Poly-L-lactic acid polymer and preparation method thereof

Abstract

The invention provides a poly-L-lactic acid polymer and a preparation method thereof, and the method comprises the following steps: replacing halogen atoms in a catalyst with an initiator containing a hydroxyl compound to generate an alkoxy compound Bi-OR, and then carrying out a polymerization reaction with L-lactide to obtain the high-molecular-weight poly-L-lactic acid polymer. The catalyst has high tolerance to water and free acid, the requirements for the free acid and the water content of the L-lactide are reduced, the L-lactide with high free acid and water content can be directly used, and the refining cost of the L-lactide is greatly reduced. The specific rotation of the poly-L-lactic acid polymer prepared by the method meets the standard, the poly-L-lactic acid polymer has high tolerance to moisture and free acid, the catalytic efficiency is high, the process stability is good, and the molecular weight can be regulated and controlled through the dosage of the initiator.

Description

Technical Field

[0001] The invention belongs to the technical field of high molecular polymers and relates to a poly (L-lactic acid) polymer and a preparation method thereof. Background Art

[0002] Poly-L-lactic acid (PLLA) is non-toxic, non-irritating, biodegradable and absorbable, high-strength, good plasticity, and easy to process and shape. It is an important biodegradable polymer material, mainly used in medical fields such as surgery, artificial skin, artificial blood vessels, bone and soft tissue defect filling, and bioresorbable scaffolds.

[0003] Poly (L-lactic acid) polymers include poly (L-lactic acid) homopolymers and poly (L-lactic acid) copolymers. Poly (L-lactic acid) homopolymers are formed by the polymerization of L-lactic acid monomers, while poly (L-lactic acid) copolymers are formed by the copolymerization of L-lactic acid and other hydrophilic segment monomers. Both have good biodegradability and biocompatibility. The molecular weight and structure of poly (L-lactic acid) polymers are strongly correlated with their mechanical properties and degradation properties, and the smaller the molecular weight, the worse the mechanical and degradation properties. High-molecular-weight poly (L-lactic acid) polymers have strength, modulus, and impact resistance close to those of general-purpose plastics, making them an effective alternative to petroleum-based polymers. Due to their biodegradability, good biocompatibility, and mechanical properties, high-molecular-weight poly (L-lactic acid) polymers can gradually replace metal fixation devices in the field of long-term in vivo fixation materials such as artificial tendons, bone nails, and bone plates. Therefore, poly (L-lactic acid) polymers have good application prospects.

[0004] Based on the good application prospects of high molecular weight poly (L-lactic acid) polymer, many scientific researchers have conducted a large number of studies on the preparation technology of high molecular weight poly (L-lactic acid) polymer. It is found that the main factors affecting polymerization are free acid and moisture. For example, the patent of publication number CN103254411A is based on the direct polycondensation of lactic acid, and the introduction of carbodiimide chain extenders improves the molecular weight of poly (L-lactic acid). For example, the patent of publication number CN106279643A uses lactic acid as raw material to dehydrate and prepare poly (L-lactic acid) intermediate, and then adds HDI chain extension to prepare high molecular weight poly (L-lactic acid). The above patents are all prepared by chain extension method, so there are more low molecular weight poly (L-lactic acid) that do not participate in the chain extension reaction in the polymerization system, which affects the stability, mechanical properties, etc. of poly (L-lactic acid) polymer. Summary of the Invention

[0005] The purpose of the present invention is to provide a poly (L-lactic acid) polymer and a preparation method thereof, so as to solve the problem that the existing preparation method has poor stability due to being greatly affected by water content and free acid.

[0006] To achieve the above object, the present invention adopts the following technical solutions: The present application provides a poly (L-lactic acid) polymer, which includes a poly (L-lactic acid) homopolymer and a poly (L-lactic acid) copolymer, and a preparation method thereof includes: S01: The catalyst, initiator and solvent are stirred and mixed at room temperature to form a catalyst solution.

[0007] The initiator and catalyst are mixed in a molar ratio of 0.1:1-30:1, and a solvent is added and stirred at room temperature for 30-70 minutes to dissolve the initiator and catalyst in the solvent to prepare a catalyst solution. Preferably, the molar ratio of the initiator and catalyst is 1:1-10:1.

[0008] This application uses a halogen-containing bismuth compound as a catalyst, and the catalyst has the following structure: , wherein R1 is Cl, Br or I, R2, R3 are selected from Cl, Br, I, -CH3, -CH2CH3, -CH2CH(CH3)2, -C6H5, 、 、 、 or .

[0009] Additionally, when R2 and R3 are selected from Cl, Br or I, R2 and R3 are different.

