulsion can be arbitrarily adjusted in volume ratio of oil to water, 6-dehydroabieticamide-N,N-dimethyl-
  • the porous material prepared by using hexylamine oxide stabilized gel emulsion as a template can adjust the pore size at will.
  • 6-dehydroabietylamide amine oxide solution add different volumes of oil (6-dehydroabieticamide amine oxide solution to oil volume ratio is 0.2:9.8, 3:7, 5:5,7 : 3, 9.9:0.1, the total volume is 4mL), and then use an ultraturrax homogenizer (IKA T18 basic, S18N-10G head) to emulsify the mixture for 2 minutes at a rate of 11000r/min.
  • the emulsion forms a white gel emulsion after standing and cooling at a low temperature.
  • the stabilizer 6-dehydroabietylamide-N,N-dimethyl-hexylamine oxide has a concentration of 0.22% of the mass of the continuous phase, and a volume fraction of the dispersed phase within the range of 1%-98% to form a gel emulsion, which is placed After one year, the gel emulsion still has no demulsification and has a very high stability. The higher the stabilizer content, the more stable the gel emulsion formed.
  • the concentration of the stabilizer 6-dehydroabietylamino-N,N-dimethyl-hexylamine oxide is 0.22%-80% of the mass of the continuous phase, and the volume fraction of the dispersed phase is formed in the range of 1%-98%
  • the gel emulsion has high stability.

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Abstract

一种松香基小分子水凝胶剂及其应用，属于超分子化学、表面活性剂科学和松脂化学利用领域。松香基小分子水凝胶剂可以在极低的浓度下使水胶凝，其临界胶凝浓度仅为0.176wt％，平均每个凝胶剂分子能够固定住13889个水分子，表现出极高的胶凝能力，形成的小分子水凝胶还表现出极强的稳定性。这种小分子水凝胶剂是由天然产物松香衍生得到，性质温和，可应用在药物缓释、组织工程、日用化学品和医药等领域。同时松香基小分子水凝胶剂6-脱氢枞酰胺基氧化胺可使大部分的油形成稳定的凝胶乳液，可应用于食品、药品、日化用品、组织工程、环境保护、水污染治理等多个领域中。

Description

一种松香基小分子水凝胶剂及其应用 技术领域
本发明涉及一种松香基小分子水凝胶剂及其应用，属于超分子化学、表面活性剂科学和松脂化学利用领域。
背景技术
分子自组装在自然界中普遍存在，在生命的起源及演化过程中起着重要的作用。水凝胶是胶体粒子在一定条件下形成的空间网络结构包裹大量水而构成。作为一类重要的软物质材料，水凝胶广泛存在于自然界和人们的日常生活中，在药物缓释、组织工程和生物模拟等领域有重要应用。随着超分子化学的发展，由小分子通过分子间作用力(疏水作用、离子相互作用、氢键、主客体作用或π-π作用等)形成的超分子水凝胶引起了人们的广泛关注。构筑超分子水凝胶的核心是小分子水凝胶剂的结构。由于分子自组装是一个极其复杂的过程，目前尚不能通过有目的地设计分子结构来获得特定功能的超分子水凝胶，因此超分子水凝胶体系的构建是巨大的挑战。而从现有的超分子水凝胶体系来看，其中分子间通过恰当的排列而产生的疏水基团之间的弱相互作用是分子自组装形成水凝胶的重要驱动力。
