Preparation method of α-cyanoacrylate and medical adhesive

Abstract

The present invention belongs to the field of biomedical technology, and in particular to a kind of preparation method and medical adhesive of α-cyanoacrylate. The preparation method of α-cyanoacrylate provided by the present invention, comprises the following steps: (1) cyanoacetic acid ester, paraformaldehyde or formalin, alkylpiperidine catalyst are subjected to condensation reaction in an organic solvent to obtain a prepolymer of α-cyanoacrylate; (2) plasticizer is added to the prepolymer of α-cyanoacrylate obtained by step (1), organic solvent and water are removed by vacuum decompression distillation, polymerization inhibitor is added, and then pyrolysis distillation is performed, and fractions are collected to obtain the crude monomer of α-cyanoacrylate; (3) the crude monomer of α-cyanoacrylate obtained by step (2) is decompressed and distilled to obtain α-cyanoacrylate. The catalyst system catalytic efficiency using the inventive method is high, and the synthesis of α-cyanoacrylate has the advantages of high conversion rate and high yield.

Description

Technical Field

[0001] The present invention belongs to the field of biomedical technology, and in particular relates to a preparation method of α-cyanoacrylate and a medical adhesive. Background Art

[0002] α-Cyanoacrylate medical adhesives have three advantages: (1) single component, solvent-free, good fluidity, and easy to cure at room temperature; (2) have certain biocompatibility and can adapt to natural tissues; (3) have stable chemical properties and do not degrade into harmful substances, so they have broad development in the medical field.

[0003] In 1949, German chemist Addis first synthesized alkyl α-cyanoacrylates, and in 1958, Eastman Kodak Company in the United States successfully produced methyl α-cyanoacrylate. Subsequently, newer technologies were used to synthesize non-toxic adhesives with relatively long carbon chains, such as butyl and octyl α-cyanoacrylates. Due to their superior properties, they have been widely used in medicine and health care, experiencing rapid development and increasing clinical application. α-Cyanoacrylates have rapidly developed in countries around the world, and production has also increased rapidly.

[0004] In the synthesis of α-cyanoacrylates, commonly used organic catalysts include piperidine, pyridine, triethylamine, and hydrocarbon amines, and commonly used inorganic catalysts include weak base catalysts such as zinc chloride and zinc acetate, and strong base catalysts such as sodium hydroxide and barium hydroxide. CN100575337C discloses a method for preparing α-cyanoacrylates, which comprises using cyanoacetic acid ester and paraformaldehyde or formaldehyde solution as raw materials, in the presence of an alkaline catalyst and a low-boiling point organic solvent capable of azeotroping with water as a dehydrating agent, and carrying out a condensation reaction at a temperature of 80-100°C and normal pressure, or in the absence of a dehydrating agent, at a temperature of 60±5°C and a vacuum degree of 0.5-50 mmHg; after complete dehydration, adding an alcohol remover, and reflux the mixture steadily for 0.5-2 hours with sufficient stirring; recovering the dehydrating agent and the alcohol remover, adding a polymerization inhibitor, and then carrying out cracking and distillation at a vacuum degree of 0.5-25 mmHg and a temperature of 160-220°C. However, the method for preparing α-cyanoacrylate disclosed in the invention has a low yield.

[0005] Currently, the existing methods for preparing α-cyanoacrylate have problems such as low catalytic efficiency of the catalyst, low synthesis conversion rate of α-cyanoacrylate, and low yield. Summary of the Invention

[0006] In view of the shortcomings of the prior art, the present invention aims to provide a method for preparing α-cyanoacrylate and a medical adhesive. The catalyst system of the present invention has high catalytic efficiency and has advantages such as high conversion rate and high yield for the synthesis of α-cyanoacrylate.

[0007] The technical solution of the present invention is:

[0008] A method for preparing α-cyanoacrylate comprises the following steps:

[0009] (1) condensing cyanoacetate, paraformaldehyde or formaldehyde solution, and an alkylpiperidine catalyst in an organic solvent to obtain a prepolymer of α-cyanoacrylate;

[0010] (2) adding a plasticizer to the α-cyanoacrylate prepolymer obtained in step (1), removing the organic solvent and water by vacuum distillation, adding a polymerization inhibitor, and then performing high-temperature cracking and distillation, collecting fractions, and obtaining a crude monomer of α-cyanoacrylate;

[0011] (3) distilling the crude monomer of α-cyanoacrylate obtained in step (2) under reduced pressure to obtain α-cyanoacrylate.