[0010] The initiator in this application is a hydroxyl-containing compound, such as ethylene glycol, benzyl alcohol, p-benzyl alcohol, butanediol, glycerol, dodecanol, 3-hydroxyphenylacetic acid, polyethylene glycol, and methoxypolyethylene glycol. Polyethylene glycol includes, but is not limited to, PEG400, PEG600, PEG1000, PEG8000, PEG20000, and the like, and methoxypolyethylene glycol includes, but is not limited to, MPEG1000, MPEG2000, MPEG5000, and the like.

[0011] When polyethylene glycol or methoxypolyethylene glycol is used as the initiator, the prepared poly-L-lactic acid polymer is a poly-L-lactic acid copolymer. When a low molecular weight alcohol such as ethylene glycol, benzyl alcohol, or p-benzyl alcohol is used as the initiator, the prepared poly-L-lactic acid polymer is a poly-L-lactic acid homopolymer.

[0012] In this application, the following reaction occurs between the catalyst and the initiator: .

[0013] The catalyst in this application has a high tolerance to moisture and free acid, which may be due to: (1) During the polymerization reaction, the initiator containing a hydroxyl compound first replaces the halogen atom in the catalyst to form an alkoxy compound Bi-OR. Since the Bi-OR chemical bond has high bond energy and is not easily broken, it has a high tolerance to free acid and moisture in the system.

[0014] (2) The energy required for chain transfer to water in this reaction system is higher than that required for ring-opening polymerization, which reduces the tendency of chain transfer during the polymerization process, improves the system's tolerance to water, and is conducive to the preparation of high molecular weight polymers.

[0015] In addition, the solvent in the present application is selected from benzene solvents such as benzene, toluene and xylene, and the amount of solvent added is based on the complete dissolution of the initiator and catalyst.

[0016] S02: Under a nitrogen atmosphere, the catalyst solution and L-lactide are polymerized at 60-220° C. to obtain a polymer product.

[0017] The catalyst solution and L-lactide were added to a reaction vessel, and the atmosphere was replaced with nitrogen three times until the catalyst and L-lactide were under a nitrogen atmosphere. The polymerization reaction was carried out at 60-220° C. for 1-15 hours to obtain a polymer product.

[0018] In the present application, the polymerization reaction temperature is preferably 140-220°C. When a lower reaction temperature of 140-180°C is selected, the melting point of the polymer will increase after the polymerization reaction reaches a certain level. If the polymerization temperature is lower than the melting point of the polymer, the polymerization reaction will be a solid-phase reaction, which will affect the diffusion of the monomer in the reaction system and lead to a broadening of the molecular weight distribution of the polymer. Therefore, the polymerization reaction temperature is more preferably 170-220°C.

[0019] In the present application, the added mass of the catalyst is 0.05‰-15‰ of the total mass of the initiator and L-lactide, preferably 0.1‰-0.8‰. The reaction time is preferably 4-10 hours.

[0020] In addition, in order to reduce the effects of free acid and moisture on the polymerization reaction, the free acid content in L-lactide is ≤200 mg / g, and the total moisture content in L-lactide and initiator is ≤0.15%.

[0021] S03: The polymer product is dissolved in a good solvent, precipitated with a poor solvent, and dried to obtain a poly (L-lactic acid) polymer.

[0022] The polymer product is dissolved in a good solvent, a poor solvent is added for precipitation, and after drying, a high molecular weight poly (L-lactic acid) polymer having a specific rotation of -155 to -160° is obtained.

[0023] The benign solvent in this application is an organic solvent well known to those skilled in the art, and is not particularly limited as long as it ensures good solubility of the polymer product therein. The benign solvent in this application is preferably selected from one of dichloromethane, chloroform, dimethyl sulfoxide, N,N-dimethylacetamide, and acetone.

[0024] The poor solvent in this application is selected from solvents well known to those skilled in the art, and can ensure that the polymer product is not dissolved. The poor solvent in this application is preferably selected from one of anhydrous ethanol, methanol, 2-methoxyethanol, petroleum ether and diethyl ether.

[0025] The present invention has the following beneficial effects: (1) The catalyst has a high tolerance to moisture and free acid, which reduces the requirements for the free acid and water content of L-lactide. L-lactide with high free acid and water content can be directly used, which greatly reduces the refining cost of L-lactide and has good economic and social benefits.

[0026] (2) The specific rotation of poly (L-lactic acid) polymer meets the standard, avoiding the problem of easy racemization during the high-temperature reaction of existing tin catalysts.

