A polycaprolactone and a method for synthesizing the same

Abstract

The present application relates to compound synthesis, and particularly to a polycaprolactone and a synthesis method thereof.The method comprises the following steps: under nitrogen protection, a polymerization monomer epsilon-caprolactone, a solvent toluene and an end-capping agent fatty alcohol are added into a reaction kettle, the reaction kettle is heated, when the temperature reaches 115+ / -5 DEG C, a catalyst is added to initiate the reaction.The method can effectively control the polymerization degree of the reaction, improve the yield and purity of the polycaprolactone, save the reaction raw materials and improve the reaction efficiency by adjusting the addition temperature of the catalyst.

Description

[0001] This application is a divisional application of Chinese invention application filed on December 30, 2022, application number 202211737571.4, entitled "A polycaprolactone and a method for synthesizing the same". Technical Field

[0002] This invention relates to compound synthesis, specifically to a polycaprolactone and a method for its synthesis. Background Technology

[0003] Polycaprolactone is a fully biodegradable material with excellent biodegradability, biocompatibility, drug permeability, and low melting point, making it widely used in biomaterials and medicine, such as surgical sutures, drug sustained-release systems, and tissue engineering scaffolds.

[0004] Polycaprolactone (PCL) exhibits good stability and effectively stimulates collagen production in the human body. It provides significant contouring effects for issues such as sunken cheeks, chin, and temples, while also enhancing skin elasticity and improving skin texture. Currently, the synthesis processes of PCL in China mainly involve anionic ring-opening polymerization, cationic ring-opening polymerization, monomer-activated ring-opening polymerization, and coordination-intercalation ring-opening polymerization. However, these synthesis processes are still largely in the early research and development stages. The degree of polymerization of PCL is unstable, and monomers and oligomers in the reaction system cannot be effectively removed after the polymerization reaction, hindering large-scale industrial production and failing to meet the standards for medical applications. Summary of the Invention

[0005] The present invention aims to solve at least one of the above-mentioned problems in the prior art.

[0006] This invention provides a method for producing polycaprolactone with stable degree of polymerization control, high purity, and the ability to meet medical application standards for large-scale industrial production.

[0007] A method for synthesizing polycaprolactone, comprising the following steps: Under nitrogen protection, the monomer ε-caprolactone, solvent toluene or xylene, and capping agent fatty alcohol are added to the reactor. The reactor is heated, and when the temperature reaches 115±5℃, a catalyst is added to initiate the reaction.

[0008] The present invention has found that, under the above reaction conditions, especially when the temperature of the reaction system is adjusted to 115±5℃ and the catalyst is added, the polymerization reaction time is shorter compared with adding the catalyst at room temperature. This can effectively control the degree of polymerization, avoid the generation of oligomers during the programmed temperature rise process after adding the catalyst at room temperature, and greatly reduce the content of oligomers and monomers in the product.

[0009] Preferably, the catalyst is stannous isooctanoate, stannous chloride, stannous octanoate, aluminum isopropoxide, or zinc divinyl isooctanoate; more preferably, stannous isooctanoate.

[0010] Under the conditions described in this invention, any catalyst capable of catalyzing the condensation reaction of ε-caprolactone can be selected. Good catalytic effects can be achieved by selecting stannous isooctanoate, stannous chloride, stannous octanoate, aluminum isopropoxide, or zinc divinyl chloride, especially when stannous isooctanoate is selected as the catalyst.

[0011] Preferably, the capping agent fatty alcohol is a fatty alcohol with 14 to 18 carbon atoms.

[0012] Preferably, the mass ratio of ε-caprolactone to fatty alcohol is 1:0.005~0.02. At the above dosage, a relatively stable polycaprolactone polymer with a weight-average molecular weight range of 35,000 to 45,000 can be generated. Polymers with a weight-average molecular weight range of 35,000 to 45,000 exhibit relatively stable properties, avoiding both polycaprolactone polymers with short degradation cycles and those with rigid structures and long degradation cycles. Therefore, it is more suitable as a material for medical devices.

[0013] Preferably, the polymerization reaction is carried out in the reactor by reflux.

[0014] Preferably, the method of the present invention further includes purifying the product after the reaction is complete. Specifically, the product obtained from the reaction is concentrated and the solvent is evaporated, ethyl acetate is added to the residue to dissolve it, and then anhydrous ethanol is added to precipitate polycaprolactone crystals.

[0015] Existing synthetic methods can all prepare polycaprolactone with a certain purity. However, because it is impossible to effectively separate and purify polycaprolactone from the oligomers and unreacted monomers generated during the reaction, it cannot meet medical requirements and cannot be produced and applied on a large scale. The present invention can effectively purify polycaprolactone through the above-mentioned operation, enabling large-scale production and application.

