CN113816875A

CN113816875A - Material monomer and preparation method and application thereof

Info

Publication number: CN113816875A
Application number: CN202111245015.0A
Authority: CN
Inventors: 夏中华; 万蕊
Original assignee: Beijing Ruigu Technology Development Co ltd
Current assignee: Beijing Jinsheng Xingyi Technology Development Co.,Ltd.; Beijing Ruigu Technology Development Co ltd
Priority date: 2021-10-26
Filing date: 2021-10-26
Publication date: 2021-12-21

Abstract

The invention relates to the field of materials, and particularly provides a material monomer and a preparation method and application thereof. The invention provides a cyanoacrylate material monomer containing a catechol functional group, which can increase the adhesive force and underwater adhesive ability of cyanoacrylate materials through the catechol functional group of a side chain.

Description

Material monomer and preparation method and application thereof

Technical Field

The invention relates to the field of materials, in particular to a material monomer and a preparation method and application thereof.

Background

Cyanoacrylate adhesives are monomeric adhesives that polymerize by free radical and anionic polymerization reactions based on esters of alpha-cyanoacrylate. Therefore, cyanoacrylate adhesives undergo rapid polymerization curing in an environment containing a slight amount of water, resulting in a failure in adhesive ability. Meanwhile, cyanoacrylate adhesives have poor underwater adhesion and are not water-resistant. Therefore, the improvement of the wet bonding capability of the cyanoacrylate adhesive is of great significance to the expansion of the application field of the products.

In view of the above, the present invention is particularly proposed.

Disclosure of Invention

The first purpose of the invention is to provide a material monomer.

The second purpose of the invention is to provide a preparation method of the material monomer.

A third object of the present invention is to provide a composition.

A fourth object of the invention is to provide the use of a material monomer or composition.

A fifth object of the present invention is to provide a polymer.

In order to achieve the above purpose of the present invention, the following technical solutions are adopted:

a material monomer has the following structural formula:

the preparation method of the material monomer comprises the steps of carrying out esterification reaction on anthracene-protected cyanoacrylate and hydroxytyrosol, and carrying out deprotection group reaction to obtain the material monomer.

A composition comprising the monomer of material described above.

Further, the composition further comprises an adjuvant.

Further, the adjuvants are selected from thickeners, stabilizers, thermal and/or photo initiators and accelerators to initiate crosslinking, colorants, plasticizers, preservatives, heat sinks, fibrous reinforcing materials.

Use of a monomer or composition of the above material in the preparation of an adhesive.

Further, the adhesive includes an adhesive for use in underwater or wet environments;

preferably, the adhesive comprises a medical adhesive including adhesives for wound adhesion, hemostasis, visceral and soft tissue wound closure, coverage, leakage occlusion, hard tissue fixation.

Further, the material to be bonded is wood, metal, ceramic, plastic or a material consisting of a mixture of the above materials.

Further, the material has water in any physical state on its surface.

A polymer obtained by crosslinking copolymerization of the above material monomer or composition under the action of anion.

Compared with the prior art, the invention has the beneficial effects that:

the invention provides a cyanoacrylate material monomer containing catechol functional groups, wherein two phenolic hydroxyl groups of catechol can form strong hydrogen bonds and compete with water to obtain hydrogen bond points, and the hydrogen bond action is favorable for polar and hydrophilic surface adsorption, and in addition, chelate and non-covalent bonds can be formed; secondly, the chemical versatility of the catechol functional group can also realize adhesion, crosslinking and solidification through different chemical reactions, the catechol can be oxidized into quinone under certain conditions, and the oxidized quinone can be rearranged and dehydrogenated to further form crosslinking. Not only can react with amino and sulfydryl through Michael addition and Schiff base, but also can form dehydroindole carboxylate through intramolecular cyclization, and finally forms crosslinking. And simultaneously, the disproportionation reaction can be carried out to form free radicals which are coupled into tannin compounds. Therefore, the adhesive force and underwater adhesive capacity of the cyanoacrylate materials can be increased through the catechol functional group of the side chain.

Detailed Description

Embodiments of the present invention will be described in detail below with reference to examples, but it will be understood by those skilled in the art that the following examples are only illustrative of the present invention and should not be construed as limiting the scope of the present invention. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer.

