Preparation method of high-yield alpha-cyanoacrylate medical adhesive

Abstract

The invention relates to a preparation method of a medical adhesive, in particular to a preparation method of a high-yield alpha-cyanoacrylate medical adhesive, which can effectively improve the yield of alpha-cyanoacrylate on the premise of ensuring high purity. The preparation method comprises the following steps: under the combined action of a phase transfer catalyst and a hydrophobic inorganic nano-dispersant, carrying out condensation polymerization on cyanoacetate and formaldehyde to prepare a poly (alpha-cyanoacrylate) prepolymer, melting the prepolymer through a programmed temperature control process, heating to remove front fractions, rapidly heating to a depolymerization temperature, and carrying out heat preservation to obtain the high-temperature-resistant formaldehyde-free flame retardant. Depolymerizing the prepolymer to generate an alpha-cyanoacrylate crude product, and rectifying the crude product under reduced pressure to obtain the high-purity alpha-cyanoacrylate medical adhesive. Compared with the prior art, the preparation method has the advantages that the high-yield poly (alpha-cyanoacrylate) prepolymer can be prepared, and the prepared alpha-cyanoacrylate medical adhesive is high in yield and high in purity.

Description

TECHNICAL FIELD

[0001] The present application relates to a preparation method of medical adhesive, in particular to a preparation method of high-yield alpha-cyanoacrylate medical adhesive which can effectively improve the yield of alpha-cyanoacrylate under the premise of ensuring high purity. BACKGROUND

[0002] Alpha-cyanoacrylate adhesive, commonly known as "instant adhesive", does not require any curing agent and can be rapidly cured at room temperature, tightly and firmly bonding two objects together. This adhesive is widely used in the industrial field and plays a key role in criminal investigation, electronics, aerospace, and biomedical fields. In particular, when used for wound closure, it not only achieves rapid and firm closure of the wound, but also inhibits scar cell proliferation, and can replace sutures and staples.

[0003] Currently, the method for producing alpha-cyanoacrylate compounds generally uses cyanacetic acid ester and formaldehyde for condensation polymerization (referred to as: condensation polymerization, hereinafter the same) to prepare poly(alpha-cyanoacrylate) prepolymer, and then the prepolymer undergoes depolymerization (referred to as: depolymerization, hereinafter the same) to generate alpha-cyanoacrylate. In order to promote mass transfer and heat transfer during the condensation polymerization reaction, organic solvents (such as dichloromethane, petroleum ether, and dimethyl carbonate, etc.) or water are often used as dispersion media. For example, patent CN 108689881 B discloses a synthesis method of alpha-cyanoacrylate n-octyl ester, which uses n-octyl cyanoacetate and polyformaldehyde as raw materials, petroleum ether as reaction medium, and alpha-cyanoacrylate n-octyl ester is prepared through condensation polymerization and depolymerization. Although the organic solvent is well dissolved with the reactants, which is beneficial for the reaction to proceed and can be recycled after the reaction, there is still an environmental risk. Generally, organic solvents are often used as dispersion media when preparing alpha-cyanoacrylate ethyl ester (commonly known as 502 adhesive) for civilian use, while for alpha-cyanoacrylate medical adhesive with strict quality requirements, there may be safety risks caused by solvent residues. In view of the fact that the use of low-boiling-point organic solvents as dispersion media leads to a lower reaction temperature, in order to ensure sufficient reaction, the reaction time must be extended, thereby increasing the process complexity. In addition, small molecules of water are generated during condensation polymerization, and in order to promote the reaction to proceed in the forward direction, a water separator is often added to the production device, which makes the device complex and difficult to control.

[0004] The polycondensation reaction of cyanoacetate and formaldehyde can also use water as the dispersion medium. Although the presence of a large amount of water inhibits the reaction from proceeding in the forward direction, the obtained prepolymer is only used for subsequent depolymerization, and thus the molecular weight requirement is not high, and generally 1000-3000 is sufficient. The reaction does not require a reaction device with a water trap, simplifying the production process. However, due to the poor water solubility of cyanoacetate, the two-phase reaction with formaldehyde often needs to introduce a surfactant to ensure the stability of the system. Patent CN 111187182 A discloses a synthesis process of n-butyl α-cyanoacrylate. In this method, water is used as the dispersion medium, and alkyl surfactants such as dodecyl dimethyl benzyl ammonium chloride, alkyl phenol polyoxyethylene ether, and sodium dodecyl benzene sulfonate are used to improve the dispersion of organic matter in water, increase the contact area of the two phases, fully mix the oil phase cyanoacetate with the water phase formaldehyde, and promote the polymerization reaction of the reactants in water. However, this method is only limited to the synthesis of short-chain ester derivatives such as n-butyl α-cyanoacrylate. In the preparation of α-cyanoacrylate compounds such as octyl α-cyanoacrylate or ethoxyethyl α-cyanoacrylate, which have large steric hindrance and low reactivity, the emulsifying effect of long-chain alkyl surfactants in the system actually inhibits the reaction, because the amphiphilic structure of the long-chain alkyl surfactants forms a more dense adsorption layer on the surface of the oil phase reactant (such as n-octyl cyanoacetate or ethoxyethyl cyanoacetate), that is, a mass transfer barrier is formed at the two-phase interface, hindering the polycondensation reaction and reducing the yield of the prepolymer. The reduction of the prepolymer yield will directly lead to the reduction of the yield of the depolymerization product α-cyanoacrylate. Improving the yield of the prepolymer is one of the important conditions for ultimately improving the yield of α-cyanoacrylate. The introduction of surfactants causes difficulties in cleaning the polycondensation product, and multiple washing causes loss of the polycondensation product. Moreover, the washing wastewater needs to be treated in the subsequent process, increasing the treatment cost. In addition, the prepolymer of poly(α-cyanoacrylate) is prepared by high-temperature depolymerization to prepare α-cyanoacrylate. Due to the high-temperature and high-vacuum depolymerization conditions, the system is unstable, and there are many side reactions, directly leading to the reduction of the purity and yield of α-cyanoacrylate. Although the purity of α-cyanoacrylate can be improved by refining, the yield of α-cyanoacrylate is further reduced. How to improve the yield of α-cyanoacrylate under the condition of ensuring high purity is a problem that the current process cannot solve.

[0005] Therefore, it is particularly important to develop a method for preparing a prepolymer of poly(α-cyanoacrylate) with high yield using water as the dispersion medium, and improving the yield and purity of α-cyanoacrylate by controlling the depolymerization process conditions, to promote the production and application of α-cyanoacrylate medical adhesive. SUMMARY

[0006] The present application is directed to the shortcomings and deficiencies in the prior art, and innovatively proposes a high-yield α-cyanoacrylate preparation method, that is, first, poly(α-cyanoacrylate) prepolymer is prepared in a polycondensation system with water as a dispersion medium by using phase transfer catalyst and hydrophobic inorganic nano dispersant combined technology, thereby promoting the reaction between oil phase and water phase reactants, and improving the yield of poly(α-cyanoacrylate) prepolymer; then, depolymerization of the poly(α-cyanoacrylate) prepolymer and purification of the α-cyanoacrylate crude product are carried out through programmed temperature technology, thereby improving the yield of the α-cyanoacrylate crude product and the yield of the purified product, and finally improving the overall yield of the α-cyanoacrylate medical adhesive.