[0012] Furthermore, the cyanoacetate in step (1) is one of methyl cyanoacetate, ethyl cyanoacetate, butyl cyanoacetate, and octyl cyanoacetate.

[0013] Furthermore, the alkylpiperidine catalyst in step (1) is a combination of one or more of 2-methylpiperidine, 3-methylpiperidine, 4-methylpiperidine, N-methylpiperidine, 2,3-dimethylpiperidine, 2,4-dimethylpiperidine, 2,6-dimethylpiperidine, 4-pyrrolidin-1-ylpiperidine, and 1-hydroxy-2,2,6,6-tetramethylpiperidine.

[0014] Furthermore, in the step (1), the molar ratio of cyanoacetate to formaldehyde is 1:1-2, calculated as formaldehyde; and the amount of the alkylpiperidine catalyst is 0.05%-5% of the mass of the cyanoacetate, calculated as mass percentage.

[0015] Furthermore, in the step (1), the molar ratio of cyanoacetate to formaldehyde is 1:1-1.5, calculated as formaldehyde; and the amount of the alkylpiperidine catalyst is 0.1%-2% of the mass of the cyanoacetate, calculated as mass percentage.

[0016] Furthermore, in the step (1), the molar ratio of cyanoacetate to formaldehyde is 1:1-1.2, calculated as formaldehyde; and the amount of the alkylpiperidine catalyst is 0.5%-1.5% of the mass of the cyanoacetate, calculated as mass percentage.

[0017] Furthermore, the organic solvent in step (1) is at least one of methanol, dichloroethane, cyclohexane, and n-heptane.

[0018] Furthermore, the reaction temperature during the condensation reaction in step (1) is 40-80° C., and the reaction time is 1-3 h.

[0019] Furthermore, the plasticizer in step (2) is at least one of dioctyl phthalate, dibutyl phthalate, diethyl phthalate, and tricresyl phosphate.

[0020] Furthermore, the volume mass ratio (mL / g) of the plasticizer to the cyanoacetate is 40-80:110-280.

[0021] Furthermore, the polymerization inhibitor in step (2) is a combination of an acidic anionic polymerization inhibitor and a free radical polymerization inhibitor.

[0022] Furthermore, the acidic anion inhibitor is one of phosphorus pentoxide, pyrophosphoric acid, and polyphosphoric acid; the free radical inhibitor is one of hydroquinone, hydroquinone, catechol, tert-butyldiphenol, and butylated hydroxyanisole.

[0023] Furthermore, the cracking temperature during the high-temperature cracking and distillation in step (2) is 180-220°C.

[0024] The principle equation of the whole reaction of the present invention is as follows:

[0025]

[0026] The present invention provides a method for preparing α-cyanoacrylate, utilizing alkylpiperidine to catalyze a formaldehyde condensation reaction. This method has the advantages of high catalytic efficiency and a high conversion rate for the synthesis of α-cyanoacrylate, significantly improving product yield. The process and the use of alkylpiperidine in the present invention prevent volatilization and loss of the catalyst during the initial synthesis process, nor does it cause solidification during the cracking process. The experimental process is highly reproducible and easily industrially implemented, thus resolving technical difficulties associated with prior art methods for preparing α-cyanoacrylate, such as low catalytic efficiency and instability of the catalyst, and low conversion rate for the synthesis of α-cyanoacrylate.

[0027] Another object of the present invention is to provide a medical adhesive comprising α-cyanoacrylate prepared by the above-mentioned method for preparing α-cyanoacrylate.

[0028] Compared with the prior art, the present invention has the following advantages:

[0029] (1) The alkylpiperidine catalyst used in the method of the present invention has high catalytic efficiency and high stability, and has the advantages of high conversion rate and high product yield for the synthesis of α-cyanoacrylate.

[0030] (2) The preparation method of α-cyanoacrylate provided by the present invention is simple, highly practical, and easy to implement industrially.