Unless otherwise defined, technical and scientific terms used herein have the same meaning as is familiar to those skilled in the art. In addition, any methods or materials similar or equivalent to those described herein can also be used in the present invention.

The invention provides a material monomer, which has the following structural formula:

the material monomer is formed by bonding a catechol group (3, 4-dihydroxyphenylalanine) to a cyanoacrylate material by a chemical bonding mode so as to improve the wet bonding capability of the cyanoacrylate material.

The preparation method of the material monomer comprises the following steps of carrying out esterification reaction on anthracene-protected cyanoacrylate and hydroxytyrosol, and carrying out deprotection group reaction to obtain the material monomer.

In a preferred embodiment, the material monomers are synthesized as follows:

the synthetic route is simple and easy to operate, and the cost is low.

The invention provides a composition containing the material monomer. In addition, other adjuvants may be present, such as thickeners, stabilizers, thermal and/or photo initiators and accelerators to initiate crosslinking, colorants, plasticizers, preservatives, heat sinks, fiber reinforcements, and the like.

In a preferred embodiment, the thickener comprises polycyanoacrylate, polylactic acid, polyglycolic acid, polycaprolactone, polyalkylacrylate, polyalkylmethacrylate; the stabilizer comprises an anionic stabilizer and a free radical stabilizer, wherein the anionic stabilizer comprises metaphosphoric acid, maleic anhydride, alkyl sulfonic acid, phosphorus pentoxide, ferric chloride (III), antimony oxide, 2,4, 6-trinitrophenol, mercaptan, alkyl sulfonyl, alkyl sulfone, alkyl sulfoxide, alkyl sulfite, sultone, sulfur dioxide and sulfur trioxide; the latter are hydroquinone, catechol and derivatives of the above compounds; initiators or accelerators include: molecules with nucleophilic function, organic or inorganic or their mixture, selected from amino, quaternary amine, hydroxyl, thiol, phosphorus-containing compound, preferably NaHCO₃，Na₂CO₃Or sodium phosphate; the colorant is selected from dyes, pigments, including PGA microfibrils, collagen microfibrils, cellulose microfibrils and olefinic microfibrils; the plasticizer comprises polyethylene glycol ester, butyl stearate, lauric acid, dioctyl glutarate, and glycerolOil triesters, dioctyl acetate, triethyl phosphate, triethyl citrate, acetyl tributyl citrate; preservatives include those conventionally used but which do not initiate polymerization of the monomers and are selected from potassium sorbate, sodium benzoate, sorbic acid, chlorocresol; the heat sink comprises a liquid miscible with the monomer that evaporates during polymerization, releasing heat from the composition; the fibrous reinforcing material comprises natural or synthetic rubber to enhance the impact resistance of the composition, preferably styrene or acrylonitrile.

The material monomer or the composition provided by the invention can be used as an adhesive, and is particularly suitable for an aqueous medium (namely a solution under water, wherein the water can be pure water, fresh water, salt water, seawater, ocean water, polluted water and water which is considered as a main solvent in a general case) or under a humid condition, and the material to be bonded can be wood, metal, ceramic, plastic or a material composed of a mixture of the materials. In addition, the material monomer or composition can also be used in medical applications, such as medical adhesives, for wound adhesion, hemostasis, visceral and soft tissue wound closure, covering, leakage stoppage, hard tissue fixation, and the like.

The invention finally provides a polymer obtained by crosslinking copolymerization of the above monomers or compositions of materials under the action of anions.

The invention is further illustrated by the following specific examples, which, however, are to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever.

EXAMPLE 1 preparation of monomer of Material

The synthetic route is as follows:

the specific operation is as follows:

(1) 300g of anthracene and 1000mL of toluene were charged in a 3000mL three-necked flask, and SO was introduced while stirring₂Gas 2h, 200g of cyanopropene were added dropwiseHeating ethyl acetate to 120 ℃, refluxing for 48h, cooling to room temperature, distilling toluene by a water pump under reduced pressure, adding 1000mL of ethanol, heating at 100 ℃, refluxing, stirring for 40 min, cooling to room temperature, and crystallizing at-20 ℃. And (4) performing suction filtration to obtain 390g of white crystalline solid-ethyl anthracenylcyanoacrylate. The yield was about 80%.