[0027] (3) The catalyst has low biological toxicity, even lower than the toxicity of zinc, which plays a role in human metabolism, and is harmless to the human body.

[0028] (4) This preparation method has high tolerance to moisture and free acid, high catalytic efficiency, good process stability, and the molecular weight can be controlled by the amount of initiator. DETAILED DESCRIPTION

[0029] In the examples of this application, L-lactide with free acid concentrations of 35.2 mg / g, 117.6 mg / g, and 208.4 mg / g, respectively, was selected and numbered SM1, SM2, and SM3. The free acid was determined by titration with potassium hydroxide solution using ethanol, the water content in the reaction system was determined according to the water determination method (Method 1, Part 4, General Rules 0832, Part 1, 2020 Edition of the Chinese Pharmacopoeia), and the specific rotation of the prepared high molecular weight poly (L-lactic acid) polymer was determined according to YY / T 0661-2017.

[0030] The technical solution of the present invention is further explained and illustrated by means of specific embodiments below.

[0031] Example 1 The present invention provides a poly (L-lactic acid) polymer, and the preparation method of the polymer includes: S101: Accurately weigh 0.0965g of dodecanol and 0.0803g of catalyst, add toluene to make the volume 10ml, and magnetically stir at room temperature for 30 minutes to form a catalyst solution. The molecular formula of the catalyst is: .

[0032] S102: The catalyst solution and 200.18 g of SM1 were added to a three-necked flask and mixed thoroughly. The water content of the reaction solution was 0.08%. The atmosphere was replaced with nitrogen three times and the polymerization reaction was carried out at 185 ± 5°C for 6 h to obtain a polymer product.

[0033] S103: dissolving the polymer product in dichloromethane, adding anhydrous ethanol for precipitation, and drying to obtain a high molecular weight poly (L-lactic acid) polymer.

[0034] Example 2 The present invention provides a poly (L-lactic acid) polymer, and the preparation method of the polymer includes: S201: Accurately weigh 0.0948g of dodecanol and 0.0814g of catalyst, add toluene to make the volume 10ml, and magnetically stir at room temperature for 30 minutes to form a catalyst solution. The molecular formula of the catalyst is: .

[0035] S202: The catalyst solution and 202.13 g of SM3 were added to a three-necked flask and mixed thoroughly. The water content of the reaction solution was 0.05%. The atmosphere was replaced with nitrogen three times and the polymerization reaction was carried out at 185 ± 5°C for 6 h to obtain a polymer product.

[0036] S203: dissolving the polymer product in dichloromethane, adding anhydrous ethanol for precipitation, and drying to obtain a high molecular weight poly (L-lactic acid) polymer.

[0037] Example 3 The present invention provides a poly (L-lactic acid) polymer, and the preparation method of the polymer includes: S301: Accurately weigh 1.0138g of MPEG2000 and 0.0806g of catalyst, add toluene to make the volume 10ml, and stir magnetically at room temperature for 70 minutes to form a catalyst solution. The molecular formula of the catalyst is: .

[0038] S302: The catalyst solution and 200.39 g of SM2 were added to a three-necked flask and mixed thoroughly. The water content of the reaction solution was 0.12%. The atmosphere was replaced with nitrogen three times and the polymerization reaction was carried out at 185 ± 5°C for 6 h to obtain a polymer product.

[0039] S303: dissolving the polymer product in dichloromethane, adding anhydrous ethanol for precipitation, and drying to obtain a high molecular weight poly (L-lactic acid) polymer.

[0040] Example 4 The present invention provides a poly (L-lactic acid) polymer, and the preparation method of the polymer includes: S401: Accurately weigh 1.1026g of MPEG2000 and 0.0414g of catalyst, add toluene to make the volume 10ml, and stir magnetically at room temperature for 60 minutes to form a catalyst solution. The molecular formula of the catalyst is: .

[0041] S402: The catalyst solution and 198.89 g of SM3 were added to a three-necked flask and mixed thoroughly. The water content of the reaction solution was 0.06%. The atmosphere was replaced with nitrogen three times and the polymerization reaction was carried out at 185 ± 5°C for 6 h to obtain a polymer product.

[0042] S403: dissolving the polymer product in dichloromethane, adding anhydrous ethanol for precipitation, and drying to obtain a high molecular weight poly (L-lactic acid) polymer.

[0043] Example 5 The present invention provides a poly (L-lactic acid) polymer, and the preparation method of the polymer includes: S501: Accurately weigh 2.5212g PEG5000 and 0.0594g catalyst, add toluene to make the volume 10ml, and stir magnetically at room temperature for 50 minutes to form a catalyst solution. The molecular formula of the catalyst is: .