[0007] The present application achieves the following measures:

[0008] A high-yield α-cyanoacrylate medical adhesive preparation method, characterized in that, in the presence of deionized water as a dispersion medium and under the combined action of phase transfer catalyst and hydrophobic inorganic nano dispersant, cyanoacetate is subjected to condensation polymerization with formaldehyde to first prepare poly(α-cyanoacrylate) prepolymer, and then through programmed temperature technology, the prepolymer is first melted, then the front fraction is removed by heating, and then the temperature is rapidly raised to the depolymerization temperature to make the prepolymer depolymerize to generate α-cyanoacrylate crude product, and high-purity α-cyanoacrylate medical adhesive is obtained after the crude product is subjected to vacuum rectification;

[0009] The phase transfer catalyst uses one or more of crown ether compounds, quaternary ammonium salt compounds and polyether compounds, the crown ether compounds are selected from one or more of 18-crown-6, 15-crown-5, 12-crown-4 and cyclodextrin, the quaternary ammonium salt compounds are selected from one or more of benzyltriethylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium chloride and tetrabutylammonium hydrogen sulfate, and the polyether compounds are selected from one or more of polyethylene glycol PEG-400, polyethylene glycol PEG-600 or polyethylene oxide.

[0010] The hydrophobic inorganic nano dispersant uses one or more of hydrophobic fumed nano silica, titanium dioxide, aluminum trioxide and carbon nanoparticles.

[0011] The present application specifically includes the following steps:

[0012] Step 1: using cyanacetic acid ester and aqueous formaldehyde as raw materials, deionized water as dispersion medium, adding phase transfer catalyst, hydrophobic inorganic nano dispersant, alkaline catalyst, under the action of mechanical stirring, carrying out polycondensation reaction, after the reaction, adding acid substance to neutralize the alkaline catalyst, preparing poly(α-cyanoacrylate) prepolymer, after cooling the prepolymer, carrying out crushing, washing, drying, obtaining prepolymer powder; wherein the mass fraction of the aqueous formaldehyde is 30wt%-40wt%, the molar ratio of cyanacetic acid ester to formaldehyde is 1mol:(1-1.1)mol, the mass ratio of cyanacetic acid ester to water is 1:(0.3-1.1), the molar ratio of cyanacetic acid ester to phase transfer catalyst is 1mol:(0.001-0.05mol), the mass ratio of cyanacetic acid ester to hydrophobic inorganic nano dispersant is 1:(0.001-0.01), preferably 1:(0.0025-0.005), the alkaline catalyst is selected from one or several of organic amine compounds and inorganic alkali compounds, wherein the organic amine compounds are selected from one or several of piperidine, pyrrolidine, triethylamine and pyridine, the inorganic alkali compounds are potassium carbonate and sodium carbonate, the mass ratio of cyanacetic acid ester to alkaline catalyst is 1:

[0013] (0.002-0.006), the alkaline catalyst needs to be diluted into aqueous solution, then added into the reaction system, the mass fraction of the alkaline catalyst aqueous solution is 0.5-5wt%, the rate of mechanical stirring is 200-1000rpm, the polycondensation reaction temperature is 50-90℃, the reaction time is 3-10h, the added acid substance is phosphoric acid;

[0014] Step 2: carrying out depolymerization reaction, adding plasticizer, water-removing agent, acid catalyst, free radical polymerization inhibitor and anion polymerization inhibitor into the poly(α-cyanoacrylate) prepolymer, wherein the ratio of the poly(α-cyanoacrylate) prepolymer to the added amount of plasticizer is 100g:(2-18)mL, the ratio of the poly(α-cyanoacrylate) prepolymer to the added amount of water-removing agent is 100g:(1-7)g, the ratio of the poly(α-cyanoacrylate) prepolymer to the added amount of acid catalyst is 100g:(0.2-1.8)g, the ratio of the poly(α-cyanoacrylate) prepolymer to the added amount of free radical polymerization inhibitor is 100g:(0.5-4)g, the ratio of the poly(α-cyanoacrylate) prepolymer to the added amount of anion polymerization inhibitor is 100g:(0.1-2)g, first melting the prepolymer at the temperature range of 50-100℃, then heating to 100-170℃ to remove the front fraction, then rapidly heating to the depolymerization temperature 170-220℃, making the prepolymer depolymerize to generate α-cyanoacrylate crude product;

[0015] Step 3: Add a dehydrating agent and a free radical polymerization inhibitor to the crude α-cyanoacrylate product, and obtain α-cyanoacrylate medical adhesive by vacuum distillation under vacuum conditions. The ratio of crude α-cyanoacrylate product to dehydrating agent is 100g:(0.5~4)g, the ratio of crude α-cyanoacrylate product to free radical polymerization inhibitor is 100g:(0.5~3)g, and the collection temperature of pure fraction is 100~140℃.

[0016] The drying process described in step 1 of this invention is selected from one or more of forced-air drying and vacuum drying, preferably vacuum drying performed on the basis of forced-air drying. The temperature range of the forced-air drying is [insert temperature range here].

[0017] The temperature is 30–60°C, preferably 45–55°C; the blowing time is 5–48 hours, preferably 10–24 hours, and more preferably 10–60 hours.

[0018] The vacuum drying process takes 10 to 12 hours, with the temperature range being 30 to 60°C, preferably 45 to 55°C; the drying time is 3 to 24 hours, preferably 5 to 18 hours, and more preferably 9 to 11 hours.

[0019] In step 1 of this invention, the formaldehyde aqueous solution preferably has a mass fraction of 36wt%-38wt%, the molar ratio of cyanoacetate to formaldehyde is preferably 1mol:1mol, the mass ratio of cyanoacetate to water is preferably 1:(0.5-0.9), more preferably 1:(0.65-0.75), the phase transfer catalyst is preferably 18-crown ether-6, the molar ratio of cyanoacetate to phase transfer catalyst is preferably 1mol:(0.005-0.01mol), and the cyanoacetate and hydrophobic inorganic nanoparticles... The mass ratio of the powder to the alkaline catalyst is 1:(0.001-0.01), preferably 1:(0.0025-0.005). The alkaline catalyst is selected as piperidine. The mass ratio of cyanoacetate to alkaline catalyst is preferably 1:(0.003-0.005). The mass fraction of the aqueous solution of the alkaline catalyst is preferably 1.5-2.5 wt%. The mechanical stirring speed is preferably 200-600 rpm, more preferably 300-500 rpm. The temperature range of the polycondensation reaction is preferably 60-90℃, more preferably 80-90℃. The reaction time is preferably 4-6 h.

[0020] The plasticizer in step 2 of the present application is selected from one or more of trimethylphenyl phosphate, dioctyl terephthalate, tributyl citrate and acetyl tributyl citrate, which can effectively reduce the apparent viscosity of the prepolymer in the depolymerization process, promote the uniform dispersion of the components in the system, and accelerate the escape of the product α-cyanoacrylate monomer vapor from the reaction system. The ratio of the amount of poly(α-cyanoacrylate) prepolymer to the amount of plasticizer is preferably 100 g:(5-15) mL, and more preferably 100 g:(8-12) mL; the water removal agent is phosphorus pentoxide to remove trace amounts of water, and the ratio of the amount of poly(α-cyanoacrylate) prepolymer to the amount of water removal agent is preferably 100 g:(3-5) g; the acidic catalyst is phosphoric acid, and the ratio of the amount of poly(α-cyanoacrylate) prepolymer to the amount of acidic catalyst is preferably 100 g:(0.5-1.5) g, and more preferably 100 g:

[0021] (0.8-1.2) g, and the ratio of the amount of poly(α-cyanoacrylate) prepolymer to the amount of radical polymerization inhibitor is preferably 100 g:(1.5-2.5) g; the anion polymerization inhibitor is selected from one or more of sulfur dioxide, p-toluenesulfonic acid, benzoic acid, phthalic anhydride, and dodecanethiol, preferably p-toluenesulfonic acid and sulfur dioxide, and more preferably sulfur dioxide; and the ratio of the amount of poly(α-cyanoacrylate) prepolymer to the amount of anion polymerization inhibitor is preferably 100 g:(0.5-1.5) g.