(2) 150g of anthracene cyanoacrylate and 500mL of ethanol are added into a 2000mL three-necked flask, the temperature is raised to 40 ℃, 200mL of 4.5mol/L KOH aqueous solution is added dropwise, after reaction is carried out for 3 hours, 500mL of water is added, stirring is carried out for 20min, insoluble matters are filtered off, filtrate is collected and is adjusted to pH 2 by 6mol/L hydrochloric acid, filtration is carried out, a filter cake is washed by a large amount of distilled water until the pH is about 5.5, and vacuum drying is carried out, so that 110g of white solid-anthracene cyanoacrylate is obtained, and the yield is about 90%.

(3) 21g of anthracyanoacrylate, 3g of DMAP and 300mL of dichloromethane are added into a 500mL round-bottom flask, the mixture is stirred until the reaction solution becomes clear, 4g of hydroxytyrosol is added, the stirring is continued for 10 minutes, and 20g of DCC is added. After stirring overnight at room temperature the reaction was monitored by TLC, filtered and concentrated, petroleum ether: ethyl acetate 5: 1 column chromatography to obtain colorless solid (3, 4-dihydroxy phenethyl (12S) -12-isocyano-9, 10-dihydro-9, 10-ethyl anthracene-12-carboxylate) 8.5 g. 80% yield.

(4) Weighing 4g of the product obtained in the step (3), 2.8g of maleic anhydride, a small amount of phosphorus pentoxide, hydroquinone and 50mL of xylene, carrying out reflux reaction at 160 ℃ for 6h, stopping the reaction, distilling off the xylene under reduced pressure, and reacting the xylene with acetone: diethyl ether 1: 3 at-20 ℃ to give 1.1g of a pale yellow oil (3, 4-dihydroxyphenethyl-2-isocyanoacrylate). 50% yield.

Example 2 shear tensile Strength

Shear tensile strength is a common indicator of adhesive bonding ability. The national pharmaceutical industry standard (YY/T0729-2009) is taken as the experimental guidance. Long strips of pigskin (2.5 cm. times.10 cm) were prepared and tested in a dry environment and a wet environment with water, respectively. And (3) drying environment: sucking 20. mu.L of monomer and dropping the monomer on 2.5X 1cm of pigskin²Quickly coating the area with the same size, quickly lapping another pigskin with the same size on the area, pressing for 10min with 10N vertical direction, and testing the fracture of the bonding area of the two pigskins at constant speed of 20mm/min by using a tensile testing machineThe shear tensile strength was calculated. The environment is wet by water: firstly, 200 mu L of distilled water is sucked and smeared on the pigskin with the thickness of 2.5 multiplied by 1cm²The test was carried out after sucking 20. mu.L of the monomer material again to coat the adhesive region. The test results are shown below.

Example 3 combination formulation

By adding the thickening agent of poly n-butyl cyanoacrylate and the plasticizer of triethyl citrate, the whole colloid is relatively viscous, can be bonded under water or a humid environment better, and can not be diffused when being dropped into water. (n-butyl cyanoacrylate quickly diffuses and solidifies into a film on the water surface when being dripped into water) in the following material monomers: thickening agent: the plasticizer is (60-80): (5-30): 5-30), and preferably is a material monomer: thickening agent: plasticizer 60:20: 20.

Example 4 curing time

20 μ L of the monomer was applied uniformly to 4 × 4cm pigskin and allowed to change phase from liquid to solid within 3 minutes after contacting the pigskin tissue. The polymerization speed of the material is greatly reduced compared with that of the traditional n-butyl cyanoacrylate adhesive (within 30 s), probably because the steric hindrance of catechol chains in monomer molecules and the polymerization inhibition of phenolic hydroxyl groups influence the thermodynamic collision efficiency of olefinic double bonds, and the complete curing time is prolonged.