超分子水凝胶在生命科学领域有广泛用途，因此以天然产物为主要原料进行小分子水凝胶剂的设计合成有助于构筑满足需要的环境友好型及生物相容型超分子水凝胶体系。松香是一种产量丰富的可再生林产资源。以松香为原料的产品或深加工产品已广泛应用于橡胶、油墨、涂料、农药、医药、食品、电子等工业和生活的各个领域中。尽管如此，到目前为止，尚无一例关于松香基超分子水凝胶体系的报道。若能获得松香基超分子水凝胶体系，将可大大拓展天然产物松香的应用范围，以及超分子水凝胶的研究范围。
此外，凝胶乳液是指在某种稳定剂存在下由分散相(内相)和连续相(外相)构成的外观呈胶冻状的乳状液体系。由于其特殊的结构及性质，凝胶乳液被广泛应用于食品、化妆品、材料、药物传输等领域。稳定剂的种类和浓度对凝胶乳液的稳定性有着重要影响。表面活性剂是最常用的稳定剂。在油水体系中，表面活性剂分子在油水界面定向排列，降低了界面能，促进了凝胶乳液的形成。然而，为了达到凝胶的效果，在凝胶乳液的制备过程中，表面活性剂的用量极大，通常要达到连续相的5-30％。同时只有在分散相体积分数大于74％以后才可以形成。这些因素严重制约着凝胶乳液的实际应用。
小分子水凝胶剂通过分子间的弱相互作用如氢键、π-π堆积、范德华力、静电、以及主客体作用等自组装形成纤维网络结构，可以使溶剂失去流动性。若将小分子胶凝剂作为一类新 型稳定剂，形成的凝胶乳液体系将不同于传统凝胶乳液体系。基于小分子凝胶剂为稳定剂的凝胶乳液，其连续相表现为凝胶态，分散相物理包裹于凝胶网络中，该类凝胶乳液体系不受连续相必须大于74％的界限，可以极大地拓宽分散相在乳液中的体积分数的范围。然而，并不是所有的小分子水凝胶剂均可以稳定凝胶乳液。小分子水凝胶剂形成的聚集结构要能够抵抗有机油相的侵蚀，并同时具有降低界面张力的效果。因此，如何设计合成符合要求的新型小分子水凝胶剂，来制备新型的凝胶乳液体系，是目前胶体化学领域关注的重点与难点。
发明内容
为了解决上述问题，本发明将松香酸引入小分子水凝胶剂结构中，获得了生物相容性好、降解性好并符合绿色化学要求的松香基超分子水凝胶体系，大大拓展了天然产物松香的应用范围，以及超分子水凝胶的研究范围。由于松香酸的主体部分为三环二萜型的刚性疏水基团，具有稳定空间构型，将其引入小分子水凝胶剂的分子结构中，获得了具有极高凝胶效率的水凝胶体系。
本发明以歧化松香中的主要成分脱氢枞酸为原料，经过系列反应，获得一种满足绿色化学要求的小分子水凝胶剂6-脱氢枞酰胺基-N,N-二甲基-己基氧化胺(R-6-OA)。进一步地，本发明以这种分子为构筑基元，来制备超分子水凝胶体系，为松香在超分子水凝胶的应用研究奠定基础。
此外，利用本发明的6-脱氢枞酰胺基-N,N-二甲基-己基氧化胺，可作为稳定剂制备一类O/W型凝胶乳液。6-脱氢枞酰胺基-N,N-二甲基-己基氧化胺在降低油水界面张力的同时，在连续相中形成的三维网络结构阻止了液滴的聚集。在这类凝胶乳液中，分散相体积分数的范围极宽，可在1％-98％(v/v)之间任意调节，打破了传统凝胶乳液分散相体积必须大于74％的定论。同时，可以使大部分的油相均形成稳定的凝胶乳液，极大拓宽了凝胶乳液的应用范围。
本发明的第一个目的是提供一种化合物，其结构式为式(1)：
Figure PCTCN2019077616-appb-000001
本发明的第二个目的是提供所述化合物的制备方法，包括：以歧化松香中的主要成分脱氢枞酸为原料，合成6-脱氢枞酰胺基-N,N-二甲基-己基氧化胺。
在一种实施方式中，所述化合物(6-脱氢枞酰胺基-N,N-二甲基-己基氧化胺)的合成路线如下：
Figure PCTCN2019077616-appb-000002
在一种实施方式中，所述化合物的合成步骤，包括：
(1)使脱氢枞酸和氯化亚砜在4-二甲氨基吡啶的催化下发生反应；得到脱氢枞酰氯粗产品；
(2)脱氢枞酰氯与1，6-己二胺反应；
(3)上一步反应得到的产物经溶解后再与滴加的甲酸和甲醛反应；
(4)上一步反应得到的化合物在催化剂柠檬酸、乙二胺四乙酸二钠的催化下，与H 2O 2反应得到6-脱氢枞酰胺基-N,N-二甲基-己基氧化胺。
在一种实施方式中，所述化合物具体的合成步骤如下：
化合物1的合成：将脱氢枞酸固体加入到带有回流冷凝管的三口瓶中，再加入催化量的4-二甲氨基吡啶，反应过程中的尾气用碱液吸收。当温度升到50℃时，缓慢滴加氯化亚砜，有大量气体生成。氯化亚砜滴加结束后，在72℃下反应3h。反应结束后，将冷却的反应产物通过减压蒸馏除去过量氯化亚砜，得化合物1粗产品。
化合物2的合成：在三口烧瓶中加入一定量的1，6-己二胺和二氯甲烷。充分搅拌下，当温度降到-20℃时，缓慢滴加化合物1的二氯甲烷溶液，滴加完成后继续反应3h。反应结束后，向混合物中加入水，用二氯甲烷萃取，有机层用水洗5-6次，然后将有机层用无水硫酸钠干燥，通过减压蒸馏除去提取物中剩余的溶剂。得到含化合物2的黄色粘稠液体。