[0031] (3) The preparation method of α-cyanoacrylate provided by the present invention is low-cost. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] Figure 1 This is the NMR spectrum of the ethyl α-cyanoacrylate monomer prepared in Example 1 of the present invention;

[0033] Figure 2 This is the NMR spectrum of the n-butyl α-cyanoacrylate monomer prepared in Example 2 of the present invention;

[0034] Figure 3 This is the NMR spectrum of the octyl α-cyanoacrylate monomer prepared in Example 3 of the present invention;

[0035] Figure 4 This is the NMR spectrum of the ethyl α-cyanoacrylate monomer prepared in Example 4 of the present invention;

[0036] Figure 5 This is the NMR spectrum of the n-butyl α-cyanoacrylate monomer prepared in Example 5 of the present invention;

[0037] Figure 6 This is the NMR spectrum of the n-butyl α-cyanoacrylate monomer prepared in Comparative Example 1;

[0038] Figure 7 This is the NMR spectrum of the α-butyl cyanoacrylate monomer prepared in Comparative Example 2. DETAILED DESCRIPTION

[0039] In order to make the technical solution of the present invention more clear, the present invention is further described in detail below in conjunction with the embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not intended to limit the present invention.

[0040] Example 1. Preparation of ethyl α-cyanoacrylate monomer

[0041] (1) 210 mL of ethylene dichloride and 2.85 g of 4-methylpiperidine catalyst were added to a 500 mL three-necked flask equipped with a thermometer, a reflux condenser, and a stirrer. After stirring for 4 minutes, 30 g of paraformaldehyde was added and the temperature was set to 70° C. After reaching the temperature, 110 g of ethyl cyanoacetate was added and the condensation reaction was carried out for 2 hours to obtain a prepolymer of ethyl α-cyanoacrylate. The temperature was raised to 90° C. and the organic solvent and the water generated by the reaction were removed and collected by a water separator.

[0042] (2) After 1 hour, 40 mL of dioctyl phthalate was added to the prepolymer of ethyl α-cyanoacrylate obtained in step (1), the temperature was maintained at 90° C., and the organic solvent and water generated during the reaction were removed by vacuum distillation. 0.6 g of phosphorus pentoxide and 1.1 g of hydroquinone were added, the temperature was maintained at 200° C., and the fractions were collected to obtain a crude monomer of ethyl α-cyanoacrylate;

[0043] (3) The crude monomer of ethyl α-cyanoacrylate obtained in step (2) is heated from room temperature to 180° C. under −0.1 MPa and distilled again to obtain ethyl α-cyanoacrylate monomer.

[0044] Example 2: Preparation of n-butyl α-cyanoacrylate monomer

[0045] (1) In a 1000 mL three-necked flask equipped with a thermometer, a reflux condenser, and a stirrer, 560 mL of methanol and 2.8 g of 2,4-dimethylpiperidine catalyst were added, and after stirring for 4 min, 60 g of paraformaldehyde was added, and the temperature was set to 70°C. After the temperature reached, 280 g of n-butyl cyanoacetate was added, and the condensation reaction was carried out for 2 h to obtain a prepolymer of n-butyl α-cyanoacrylate. After the reaction was completed, the temperature was raised to 90°C, and the organic solvent and the water generated by the reaction were removed and collected through a water separator;

[0046] (2) After 1 hour, 80 mL of dioctyl phthalate was added to the prepolymer of n-butyl α-cyanoacrylate obtained in step (1), the temperature was maintained at 90° C., and the organic solvent and water generated during the reaction were removed by vacuum distillation. 3 g of phosphorus pentoxide and 5 g of hydroquinone were added, the temperature was maintained at 200° C., and the fractions were collected to obtain a crude monomer of n-butyl α-cyanoacrylate;

[0047] (3) The crude monomer of n-butyl α-cyanoacrylate obtained in step (2) is heated from room temperature to 180° C. under vacuum conditions and distilled again to obtain n-butyl α-cyanoacrylate monomer.