Example 5 evaluation of biological safety

Cytotoxicity

Part 5 of the biological evaluation of medical devices according to GB/T16886.5-2017: the in vitro cytotoxicity test method adopts sterile normal saline injection and sterile normal saline injection with the volume fraction of 2 percent DMSO as leaching liquor to carry out MTT method test. The product is taken out and added into a 6-hole plate under aseptic condition,applying 10 μ L of the extract to each well, and adding 5% CO₂After 2 days of curing in a 37 ℃ incubator. According to 6cm²The leaching solution is added in the ratio of/mL, and leached for 72 hours at 37 ℃ under the condition of shaking at 100 rpm. The cells were diluted to 25%, 12.5%, 6.25%, and 3.125% with serum-containing MEM medium before being contacted, while blank, negative, and positive controls were set. NCTCL929 cells in a logarithmic growth phase are selected for the test, the appearance of the cells is observed after the sample is contacted with the cells for 24 hours, and the survival rate of the cells is determined by an MTT method.

Experimental materials and instruments: the kit comprises the product, MEM culture medium, fetal calf serum, penicillin, streptomycin, normal saline, DMSO, a carbon dioxide incubator, NCTC L929 mouse fibroblast, pancreatin, a 96-well culture plate, a microscope (Olympus model: IX71), MTT, isopropanol, a mixing machine (eppendort, model: MIXMATE) and an enzyme labeling machine (Thermo SCIENTIFIC, model: MIXMATE).

TABLE 1 in vitro cytotoxicity test morphology observations

TABLE 2 polar leach liquor group in vitro cytotoxicity test MTT test results

TABLE 3 MTT test results of in vitro cytotoxicity experiments of nonpolar leach liquor components

Note: the absorbance values were OD570nm-OD650 nm.

The experimental results are as follows: the cell morphology shown in tables 1, 2 and 3 shows that discrete particles exist in cytoplasm of the non-polar leach liquor and the polar leach liquor cultured cells of each concentration of the product, no cells are dissolved, and no cell proliferation is reduced. The cell survival rate of 25% of the non-polar leaching solution of the product is 97% and the cell survival rate of 25% of the polar leaching solution is 92% through MTT method detection. The product, namely 25 percent of non-polar leaching liquor and 25 percent of polar leaching liquor, has no potential cytotoxicity reaction.

Sensitization

Part 10 of the biological evaluation of medical devices according to GB/T16886.10-2005: and in the stimulation and delayed hypersensitivity tests, 0.9 percent sodium chloride injection (one group) and fresh vegetable oil (two groups) are selected as leaching liquor, 0.1mL is injected into each injection point in an intradermal way, and the skin condition of the animal excitation part is observed and recorded after 24 hours and 48 hours of excitation.

Experimental materials and instruments: guinea pig, Freund's adjuvant (SIGMA F5881-10ml CAS9007-81-2), 0.9% sodium chloride injection, cotton seed oil, syringe, the product.

The experimental results are as follows:

TABLE 4 skin sensitization test

The experimental results are shown in the table, and the product has no skin sensitization reaction.

Intradermal reaction

Part 10 of the biological evaluation of medical devices according to GB/T16886.10-2005: stimulation and delayed hypersensitivity tests.

Experimental materials and instruments: healthy rabbits, syringes, 0.9% sodium chloride injection, cottonseed oil and the product.

TABLE 5 intradermal stimulation test

The experimental results are as follows: as shown in Table 5, after the injection of the leaching liquor of the product, the difference between the average scores of the product group and the control group is less than 1.0, and the product has no skin irritation.

Skin irritation

The experimental purposes and methods: the product is tested for skin irritation. Part 10 of the biological evaluation of medical devices according to GB/T16886.10-2005: stimulation and delayed type hypersensitivity tests, the skin condition of the application site was observed at 1, 24, 48 and 72 hours after 0.1mL of the product was applied to the skin of rabbits at home and blocked for 4 hours.

Experimental materials and instruments: rabbit, the product, depilatory, pipettor, medical gauze.

TABLE 6 acute skin irritation test results of this product for rabbits

The experimental results are as follows: as shown in Table 6, the skin of the experimental area does not have any erythema and/or edema symptoms, and the product has no irritation on the skin of the rabbits.

Acute systemic toxicity

Purpose of the experiment: the acute toxicity of the product is respectively evaluated by adopting the modes of direct polymer gavage and leaching liquor injection.

