Synthetic method for dynamically regulating PCL-PEG diblock copolymer

Abstract

The invention discloses a synthetic method of a dynamically regulated PCL-PEG diblock copolymer, the synthetic method is divided into three stages, and the synthetic method specifically comprises the following steps: a first stage: firstly, respectively putting toluene, epsilon-CL, Sn (Oct) and mPEG into a Schlenk bottle, and carrying out anhydrous and anaerobic treatment, the mass ratio of epsilon-CL to mPEG being (1-3): 1; the second stage: b, mixing: after replacing the mixture with nitrogen for three times, placing the mixture in a constant-temperature oil bath at 80-120 DEG C to react for 12 hours; c, after the constant-temperature oil bath reaction in the step b is carried out for 5-7 hours, adding mPEG with the same amount as the mPEG in the first stage again, and continuously reacting to form a polymerization product; and a third stage: d, after the reaction is finished, dissolving the polymerization product with chloroform, then carrying out condensation in methanol, and finally, carrying out vacuum drying on the polymerization product at room temperature for 24 hours to obtain the PCL-PEG diblock copolymer. The synthesis method is simple in step, and the synthesized copolymer is large in molecular weight, high in solubility, good in physicochemical property, high in safety and beneficial to application of medical polymers.

Description

Technical Field

[0001] The present invention relates to the technical field of polymer materials, and in particular to a method for dynamically regulating the synthesis of a PCL-PEG diblock copolymer. Background Art

[0002] Copolymers of polycaprolactone (PCL) and polyethylene glycol (PEG) have attracted widespread attention in the field of biomedical materials due to their excellent biodegradability and biocompatibility. Existing PCL-PEG copolymerization techniques are primarily achieved through ring-opening polymerization (ROP), typically using PEG as an initiator to initiate the polymerization of ε-caprolactone (ε-CL) to form PCL-PEG diblock copolymers.

[0003] Chinese patent application number 201880092791.1 discloses a method for selecting a hydrophobic biocompatible polymer and a hydrophilic biocompatible polymer. The hydrophobic polymer Y can be polyglycolic acid, PCL, polylactic acid, etc., while the hydrophilic polymer X can be methoxy PEG, dihydroxy polyethylene glycol, etc. In the presence of a catalyst, the hydrophobic and hydrophilic biocompatible polymers are polymerized to prepare copolymers of various structures (X-Y, Y-X-Y, or X-Y-X).

[0004] U.S. patent application No. 14 / 079171 discloses a thermoplastic polyurethane prepared by reacting ε-CL, PEG, and a lysine-derived diisocyanate. Both ε-CL and PEG have a molecular weight of 10,000 g / mol. By adjusting the weight ratio of PCL to PEG (e.g., 70:30, 60:40, etc.), polymers with varying properties can be prepared.

[0005] Although the existing PCL-PEG copolymerization technology has achieved certain results, it still has the following shortcomings: 1. The post-processing steps are complex and demanding.

[0006] Existing post-processing methods for preparing PEG-PCL composites require multiple centrifugations, refrigeration (below 4°C for 24 hours), or UV cross-linking (under 390-410 μW / cm²). These steps significantly increase production cycle time and equipment costs, and require extremely high process stability, hindering industrial scale-up.

[0007] 2. Biosafety controversy regarding the use of solvents.

[0008] The synthesis process in existing technologies relies on organic solvents such as dichloromethane (DCM). Although the solvent is removed by vacuum drying, trace residues may not meet the strict safety standards of some medical devices and require additional purification steps.

[0009] 3. The polymerization conditions are vague and the repeatability is low.

[0010] The synthesis process in the existing technology does not clearly define key parameters such as catalyst type, reaction temperature, and time. In actual operation, fluctuations in conditions can easily lead to differences in reaction efficiency and poor reproducibility, which is not conducive to large-scale production.

[0011] Therefore, it is necessary to provide a method for preparing a copolymer with high solubility, good physicochemical properties, simple post-processing steps, and good safety. Summary of the Invention

[0012] The purpose of the present invention is to provide a method for dynamically regulating the synthesis of PCL-PEG diblock copolymers, solve the problems existing in the prior art by optimizing reaction conditions and raw material ratios, and improve the solubility, physicochemical properties and biosafety of the polymers.

[0013] To achieve the above object, the present invention provides the following technical solutions: A method for dynamically regulating the synthesis of PCL-PEG diblock copolymers is divided into three stages, specifically comprising the following steps: Phase 1: First, toluene, ε-CL, Sn(Oct)2 and mPEG were placed in a Schlenk flask for anhydrous and oxygen-free treatment, and the mass ratio of the ε-CL to mPEG was 1-3:1; Phase 2: b. Mixing, the mixture was replaced with nitrogen three times, and then placed in a constant temperature oil bath at 80°C-120°C to react for 12 hours; c. After the constant temperature oil bath reaction in step b is carried out for 5-7 hours, the same amount of mPEG as in the first stage is added again and the reaction is continued to form a polymer product; Phase 3: d. After the reaction is completed, the polymer product is dissolved in chloroform and then coagulated in methanol. Finally, the polymer product is placed in vacuum drying at room temperature for 24 hours to obtain a PCL-PEG diblock copolymer.