[0022] In step 2 of the present application, the melting temperature of the prepolymer is preferably 60-90°C, and more preferably 70-80°C, and the temperature for removing the front fraction is preferably 140-170°C, and more preferably 160-170°C; and the reaction temperature of the depolymerization reaction is preferably 180-210°C, and more preferably 190-200°C.

[0023] In step 3 of the present application, there are different reaction temperatures and fraction collection temperatures for different types of α-cyanoacrylate due to the differences in their physical and chemical properties. The reaction temperature for the vacuum distillation of the crude butyl α-cyanoacrylate is 60-120°C, and preferably 80-100°C; the vapor temperature for the pure fraction of butyl α-cyanoacrylate is 50-80°C, and preferably 60-70°C; the reaction temperature for the vacuum distillation of the crude octyl α-cyanoacrylate is 100-140°C, and preferably 120-135°C; the vapor temperature for the pure fraction of octyl α-cyanoacrylate is 90-120°C, and preferably 100-110°C; the reaction temperature for the vacuum distillation of the crude alkoxy α-cyanoacrylate is 80-120°C, and preferably 90-110°C; and the vapor temperature for the pure fraction of alkoxy α-cyanoacrylate is 90-120°C, and preferably 100-110°C.

[0024] Compared with the prior art, the present invention has the following beneficial effects: (1) By using the combined technology of 18-crown ether-6 isophase transfer catalyst and hydrophobic inorganic nano-dispersant, high-yield poly(α-cyanoacrylate) prepolymer can be prepared. Nanoparticles have a high specific surface area, which can be adsorbed on the surface of cyanoacetate oil droplets to form a barrier to prevent oil droplet aggregation, and promote the formation of smaller, more stable and more numerous oil droplets of cyanoacetate, thereby significantly increasing the total oil-water interface area. The 18-crown ether-6 isophase transfer catalyst can continuously transfer formaldehyde in the aqueous phase to the oil phase interface at the oil-water interface to react with cyanoacetate, promote the condensation reaction of cyanoacetate and formaldehyde in the aqueous dispersion medium, and improve the reaction yield and relative molecular mass of poly(α-cyanoacrylate) prepolymer. (2) The depolymerization of poly(α-cyanoacrylate) prepolymer and the purification of crude α-cyanoacrylate product are carried out by temperature control by program, reducing side reactions, and precisely controlling the reaction temperature and fraction collection temperature during the depolymerization reaction and vacuum distillation purification process. The pre-fraction, pure fraction and post-fraction are separated to obtain α-cyanoacrylate medical adhesive with high yield and high purity. (3) The intermediate product of the preparation of α-cyanoacrylate medical adhesive, namely poly(α-cyanoacrylate) prepolymer, can be stored stably at room temperature for a long time. The prepolymer can be mass-produced and subsequent reactions can be carried out according to the order demand, which is convenient for process production. (4) By crushing, cleaning and drying the above prepolymer, the present invention reduces the amount of unreacted reactants, especially formaldehyde residue, and effectively improves the biocompatibility of the material. (5) By crushing, cleaning and drying the above prepolymer, the present invention removes residual moisture and alkaline catalyst, avoids solidification inside the reaction system during the depolymerization reaction, and improves the yield of α-cyanoacrylate medical adhesive. (6) The present invention constructs an aqueous reaction system for preparing α-cyanoacrylate medical adhesives, which avoids the use of organic solvents in traditional processes, reduces environmental pollution and operator exposure risks, and at the same time reduces the residual organic solvents in the product, thereby improving the biocompatibility of the product. Attached image description:

[0025] Appendix Figure 1 This is the 1H NMR spectrum of α-cyanoacrylate obtained in Example 1 of this invention.

[0026] Appendix Figure 2 This is the 1H NMR spectrum of n-octyl cyanoacrylate obtained in Example 2 of this invention.

[0027] Appendix Figure 3 This is the 1H NMR spectrum of ethoxyethyl α-cyanoacrylate obtained in Example 3 of this invention. (Attached) Figure 4The lap-shear strength and wound closure strength of the α-cyanoacrylate medical adhesive obtained in Embodiments 1-3 of the present application. DETAILED DESCRIPTION

[0028] The present application will be described in detail below through specific embodiments.

[0029] The present application provides a method for preparing α-cyanoacrylate medical adhesive with high yield. The method uses deionized water as the dispersion medium, and under the joint action of phase transfer catalyst and hydrophobic inorganic nano-dispersant, the poly(α-cyanoacrylate) prepolymer is prepared by condensation polymerization of cyanoacetate and aqueous formaldehyde solution. Through the programmed temperature process, the prepolymer is first melted at a lower temperature, then the temperature is programmed to a medium temperature to remove the front fraction, and then the temperature is quickly raised to the depolymerization temperature to make the prepolymer depolymerize to generate the crude product of α-cyanoacrylate. After the crude product is subjected to vacuum rectification, the α-cyanoacrylate medical adhesive with high purity is obtained. The above method uses nanoparticles to promote cyanoacetate to form smaller, more stable and more numerous oil droplets, significantly increases the total oil-water interface area, and uses phase transfer catalyst to promote the reaction of oil phase cyanoacetate and water phase formaldehyde at the oil-water interface. The combination of nanoparticles and phase transfer catalyst improves the yield and relative molecular mass of the prepolymer. At the same time, the programmed temperature and the separation of the front and rear fractions are used to obtain the α-cyanoacrylate medical adhesive with high purity and high yield.

[0030] The α-cyanoacrylate medical adhesive includes α-cyanoacrylate alkyl ester and α-cyanoacrylate alkoxy ester, etc. according to the different side chain ester groups. The α-cyanoacrylate alkyl ester includes α-cyanoacrylate n-butyl ester, α-cyanoacrylate isobutyl ester, α-cyanoacrylate n-octyl ester, α-cyanoacrylate sec-octyl ester, α-cyanoacrylate isooctyl ester, etc. The α-cyanoacrylate alkoxy ester includes α-cyanoacrylate methoxyethyl ester and α-cyanoacrylate ethoxyethyl ester, etc. The side chain ester group of the α-cyanoacrylate medical adhesive determines its properties, including mechanical properties, flexibility, degradation performance and biocompatibility. At present, there are mainly two kinds of α-cyanoacrylate as medical adhesive applied to medical purposes, which are α-cyanoacrylate butyl ester and α-cyanoacrylate octyl ester; α-cyanoacrylate alkoxy ester with good film flexibility such as α-cyanoacrylate ethoxyethyl ester has gradually become a new research and development direction of future medical adhesive.

[0031] The method of the present application specifically includes the following steps:

[0032] Step (1) is carried out by using cyanoacetate and aqueous formaldehyde as raw materials, deionized water as dispersion medium, adding phase transfer catalyst, hydrophobic inorganic nano dispersant, alkaline catalyst, and under the action of mechanical stirring, the poly (α-cyanoacrylate) prepolymer is prepared by condensation polymerization reaction, then the prepolymer is cooled and then crushed, washed and dried to obtain the prepolymer powder, wherein the mass fraction of the aqueous formaldehyde solution is preferably 30wt%-40wt%, preferably 36wt%-38wt%; the molar ratio of cyanoacetate to formaldehyde is 1mol:(1-1.1)mol, preferably 1mol:1mol; the mass ratio of cyanoacetate to water is 1:(0.3-1.1), preferably 1:(0.5-0.9), more preferably 1:(0.65-0.75);

