Synthetic method of medical cyanoacrylate adhesive with low formaldehyde residue

Abstract

The invention relates to the technical field of instant adhesives, and particularly discloses a synthesis method of a medical cyanoacrylate adhesive with low formaldehyde residue, which adopts a method of adding a formaldehyde reaction removal agent after the condensation polymerization of cyanoacetate and formaldehyde is finished to effectively remove the formaldehyde which is not completely reacted, so that the formaldehyde residue is reduced. The method provided by the invention has the advantages that the formaldehyde residue in the alpha-cyanoacrylate is obviously reduced, the clinical use safety of the alpha-cyanoacrylate is improved, and the method provided by the invention is simple and easy to operate; meanwhile, the requirement on equipment is not high, the investment is less, and the process is simple, convenient and very economical.

Description

Technical Field

[0001] The invention belongs to the technical field of instant adhesives, and in particular relates to a method for synthesizing a medical cyanoacrylate adhesive with low formaldehyde residue. Background Art

[0002] Due to its special chemical structure, α-cyanoacrylate is very easy to encounter Lewis alkaline substances (such as water, amino acids, proteins, etc.) at room temperature, and undergo rapid polymerization to achieve strong adhesion. At the same time, this type of substance has good biocompatibility and chemical stability, is solvent-free, and has low toxicity. When it comes into contact with the surface of human skin or wounds, it can react quickly with trace alkaline substances (proteins, tissue fluids, blood, water, etc.) to form a tough adhesive film, thereby effectively sealing tiny wounds. Therefore, α-cyanoacrylate, such as n-butyl cyanoacrylate and n-octyl cyanoacrylate, are widely used in the rapid bonding of micro-wounds on the body surface and the rapid hemostasis of internal organs.

[0003] However, existing cyanoacrylate medical adhesives often have formaldehyde residues (>1000ppm) during the synthesis process. Formaldehyde is a toxic and harmful substance that poses a great threat to human health. Even a trace amount of formaldehyde residue in medical adhesives may cause allergic reactions or other adverse reactions in patients, thereby affecting the safety and use effect of medical adhesives.

[0004] In order to solve this problem, researchers have conducted a lot of research and exploration. For example, in patent CN101580810A, a method for reducing the residual formaldehyde in cyanoacrylate medical glue is provided, which reduces the residual free formaldehyde by optimizing the synthesis conditions and adding a specific catalyst. However, this method still has some shortcomings in practical application, such as harsh reaction conditions, high catalyst cost, and still high residual formaldehyde.

[0005] In addition, in patent CN103555137A, a method for synthesizing cyanoacrylate medical adhesive using formaldehyde as raw material is proposed, and the method reduces the residual amount of formaldehyde by changing the reaction steps and reaction conditions. However, this method still cannot completely avoid the generation and residual of free formaldehyde, and the reaction process is relatively complicated, which is not conducive to industrial production. Therefore, it is necessary to provide a more effective, simple and low-cost synthesis method to reduce the residual amount of formaldehyde in cyanoacrylate medical adhesive and improve its safety and use effect. Summary of the invention

[0006] The object of the present invention is to provide a method for synthesizing a medical cyanoacrylate glue with low formaldehyde residue, so as to solve the problems raised in the above background technology.

[0007] To achieve the above object, the present invention provides the following technical solutions:

[0008] A method for synthesizing a medical cyanoacrylate adhesive with low formaldehyde residue comprises the following steps:

[0009] 1) α-cyanoacetate, 92% polyoxymethylene and an alkaline catalyst are mixed in an organic solvent in a certain proportion and heated to carry out a polycondensation reaction;

[0010] 2) adding phosphoric acid to terminate the reaction, and then adding a formaldehyde reaction remover to remove the incompletely reacted formaldehyde;

[0011] 3) stopping stirring, allowing the product in step 2) to stand to separate water, and extracting the upper layer of water;

[0012] 4) Add purified water to the product of step 3) to wash it, and then repeat the operation in step 3);

[0013] 5) dehydrating and desolventizing the product obtained in step 4) to obtain a cyanoacrylate prepolymer;

[0014] 6) adding antioxidant 2246 and p-toluenesulfonic acid to the prepolymer, and then cracking it at high temperature under vacuum conditions to obtain a crude monomer;

[0015] 7) The crude monomer is distilled and purified under vacuum to obtain high-purity α-cyanoacrylate.

[0016] Preferably, the α-cyanoacetate in step 1) is one of n-butyl cyanoacetate, isobutyl cyanoacetate, n-octyl cyanoacetate or sec-octyl cyanoacetate.

[0017] Preferably, the alkaline catalyst in step 1) is a mixture of piperidine and piperidine phosphate, and the weight ratio of piperidine to piperidine phosphate is 1:1.