化合物3的合成：将含化合物2的混合物溶于乙醇中，室温下依次缓慢滴加甲酸、甲醛溶液。滴加完成后于80℃反应8h。反应完成后，用15％的NaOH溶液调节产物pH＝11，用乙醚萃取，萃取液用无水硫酸钠干燥，减压下除去溶剂后，得到含化合物3的黄色粘稠液体。
化合物4的合成：将化合物3溶于乙醇中，再加入催化量的柠檬酸、乙二胺四乙酸二钠。当温度升到55℃时，缓慢滴加30％H 2O 2。滴加完成后于80℃反应5h。反应完成后，通过减压蒸馏除去乙醇。用硅胶柱层析纯化产物(洗脱剂为乙酸乙酯:甲醇＝4:1)，得到化合物4，经真空干燥后为白色粉末状固体。
本发明的第三个目的是提供一种超分子水凝胶，包括利用本发明的6-脱氢枞酰胺基-N,N-二甲基-己基氧化胺作为凝胶因子。
在一种实施方式中，所述超分子水凝胶，是6-脱氢枞酰胺基-N,N-二甲基-己基氧化胺与水接触后形成的。
在一种实施方式中，所述超分子水凝胶，是在温度低于40℃下形成的。
在一种实施方式中，所述超分子水凝胶中6-脱氢枞酰胺基-N,N-二甲基-己基氧化胺的浓度范围为3mmol·L -1-1000mmol·L -1。
本发明的第三个目的是提供一种缓释材料，包含本发明的6-脱氢枞酰胺基-N,N-二甲基-己基氧化胺及需要缓释的物质。
在一种实施方式中，所述需要缓释的物质为功能因子，包括：药物、营养因子等。
在一种实施方式中，所述缓释材料，是将需要缓释的物质分散在水中，然后利用6-脱氢枞酰胺基-N,N-二甲基-己基氧化胺作为凝胶骨架形成水凝胶。
本发明的第四个目的是提供一种医药伤口敷料，以本发明的6-脱氢枞酰胺基-N,N-二甲基-己基氧化胺作为凝胶骨架形成水凝胶，水凝胶中含有抗炎或者抗菌成分。
本发明的第五个目的是提供一种水土保湿剂，包括利用本发明的6-脱氢枞酰胺基-N,N-二甲基-己基氧化胺。水土保湿剂能够吸收大量的水并缓慢地释放出来，具有保湿抗旱的效果。
本发明的第六个目的是提供一种水凝胶面膜，以本发明的6-脱氢枞酰胺基-N,N-二甲基-己基氧化胺作为主要凝胶骨架形成水凝胶。可选地，面膜内还注入胶原蛋白、透明质酸、熊果苷、烟酰胺等物质中的一种或者多种。
本发明的第七个目的是提供一种细胞培养的方法，包括利用本发明的6-脱氢枞酰胺基-N,N-二甲基-己基氧化胺作为凝胶骨架形成水凝胶，为细胞的生长提供三维的环境。
本发明还提供所述6-脱氢枞酰胺基-N,N-二甲基-己基氧化胺在药物缓释、组织工程、细胞培养、污水处理和日用化学品等领域的应用。
本发明的第八个目的是提供一种O/W型凝胶乳液，所述O/W型凝胶乳液的稳定剂包括6-脱氢枞酰胺基-N,N-二甲基-己基氧化胺(R-6-OA)，其分子结构如下：
Figure PCTCN2019077616-appb-000003
在一种实施方式中，所述凝胶乳液中6-脱氢枞酰胺基-N,N-二甲基-己基氧化胺的浓度范围为连续相质量的0.22％-80％，分散相体积分数在1％-98％。可选地，所述O/W型凝胶乳液 体系由水相、油相、松香基氧化胺表面活性剂所组成。可选地，所述O/W型凝胶乳液的制备通过均质机或手摇均可以形成；具体地，可以是将6-脱氢枞酰胺基-N,N-二甲基-己基氧化胺溶于水中，然后加入油相，经均质法或手摇法制备得到。可选地，所述油相可以是脂肪烃类矿物油、三甘油酯或食用油；具体地，所述O/W型凝胶乳液的制备方法是将6-脱氢枞酰胺基-N,N-二甲基-己基氧化胺溶于水中，加热使其完全溶解后，加入相应比例的油相，均质后使油水两相充分混合形成乳液，降温后即获得凝胶乳液。
本发明的第九个目的是提供所述凝胶乳液的应用。可选地，所述应用包括用于食品、化妆品、材料、药物传输等领域。
可选地，所述食品领域的应用，可以仿制饱和脂肪酸的质构特性，设计低脂食品；作为功能因子的递送体系，包埋益生菌、风味物质等。凝胶乳液可作为脂肪替代物，能够有效的降低饱和脂肪酸的含量，提高多不饱和脂肪酸、人体必需氨基酸、矿物质等含量。以6-脱氢枞酰胺基-N,N-二甲基-己基氧化胺形成的凝胶为连续相、葵花籽油作为分散相制备凝胶乳液，可作为猪脂的替代物，降低新鲜肉制品中的饱和脂肪酸含量。
可选地，所述化妆品领域的应用，具体包括：凝胶乳液中加入保湿成分，制备可涂抹式面膜，提高锁水功能的同时不会有油腻的感觉；在内相中添加活性物，通过两相界面释放，延缓有效成分的释放速度，延长有效成分的作用时间，达到控制释放和延时释放的作用。
可选地，所述材料领域的应用，是用于多孔材料的合成。
可选地，所述药物传输领域的应用，具体包括：将药物分子包埋在凝胶乳液体系中，提高药物分子稳定性的同时，达到对药物分子缓慢释放的目的。
本发明的第十个目的是提供一种油品运输方法，所述方法是：在油中加入6-脱氢枞酰胺基-N,N-二甲基-己基氧化胺作为稳定剂，得到固态或半固态油品以便于运输。