[0016] Preferably, the temperature for concentrating and evaporating the solvent is 35~45℃.

[0017] Preferably, the volume ratio of ε-caprolactone, ethyl acetate, and anhydrous ethanol is 1:1.5~2.5:8~10. At the above dosage, effective purification of polycaprolactone can be achieved.

[0018] Preferably, the crystallization temperature is 24~26℃.

[0019] More preferably, the volume ratio of ε-caprolactone, ethyl acetate and anhydrous ethanol is 1:2:8 to 10.

[0020] Preferably, before concentrating and evaporating the solvent from the reaction product, the product is treated as follows: the product is dissolved in ethyl acetate, the solution system separates into layers, the organic phase is washed with purified water, the solution system separates into layers again, and the organic phase is dried to remove moisture. Through the above operations, residual tin-like substances from the catalyst in the reaction system can be effectively removed.

[0021] As a preferred operating method, when adding ethyl acetate to the residue after evaporating the solvent to dissolve the residue, the mass-to-volume ratio of the residue to ethyl acetate is 1:7~10.

[0022] As a preferred operating method, after the solution system separates into layers again, the organic phase is dried by mixing anhydrous sulfate with the organic phase. Magnesium sulfate, sodium sulfate, etc. can be selected as the organic phase. As a preferred operating mode, the method of the present invention includes the following steps: 1) Polymerization reaction: Under nitrogen protection, add the monomer ε-caprolactone and the solvent toluene or xylene to the reactor. Stir thoroughly to ensure that ε-caprolactone is fully dissolved in the solvent. Add the capping agent fatty alcohol and heat the reactor. When the temperature reaches 115±5℃, add the catalyst to initiate the reaction. Continue heating the reactor until the temperature reaches 110~120℃. 2) Product purification: After the polymerization reaction is completed, the product obtained by the reaction is dissolved in ethyl acetate. After the solution system is separated into layers, the organic phase is washed with purified water. After the solution system is separated into layers again, the organic phase is separated and dried to remove water. The dried organic phase is heated to evaporate the organic solvent to obtain the residue. Ethyl acetate is added to the residue to dissolve it, and then anhydrous ethanol is added to precipitate polycaprolactone crystals.

[0023] The synthetic route for polycaprolactone described in this invention is as follows:

[0024] This invention also protects polycaprolactone prepared by the method described herein, which is actually a polycaprolactone-fatty alcohol copolymer.

[0025] The structural formula of the polycaprolactone-fatty alcohol copolymer of the present invention is as follows:

[0026] Where x is 6~18 and n is 306~394.

[0027] The polycaprolactone described in this invention has a molecular weight of 35,000 to 45,000 and a degree of polymerization of 306 to 394.

[0028] The polycaprolactone-fatty alcohol copolymer described in this invention has plasticity, certain rigidity, long degradation cycle, and is non-toxic and pollution-free, making it more suitable as a material for medical devices.

[0029] The present invention has the following beneficial effects: 1) The method described in this invention can effectively control the degree of polymerization of the reaction by adjusting the catalyst addition temperature, thereby increasing the yield of polycaprolactone polymer, saving reaction raw materials, and improving reaction efficiency.

[0030] 2) The present invention further proposes a purification scheme for the product, which can ideally purify the product to obtain polycaprolactone with a purity that meets medical requirements.

[0031] In summary, by optimizing the reaction and purification steps, this invention yields a polycaprolactone with high purity that meets medical requirements and can be produced on a large industrial scale. Attached Figure Description

[0032] Figure 1 The spectrum of polycaprolactone monomer detection; Figure 2 Structure confirmed by 1H NMR spectrum; Figure 3 This is a process flow diagram of the present invention. Detailed Implementation

[0033] The following examples are used to illustrate the present invention, but are not intended to limit the scope of the invention.

[0034] All raw materials and reagents used in the following examples were purchased.

[0035] Example 1 This embodiment provides a method for synthesizing polycaprolactone (its process flow diagram is shown below). Figure 3 ), including the following steps: 1) Polymerization reaction: Under nitrogen protection, 3.0 kg of ε-caprolactone monomer and 7.5 L of toluene solvent were added to a 20 L glass-lined / glass reactor. The mixture was stirred thoroughly to dissolve ε-caprolactone in toluene. 18.41 g of tetradecyl alcohol capping agent was added. The reactor was heated. When the temperature reached 115±5℃, 42.59 g of stannous isooctanoate catalyst was added to initiate the reaction. The reaction was carried out under reflux and monitored by GPC until the reaction was complete. 2) Product purification: After the polymerization reaction was completed, the product obtained from the reaction was dissolved in 21L of ethyl acetate. After the solution system separated into layers, the organic phase was washed with purified water. After the washed system separated into layers again, the organic phase was taken out and thoroughly mixed with anhydrous magnesium sulfate to remove the water in the organic phase. Then, the anhydrous magnesium sulfate was removed by filtration. The obtained organic phase was heated to evaporate the organic solvent at 40°C to obtain the residue. 6L of ethyl acetate was added to the residue to dissolve it. Then, 12L of anhydrous ethanol was added to precipitate polycaprolactone crystals. After filtering and drying the crystals, polycaprolactone was obtained.