[0044] S502: The catalyst solution and 199.74 g of SM3 were added to a three-necked flask and mixed evenly. The water content of the reaction solution was 0.04%. The atmosphere was replaced with nitrogen three times and the polymerization reaction was carried out at 185 ± 5 °C for 4 h to obtain a polymer product.

[0045] S503: dissolving the polymer product in dichloromethane, adding anhydrous ethanol for precipitation, and drying to obtain a high molecular weight poly (L-lactic acid) polymer.

[0046] Example 6 The present invention provides a poly (L-lactic acid) polymer, and the preparation method of the polymer includes: S601: Accurately weigh 2.5376g mPEG5000 and 0.0592g catalyst, add toluene to make the volume 10ml, and magnetically stir at room temperature for 30 minutes to form a catalyst solution. The molecular formula of the catalyst is: .

[0047] S602: The catalyst solution and 202.17 g of SM3 were added to a three-necked flask and mixed thoroughly. The water content of the reaction solution was 0.09%. The atmosphere was replaced with nitrogen three times and the polymerization reaction was carried out at 185 ± 5°C for 6 h to obtain a polymer product.

[0048] S603: dissolving the polymer product in dichloromethane, adding anhydrous ethanol for precipitation, and drying to obtain a high molecular weight poly (L-lactic acid) polymer.

[0049] Example 7 The present invention provides a poly (L-lactic acid) polymer, and the preparation method of the polymer includes: S701: Accurately weigh 4.0261g PEG8000 and 0.1039g catalyst, add toluene to make up to 10ml, and stir magnetically at room temperature for 30 minutes to form a catalyst solution. The molecular formula of the catalyst is: .

[0050] S702: Add the catalyst solution and 202.17 g of SM3 to a three-necked flask and mix thoroughly. The water content of the reaction solution is 0.11%. Nitrogen is replaced three times. Polymerization is carried out at 185 ± 5°C for 8 h to obtain a polymer product.

[0051] S703: dissolving the polymer product in dichloromethane, adding anhydrous ethanol for precipitation, and drying to obtain a high molecular weight poly (L-lactic acid) polymer.

[0052] Comparative Example 1 The comparative example of the present application provides a poly (L-lactic acid) polymer, the preparation method of which comprises: D101: Accurately weigh 0.0965 g of dodecanol and 0.0809 g of stannous octoate, add toluene to make the volume 10 ml, and magnetically stir at room temperature for 30 min to form a stannous octoate / alcohol solution.

[0053] D102: Add the stannous octoate / alcohol solution and 200.25 g of SM1 to a three-necked flask and mix thoroughly. The water content of the reaction solution is 0.07%. Replace the atmosphere with nitrogen three times and polymerize at 185 ± 5°C for 6 h to obtain a polymer product.

[0054] D103: The polymer product was dissolved in dichloromethane, anhydrous ethanol was added for precipitation, and a high molecular weight poly (L-lactic acid) polymer was obtained after drying.

[0055] Comparative Example 2 The comparative example of the present application provides a poly (L-lactic acid) polymer, the preparation method of which comprises: D201: Accurately weigh 5.171 g mPEG5000 and 0.0597 g stannous octoate, add toluene to make up to 10 ml, and magnetically stir at room temperature for 30 min to form a stannous octoate / alcohol solution.

[0056] D202: Add the stannous octoate / alcohol solution and 200.25 g of SM1 to a three-necked flask and mix thoroughly. The water content of the reaction solution is 0.07%. Replace the atmosphere with nitrogen three times and polymerize at 210 ± 5°C for 6 h to obtain a polymer product.

[0057] D203: The polymer product was dissolved in dichloromethane, anhydrous ethanol was added for precipitation, and a high molecular weight poly (L-lactic acid) polymer was obtained after drying.

[0058] Comparative Example 3 The comparative example of the present application provides a poly (L-lactic acid) polymer, the preparation method of which comprises: D301: Accurately weigh 5.1493g PEG5000 and 0.0602g catalyst, add toluene to make up to 10ml, and stir magnetically at room temperature for 30 minutes to form a catalyst solution. The molecular formula of the catalyst is: .

[0059] D302: Add the catalyst solution and 200.03 g of SM3 to a three-necked flask and mix thoroughly. The water content of the reaction solution is 0.05%. Replace the atmosphere with nitrogen three times and conduct a polymerization reaction at 185 ± 5°C for 4 h to obtain a polymer product.

[0060] D303: The polymer product is dissolved in dichloromethane, anhydrous ethanol is added for precipitation, and a high molecular weight poly (L-lactic acid) polymer is obtained after drying.