可选地，所述油品运输方法，还包括在运输后进行外界刺激以破乳。可选地，所述外界刺激包括加入外界刺激响应物，比如甲醇、乙醇等醇类物质，破坏连续相中6-脱氢枞酰胺基-N,N-二甲基-己基氧化胺的凝胶结构，同时醇类的加入降低了6-脱氢枞酰胺基-N,N-二甲基-己基氧化胺分子在油水界面形成的吸附膜的稳定性，从而使乳液破乳。可选地，所述外界刺激还可以是加热，比如加热至40℃以上。加热后首先破坏连续相的凝胶态，使凝胶乳液成为具有流动性的乳液，继续加热使得液珠的布朗运动加剧，引起液珠的絮凝和聚结，从而使凝胶乳液破乳。
本发明的第十一个目的是提供一种多孔材料合成方法，所述方法是：在水相中加入交联剂、引发剂后在热的状态下制备含6-脱氢枞酰胺基-N,N-二甲基-己基氧化胺的乳液，在已制备好的乳液中加入还原剂。搅拌均匀后，将乳液转移到模具中降温形成凝胶乳液后固化。将 固化好的整料洗去凝胶乳液后真空干燥。由于6-脱氢枞酰胺基-N,N-二甲基-己基氧化胺稳定的凝胶乳液油水体积比可以任意调控，因此以6-脱氢枞酰胺基-N,N-二甲基-己基氧化胺稳定的凝胶乳液为模板制备的多孔材料可以任意调节孔径的大小。
本发明的第十二个目的提供一种功能因子传递系统，包括利用6-脱氢枞酰胺基-N,N-二甲基-己基氧化胺制备O/W型凝胶乳液，所述功能因子包埋在凝胶乳液中。可选地，所述功能因子包括但不限于：益生菌、风味物质、营养物质、药物等。
本发明的有益效果
将松香衍生物脱氢枞酸通过简单的合成步骤就可得到满足“绿色化学”要求的松香基小分子6-脱氢枞酰胺基-N,N-二甲基-己基氧化胺。6-脱氢枞酰胺基-N,N-二甲基-己基氧化胺通过分子自组装可以形成截面直径约为10nm的左手螺旋纤维结构，在常温下即可使水胶凝，其临界胶凝浓度仅为0.176％，平均每个凝胶剂分子能够固定住13889个水分子，具有极高的凝胶效率。这种小分子水凝胶剂来源于天然产物松香，性能温和无毒，在药物缓释、组织工程、细胞培养、污水处理和日用化学品等领域有着重要应用。
本发明6-脱氢枞酰胺基-N,N-二甲基-己基氧化胺，可用于制备O/W型凝胶乳液产品，具有工艺简单、乳液稳定性良好、环境友好和经济性等优点。相比于传统的表面活性剂稳定的凝胶乳液体系，该类O/W型凝胶乳液所需的表面活性剂6-脱氢枞酰胺基氧化胺的用量远低于传统表面活性剂的用量，最低仅为连续相质量的0.22％。同时分散相的体积分数可在1％-98％(v/v)之间任意调节，打破了传统凝胶乳液中连续相体积比必须大于74％的定论，大大扩展了凝胶乳液的类型和应用范围。利用本发明中的松香基表面活性剂6-脱氢枞酰胺基-N,N-二甲基-己基氧化胺作为稳定剂，大部分的油均可以形成稳定的凝胶乳液。可见本发明具有广泛的应用前景和重要的应用价值。
附图说明
图1为6-脱氢枞酰胺基-N,N-二甲基-己基氧化胺的分子结构。
图2为2-脱氢枞酰胺基-N,N-二甲基-乙基氧化胺的分子结构。
图3为3-脱氢枞酰胺基-N,N-二甲基-丙基氧化胺的分子结构。
图4为6-脱氢枞酰胺基-N,N-二甲基-己基氧化胺的氢核磁共振谱图。
图5为6-脱氢枞酰胺基-N,N-二甲基-己基氧化胺形成凝胶的外观照片(浓度从左到右分别为4mmol·L -1、10mmol·L -1、15mmol·L -1、20mmol·L -1、25mmol·L -1)。
图6为5mmol·L -1的6-脱氢枞酰胺基-N,N-二甲基-己基氧化胺形成凝胶的动态剪切图(G为储能模量，实心符号；G″为损耗模量，空心符号)。
图7为5mmol·L -1的2-脱氢枞酰胺基-N,N-二甲基-乙基氧化胺水溶液(实心符号)和3- 脱氢枞酰胺基-N,N-二甲基-丙基氧化胺水溶液(空心符号)的稳态剪切图。
图8为5mmol·L -1的6-脱氢枞酰胺基-N,N-二甲基-己基氧化胺凝胶的原位冷冻透射电镜图。
图9为5mmol·L -1的6-脱氢枞酰胺基-N,N-二甲基-己基氧化胺凝胶的圆二色光谱图。
图10为37℃下20mmol·L -1的R-6-OA包埋罗丹明B的释放曲线。
图11为经培养后的L929细胞的激光共聚焦显微照片。
图12为6-脱氢枞酰胺基-N,N-二甲基-己基氧化胺的表面张力γ随浓度C的变化关系图。
图13为20mmol·L -16-脱氢枞酰胺基氧化胺稳定的不同油水比例下十二烷/水凝胶乳液外观照片(从左到右边十二烷/水体积比例为9:1、8:2、7:3、6:4、5:5、4:6、3:7、2:8、1:9)。
图14为20mmol·L -1的6-脱氢枞酰胺基氧化胺稳定的十二烷/水(V 水；V 油＝1：1)凝胶乳液的动态剪切图(G为储能模量，实心符号；G″为损耗模量，空心符号)。
图15为20mmol·L -1的6-脱氢枞酰胺基氧化胺稳定的十二烷/水(V 水；V 油＝8：2)凝胶乳液的激光共聚焦显微照片。
图16为20mmol·L -1的6-脱氢枞酰胺基氧化胺稳定的十二烷/水(V 水；V 油＝2：8)凝胶乳液的激光共聚焦显微照片。
具体实施方式