[0048] Example 3: Preparation of n-octyl α-cyanoacrylate monomer

[0049] (1) 405 mL of dichloroethane and 0.88 g of 2-methylpiperidine catalyst were added to a 1000 mL three-necked flask equipped with a thermometer, a reflux condenser, and a stirrer. After stirring for 4 minutes, 30 g of paraformaldehyde was added and the temperature was set to 70° C. After the temperature reached, 190 g of n-octyl cyanoacetate was added and the condensation reaction was carried out for 2 hours to obtain a prepolymer of n-octyl α-cyanoacrylate. After the reaction was completed, the temperature was raised to 90° C. and the organic solvent and the water generated by the reaction were removed and collected by a water separator.

[0050] (2) After 1 hour, 60 mL of dioctyl phthalate was added to the prepolymer of n-octyl α-cyanoacrylate obtained in step (1), the temperature was maintained at 90° C., and the organic solvent and water generated during the reaction were removed by vacuum distillation. 2 g of phosphorus pentoxide and 3 g of hydroquinone were added, the temperature was maintained at 200° C., and the fractions were collected to obtain a crude monomer of n-octyl α-cyanoacrylate;

[0051] (3) The crude monomer of n-octyl α-cyanoacrylate obtained in step (2) is heated from room temperature to 180° C. under vacuum conditions, and distilled again to obtain n-octyl α-cyanoacrylate monomer.

[0052] Example 4: Preparation of ethyl α-cyanoacrylate monomer

[0053] (1) 220 mL of dichloroethane and 1.89 g of N-methylpiperidine catalyst were added to a 500 mL three-necked flask equipped with a thermometer, a reflux condenser, and a stirrer. After stirring for 4 min, 30 g of paraformaldehyde was added and the temperature was set to 70° C. After reaching the temperature, 110 g of ethyl cyanoacetate was added and the condensation reaction was carried out for 2 h to obtain a prepolymer of ethyl α-cyanoacrylate. After the reaction was completed, the temperature was raised to 90° C. and the organic solvent and the water generated by the reaction were removed and collected by a water separator;

[0054] (2) After 1 hour, 40 mL of dibutyl phthalate was added to the prepolymer of ethyl α-cyanoacrylate obtained in step (1), the temperature was maintained at 90° C., and the organic solvent and water generated during the reaction were removed by vacuum distillation. 0.6 g of phosphorus pentoxide and 1.1 g of hydroquinone were added, the temperature was maintained at 200° C., and the fractions were collected to obtain a crude monomer of ethyl α-cyanoacrylate;

[0055] (3) The crude monomer of ethyl α-cyanoacrylate obtained in step (2) is heated from room temperature to 180° C. under vacuum conditions, and distilled again to obtain ethyl α-cyanoacrylate monomer.

[0056] Example 5: Preparation of n-butyl α-cyanoacrylate monomer

[0057] (1) In a 1000 mL three-necked flask equipped with a thermometer, a reflux condenser, and a stirrer, 560 mL of methanol and 3.4 g of a catalyst, 4-pyrrolidin-1-ylpiperidine, were added. After stirring for 4 min, 60 g of paraformaldehyde was added and the temperature was set to 70° C. After the temperature reached, 280 g of n-butyl cyanoacetate was added and the condensation reaction was carried out for 2 h to obtain a prepolymer of n-butyl α-cyanoacrylate. After the reaction was completed, the temperature was raised to 90° C., and the organic solvent and the water generated by the reaction were removed and collected by a water separator;

[0058] (2) After 1 hour, 80 mL of dioctyl phthalate was added to the prepolymer of n-butyl α-cyanoacrylate obtained in step (1), the temperature was maintained at 90° C., and the organic solvent and water generated during the reaction were removed by vacuum distillation. 3 g of phosphorus pentoxide and 5 g of hydroquinone were added, the temperature was maintained at 200° C., and the fractions were collected to obtain a crude monomer of n-butyl α-cyanoacrylate;

[0059] (3) The crude monomer of n-butyl α-cyanoacrylate obtained in step (2) is heated from room temperature to 180° C. under vacuum conditions and distilled again to obtain n-butyl α-cyanoacrylate monomer.