[0033] The phase transfer catalyst is selected from one or more of crown ether compounds, quaternary ammonium salt compounds and polyether compounds, preferably crown ether compounds. The crown ether compounds are selected from one or more of 18-crown-6, 15-crown-5, 12-crown-4 and cyclodextrin, preferably 18-crown-6, the quaternary ammonium salt compounds are selected from one or more of benzyltriethylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium chloride and tetrabutylammonium hydrogen sulfate; the polyether compounds are selected from one or more of polyethylene glycol (PEG-400), polyethylene glycol (PEG-600) and polyethylene oxide. The phase transfer catalyst is a catalyst that can promote the transfer of reactants from one phase to another phase to participate in the reaction, which can accelerate the rate and conversion rate of heterogeneous reactions. They are usually used in reactions between aqueous phase and organic oil phase, which can transfer the reactants in the aqueous phase to the oil phase to promote the reaction. In the reaction of cyanoacetate and formaldehyde, the phase transfer catalyst constantly transfers the formaldehyde in the aqueous phase to the oil phase to react with cyanoacetate, which improves the yield of the reaction and the relative molecular mass of the prepolymer; the mass ratio of cyanoacetate to hydrophobic inorganic nano dispersant is 1:

[0034] (0.001-0.01), preferably 1:(0.0025-0.005). The nanoparticles promote the formation of smaller, more stable and more numerous oil droplets of cyanoacetate, significantly increase the total oil-water interface area, and promote the better role of the phase transfer catalyst;

[0035] The mass ratio of the cyanacetic ester to the phase transfer catalyst is 1: (0.001-0.05), preferably 1: (0.005-0.01); the basic catalyst is selected from one or more of organic amine compounds and inorganic base compounds, the organic amine compounds are selected from one or more of piperidine, pyrrolidine, triethylamine and pyridine, preferably piperidine, the inorganic base compounds are selected from weakly basic substances such as potassium carbonate and sodium carbonate; the mass ratio of the cyanacetic ester to the basic catalyst is 1:

[0036] (0.002-0.006), preferably 1: (0.003-0.005);

[0037] The basic catalyst needs to be diluted into an aqueous solution before being added into the reaction system. The mass fraction of the aqueous solution of the basic catalyst is selected from 0.5-5 wt%, preferably 1.5-2.5 wt%. Direct addition of the undiluted basic catalyst will cause the polycondensation reaction of the cyanacetic ester and formaldehyde to proceed rapidly, and the exothermic process will release a large amount of heat, causing the temperature of the reaction system to rise sharply. The rapid rise in temperature will change the properties of the prepolymer, reduce the yield of the prepolymer and the relative molecular mass;

[0038] The rate of the mechanical stirring is selected from 200-1000 rpm, preferably 200-600 rpm, more preferably 300-500 rpm; the polycondensation reaction has a reaction temperature selected from 50-90℃, preferably 60-90℃, more preferably 80-90℃. The reaction time is selected from 3-10 h, preferably 4-6 h; the acidic substance is preferably phosphoric acid; the drying process is selected from one or more of air drying and vacuum drying, preferably vacuum drying based on air drying. The temperature of the air drying is selected from 30-60℃, preferably 45-55℃; the air drying time is selected from 5-48 h, preferably 10-24 h, more preferably 10-12 h; the temperature of the vacuum drying is selected from 30-60℃, preferably 45-55℃; the drying time is selected from 3-24 h, preferably 5-18 h, more preferably 9-11 h;

[0039] Step (2) adding a plasticizer, a water-removing agent, an acidic catalyst, a free radical polymerization inhibitor and an anionic polymerization inhibitor into the poly (α-cyanoacrylate) prepolymer, and through a programmed temperature process, melting the prepolymer at a lower temperature, then programmed heating to a medium temperature to remove the front fraction, and then rapidly heating to the depolymerization temperature to make the prepolymer depolymerize to generate a crude α-cyanoacrylate product;

[0040] The plasticizer is selected from one or more of tri-methyl benzene phosphate, dioctyl terephthalate, tri-butyl citrate and acetyl tri-butyl citrate. The plasticizer can effectively reduce the apparent viscosity of the prepolymer during the depolymerization process, promote the uniform dispersion of the components in the system, and accelerate the escape of the product α-cyano acrylate monomer vapor from the reaction system;

[0041] The ratio of the poly(α-cyano acrylate) prepolymer to the added amount of the plasticizer is 100 g:(2-18) mL, preferably 100 g:(5-15) mL, and more preferably 100 g:(8-12) mL;

[0042] The water removal agent is phosphorus pentoxide. The depolymerization process is accompanied by the generation of a small amount of water, which acts as an anion polymerization initiator, initiating the secondary polymerization of α-cyano acrylate monomers, reducing the reaction yield. The present application removes the trace amount of water by adding a water removal agent;

[0043] The ratio of the poly(α-cyano acrylate) prepolymer to the added amount of the water removal agent is 100 g:(1-7) g, preferably 100 g:(3-5) g;

[0044] The acidic catalyst is phosphoric acid. The ratio of the poly(α-cyano acrylate) prepolymer to the added amount of the acidic catalyst is 100 g:(0.2-1.8) g, preferably 100 g:(0.5-1.5) g, and more preferably 100 g:

[0045] (0.8-1.2) g;

[0046] The radical polymerization inhibitor is one or more of hydroquinone, tert-butyl hydroquinone, p-hydroxyanisole, and p-benzoquinone, preferably hydroquinone. The generated α-cyano acrylate monomers in the depolymerization process may be heated to initiate radical polymerization at high temperatures, reducing the reaction yield. The present application effectively captures the active radicals generated in the reaction system by introducing a radical polymerization inhibitor, thereby inhibiting the occurrence of secondary polymerization;

[0047] The ratio of the poly(α-cyano acrylate) prepolymer to the added amount of the radical polymerization inhibitor is 100 g:(0.5-4) g, preferably 100 g:(1.5-2.5) g;

[0048] The anion polymerization inhibitor is selected from one or more of sulfur dioxide, p-toluenesulfonic acid, benzoic acid, phthalic anhydride, and dodecanethiol, preferably p-toluenesulfonic acid and sulfur dioxide, and more preferably sulfur dioxide. In the depolymerization reaction process, there may be a small amount of residual water and alkaline catalyst. The present application inhibits anionic secondary polymerization by adding an anion polymerization inhibitor to improve the reaction yield;

[0049] The ratio of the poly (α-cyanoacrylate) prepolymer to the anionic polymerization inhibitor is 100g:(0.1-2) g, preferably 100g:(0.5-1.5) g;

[0050] The vacuum degree of the vacuum environment of the depolymerization reaction is less than -0.1 MPa;

[0051] The melting temperature of the prepolymer is selected from 50-100℃, preferably 60-90℃, more preferably 70-80℃; and the temperature for removing the forefraction is selected from 100-170℃, preferably 140-170℃, more preferably 160-170℃;

[0052] The reaction temperature of the depolymerization reaction is 170-220℃, preferably 180-210℃, more preferably 190-200℃; a too low reaction temperature results in incomplete depolymerization reaction, increased residual amount of the prepolymer, decreased yield of the target product, and significantly reduced reaction rate. A too high reaction temperature will induce side reactions such as ester group cleavage of the prepolymer, accelerate the decomposition and oxidation process of the α-cyanoacrylate monomer, and intensify the diffusion of low-boiling impurities into the product;

[0053] In step (3), the α-cyanoacrylate crude product is added with a water-removing agent and a free radical polymerization inhibitor, and an α-cyanoacrylate medical adhesive is prepared by vacuum distillation under reduced pressure. The temperature for collecting the pure fraction is selected from 100-140℃, preferably 110-130℃;

[0054] The ratio of the α-cyanoacrylate crude product to the amount of water removing agent is 100g:(0.5-4)g, preferably 100g:(1.5-2.5)g; the ratio of the α-cyanoacrylate crude product to the amount of radical polymerization inhibitor is 100g:(0.5-3)g, preferably 100g:(0.5-1.5)g; in view of the differences in the physical and chemical properties of different types of α-cyanoacrylates, there are different reaction temperatures and distillate collection temperatures in the step (3). Taking a common type of α-cyanoacrylate medical adhesive as an example, the reaction temperature for vacuum rectification of the α-cyanoacrylate butyl ester crude product is 60-120°C, preferably 80-100°C, the vapor temperature of the α-cyanoacrylate butyl ester pure distillate is 50-80°C, preferably 60-70°C, the reaction temperature for vacuum rectification of the α-cyanoacrylate octyl ester crude product is 100-140°C, preferably 120-135°C, the vapor temperature of the α-cyanoacrylate octyl ester pure distillate is 90-120°C, preferably 100-110°C, and the reaction temperature for vacuum rectification of the α-cyanoacrylate alkoxy ester crude product is 80-120°C, preferably 90-110°C. The vapor temperature of the α-cyanoacrylate alkoxy ester pure distillate is 90-120°C, preferably 100-110°C.