6-脱氢枞酰胺基-N,N-二甲基-己基氧化胺的合成路线如下：
Figure PCTCN2019077616-appb-000004
实施例1:化合物1的合成
将脱氢枞酸固体(30g，0.1mol)加入装有尾气吸收装置和回流冷凝管的三口瓶中，加入少量4-二甲氨基吡啶(DMAP)作为催化剂，在温度升到50℃时，开始缓慢滴加氯化亚砜(17.94g，0.15mol)。该过程有大量酸性气体生成，用尾气吸收装置吸收。滴加完毕后，设置温度为72℃，继续反应3h。反应结束后，减压旋蒸除去过量的氯化亚砜，制得化合物1粗品。
实施例2：化合物2的合成
在三口烧瓶中加入1，6-己二胺(58.1g，0.5mol)和二氯甲烷并充分搅拌。在温度为-20℃时， 缓慢滴加脱氢枞酰氯(0.1mol)的二氯甲烷溶液，滴加完成后继续反应3h。反应结束后，将产物转移至1000mL的烧杯中，向混合物中加入水，用二氯甲烷萃取，得到的有机层用水洗5-6次后，将有机层用无水硫酸钠干燥，减压下去除溶剂，得到的化合物2为黄色粘稠液体。
实施例3：化合物3的合成
将化合物2溶于乙醇中，室温下依次缓慢滴加88％甲酸(26.15g，0.5mol)、30％甲醛(50.03g，0.5mol)溶液。滴加完成后于80℃反应8h。反应完成后，用15％的NaOH溶液调节产物pH＝11，用乙醚萃取。有机层用无水硫酸钠干燥，在减压下去除溶剂，得到的化合物3为黄色粘稠液体。
实施例4：化合物4的合成
将化合物3溶于乙醇中，再加入少量柠檬酸、乙二胺四乙酸二钠。当温度升到55℃时，缓慢滴加30％H 2O 2(17g，0.15mol)，滴加完成后于80℃反应5h。反应完成后，通过减压蒸馏除去乙醇。用硅胶柱层析纯化产物(洗脱剂为乙酸乙酯:甲醇＝4:1)，得到化合物4。经真空干燥后为白色粉末状固体。
实施例5:2-脱氢枞酰胺基-N,N-二甲基-乙基氧化胺和3-脱氢枞酰胺基-N,N-二甲基-丙基氧化胺的合成
将化合物1分别与N,N-二甲基乙二胺和N,N-二甲基丙二胺反应，再经过H 2O 2氧化和柱层析分离后，得到两种对比物2-脱氢枞酰胺基-N,N-二甲基-乙基氧化胺和3-脱氢枞酰胺基-N,N-二甲基-丙基氧化胺，经干燥后均为白色粉末状固体。
实施例6：6-脱氢枞酰胺基-N,N-二甲基-己基氧化胺的结构和纯度测定
称取适量松香基小分子水凝胶剂6-脱氢枞酰胺基-N,N-二甲基-己基氧化胺放置在核磁管中，用氘代试剂DMSO溶解。用Aduance III核磁共振仪在25℃下进行 1H NMR测试。 1H的共振频率为400MHz。从图4中6-脱氢枞酰胺基-N,N-二甲基-己基氧化胺的氢核磁共振谱图可以看出，各氢的化学位移与目标产物6-脱氢枞酰胺基-N,N-二甲基-己基氧化胺相符，说明获得了终产品。同时，谱图上没有杂峰，说明产品达到很高的纯度。
1H NMR(400MHz,DMSO)δ7.61(t,1H,N20-1H),7.16(d,1H,C11-1H),7.03–6.92(d,1H C14-1H),6.84(s,1H,C12-1H),3.17–2.97(m,4H,C26-2H,C21-2H),2.95(s,6H,C27-3H,C28-3H),2.85–2.64(m,3H,C8-2H,C15-1H),2.26(d,1H,C4-1H),2.04(d,1H,C6-1H),1.77–1.57(m,6H,C25-2H,C22-2H,C2-1H,C7-1H),1.40(m,5H,C3-2H,C7-1H,C2-1H,C4-1H),1.26(m,4H,C23-2H,C24-2H),1.16(s,3H,C18-3H),1.14(d,9H,C16-3H,C17-3H,C19-3H)。
实施例7:凝胶性能测定
取1mL去离子水，向其中加入6-脱氢枞酰胺基-N,N-二甲基-己基氧化胺(浓度分别为4 mmol·L -1、10mmol·L -1、15mmol·L -1、20mmol·L -1、25mmol·L -1)，将溶液加热到40℃使6-脱氢枞酰胺基-N,N-二甲基-己基氧化胺完全溶解，然后在室温下静置，观察溶液状态。
从图5中6-脱氢枞酰胺基-N,N-二甲基-己基氧化胺形成凝胶的外观照片(从左到右浓度分别为4mmol·L -1、10mmol·L -1、15mmol·L -1、20mmol·L -1、25mmol·L -1)可以看出，当6-脱氢枞酰胺基-N,N-二甲基-己基氧化胺的浓度大于4mmol·L -1时便可支撑自身的重力，具有倒置不流动的特点，形成的凝胶具有较好的粘弹性。
4mmol·L -1的6-脱氢枞酰胺基-N,N-二甲基-己基氧化胺形成的水凝胶中，6-脱氢枞酰胺基-N,N-二甲基-己基氧化胺的临界胶凝浓度仅为0.176％。经换算，平均每个凝胶剂分子能够固定住13889个水分子，具有极高的凝胶效率。
实施例8：6-脱氢枞酰胺基-N,N-二甲基-己基氧化胺形成的水凝胶的粘弹性测量