[0018] Preferably, the molar ratio of cyanoacetate to formaldehyde in step 1) is (1.03-1.1):1.

[0019] Preferably, the molar ratio of cyanoacetate to formaldehyde in step 1) is (1.05-1.1):1.

[0020] Preferably, the mass ratio of the alkaline catalyst to formaldehyde in step 1) is (0.003-0.007):1.

[0021] Preferably, the mass ratio of the neutral alkaline catalyst to formaldehyde in step 1) is 0.005:1.

[0022] Preferably, the reaction time in step 1) is 2 to 3 hours, and the formaldehyde removal agent in step 2) is any one or more combinations of sodium sulfite, sodium hydrogen sulfite, and sodium thiosulfate.

[0023] Preferably, the mass ratio of the formaldehyde reaction removing agent to formaldehyde in step 2) is (0.001-0.005):1, and the formaldehyde reaction removing time in step 2) is 30-60 min; the standing water separation time in step 3) is 30 min-2 h; and the mass ratio of purified water to formaldehyde in step 4) is (0.5-1):1.

[0024] Preferably, the formaldehyde removal reaction time in step 2) is 30 minutes.

[0025] Preferably, the standing water separation time in step 3) is 1 to 2 hours.

[0026] Preferably, in step 4), the mass ratio of purified water to formaldehyde is (0.5-0.8):1.

[0027] Preferably, the water washing time in step 4) is 20 min to 40 min, the vacuum degree in step 6) is maintained within 20 mmHg, and the cracking temperature is 160 to 210°C.

[0028] Preferably, the washing time in step 4) is 30 minutes.

[0029] Preferably, in step 7), the vacuum degree is maintained within 20 mmHg and the distillation temperature is 60-90°C.

[0030] Compared with the prior art, the present invention has the following beneficial effects:

[0031] 1. The present invention adopts a method of adding a formaldehyde reaction remover after the polycondensation reaction of cyanoacetate and formaldehyde is completed, thereby effectively removing incompletely reacted formaldehyde, significantly reducing residual formaldehyde in α-cyanoacrylate, and improving the safety of α-cyanoacrylate in clinical use.

[0032] 2. The method provided by the present invention is simple and easy to operate; at the same time, it has low requirements on equipment and requires less investment, and is a simple and very economical process. DETAILED DESCRIPTION

[0033] The following will be combined with the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative work are within the scope of protection of the present invention.

[0034] Embodiment 1:

[0035] Preparation of α-octyl cyanoacrylate

[0036] 705.03g of 2-octyl cyanoacetate, 100g of polyoxymethylene, and 0.005g of catalyst were heated in an organic solvent for reaction for 2.5h, phosphoric acid was added to terminate the reaction, and then 0.002g of sodium sulfite, a formaldehyde reaction remover, was added. Stirring was stopped after 30min, and the mixture was allowed to stand for 1h to separate water, and the upper layer of water was extracted. Then, 80g of purified water was added, and after washing with water for 30min, dehydration and desolvation were performed to obtain a cyanoacrylate prepolymer. Then, antioxidant 2246 and p-toluenesulfonic acid were added to the prepolymer, and cracking was performed under a vacuum of 10mmHg, and the fractions at 160-210°C were collected to obtain a crude cyanoacrylate. The crude product was then purified under a vacuum of 10mmHg, and the fractions at 60-90°C were collected to obtain a high-purity 2-octyl α-cyanoacrylate. Finally, a sample was taken for free formaldehyde detection.

[0037] Embodiment 2:

[0038] Preparation of α-octyl cyanoacrylate

[0039] 705.03g of 2-octyl cyanoacetate, 100g of polyoxymethylene, and 0.005g of catalyst were heated in an organic solvent for reaction for 2.5h, phosphoric acid was added to terminate the reaction, and then 0.004g of sodium bisulfite, a formaldehyde reaction remover, was added. Stirring was stopped after 30min, and the mixture was allowed to stand for 1h to separate water, and the upper layer of water was extracted. Then, 80g of purified water was added, and after washing with water for 30min, dehydration and desolvation were performed to obtain a cyanoacrylate prepolymer. Then, antioxidant 2246 and p-toluenesulfonic acid were added to the prepolymer, and cracking was performed under a vacuum of 10mmHg, and the fractions at 160-210°C were collected to obtain a crude cyanoacrylate. The crude product was then purified under a vacuum of 10mmHg, and the fractions at 60-90°C were collected to obtain a high-purity 2-octyl α-cyanoacrylate. Finally, a sample was taken for free formaldehyde detection.