(1) The experimental method comprises the following steps: according to GB/T-14233.2-2005, 10g/kg of biodegradable medical gel polymer is administrated by intragastric administration to mice.

The experimental results are as follows: after the mice are subjected to gastric lavage, no toxic reaction occurs, the mice are killed and examined for diseases after 4 days, and no abnormality is observed by naked eyes.

(2) The experimental method comprises the following steps: the polymer colloid leaching liquor (leaching ratio is 1.25 cm)²mL, the leaching medium is sterile physiological saline) are respectively injected into tail vein and abdominal cavity, and the dosage is 50 mL/kg.

Experimental materials and instruments: 2% methylcellulose solution, product, Kunming mouse, model JA1003 electronic balance (Shanghai Yueping scientific instruments Co., Ltd.).

The experimental results are as follows: no significant toxicity was observed, mice did not show special toxicant symptoms, no death, and normal weight gain, similar to normal controls.

The experiments indicate that no acute toxicity of mice is observed under the experimental conditions of the product.

Hemolysis of blood

The experimental method is carried out according to GB/T14233.2-2005, GB/T16886.12-2017. Healthy adult rabbits with the body weight of more than 2.0kg are selected, blood is collected from the heart on the test day, and diluted anticoagulated rabbit blood is prepared after anticoagulation. The test sample contained 5% CO₂Curing the mixture in a constant-temperature incubator at 37 ℃ for 2d, adding 0.9% sodium chloride injection, leaching for 72h at 37 ℃, and respectively collecting 10mL of leaching liquor to test sample tubes; adding 10mL of 0.9% sodium chloride injection into each tube of the negative control group; the positive control group added 10mL of purified water per tube. Each set operated 3 tubes in parallel. And (3) after the temperature is kept for 30min, 0.2mL of diluted anticoagulated rabbit blood is added into each test tube, and the temperature is kept for 60min after the mixture is uniformly mixed. After the liquid in the tube was poured out, it was centrifuged, and absorbance was measured at a wavelength of 545nm with an ultraviolet spectrophotometer, and the hemolysis ratio (%) of the test sample was calculated.

Experimental materials and instruments: adult rabbit, anticoagulant, 0.9% sodium chloride injection, the product, a constant temperature water bath kettle and an ultraviolet spectrophotometer.

The experimental results are as follows: the product has the hemolysis rate of 0.2 percent under the above experimental conditions, has no obvious hemolysis risk and conforms to the GB/T14233.2-2005 standard.

The invention synthesizes the cyanoacrylate material monomer containing catechol functional group by a chemical synthesis mode. The monomer is liquid at normal temperature, and can be polymerized under the condition of anion due to containing cyanoacrylate functional group. And because it contains catechol functional group, it can maintain the adhesive ability in wet environment, and improve the wet adhesive ability without reducing the original adhesive ability of cyanoacrylate material.

While particular embodiments of the present invention have been illustrated and described, it would be obvious that various other changes and modifications can be made without departing from the spirit and scope of the invention. It is therefore intended to cover in the appended claims all such changes and modifications that are within the scope of this invention.

Claims

1. A material monomer, characterized by the structural formula:

2. the method for preparing the material monomer according to claim 1, wherein the material monomer is obtained by esterification of anthracene-protected cyanoacrylate with hydroxytyrosol followed by deprotection group reaction.

3. A composition comprising the material monomer of claim 1.

4. The composition of claim 3, wherein the composition further comprises an adjuvant.

5. Composition according to claim 4, characterized in that the adjuvants are chosen from thickeners, stabilizers, thermal and/or photo initiators and accelerators to initiate crosslinking, colorants, plasticizers, preservatives, heat-dissipating agents, fibrous reinforcing materials.

6. Use of a material monomer according to claim 1 or a composition according to any one of claims 3 to 5 in the preparation of an adhesive.

7. Use according to claim 6, wherein the adhesive comprises an adhesive for underwater or humid environments;

8. Use according to claim 7, characterized in that the material to be bonded is wood, metal, ceramic, plastic or a material consisting of a mixture of the aforementioned materials.

9. Use according to claim 8, wherein the material has water in any physical state on its surface.

10. A polymer obtained by anionic cross-linking copolymerization of a monomer according to claim 1 or a composition according to any one of claims 3 to 5.