[0061] The molecular weight Mw, distribution and specific rotation of the poly (L-lactic acid) polymers prepared in Examples 1-7 and Comparative Examples 1-3 were calculated respectively to obtain Table 1.

[0062] Table 1: Related parameters of poly (L-lactic acid) polymers prepared in Examples 1-7 and Comparative Examples 1-3 As can be seen from Table 1: (1) Comparing Examples 1-7 with Comparative Examples 1 and 2, it can be seen that the molecular weight of the poly-L-lactic acid polymer prepared in Comparative Examples 1 and 2 is 19.38-22.17w, with a distribution of 1.36-1.42, and a large fluctuation in specific rotation; while the molecular weight of the poly-L-lactic acid polymer prepared in Examples 1-7 of the present application is 38.65-41.87w, with a distribution of 1.17-1.32, and a stable specific rotation within the range of -155° to -160°. It can be seen that the molecular weight of the poly-L-lactic acid polymer prepared using the catalyst in the present application is much greater than the molecular weight of the poly-L-lactic acid polymer prepared using stannous octoate as a catalyst, and the molecular weight distribution is narrow and the specific rotation is stable. This indicates that the catalyst in the examples of the present application has a higher tolerance to free acid content ≤200 mg / g and water content ≤0.15% during the polymerization process within the specified range than stannous octoate, and the prepared poly-L-lactic acid polymer has a higher molecular weight.

[0063] (2) Comparison of Example 5 and Comparative Example 3 shows that, under the same catalyst conditions, doubling the amount of initiator decreases the molecular weight of the resulting poly-L-lactic acid polymer. This indicates that, under the same catalyst conditions, the amount of initiator used is inversely proportional to the molecular weight of the poly-L-lactic acid polymer obtained by the polymerization reaction. Therefore, the molecular weight of the poly-L-lactic acid polymer can be accurately controlled by adjusting the amount of initiator used.

[0064] The above description is merely a preferred embodiment of the present application and is not intended to limit the present application. Various modifications and variations are possible for those skilled in the art. Any modifications, equivalent substitutions, or improvements made within the spirit and principles of the present application shall be included within the scope of protection of the present application.

Claims

1. A method for preparing a poly (L-lactic acid) polymer, characterized in that: include: Stirring and mixing the catalyst, initiator and solvent at room temperature to form a catalyst solution; Under a nitrogen atmosphere, the catalyst solution and L-lactide are polymerized at 60-220° C. to obtain a polymer product; The polymer product is dissolved in a good solvent, precipitated in a poor solvent, and dried to obtain a poly (L-lactic acid) polymer.

2. The method for preparing the poly (L-lactic acid) polymer according to claim 1, wherein: The catalyst has the following structure: , wherein R1 is Cl, Br or I, R2, R3 are selected from Cl, Br, I, -CH3, -CH2CH3, -CH2CH(CH3)2, -C6H5, 、 、 、 or .

3. The method for preparing the poly (L-lactic acid) polymer according to claim 2, wherein: When R2 and R3 are selected from Cl, Br or I, R2 and R3 are different.

4. The method for preparing poly (L-lactic acid) polymer according to claim 1, wherein: The initiator is selected from one of ethylene glycol, benzyl alcohol, p-benzyl alcohol, butanediol, glycerol, dodecanol, 3-hydroxyphenylacetic acid, polyethylene glycol and methoxypolyethylene glycol.

5. The method for preparing poly (L-lactic acid) polymer according to claim 1, wherein: The solvent is selected from one of benzene, toluene and xylene; the good solvent is selected from one of dichloromethane, chloroform, dimethyl sulfoxide, N,N-dimethylacetamide and acetone; the poor solvent is selected from one of anhydrous ethanol, methanol, 2-methoxyethanol, petroleum ether and ether.

6. The method for preparing poly (L-lactic acid) polymer according to claim 1, characterized in that: The molar ratio of the initiator to the catalyst is 0.1:1-30:

1.

7. The method for preparing poly (L-lactic acid) polymer according to claim 1, characterized in that: The added mass of the catalyst is 0.05‰-15‰ of the total mass of the initiator and L-lactide.

8. The method for preparing poly (L-lactic acid) polymer according to claim 1, characterized in that: The free acid content in the L-lactide is ≤200 mg / g, and the total moisture content in the L-lactide and the initiator is ≤0.15%.

9. The method for preparing poly (L-lactic acid) polymer according to claim 1, characterized in that: The specific rotation of the poly (L-lactic acid) polymer is -155 to -160°.

10. A poly (L-lactic acid) polymer, characterized in that: The method is prepared according to any one of claims 1 to 9.

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