[0040] Embodiment three:

[0041] Preparation of α-octyl cyanoacrylate

[0042] 672.98g of 2-octyl cyanoacetate, 100g of polyoxymethylene, and 0.005g of catalyst were heated in an organic solvent for reaction for 2.5h, phosphoric acid was added to terminate the reaction, and 0.004g of a mixture of sodium bisulfite and sodium sulfite (mass ratio 1:1) was added. Stirring was stopped after 30min, and the mixture was allowed to stand for 1h to separate water, and the upper layer of water was extracted. Then, 60g of purified water was added, and after washing with water for 30min, dehydration and desolvation were performed to obtain a cyanoacrylate prepolymer. Then, antioxidant 2246 and p-toluenesulfonic acid were added to the prepolymer, and cracking was performed under a vacuum of 10mmHg, and the fractions at 160-210°C were collected to obtain a crude cyanoacrylate. The crude product was then purified under a vacuum of 10mmHg, and the fractions at 60-90°C were collected to obtain high-purity 2-octyl α-cyanoacrylate. Finally, sampling was performed for free formaldehyde detection.

[0043] Embodiment 4:

[0044] Preparation of α-octyl cyanoacrylate

[0045] 672.98g of 2-octyl cyanoacetate, 100g of polyoxymethylene, and 0.005g of catalyst were heated in an organic solvent for reaction for 2.5h, phosphoric acid was added to terminate the reaction, and 0.002g of sodium thiosulfate was added. Stirring was stopped after 30min, and the mixture was allowed to stand for 1h to separate water, and the upper layer of water was extracted. Then, 60g of purified water was added, and after washing with water for 30min, dehydration and desolvation were performed to obtain a cyanoacrylate prepolymer. Then, antioxidant 2246 and p-toluenesulfonic acid were added to the prepolymer, and the mixture was cracked under a vacuum of 10mmHg, and the fractions at 160-210°C were collected to obtain a crude cyanoacrylate. The crude product was then purified under a vacuum of 10mmHg, and the fractions at 60-90°C were collected to obtain high-purity 2-octyl α-cyanoacrylate. Finally, a sample was taken for free formaldehyde detection.

[0046] Comparative Example 1

[0047] Preparation of α-octyl cyanoacrylate

[0048] 705.03g of 2-octyl cyanoacetate, 100g of polyoxymethylene, and 0.005g of catalyst were heated in an organic solvent for reaction for 2.5h, and phosphoric acid was added to terminate the reaction. The mixture was allowed to stand for 1h to separate water, and the upper layer of water was extracted. Then, 80g of purified water was added, and after washing with water for 30min, dehydration and desolvation were performed to obtain a cyanoacrylate prepolymer. Then, antioxidant 2246 and p-toluenesulfonic acid were added to the prepolymer, and the mixture was cracked under a vacuum of 10mmHg, and the fractions at 160-210°C were collected to obtain a crude cyanoacrylate. The crude product was then purified under a vacuum of 10mmHg, and the fractions at 60-90°C were collected to obtain a high-purity 2-octyl α-cyanoacrylate. Finally, a sample was taken for free formaldehyde detection.

[0049] Comparative Example 2

[0050] Preparation of α-octyl cyanoacrylate

[0051] 705.03g of sec-octyl cyanoacetate, 100g of polyoxymethylene, and 0.005g of catalyst were heated in an organic solvent for reaction for 2.5h, phosphoric acid was added to terminate the reaction, the mixture was allowed to stand for 1h to separate water, and the upper layer of water was extracted. Then, dehydration and desolventization were performed to obtain a cyanoacrylate prepolymer. Then, antioxidant 2246 and p-toluenesulfonic acid were added to the prepolymer, and the prepolymer was cracked under a vacuum of 10mmHg, and the fractions at 160-210°C were collected to obtain a crude cyanoacrylate. The crude product was then purified under a vacuum of 10mmHg, and the fractions at 60-90°C were collected to obtain high-purity sec-octyl α-cyanoacrylate. Finally, sampling was performed for free formaldehyde detection.

[0052] Free formaldehyde detection:

[0053] Test object: secondary octyl α-cyanoacrylate prepared in Examples 1-4 and Comparative Examples 1-2.

[0054] Test index: unreacted free formaldehyde in the secondary octyl α-cyanoacrylate obtained in Examples 1-4 and Comparative Examples 1-2.

[0055] Test method: Acetylacetone colorimetric method. For specific steps, please refer to the acetylacetone colorimetric method in the Pharmacopoeia of the People's Republic of China (2020 edition, Volume III), and record the results in Table 1.