[0060] Comparative Example 1

[0061] (1) In a 1000 mL three-necked flask equipped with a thermometer, a reflux condenser, and a stirrer, 560 mL of methanol and 3.4 g of triethylamine catalyst were added. After stirring for 4 minutes, 60 g of paraformaldehyde was added and the temperature was set to 70° C. After the temperature reached, 280 g of n-butyl cyanoacetate was added and the condensation reaction was carried out for 2 hours to obtain a prepolymer of n-butyl α-cyanoacrylate. After the reaction was completed, the temperature was raised to 90° C. and the organic solvent and the water generated by the reaction were removed and collected by a water separator;

[0062] (2) After 1 hour, 80 mL of dioctyl phthalate was added to the prepolymer of n-butyl α-cyanoacrylate obtained in step (1), the temperature was maintained at 90° C., and the organic solvent and water generated during the reaction were removed by vacuum distillation. 3 g of phosphorus pentoxide and 5 g of hydroquinone were added, the temperature was maintained at 200° C., and the fractions were collected to obtain a crude monomer of n-butyl α-cyanoacrylate;

[0063] (3) The crude monomer of n-butyl α-cyanoacrylate obtained in step (2) is heated from room temperature to 180° C. under vacuum conditions, and distilled again to obtain n-butyl α-cyanoacrylate monomer.

[0064] Comparative Example 2

[0065] (1) In a 1000 mL three-necked flask equipped with a thermometer, a reflux condenser, and a stirrer, 560 mL of methanol and 3.4 g of pyridine catalyst were added, and after stirring for 4 min, 60 g of paraformaldehyde was added, and the temperature was set to 70°C. After the temperature reached, 280 g of n-butyl cyanoacetate was added, and the condensation reaction was carried out for 2 h to obtain a prepolymer of n-butyl α-cyanoacrylate. After the reaction was completed, the temperature was raised to 90°C, and the organic solvent and the water generated by the reaction were removed and collected through a water separator;

[0066] (2) After 1 hour, 80 mL of dioctyl phthalate was added to the prepolymer of n-butyl α-cyanoacrylate obtained in step (1), the temperature was maintained at 90° C., and the organic solvent and water generated during the reaction were removed by vacuum distillation. 3 g of phosphorus pentoxide and 5 g of hydroquinone were added, the temperature was maintained at 200° C., and the fractions were collected to obtain a crude monomer of n-butyl α-cyanoacrylate;

[0067] (3) The crude monomer of n-butyl α-cyanoacrylate obtained in step (2) is heated from room temperature to 180° C. under vacuum conditions and distilled again to obtain n-butyl α-cyanoacrylate monomer.

[0068] Test Example 1: Detection of Product Yield and Purity

[0069] 1.1 Detection of product yield

[0070] Take the products obtained in Example 1, Example 2, Example 3, Example 4, Example 5, Comparative Example 1, and Comparative Example 2, and calculate the product yield. The relative molecular mass of the raw material cyanoacetic acid ester is M1, the feed mass is A, and the relative molecular mass of the obtained product is M2. Assuming that the mass of the product obtained by complete reaction is B=M2*A / M1, the actual mass of the product obtained is C, and the product yield (%)=C / B×100%;

[0071] 1.2 Product purity detection

[0072] The purity of the products obtained in Example 1, Example 2, Example 3, Example 4, Example 5, Comparative Example 1 and Comparative Example 2 of the present invention was determined by gas chromatography. The nuclear magnetic resonance spectrum of the ethyl α-cyanoacrylate monomer obtained in Example 1 of the present invention is as follows: Figure 1 As shown, the NMR spectrum of the α-cyanoacrylate n-butyl ester monomer obtained in Example 2 of the present invention is as follows Figure 2 As shown, the NMR spectrum of the α-octyl cyanoacrylate monomer obtained in Example 3 of the present invention is as follows Figure 3 As shown, the nuclear magnetic spectrum of the ethyl α-cyanoacrylate monomer obtained in Example 4 of the present invention is as follows Figure 4 As shown, the NMR spectrum of the α-cyanoacrylate n-butyl ester monomer obtained in Example 5 of the present invention is as follows Figure 5 As shown, the NMR spectrum of the α-butyl cyanoacrylate monomer obtained in Comparative Example 1 is as follows Figure 6 As shown, the NMR spectrum of the α-butyl cyanoacrylate monomer obtained in Comparative Example 2 is as follows Figure 7 The H numbers marked on the molecular structure in the figure correspond to the positions with the same numbers on the NMR spectrum. The yield and purity test results of the products obtained in Examples 1-5 of the present invention and Comparative Examples 1-2 are shown in Table 1.