将6-脱氢枞酰胺基-N,N-二甲基-己基氧化胺浓度为5mmol·L -1的凝胶先升温至45℃后再降温至25℃，等待测样品完全成凝胶后在25℃下进行流变性能的测试。动态扫描前，先进行应力扫描以确定测试样品的线性粘弹区，样品的测试均在线性粘弹区内进行。从图6中5mmol·L -1的6-脱氢枞酰胺基-N,N-二甲基-己基氧化胺形成凝胶的动态剪切图可以看出，在测试的频率范围内，6-脱氢枞酰胺基-N,N-二甲基-己基氧化胺形成凝胶的弹性模量始终大于粘性模量，说明该凝胶体系具有较好的弹性。在测试的频率范围0.01-100rad·s -1内，测得凝胶相应的弹性模量为10.8Pa-12.7Pa，粘性模量为0.5Pa-1.85Pa，可见该样品的弹性模量始终大于粘性模量，表现出明显的弹性性质。
实施例9：对比物2-脱氢枞酰胺基-N,N-二甲基-乙基氧化胺和3-脱氢枞酰胺基-N,N-二甲基-丙基氧化胺水溶液的粘弹性测量
从图7中5mmol·L -1两者的稳态剪切图可知，无论是在高剪切速率还是低剪切速率下，体系粘度不随剪切速率的变化而变化，为一常数，与水的粘度相当，且始终表现为牛顿流体。由此可见，2-脱氢枞酰胺基-N,N-二甲基-乙基氧化胺和3-脱氢枞酰胺基-N,N-二甲基-丙基氧化胺均不能形成凝胶。
实施例10：6-脱氢枞酰胺基-N,N-二甲基-己基氧化胺构筑凝胶体系的微观形貌测量
采用在环境可控的低温制样装置Cryoplunge TM3进行样品的制备，环境温度控制在25℃。将装置腔体内的相对湿度调到大于90％，用移液枪移取约5μL的样品到微栅表面上，通过Cp3两侧的滤纸拍打样品对微栅表面液滴进行吸收，以获取极薄的一层液膜。然后将样品快速插入到液氮冷却的液态乙烷中。将冷冻后的样品转移到液氮冷却的样品杆中，转移到透射电镜中进行观察，操作电压为120kV。从图8中5mmol·L -1的6-脱氢枞酰胺基-N,N-二甲基-己基氧化胺水凝胶样品的原位冷冻透射电镜照片可以看出，该水凝胶的微观形态是较为刚 性的纳米纤维，截面直径约为10nm，长度超过2μm。
6-脱氢枞酰胺基-N,N-二甲基-己基氧化胺水凝胶还表现出极强的稳定性。原因在于，6-脱氢枞酰胺基-N,N-二甲基-己基氧化胺分子通过分子自组装形成直径约为10nm的左手螺旋的纤维结构。纤维之间相互缠绕形成三维网络状结构，然后通过毛细作用和表面张力等作用固定住水分子，进而形成了稳定的水凝胶。
实施例11：5mmol·L -1的6-脱氢枞酰胺基-N,N-二甲基-己基氧化胺形成凝胶的圆二色光谱图的测量
在型号为MOS-450的圆二色光谱仪上进行测定。在300-180nm的波长范围内每间隔0.1nm进行一次记录。凝胶样品用0.1mm的石英样品池进行测定。从图9中5mmol·L -1的6-脱氢枞酰胺基-N,N-二甲基-己基氧化胺凝胶的圆二色光谱图可以看出，凝胶样品表现出了很强的CD信号，在190-212nm波长范围内表现出正的吸收峰，在212-300nm波长范围内表现出负的吸收峰，这说明体系中形成的纳米纤维是一种左手螺旋的手性聚集结构。
实施例12：凝胶缓释性能测试
将罗丹明B包埋到20mmol·L -1的6-脱氢枞酰胺基-N,N-二甲基-己基氧化胺形成的水凝胶中，在37℃的恒温振荡水浴箱中进行体外释放实验。利用紫外—可见分光光度计测量释放液吸光度，得到体外释放曲线。由图10可知，5小时内对罗丹明B的释放率仅为28％，40小时后对罗丹明B的释放率为76％，此后表现为更加缓慢的释放。由此可见，6-脱氢枞酰胺基-N,N-二甲基-己基氧化胺形成的水凝胶具有良好的缓释能力，可用于药物缓释等领域。
实施例13：6-脱氢枞酰胺基-N,N-二甲基-己基氧化胺形成的水凝胶用于细胞培养
在无菌条件下将L929细胞包封在6-脱氢枞酰胺基-N,N-二甲基-己基氧化胺凝胶中进行3D细胞培养。在溶胶的状态下加入细胞悬浮液，在30秒内形成细胞/水凝胶体系，并进一步在37℃下孵育15分钟。此后，将含有10％FBS胎牛血清和1％青霉素/链霉素的2mL RPMI-1640培养基温和地加入培养皿中，将细胞/水凝胶体系在37℃、5％CO 2的湿润气氛中培养。培养1小时后更换培养基，然后每12小时更换一次。培养24、48和96小时后，将细胞/水凝胶体系用FDA/PI染色，通过共聚焦激光扫描显微镜观察细胞。由图11可知，由于6-脱氢枞酰胺基-N,N-二甲基-己基氧化胺水凝胶优异的生物相容性，L929细胞在凝胶中具有较高的活力和增殖力。由此可见6-脱氢枞酰胺基-N,N-二甲基-己基氧化胺水凝胶可作为3D细胞培养支架，在细胞治疗和组织再生方面具有应用潜力。
实施例14:
表面张力的测定。配制一系列不同浓度的表面活性剂水溶液，于25℃下用吊环法测定其 表面张力，绘制样品水溶液的浓度和表面张力的关系曲线。