[0036] Example 2 This embodiment provides a method for synthesizing polycaprolactone, comprising the following steps: 1) Polymerization reaction: Under nitrogen protection, 3.0 kg of ε-caprolactone monomer and 7.5 L of xylene solvent were added to a 20 L glass reactor. The mixture was stirred thoroughly to dissolve ε-caprolactone in toluene. 20.82 g of hexadecyl alcohol capping agent was added. The reactor was heated. When the temperature reached 115 ± 5 °C, 42.59 g of stannous isooctanoate catalyst was added to initiate the reaction. The reaction was carried out under reflux and monitored by GPC until the reaction was complete. 2) Product purification: After the polymerization reaction was completed, the product obtained from the reaction was dissolved in 21L of ethyl acetate. After the solution system separated into layers, the organic phase was washed with purified water. After the washed system separated into layers again, the organic phase was taken out and thoroughly mixed with anhydrous magnesium sulfate to remove the water in the organic phase. Then, the anhydrous magnesium sulfate was removed by filtration. The obtained organic phase was heated to evaporate the organic solvent at 40°C to obtain the residue. 6L of ethyl acetate was added to the residue to dissolve it. Then, 12L of anhydrous ethanol was added to precipitate polycaprolactone crystals. After filtering and drying the crystals, polycaprolactone was obtained.

[0037] Example 3 This embodiment provides a method for synthesizing polycaprolactone, comprising the following steps: 1) Polymerization reaction: Under nitrogen protection, 3.0 kg of ε-caprolactone monomer and 7.5 L of toluene solvent were added to a 20 L glass reactor. The mixture was stirred thoroughly to dissolve ε-caprolactone in toluene. 23.23 g of capping agent octadecyl alcohol was added. The reactor was heated. When the temperature reached 115 ± 5 °C, 42.59 g of stannous isooctanoate catalyst was added to initiate the reaction. The reaction was carried out under reflux and monitored by GPC until the reaction was complete. 2) Product purification: After the polymerization reaction was completed, the product obtained from the reaction was dissolved in 21L of ethyl acetate. After the solution system separated into layers, the organic phase was washed with purified water. After the washed system separated into layers again, the organic phase was taken out and thoroughly mixed with anhydrous magnesium sulfate to remove the water in the organic phase. Then, the anhydrous magnesium sulfate was removed by filtration. The obtained organic phase was heated to evaporate the organic solvent at 40°C to obtain the residue. 6L of ethyl acetate was added to the residue to dissolve it. Then, 12L of anhydrous ethanol was added to precipitate polycaprolactone crystals. After filtering and drying the crystals, polycaprolactone was obtained.

[0038] Comparative Example 1 The only difference between this embodiment and Example 1 is that the catalyst is added at the initial addition of the reactants. Specifically, the steps include the following: 1) Polymerization reaction: Under nitrogen protection, 3.0 kg of ε-caprolactone monomer and 7.5 L of toluene solvent were added to a 20 L glass reactor. The mixture was stirred thoroughly to dissolve ε-caprolactone in toluene. 18.41 g of tetradecanol capping agent and 42.59 g of stannous isooctanoate catalyst were added to initiate the reaction. The reaction was carried out under reflux and GPC monitoring was performed until the reaction was complete. 2) Product purification: After the polymerization reaction was completed, the product obtained from the reaction was dissolved in 21L of ethyl acetate. After the solution system separated into layers, the organic phase was washed with purified water. After the washed system separated into layers again, the organic phase was taken out and thoroughly mixed with anhydrous magnesium sulfate to remove the water in the organic phase. Then, the anhydrous magnesium sulfate was removed by filtration. The obtained organic phase was heated to evaporate the organic solvent at 40°C to obtain the residue. 6L of ethyl acetate was added to the residue to dissolve it. Then, 12L of anhydrous ethanol was added to precipitate polycaprolactone crystals. After filtering and drying the crystals, polycaprolactone was obtained.