[0055] Example 1

[0056] In this example, compared with the conventional technology, first, 18-crown-6 ether-6 and hydrophobic fumed nano-silica are used to prepare a poly(α-cyanoacrylate butyl ester) prepolymer; then α-cyanoacrylate butyl ester is prepared by programmed temperature depolymerization, which specifically includes the following steps:

[0057] (1) Take 0.72g piperidine and 35.28g deionized water and add them to a sample bottle to prepare a 2wt% piperidine aqueous solution for standby use. Take 6.34g of 18-crown-6 ether-6, 0.85g of hydrophobic fumed nano-silica and 120.00g of deionized water and add them to a 1000mL three-necked round-bottom flask in sequence, place the three-necked flask in a 50°C oil bath, and use a mechanical stirrer with a speed of 300rpm to stir it, after 10min, the dispersant is uniformly dispersed in the water. Add 169.20g of cyanoacetic acid n-butyl ester and 97.30g of 37.00wt% formaldehyde aqueous solution to the three-necked flask in sequence, when the liquid temperature in the three-necked flask rises to 50°C, add the above-mentioned 2wt% piperidine aqueous solution dropwise through a constant pressure funnel, and complete the dropwise addition within 10-20min. Increase the oil bath temperature to 90°C, and continue the reaction for 5h by mechanical stirring at a speed of 300rpm. After 5h of reaction, add 1.84g of phosphoric acid to the three-necked flask to neutralize the piperidine, and after stirring for 10min, the reaction is terminated, and 180.36g of prepolymer is obtained, with a yield of 98.3%.

[0058] (2) The upper layer liquid in the three-necked flask was discharged, and the poly(n-butyl α-cyanoacrylate) prepolymer was quickly removed from the flask and placed in a 3000 mL beaker. 2000 mL of deionized water was added to the 3000 mL beaker, and then the prepolymer was washed under mechanical stirring at 500 rpm for 10 min, after which the deionized water was removed by suction filtration. The prepolymer was added to a pulverizer and pulverized to obtain poly(n-butyl α-cyanoacrylate) prepolymer powder. The prepolymer powder was evenly spread on a tray and placed in a forced air drying oven for drying at a temperature of 50°C for 12 h, with the tray being turned over several times to ensure uniform drying. Then, the prepolymer was transferred to a vacuum drying oven and dried at a temperature of 50°C for 8 h, with the vacuum degree in the vacuum drying oven being maintained below -0.1 MPa to completely remove the water contained in the prepolymer.

[0059] (3) A dry 250 mL single-necked round-bottom flask was taken, and 1.80 g of hydroquinone and 3.60 g of P2O5 were added to the single-necked flask, which was sealed with a plug and reserved. A 1000 mL straight three-necked round-bottom flask was sequentially charged with 18 mL of cresyl phosphate, 180 g of poly(n-butyl α-cyanoacrylate) prepolymer powder, 1.80 mL of phosphoric acid, 3.60 g of hydroquinone, and 1.80 g of p-toluenesulfonic acid. The three-necked flask was placed in an 80°C oil bath, and the prepolymer was slowly melted after being heated, and the raw materials were fully mixed and uniformly distributed by mechanical stirring at 200 rpm. After the prepolymer was completely melted, the oil bath temperature was increased to 120°C, the vacuum system was opened, and the vacuum degree of the reaction system was adjusted to be less than -0.10 MPa. A small amount of water was quickly removed from the reaction system under vacuum. The vacuum system was closed, 7.20 g of P2O5 was added to the three-necked flask, and the above dry 250 mL single-necked round-bottom flask was used as the crude n-butyl α-cyanoacrylate product receiving bottle. The vacuum system was opened, the oil bath temperature was increased to 180°C, and the front fraction was collected. Then the temperature of the reaction system was quickly increased to 193°C, and the poly(n-butyl α-cyanoacrylate) prepolymer was depolymerized into monomers at high temperature. The fraction collected at 100-130°C was the crude n-butyl α-cyanoacrylate monomer. 146.16 g of crude monomer was collected, with a yield of 81.2%.

[0060] (4) A vacuum distillation apparatus was installed on a receiving flask containing the crude product and a certain amount of hydroquinone and P2O5. The receiving flask containing the crude α-cyanoacrylate was heated to 95°C, and the fraction at 60–70°C was collected to obtain α-cyanoacrylate n-butyl ester as a medical adhesive monomer. After distillation, 200 ppm of hydroquinone was added to the α-cyanoacrylate n-butyl ester monomer, and the mixture was sealed and stored in a drying tower. 132.49 g of monomer was obtained, with a yield of 90.7%. Based on n-butyl cyanoacetate, the overall yield of this preparation process was 72.4%. The purity of α-cyanoacrylate n-butyl ester was determined to be 99.52% by gas chromatography-mass spectrometry.

[0061] The chemical structure of α-cyanoacrylate (BCA) monomer was characterized using liquid nuclear magnetic resonance spectroscopy, and its 1H NMR spectrum is shown below. Figure 1 As shown.

[0062] According to standard YY / T 0729-2009, its lap-shear strength and wound closure strength were tested, such as... Figure 4 As shown.

[0063] Example 2

[0064] This example uses 18-crown ether-6 and hydrophobic fumed silica nanoparticles to prepare poly(octyl α-cyanoacrylate) prepolymer, and then prepares octyl α-cyanoacrylate by temperature-programmed depolymerization. The specific steps include:

[0065] (1) Weigh 1.01 g piperidine and 49.49 g deionized water and add them to a sample vial to prepare a 2 wt% piperidine aqueous solution for later use. Weigh 6.34 g of 18-crown ether-6, 1.182 g of hydrophobic fumed silica nanoparticles, and...

[0066] 167.66g of deionized water was added sequentially to a 1000mL three-necked round-bottom flask, and the flask was placed in a slanted three-necked round-bottom flask.

[0067] In an oil bath at 50°C, the mixture was stirred at 300 rpm for 10 minutes until the dispersant was evenly dispersed in the water. 236.4 g of n-octyl cyanoacetate and 97.30 g of a 37.00 wt% formaldehyde aqueous solution were added sequentially to a three-necked flask. When the liquid temperature in the flask reached 50°C, the above-mentioned 2 wt% piperidine aqueous solution was added dropwise through a constant-pressure funnel over 10–20 minutes. The oil bath temperature was raised to 90°C, and the reaction was continued for 5 hours with mechanical stirring at 300 rpm. After 5 hours of reaction, 2.57 g of phosphoric acid was added to the three-necked flask to neutralize the piperidine. The reaction was terminated after stirring for 10 minutes, yielding 246.7 g of prepolymer, with a yield of 98.4%.

[0068] (2) is the same as step (2) in Example 1.