从图12中6-脱氢枞酰胺基-N,N-二甲基-己基氧化胺的表面张力γ随浓度C的变化关系图可知，表面活性剂6-脱氢枞酰胺基-N,N-二甲基-己基氧化胺的临界胶束浓度为0.56mmol·L -1，γ cmc为35mN·m -1。表明6-脱氢枞酰胺基-N,N-二甲基-己基氧化胺具有良好的表面活性，可以用来稳定乳液。
实施例15:
将一定量的6-脱氢枞酰胺基氧化胺加入到22mm(d)×52mm(h)的玻璃瓶中，玻璃瓶总体积为10mL。加入一定量去离子水后在50℃水浴中加热直至6-脱氢枞酰胺基氧化胺完全溶解，得到透明溶液。向6-脱氢枞酰胺基氧化胺溶液中加入不同体积的油(6-脱氢枞酰胺基氧化胺溶液与油的体积比为1:9，2:8，3:7，4:6，5:5，6:4，7：3，8:2，9:1，总体积是4mL)，然后使用ultraturrax均化器(IKA T18 basic，S18N-10G head)以11000r/min将混合物乳化2分钟。乳液在低温下静置冷却后形成白色的凝胶乳液。
图13中20mmol·L -1的6-脱氢枞酰胺基氧化胺稳定的不同油水比例下十二烷/水凝胶乳液外观照片可以看出，油相的体积分数在10％-90％的范围内，均能形成稳定的凝胶乳液，并且未有水相析出。
实施例16:
通过流变仪(Discovery DHR-2,TA)测定体系的动态流变行为。测试中采用的锥板(ETC)的锥角为2°，直径为40mm，锥板与平台的间距为48μm，测定温度为25℃。首先测定样品随应力变化(0.1～1000Pa)的弹性模量(G')及粘性模量值(G”)，保证每个样品的后续测试都位于线性粘弹区。然后将应力确定为0.8Pa，再对样品进行频率扫描(0.1～100rad/s)，记录G'和G”随频率变化的趋势。
从图14中20mmol·L -1的6-脱氢枞酰胺基氧化胺形成的凝胶和其稳定的十二烷/水(V 水；V 油＝1：1)凝胶乳液的储存模量G′和损耗模量G″剪切频率的变化曲线可以看出，在测试的频率0.01-100rad·s -1的范围内，测得相对应凝胶乳液的弹性模量为67Pa-14Pa，粘性模量为45Pa-3Pa，6-脱氢枞酰胺基氧化胺稳定的十二烷/水凝胶乳液的弹性模量始终大于粘性模量，凝胶乳液表现出弹性的性质。
实施例17:
凝胶乳液的微观结构采用德国徕卡公司TCS SP8激光共聚焦显微镜进行观察。在一定量的6-脱氢枞酰胺基氧化胺的水溶液中加入1×10 -3mol·L -1的罗丹明B为指示剂，制备凝胶乳液。图15中20mmol·L -1的6-脱氢枞酰胺基氧化胺稳定的十二烷/水(V 水；V 油＝8：2)凝胶 乳液的激光共聚焦照片可以看出，当分散相的体积分数小于74％时，凝胶乳液的液滴为规则的球形。而图16中20mmol·L -1的6-脱氢枞酰胺基氧化胺稳定的十二烷/水(V 水；V 油＝2：8)凝胶乳液的激光共聚焦照片可以看出，当分散相的体积分数大于74％时，液滴之间的高密度挤压使得使乳液失去流动性，乳液液滴为多面体形。当分散相体积分数小于74％时，6-脱氢枞酰胺基氧化胺在连续相中聚集形成了三维网络结构，阻止了液滴的聚并，从而形成了凝胶乳液。
实施例18：在油品运输方面的应用
在油中加入6-脱氢枞酰胺基-N,N-二甲基-己基氧化胺作为稳定剂，得到固态或半固态油品，减少油罐车储油容器溢油现象的发生，以便于运输。
运输后，需要使用时，可进行外界刺激以破乳。
所述外界刺激可以是加入外界刺激响应物，比如甲醇、乙醇等醇类物质，破坏连续相中6-脱氢枞酰胺基-N,N-二甲基-己基氧化胺的凝胶结构。同时醇类的加入降低了6-脱氢枞酰胺基-N,N-二甲基-己基氧化胺分子在油水界面形成的吸附膜的稳定性水的极性，从而使乳液破乳。
所述外界刺激还可以是升高温度，比如将凝胶乳液加热至40℃以上时，破坏了连续相的凝胶结构，使凝胶乳液成为一般的乳液，加热还可以使得液珠的布朗运动加剧，引起液珠的絮凝和聚结，从而使凝胶乳液破乳。
实施例19：在制备多孔材料方面的应用
以O/W型凝胶乳液为模板制备的表面亲水型多孔材料，具有较好的生物相容性，在组织工程支架方面有潜在的应用价值。
在去离子水中加入6-脱氢枞酰胺基-N,N-二甲基-己基氧化胺，加热使其完全溶解。将交联剂N，N′-亚甲基双丙烯酰胺、引发剂过硫酸铵和甲基丙烯酸2-羟乙酯溶解在上述6-脱氢枞酰胺基-N,N-二甲基-己基氧化胺溶液中，混合均匀后加入十二烷，然后使用ultraturrax均化器(IKA T18 basic，S18N-10G head)以11000r/min将混合物乳化2分钟，形成O/W乳液。然后在乳液中加入还原剂N,N,N,N-四甲基乙二胺。在11000r/min下继续搅拌30秒后，将乳液转移到模具(聚乙烯容器)中冷却后形成凝胶乳液，并在室温下固化1小时。将得到的固体浸入丙醇中24小时并在60℃下真空干燥后得到聚合物多孔材料。。
由于6-脱氢枞酰胺基-N,N-二甲基-己基氧化胺稳定的凝胶乳液油水体积比可以任意调控，因此以6-脱氢枞酰胺基-N,N-二甲基-己基氧化胺稳定的凝胶乳液为模板制备的多孔材料可以任意调节孔径的大小。
实施例20：凝胶乳液稳定性测试