[0039] Comparative Example 2 Compared with Example 2, the only difference in this embodiment is that, in addition to the different catalyst addition time in step 1), the amount of purification reagent used in step 2) is also different. Specifically, it includes the following steps: 1) Polymerization reaction: Under nitrogen protection, 3.0 kg of ε-caprolactone monomer and 7.5 L of toluene solvent were added to a 20 L glass reactor. The mixture was stirred thoroughly to dissolve ε-caprolactone in toluene. 20.82 g of hexadecyl alcohol capping agent and 42.59 g of stannous isooctanoate catalyst were added to initiate the reaction. During the reaction, the system was programmed to be heated to reflux and the reflux reaction was carried out. The reflux reaction was then maintained for 18 h, and GPC monitoring was performed until the reaction was complete. 2) Product purification: After the polymerization reaction was completed, the product obtained from the reaction was dissolved in 21 L of ethyl acetate. After the solution system separated into layers, the organic phase was washed with purified water. After the solution system separated into layers again, the organic phase was thoroughly mixed with anhydrous magnesium sulfate. The anhydrous magnesium sulfate was removed by filtration. The obtained organic phase was heated to evaporate the organic solvent at 40°C to obtain the residue. 9 L of ethyl acetate was added to the residue to dissolve it. Then, 12 L of anhydrous ethanol was added to precipitate polycaprolactone crystals. The crystals were filtered and dried to obtain polycaprolactone.

[0040] Experimental Example 1 This experimental example demonstrates the liquid chromatography analysis of the polycaprolactone obtained in Example 1, as shown in the figure below. Figure 1 : Depend on Figure 1 It can be seen that the polycaprolactone obtained by the process of Example 1 has no residue of the starting material monomer caprolactone, indicating that the process has an ideal removal effect on caprolactone.

[0041] This experimental example also confirmed the 1H NMR structure of the polycaprolactone obtained in Example 1, as shown in the figure below. Figure 2 As shown in the figure, the polycaprolactone material is synthesized using a capping agent. According to the NMR 1H spectrum analysis, the capping agent is one of tetradecyl alcohol, hexadecyl alcohol, or octadecyl alcohol.

[0042] Experimental Example 2 This experimental example analyzes the products obtained in Examples 1-4 and Comparative Examples 1-2, and the results are as follows: Table 1

[0043] As can be seen from the above data, the polycaprolactone prepared by the method of the present invention has a high degree of polymerization and a high weight-average molecular weight. Moreover, the yield is significantly improved through the dual optimization of the synthesis method and the recovery method.

[0044] Although the present invention has been described in detail above with general descriptions and specific embodiments, modifications or improvements can be made to it, which will be obvious to those skilled in the art. Therefore, all such modifications or improvements made without departing from the spirit of the present invention fall within the scope of protection claimed by the present invention.

Claims

1. A method for synthesizing polycaprolactone, characterized in that, The process includes the following steps: under nitrogen protection, adding the polymeric monomer ε-caprolactone, solvent toluene or xylene, and end-capping agent fatty alcohol to the reactor, heating the reactor, and when the temperature reaches 115±5℃, adding a catalyst to initiate the reaction, wherein the weight-average molecular weight of the polycaprolactone is 35000~45000.

2. The synthesis method according to claim 1, characterized in that, The catalyst is stannous isooctanoate, stannous chloride, stannous octanoate, aluminum isopropoxide, or zinc divinyl isooctanoate; preferably stannous isooctanoate.

3. The synthesis method according to claim 1 or 2, characterized in that, The capping agent, fatty alcohol, is a fatty alcohol with 14 to 18 carbon atoms.

4. The synthesis method according to any one of claims 1 to 3, characterized in that, The mass ratio of ε-caprolactone to fatty alcohol is 1:0.005~0.

02.

5. The synthesis method according to any one of claims 1 to 4, characterized in that, The polymerization reaction is carried out in the reactor via reflux.

6. The synthesis method according to any one of claims 1 to 5, characterized in that, It also includes the purification of the product after the reaction is complete, which involves concentrating the product obtained from the reaction, evaporating the solvent, adding ethyl acetate to the residue to dissolve it, and then adding anhydrous ethanol to precipitate polycaprolactone crystals.

7. The synthesis method according to claim 6, characterized in that, The volume ratio of ε-caprolactone, ethyl acetate and anhydrous ethanol is 1:1.5~2.5:8~10, and / or the crystallization temperature is 24~26℃.

8. The synthesis method according to claim 7, characterized in that, Before concentrating and evaporating the solvent from the reaction product, the reaction product was treated as follows: the reaction product was dissolved in ethyl acetate, the solution system was separated into layers, the organic phase was washed with purified water, the solution system was separated into layers again, and the organic phase was dried.

9. A polycaprolactone, characterized in that, It is prepared by the method described in any one of claims 1 to 8.

10. A polycaprolactone-fatty alcohol copolymer, characterized in that, Its structural formula is: Where x is 6 to 18 and n is 306 to 394.

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