[0073] Table 1 Yield and purity test results of the products obtained in Examples 1-5 and Comparative Examples 1-2 of the present invention

[0074] Group catalyst Yield purity Example 1 4-Methylpiperidine 71％ 98.5％ Example 2 2,4-Dimethylpiperidine 73％ 98.5％ Example 3 2-Methylpiperidine 70％ 98.5％ Example 4 N-Methylpiperidine 74％ 98.5％ Example 5 4-Pyrrolidin-1-ylpiperidine 80％ 99％ Comparative Example 1 Triethylamine 35％ 98.5％ Comparative Example 2 Pyridine 33％ 98％

[0075] Depend on Figure 1-7 It can be concluded that the ratio of the peak areas on the NMR spectrum is substantially equal to the ratio of the number of H atoms at different positions in the molecular structure, indicating that the obtained product is the expected product. As can be seen in Table 1, the yield of the product obtained using the catalyst of the present invention is significantly higher than the yield of the product obtained using the catalysts of Comparative Examples 1 and 2.

Claims

1. A method for preparing α-cyanoacrylate, characterized in that: The following steps are involved: (1) condensing cyanoacetate, paraformaldehyde or formaldehyde aqueous solution, and alkylpiperidine catalyst in an organic solvent to obtain a prepolymer of α-cyanoacrylate; (2) adding a plasticizer to the α-cyanoacrylate prepolymer obtained in step (1), removing the organic solvent and water by vacuum distillation, adding a polymerization inhibitor, and then performing high-temperature cracking and distillation, collecting the fractions, and obtaining a crude monomer of α-cyanoacrylate; (3) The crude monomer of α-cyanoacrylate obtained in step (2) is distilled under reduced pressure to obtain α-cyanoacrylate.

2. The method for preparing α-cyanoacrylate according to claim 1, wherein Step (1) The cyanoacetate is one of methyl cyanoacetate, ethyl cyanoacetate, butyl cyanoacetate and octyl cyanoacetate.

3. The method for preparing α-cyanoacrylate according to claim 1, wherein The alkylpiperidine catalyst in step (1) is a combination of one or more of 2-methylpiperidine, 3-methylpiperidine, 4-methylpiperidine, N-methylpiperidine, 2,3-dimethylpiperidine, 2,4-dimethylpiperidine, 2,6-dimethylpiperidine, 4-pyrrolidin-1-ylpiperidine, and 1-hydroxy-2,2,6,6-tetramethylpiperidine.

4. The method for preparing α-cyanoacrylate according to claim 1, wherein In the step (1), the molar ratio of cyanoacetate to formaldehyde is 1:1-2, calculated as formaldehyde; and the amount of alkylpiperidine catalyst used is 0.05%-5% of the mass of cyanoacetate, calculated as mass percentage.

5. The method for preparing α-cyanoacrylate according to claim 1, wherein The organic solvent in step (1) is at least one of methanol, dichloroethane, cyclohexane, and n-heptane.

6. The method for preparing α-cyanoacrylate according to claim 1, wherein The reaction temperature for the condensation reaction in step (1) is 40-80° C., and the reaction time is 1-3 h.

7. The method for preparing α-cyanoacrylate according to claim 1, wherein The polymerization inhibitor in step (2) is a combination of an acidic anionic polymerization inhibitor and a free radical polymerization inhibitor.

8. The method for preparing α-cyanoacrylate according to claim 7, wherein: The acidic anion polymerization inhibitor is one of phosphorus pentoxide, pyrophosphoric acid, and polyphosphoric acid; the free radical polymerization inhibitor is one of hydroquinone, hydroquinone, catechol, tert-butyldiphenol, and butylated hydroxyanisole.

9. The method for preparing α-cyanoacrylate according to claim 1, wherein The cracking temperature during the high-temperature cracking and distillation in step (2) is 180-220°C.

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