[0056] Table 1

[0057] Group Free formaldehyde residue Example 1 433ppm Example 2 468ppm Example 3 296ppm Example 4 627ppm Comparative Example 1 1156ppm Comparative Example 2 1200ppm

[0058] From the above, we can see that the free formaldehyde residual detection in this implementation is the least:

[0059] It is worth noting that when the molar ratio of cyanoacetate to formaldehyde in step 1) is (1.05-1.1):1, the mass ratio of the alkaline catalyst to formaldehyde in step 1) is 0.005:1, the formaldehyde reaction removal time in step 2) is 30 minutes, the standing water separation time in step 3) is 1-2 hours, the mass ratio of purified water to formaldehyde in step 4) is (0.5-0.8):1, the vacuum degree in step 6) is maintained within 20 mmHg, the cracking temperature is 160-210°C, the water washing time in step 4) is 30 minutes, the vacuum degree in step 7) is maintained within 20 mmHg, and the distillation temperature is 60-90°C, the product prepared by the present invention is optimal.

[0060] It will be appreciated that in the development of any actual implementation, as in any engineering or design project, numerous implementation-specific decisions may be made. Such a development effort may be complex and time-consuming, but will be a routine task of design, fabrication, and production for those of ordinary skill having the benefit of this disclosure without undue experimentation.

[0061] It should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention rather than to limit it. Although the present invention has been described in detail with reference to the preferred embodiments, those skilled in the art should understand that the technical solutions of the present invention may be modified or replaced by equivalents without departing from the spirit and scope of the technical solutions of the present invention, which should all be included in the scope of the claims of the present invention.

Claims

1. A method for synthesizing a medical cyanoacrylate glue with low formaldehyde residue, characterized in that: The following steps are involved: 1) α-cyanoacetate, 92% polyoxymethylene and an alkaline catalyst are mixed in an organic solvent in a certain proportion and heated to carry out a polycondensation reaction; 2) adding phosphoric acid to terminate the reaction, and then adding a formaldehyde reaction remover to remove the incompletely reacted formaldehyde; 3) stopping stirring, allowing the product in step 2) to stand to separate water, and extracting the upper layer of water; 4) Add purified water to the product of step 3) to wash it, and then repeat the operation in step 3); 5) dehydrating and desolventizing the product obtained in step 4) to obtain a cyanoacrylate prepolymer; 6) adding antioxidant 2246 and p-toluenesulfonic acid to the prepolymer, and then cracking it at high temperature under vacuum conditions to obtain a crude monomer; 7) The crude monomer is distilled and purified under vacuum to obtain high-purity α-cyanoacrylate.

2. The method for synthesizing a medical cyanoacrylate adhesive with low formaldehyde residue according to claim 1, characterized in that: The α-cyanoacetate described in step 1) is one of n-butyl cyanoacetate, isobutyl cyanoacetate, n-octyl cyanoacetate or sec-octyl cyanoacetate, and the alkaline catalyst described in step 1) is a mixture of piperidine and piperidine phosphate, and the weight ratio of piperidine to piperidine phosphate is 1:

1.

3. The method for synthesizing a medical cyanoacrylate adhesive with low formaldehyde residue according to claim 1, characterized in that: The molar ratio of cyanoacetate to formaldehyde in step 1) is (1.03-1.1):

1.

4. The method for synthesizing a medical cyanoacrylate adhesive with low formaldehyde residue according to claim 1, characterized in that: The mass ratio of the alkaline catalyst to formaldehyde in step 1) is (0.003-0.007):

1.

5. The method for synthesizing a medical cyanoacrylate adhesive with low formaldehyde residue according to claim 1, characterized in that: The reaction time in step 1) is 2 to 3 hours, and the formaldehyde removal agent in step 2) is any one or more combinations of sodium sulfite, sodium hydrogen sulfite, and sodium thiosulfate.

6. The method for synthesizing a medical cyanoacrylate adhesive with low formaldehyde residue according to claim 1, characterized in that: The mass ratio of the formaldehyde reaction removing agent to formaldehyde in step 2) is (0.001-0.005):1, and the formaldehyde reaction removing time in step 2) is 30-60 minutes; the standing water separation time in step 3) is 30 minutes to 2 hours; and the mass ratio of purified water to formaldehyde in step 4) is (0.5-1):

1.

7. The method for synthesizing a medical cyanoacrylate adhesive with low formaldehyde residue according to claim 1, characterized in that: The water washing time in step 4) is 20 min to 40 min; the vacuum degree in step 6) is maintained within 20 mmHg, and the cracking temperature is 160 to 210°C.

8. The method for synthesizing a medical cyanoacrylate adhesive with low formaldehyde residue according to claim 1, characterized in that: In the step 7), the vacuum degree is maintained within 20 mmHg and the distillation temperature is 60-90°C.