向0.22％的6-脱氢枞酰胺基氧化胺溶液中加入不同体积的油(6-脱氢枞酰胺基氧化胺溶液与油的体积比为0.2:9.8，3:7，5:5，7：3，，9.9:0.1，总体积是4mL)，然后使用ultraturrax均化器(IKA T18 basic，S18N-10G head)以11000r/min的速率将混合物乳化2分钟。乳液在低温下静置冷却后形成白色的凝胶乳液。
将已制备好的凝胶乳液置于20℃恒温箱中，观察凝胶乳液的稳定性，结果如下表1所示。稳定剂6-脱氢枞酰胺基-N,N-二甲基-己基氧化胺的浓度为连续相质量的0.22％、分散相体积分数在1％-98％的范围内形成凝胶乳液，放置一年后凝胶乳液仍未发生破乳现象，具有很高的稳定性。稳定剂含量越高，形成的凝胶乳液越稳定。因此稳定剂6-脱氢枞酰胺基-N,N-二甲基-己基氧化胺的浓度范围为连续相质量的0.22％-80％、分散相体积分数在1％-98％的范围内形成凝胶乳液具有很高的稳定性。
表1 0.22％的6-脱氢枞酰胺基-N,N-二甲基-己基氧化胺稳定凝胶乳液的稳定性
Figure PCTCN2019077616-appb-000005

Claims (17)

  1. 一种超分子水凝胶，其特征在于，所述超分子水凝胶利用包括6-脱氢枞酰胺基-N,N-二甲基-己基氧化胺作为凝胶因子；
    6-脱氢枞酰胺基-N,N-二甲基-己基氧化胺的结构式为式(1)：
    Figure PCTCN2019077616-appb-100001
  2. 根据权利要求1所述的超分子水凝胶，其特征在于，所述超分子水凝胶中6-脱氢枞酰胺基-N,N-二甲基-己基氧化胺的浓度范围是3mmol·L -1-1000mmol·L -1。
  3. 一种化合物，其特征在于，所述化合物为6-脱氢枞酰胺基-N,N-二甲基-己基氧化胺，其结构式为式(1)：
    Figure PCTCN2019077616-appb-100002
  4. 权利要求3所述化合物的制备方法，其特征在于，所述制备方法如下：
    Figure PCTCN2019077616-appb-100003
  5. 权利要求3所述6-脱氢枞酰胺基-N,N-二甲基-己基氧化胺在药物缓释、组织工程、细胞培养、污水处理或者日用化学品等领域的应用。
  6. 一种缓释材料，其特征在于，所述缓释材料包含权利要求3的6-脱氢枞酰胺基-N,N-二甲基-己基氧化胺及需要缓释的物质。
  7. 一种医药伤口敷料，其特征在于，所述医药伤口敷料以权利要求3的6-脱氢枞酰胺基-N,N-二甲基-己基氧化胺作为凝胶骨架形成水凝胶，水凝胶中含有抗炎或者抗菌成分。
  8. 一种水土保湿剂，其特征在于，所述水土保湿剂包括利用权利要求3的6-脱氢枞酰胺基-N,N-二甲基-己基氧化胺。
  9. 一种水凝胶面膜，其特征在于，所述水凝胶面膜以权利要求3的6-脱氢枞酰胺基-N,N- 二甲基-己基氧化胺作为主要凝胶骨架形成水凝胶。可选地，面膜内还注入胶原蛋白、透明质酸、熊果苷、烟酰胺等物质中的一种或者多种。
  10. 一种细胞培养支架，其特征在于，所述细胞培养支架包括利用权利要求3的6-脱氢枞酰胺基-N,N-二甲基-己基氧化胺作为凝胶骨架形成水凝胶，为细胞的生长提供三维的环境。
  11. 一种O/W型凝胶乳液，其特征在于，所述O/W型凝胶乳液的稳定剂包括权利要求3所述的6-脱氢枞酰胺基-N,N-二甲基-己基氧化胺，它的分子结构如下：
    Figure PCTCN2019077616-appb-100004
  12. 根据权利要求11所述的O/W型凝胶乳液，其特征在于，所述凝胶乳液中6-脱氢枞酰胺基-N,N-二甲基-己基氧化胺的浓度范围为连续相质量的0.22％-80％，分散相体积分数在1％-98％。
  13. 一种油品运输方法，其特征在于，所述方法是在油中加入权利要求3所述的6-脱氢枞酰胺基-N,N-二甲基-己基氧化胺作为稳定剂，得到固态或半固态油品以便于运输。
  14. 一种多孔材料合成方法，其特征在于，所述方法是在水相中加入交联剂、引发剂后在热的状态下制备含权利要求3所述的6-脱氢枞酰胺基-N,N-二甲基-己基氧化胺的乳液，在已制备好的乳液中加入还原剂；搅拌均匀后，将乳液转移到模具中降温形成凝胶乳液后固化；将固化好的整料洗去凝胶乳液后干燥。
  15. 一种功能因子传递系统，其特征在于，包括利用权利要求3所述的6-脱氢枞酰胺基-N,N-二甲基-己基氧化胺制备O/W型凝胶乳液，所述功能因子包埋在凝胶乳液中；可选地，所述功能因子包括：益生菌、风味物质、营养物质或药物。
  16. 权利要求11所述O/W型凝胶乳液的应用。
  17. 根据权利要求16所述的应用，所述应用包括用于：食品、化妆品、材料、药物传输等领域。
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