[0069] (3) Take a dry 250 mL single neck round bottom flask, add 2.45 g of hydroquinone and 4.90 g of P2O5 into the single neck flask, seal the neck with a plug, and reserve. In a 1000 mL straight three neck round bottom flask, add 24.5 mL of tricresyl phosphate, 245 g of poly(n-octyl α-cyanoacrylate) prepolymer powder, 2.45 mL of phosphoric acid, 4.90 g of hydroquinone and 2.45 g of p-toluenesulfonic acid in sequence. Put the three neck flask into an 80 °C oil bath, and the prepolymer is slowly melted after heating, and the raw materials are fully mixed and uniformly distributed by mechanical stirring at 200 rpm. When the prepolymer is completely melted, increase the oil bath temperature to 120 °C, open the vacuum system, and adjust the vacuum degree of the reaction system to less than -0.10 MPa. A small amount of moisture is quickly removed from the reaction system under vacuum. Close the vacuum system, quickly add 9.80 g of P2O5 to the three neck flask, and use the above-mentioned dry 250 mL single neck round bottom flask as the crude n-octyl α-cyanoacrylate product receiving bottle. Open the vacuum system, increase the oil bath temperature to 190 °C, and collect the front fraction. Then quickly increase the temperature of the reaction system to 200 °C, and the poly(n-octyl α-cyanoacrylate) prepolymer is depolymerized into monomer at high temperature. The fraction collected at 120-140 °C is the crude n-octyl α-cyanoacrylate monomer. 175.2 g of crude monomer is collected, with a yield of 71.5%.

[0070] (4) Install a vacuum distillation device on the receiving bottle containing the crude product and a certain amount of hydroquinone and P2O5. Heat the n-octyl α-cyanoacrylate crude product receiving bottle to 135 °C, and collect the fraction at 100-110 °C to obtain the n-octyl α-cyanoacrylate medical adhesive monomer. After distillation is complete, add 200 ppm of hydroquinone to the n-octyl α-cyanoacrylate monomer and seal it in a dry tower for storage. 157.87 g of monomer is obtained, with a yield of 90.1%. Based on n-octyl cyanoacetate, the total yield of this preparation process is 63.4%. The purity of n-octyl α-cyanoacrylate is 99.42% as determined by gas chromatography-mass spectrometry.

[0071] The chemical structure of the n-octyl α-cyanoacrylate (OCA) monomer is characterized by liquid nuclear magnetic resonance spectrometer, and the nuclear magnetic hydrogen spectrum (1H - NMR) is as shown in Figure 2 .

[0072] The lap-shear strength and wound closure strength are tested according to the standard YY / T 0729-2009, as shown in Figure 4 .

[0073] Example 3

[0074] The poly(α-cyanoacrylate ethoxyethyl ester) prepolymer is prepared by using 18-crown-6 and hydrophobic fumed silica, and the α-cyanoacrylate ethoxyethyl ester is prepared by programmed temperature depolymerization, specifically including:

[0075] (1) The poly(α-cyanoacrylate ethoxyethyl ester) prepolymer is prepared by using ethoxyethyl cyanoacetate as a reference, and the other raw materials are added into the reaction system in the same ratio, feeding mode and sequence, and the polycondensation reaction is carried out, and the yield is 90.5%.

[0076] (2) The side chain ester group of the poly(α-cyanoacrylate ethoxyethyl ester) prepolymer contains an ether bond with good flexibility, and the relative molecular mass of the prepolymer is low. The prepolymer is in a viscous flow state at room temperature, and is not suitable for washing the prepolymer by the steps in Examples 1 and 2. After the completion of the polycondensation reaction, the reaction system is allowed to stand for 3 h, and after the system is layered, the supernatant is removed. The temperature of the reaction system is raised to 110°C, and the reaction system is subjected to water separation for 1 h.

[0077] (3) The α-cyanoacrylate ethoxyethyl ester crude product is prepared by using the poly(α-cyanoacrylate ethoxyethyl ester) prepolymer as a reference, and the other raw materials are added into the reaction system in the same ratio, feeding mode and sequence, and the polycondensation reaction is carried out. The melting temperature of the prepolymer in this step is 60°C, the temperature for collecting the front fraction is 185°C, the reaction temperature is 195°C, and the temperature for collecting the pure fraction is 100-120°C.

[0078] (4) The reaction temperature in this step is 105°C, and the fraction collected is 65-75°C. The total yield of this preparation process is 47.8% based on ethoxyethyl cyanoacetate. The purity of the α-cyanoacrylate ethoxyethyl ester is 99.38% determined by gas chromatography-mass spectrometry.

[0079] The chemical structure of the α-cyanoacrylate ethoxyethyl ester (EOCA) monomer is characterized by a liquid nuclear magnetic resonance spectrometer, and the nuclear magnetic hydrogen spectrum (1H - NMR) is as shown in Figure 3 .

[0080] The lap-shear strength and wound closure strength are tested according to the standard YY / T 0729-2009, as shown in Figure 4 .

[0081] Comparative Example 1

[0082] This example changes the type of dispersant, and sodium dodecyl sulfate is used to prepare poly (n-octyl α-cyanoacrylate) prepolymer, and then n-octyl α-cyanoacrylate is prepared by programmed temperature depolymerization, which is a comparative example for further illustrating the performance of the technical scheme of the present application. Specifically, surfactant sodium dodecyl sulfate (SDS) is used as a dispersant instead of phase transfer catalyst 18-crown-6 and hydrophobic fumed nano-silica as a nano-dispersant to prepare n-octyl α-cyanoacrylate. The rest of the experimental conditions (including raw material ratio, feeding method, feeding sequence, reaction time, etc.) are the same as those in Example 2. In the process of preparing poly (n-octyl α-cyanoacrylate) prepolymer, the yield of this comparative example is 78.3%, which is significantly lower than the prepolymer yield in Example 2. Based on n-octyl cyanoacetate, the total yield of n-octyl α-cyanoacrylate is 43.8%.

[0083] Comparative Example 2

[0084] This example changes the type of dispersant, and sodium dodecyl sulfate is used to prepare poly (n-octyl α-cyanoacrylate) prepolymer, and then n-octyl α-cyanoacrylate is prepared by programmed temperature depolymerization, which is a comparative example for further illustrating the performance of the technical scheme of the present application. Specifically,

[0085] Surfactant sodium dodecyl sulfate (SDS) is used as a dispersant instead of phase transfer catalyst 18-crown-6 and hydrophobic fumed nano-silica as a nano-dispersant to prepare n-octyl α-cyanoacrylate. The rest of the experimental conditions (including raw material ratio, feeding method, feeding sequence, reaction time, etc.) are the same as those in Example 3. In the process of preparing poly (n-octyl α-cyanoacrylate) prepolymer, the yield of this comparative example is 78.3%, which is significantly lower than the prepolymer yield in Example 2. Based on n-octyl cyanoacetate, the total yield of n-octyl α-cyanoacrylate is 43.8%.

[0086] Comparative Example 3

[0087] This example changes the type of dispersant, and sodium dodecyl sulfate is used to prepare poly (n-octyl α-cyanoacrylate) prepolymer, and then n-octyl α-cyanoacrylate is prepared by programmed temperature depolymerization, which is a comparative example for further illustrating the performance of the technical scheme of the present application. Specifically,

[0088] In the process of polycondensation of n-butyl cyanoacetate and formaldehyde, only hydrophobic fumed nano-silica is added as a nano-dispersant to prepare n-butyl α-cyanoacrylate. The rest of the experimental conditions (including raw material ratio, feeding method, feeding sequence, reaction time, etc.) are the same as those in Example 1. The yield of poly (n-butyl α-cyanoacrylate) prepolymer is 93.2%, which reduces the yield of the prepolymer. At the same time, based on n-butyl cyanoacetate, the total yield of n-butyl α-cyanoacrylate is also reduced to 65.6%.

[0089] Comparative Example 4

[0090] In this example, the type of dispersant is changed, and only hydrophobic fumed nano-silica is used to prepare poly (α-cyanoacrylate) prepolymers of octyl cyanoacrylate, and then α-cyanoacrylate is prepared by programmed temperature depolymerization. Specifically, in the polycondensation process of n-octyl cyanoacetate and formaldehyde, only hydrophobic fumed nano-silica is added as a nano-dispersant to prepare α-cyanoacrylate. The remaining experimental conditions (including raw material ratio, feeding method, feeding sequence, reaction time, etc.) are the same as those in Example 2. The yield of poly (α-cyanoacrylate) prepolymer is 90.8%, and the yield of the prepolymer is reduced. At the same time, the total yield of α-cyanoacrylate is also reduced to 56.4% based on n-octyl cyanoacetate.

[0091] Comparative Example 5

[0092] In this example, the type of dispersant is changed, and only hydrophobic fumed nano-silica is used to prepare poly (α-cyanoacrylate) prepolymers of ethoxyethyl cyanoacrylate, and then α-cyanoacrylate is prepared by programmed temperature depolymerization. Specifically, in the polycondensation process of ethoxyethyl cyanoacetate and formaldehyde, only hydrophobic fumed nano-silica is added as a nano-dispersant to prepare α-cyanoacrylate. The remaining experimental conditions (including raw material ratio, feeding method, feeding sequence, reaction time, etc.) are the same as those in Example 3. The yield of poly (α-cyanoacrylate) prepolymer is 84.1%, and the yield of the prepolymer is reduced. At the same time, the total yield of α-cyanoacrylate is also reduced to 40.6% based on ethoxyethyl cyanoacetate.

[0093] Comparative Example 6

[0094] In this example, the polycondensation process uses both 18-crown-6 and hydrophobic fumed nano-silica to prepare poly (α-cyanoacrylate) prepolymers of butyl cyanoacrylate, but the depolymerization process does not use programmed temperature, and the depolymerization temperature is directly raised to 193°C to prepare α-cyanoacrylate. Specifically,

[0095] The poly (α-cyanoacrylate) prepolymer and the corresponding raw materials are added to a three-necked flask, the vacuum system is started, and the temperature is directly raised to 193°C for depolymerization. The fraction is collected to obtain crude α-cyanoacrylate monomer. The crude monomer is purified by vacuum distillation to obtain α-cyanoacrylate medical adhesive. The remaining experimental conditions (including raw material ratio, feeding method, feeding sequence, reaction time, etc.) are the same as those in Example 1. Based on n-butyl cyanoacetate, the total yield of α-cyanoacrylate is 64.3%. The purity of α-cyanoacrylate is 98.56% as determined by gas chromatograph.

[0096] Comparative Example 7

[0097] The poly (α-cyanoacrylic acid ethoxyethyl ester) prepolymer is prepared by using 18-crown-6 and hydrophobic fumed nano-silica in the polycondensation process, and the difference is that the depolymerization process has no programmed temperature rise, and the depolymerization temperature is directly raised to 195°C to prepare α-cyanoacrylic acid ethoxyethyl ester. Specifically, the poly (α-cyanoacrylic acid ethoxyethyl ester) prepolymer and the corresponding raw materials are added to a three-necked flask, the vacuum system is started, and the temperature is directly raised to 195°C for depolymerization. The α-cyanoacrylic acid ethoxyethyl ester crude monomer is collected by distillation. The crude monomer is purified by reduced pressure distillation to obtain an α-cyanoacrylic acid ethoxyethyl ester medical adhesive. The rest of the experimental conditions (including raw material ratio, feeding method, feeding sequence, reaction time, etc.) are the same as those in Example 3. Based on cyanoacetic acid ethoxyethyl ester, the total yield of α-cyanoacrylic acid ethoxyethyl ester is 34.7%. The purity of α-cyanoacrylic acid ethoxyethyl ester is 95.19% as determined by a gas chromatograph.

[0098] The poly (α-cyanoacrylic acid ethoxyethyl ester) prepolymer and the corresponding raw materials are added to a three-necked flask, the vacuum system is started, and the temperature is directly raised to 195°C for depolymerization. The α-cyanoacrylic acid ethoxyethyl ester crude monomer is collected by distillation. The crude monomer is purified by reduced pressure distillation to obtain an α-cyanoacrylic acid ethoxyethyl ester medical adhesive. The rest of the experimental conditions (including raw material ratio, feeding method, feeding sequence, reaction time, etc.) are the same as those in Example 3. Based on cyanoacetic acid ethoxyethyl ester, the total yield of α-cyanoacrylic acid ethoxyethyl ester is 34.7%. The purity of α-cyanoacrylic acid ethoxyethyl ester is 95.19% as determined by a gas chromatograph.

[0099] Comparative Example 8

[0100] The poly (α-cyanoacrylic acid ethoxyethyl ester) prepolymer is prepared by using 18-crown-6 and hydrophobic fumed nano-silica in the polycondensation process, and the difference is that the depolymerization process has no programmed temperature rise, and the depolymerization temperature is directly raised to 195°C to prepare α-cyanoacrylic acid ethoxyethyl ester. Specifically, the poly (α-cyanoacrylic acid ethoxyethyl ester) prepolymer and the corresponding raw materials are added to a three-necked flask, the vacuum system is started, and the temperature is directly raised to 195°C for depolymerization. The α-cyanoacrylic acid ethoxyethyl ester crude monomer is collected by distillation. The crude monomer is purified by reduced pressure distillation to obtain an α-cyanoacrylic acid ethoxyethyl ester medical adhesive. The rest of the experimental conditions (including raw material ratio, feeding method, feeding sequence, reaction time, etc.) are the same as those in Example 3. Based on cyanoacetic acid ethoxyethyl ester, the total yield of α-cyanoacrylic acid ethoxyethyl ester is 34.7%. The purity of α-cyanoacrylic acid ethoxyethyl ester is 95.19% as determined by a gas chromatograph.

[0101] In summary, by using the preparation method of the high-yield alpha-cyanoacrylate medical adhesive provided by the application, examples 1-3 successfully prepared various types of alpha-cyanoacrylate medical adhesives with high yield and high purity under the synergistic effect of phase transfer catalyst 18-crown-6 and nanodispersion agent hydrophobic fumed nanosilica, and with water as the dispersion medium. And through comparative tests, it is shown that: (1) compared with comparative examples 1-2, the use of the synergistic effect of the phase transfer catalyst and the nanodispersion agent instead of the surfactant can significantly improve the product yield; (2) compared with comparative examples 3-5, while the nanodispersion agent improves the contact area of the reactants, the use of the phase transfer catalyst further improves the reaction degree of the raw materials and the product yield; (3) compared with comparative examples 6-8, the use of the programmed temperature method for depolymerization reaction effectively inhibits the side reactions in the reaction process, improves the reaction yield, and significantly improves the product purity.

Claims

1. A process for preparing a high yield of α-cyanoacrylate medical adhesive, characterized by, The poly(alpha-cyanoacrylate) prepolymer is prepared by condensation polymerization of cyanoacetate and formaldehyde aqueous solution in the presence of phase transfer catalyst and hydrophobic inorganic nano-dispersant with deionized water as dispersion medium. The prepolymer is then melted by programmed temperature process, and then the front fraction is removed by heating, and then the prepolymer is rapidly heated to depolymerization temperature to make the prepolymer depolymerize to form alpha-cyanoacrylate crude product. The crude product is subjected to vacuum rectification to obtain high-purity alpha-cyanoacrylate medical adhesive. The phase transfer catalyst is one or more of crown ether compounds, quaternary ammonium salt compounds and polyether compounds. The crown ether compounds are one or more of 18-crown-6, 15-crown-5, 12-crown-4 and cyclodextrin. The quaternary ammonium salt compounds are one or more of benzyltriethylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium chloride and tetrabutylammonium hydrogen sulfate. The polyether compounds are one or more of polyethylene glycol PEG-400, polyethylene glycol PEG-600 or polyethylene oxide. The hydrophobic inorganic nano-dispersant is one or more of hydrophobic fumed nano-silica, titanium dioxide, aluminum trioxide and carbon nanoparticles.

2. The method for preparing a high-yield α-cyanoacrylate medical adhesive according to claim 1, characterized in that, The method comprises the following steps: Step 1: cyanoacetate and formaldehyde aqueous solution are used as raw materials, deionized water is used as dispersion medium, phase transfer catalyst, hydrophobic inorganic nano-dispersant and alkaline catalyst are added, and condensation polymerization is carried out under the action of mechanical stirring. After the reaction is completed, the alkaline catalyst is neutralized by adding acidic substance to obtain poly(alpha-cyanoacrylate) prepolymer. The prepolymer is cooled and then subjected to crushing, washing and drying to obtain prepolymer powder. The mass fraction of the formaldehyde aqueous solution is 30wt%-40wt%, the molar ratio of cyanoacetate to formaldehyde is 1mol:(1-1.1)mol, the mass ratio of cyanoacetate to water is 1:(0.3-1.1), the molar ratio of cyanoacetate to phase transfer catalyst is 1mol:(0.001-0.05mol), the alkaline catalyst is one or more of organic amine compounds and inorganic base compounds, the organic amine compounds are one or more of piperidine, pyrrolidine, triethylamine and pyridine, the inorganic base compounds are potassium carbonate and sodium carbonate, the mass ratio of cyanoacetate to alkaline catalyst is 1:(0.002-0.006), the alkaline catalyst is diluted into aqueous solution, and then added into the reaction system. The mass fraction of the alkaline catalyst aqueous solution is 0.5wt%-5wt%, the mechanical stirring rate is 200rpm-1000rpm, the condensation polymerization temperature is 50°C-90°C, the reaction time is 3h-10h, and the acidic substance is phosphoric acid. Step 2: Perform depolymerization reaction, add plasticizer, water-removing agent, acidic catalyst, free radical polymerization inhibitor and anionic polymerization inhibitor to the poly (α-cyanoacrylate) prepolymer, wherein the ratio of the poly (α-cyanoacrylate) prepolymer to the plasticizer is 100g:(2-18)mL, the ratio of the poly (α-cyanoacrylate) prepolymer to the water-removing agent is 100g:(1-7)g, the ratio of the poly (α-cyanoacrylate) prepolymer to the acidic catalyst is 100g:(0.2-1.8)g, the ratio of the poly (α-cyanoacrylate) prepolymer to the free radical polymerization inhibitor is 100g:(0.5-4)g, and the ratio of the poly (α-cyanoacrylate) prepolymer to the anionic polymerization inhibitor is 100g:(0.1-2)g, melt the prepolymer at a temperature of 50-100℃, then heat to 100-170℃ to remove the front fraction, and then rapidly heat to the depolymerization temperature of 170-220℃ to depolymerize the prepolymer to generate α-cyanoacrylate crude product; Step 3: Add water-removing agent and free radical polymerization inhibitor to the α-cyanoacrylate crude product, and perform vacuum distillation under reduced pressure to obtain α-cyanoacrylate medical adhesive, wherein the ratio of the α-cyanoacrylate crude product to the water-removing agent is 100g:(0.5-4)g, the ratio of the α-cyanoacrylate crude product to the free radical polymerization inhibitor is 100g:(0.5-3)g, and the temperature range for collecting the pure fraction is 100-140℃.

3. The process for preparing a high yield of α-cyanoacrylate medical adhesive according to claim 2, characterized by, The drying in step 1 is vacuum drying based on air drying, wherein the temperature range for air drying is 30-60℃, the air blowing time is 5-48h, the temperature range for vacuum drying is 30-60℃, and the drying time is 3-24h.

4. The process for preparing a high yield of α-cyanoacrylate medical adhesive according to claim 2, wherein the process is characterized by, In step 1, the mass fraction of the formaldehyde aqueous solution is 36wt%-38wt%.

5. The process for preparing a high yield of α-cyanoacrylate medical adhesive according to claim 2, wherein the process is characterized by, In step 1, the molar ratio of the cyanoacetate to formaldehyde is 1mol:1mol, the mass ratio of the cyanoacetate to water is 1:(0.5-0.9), the phase transfer catalyst is 18-crown-6, the molar ratio of the cyanoacetate to the phase transfer catalyst is 1mol:(0.005-0.01mol), the hydrophobic inorganic nano-dispersant is silicon dioxide, the mass ratio is 1:(0.001-0.01), the basic catalyst is piperidine, the mass ratio of the cyanoacetate to the basic catalyst is 1:(0.003-0.005), and the mass fraction of the aqueous solution of the basic catalyst is 1.5-2.5wt%.

6. The process for preparing a high yield of α-cyanoacrylate medical adhesive according to claim 2, wherein the process is characterized by, In step 1, the rate of mechanical stirring is 200-600rpm, the temperature range for the polycondensation reaction is 60-90℃, and the reaction time is 4-6h.

7. The process for preparing a high yield of α-cyanoacrylate medical adhesive according to claim 2, wherein the process is characterized by, In step 2, the plasticizer is selected from one or more of tricresyl phosphate, dioctyl terephthalate, tributyl citrate and acetyl tributyl citrate, the plasticizer can effectively reduce the apparent viscosity of the prepolymer in the depolymerization process, promote the uniform dispersion of the components in the system, and accelerate the escape of the product α-cyanoacrylate monomer vapor from the reaction system, the ratio of the amount of the poly(α-cyanoacrylate) prepolymer to the amount of the plasticizer is 100g:(5-15)mL, the water removal agent is phosphorus pentoxide to remove trace amounts of water, the ratio of the amount of the poly(α-cyanoacrylate) prepolymer to the amount of the water removal agent is 100g:(3-5)g, the acidic catalyst is phosphoric acid, the ratio of the amount of the poly(α-cyanoacrylate) prepolymer to the amount of the acidic catalyst is 100g:(0.5-1.5)g, the free radical polymerization inhibitor is selected from one or more of hydroquinone, tert-butyl hydroquinone, p-hydroxyanisole, and p-benzoquinone, the ratio of the amount of the poly(α-cyanoacrylate) prepolymer to the amount of the free radical polymerization inhibitor is 100g:(1.5-2.5)g, and the anionic polymerization inhibitor is selected from one or more of sulfur dioxide, p-toluenesulfonic acid, benzoic acid, phthalic anhydride, and dodecanethiol, the ratio of the amount of the poly(α-cyanoacrylate) prepolymer to the amount of the anionic polymerization inhibitor is 100g:(0.5-1.5)g.

8. The process for preparing a high yield of α-cyanoacrylate medical adhesive according to claim 2, wherein In step 2, the melting temperature of the prepolymer is 60-90°C, the temperature for removing the front fraction is 140-170°C, and the reaction temperature for the depolymerization reaction is 180-210°C.

9. The process for preparing a high yield of α-cyanoacrylate medical adhesive according to claim 2, wherein In step 3, the reaction temperature for the vacuum distillation of the crude butyl α-cyanoacrylate is 60-120°C, the vapor temperature for the pure fraction of the butyl α-cyanoacrylate is 50-80°C, the reaction temperature for the vacuum distillation of the crude octyl α-cyanoacrylate is 100-140°C, the vapor temperature for the pure fraction of the octyl α-cyanoacrylate is 90-120°C, the reaction temperature for the vacuum distillation of the crude alkoxy α-cyanoacrylate is 80-120°C, and the vapor temperature for the pure fraction of the octyl α-cyanoacrylate is 90-120°C.

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