[0014] Preferably, the molecular weight of mPEG in the first stage is 1000-2000, and the molecular weight of mPEG in the second stage is 1000-3000.

[0015] Preferably, the toluene is 10 mL, and the Sn(Oct)2 is 0.01-0.1 mL.

[0016] The present invention also relates to a use of a PCL-PEG diblock copolymer in preparing facial fillers, tissue repair materials, degradable hydrogels or tissue engineering materials.

[0017] Compared with the prior art, the present invention has the following beneficial effects: The method for synthesizing a dynamic control PCL-PEG diblock copolymer provided by the present invention, by adding mPEG in sections during the reaction process, can dynamically control the length and structure of the PEG block in the polymer chain, optimize the distribution and interaction of the PEG segments, thereby improving the solubility of the PCL-PEG diblock copolymer; in addition, by adjusting the feed mass ratio of ε-CL and mPEG, the temperature and reaction time of the constant temperature oil bath, and the reaction conditions such as the secondary addition time of mPEG and the molecular weight of mPEG, thereby achieving the best block effect, the diblock copolymer obtained by this synthesis method has good solubility and good dispersion effect, significantly improving the efficiency and repeatability of the polymerization reaction, making the synthesis of the polymer more stable, and the synthesis method of the present invention is simple and reproducible. The PCL-PEG diblock copolymer synthesized by the synthesis method of the present invention has broad application prospects in the biomedical field, especially in the field of medical beauty. For example, as a facial filler, tissue repair material or degradable hydrogel, it has the effect of activating collagen regeneration and achieving anti-aging effects. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] In order to more clearly illustrate the technical solutions of the embodiments of the present application, the following is a brief introduction to the drawings required for use in the embodiments. It should be understood that the following drawings only show certain embodiments of the present application and therefore should not be regarded as limiting the scope. For ordinary technicians in this field, other relevant drawings can be obtained based on these drawings without creative work.

[0019] Figure 1 The 1H NMR spectrum of the PCL-PEG diblock copolymer in Example 1 is provided; Figure 2 Provided is a GPC chart of the PCL-PEG diblock copolymer in Example 1; Figure 3 The 1H NMR spectrum of the PCL-PEG diblock copolymer in Comparative Example 1 is provided; Figure 4 Provided is the GPC chart of the PCL-PEG diblock copolymer in Comparative Example 1; Figure 5 The 1H NMR spectrum of the PCL-PEG diblock copolymer in Comparative Example 2 is provided; Figure 6 Provided is the GPC chart of the PCL-PEG diblock copolymer in Comparative Example 3; Figure 7a A schematic diagram of the PCL-PEG diblock copolymer in Example 3 after one month is provided.

[0020] Figure 7bA schematic diagram of the PCL-PEG diblock copolymer in Comparative Example 4 after one month is provided. DETAILED DESCRIPTION

[0021] The technical solution of the present invention will be described clearly and completely below in conjunction with the accompanying drawings of the present invention. 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.

[0022] Exemplary embodiments will be described in detail herein, with examples illustrated in the accompanying drawings. In the following description, when referring to the drawings, identical numerals in different figures represent identical or similar elements, unless otherwise indicated. The embodiments described in the following exemplary embodiments are not intended to represent all possible embodiments consistent with the present disclosure. Rather, they are merely examples of apparatus and methods consistent with certain aspects of the present disclosure, as detailed in the appended claims.

[0023] The present invention relates to a method for dynamically regulating the synthesis of a PCL-PEG diblock copolymer, comprising the following steps: Phase 1: a. First, 10 mL of toluene, 4-9 g of ε-CL, 0.01-0.1 mL of Sn(Oct)2, and 1-4 g of mPEG were placed in a Schlenk flask for anhydrous and oxygen-free treatment. Phase 2: b. Mixing, the mixture was replaced with nitrogen three times, and then placed in a constant temperature oil bath at 80°C-120°C to react for 12 hours; c. After the constant temperature oil bath reaction in step b is carried out for 5-7 hours, the same amount of mPEG as in the first stage is added again and the reaction is continued to form a polymer product; Phase 3: d. After the reaction is completed, the polymer product is dissolved in chloroform and then coagulated in methanol. Finally, the polymer product is placed in vacuum drying at room temperature for 24 hours to obtain a PCL-PEG diblock copolymer.

[0024] In some preferred embodiments of the present invention, the anhydrous and oxygen-free treatment of toluene, ε-CL, Sn(Oct)2, and mPEG in step a is performed in a Schlenk flask, using a freeze-evacuation-thaw cycle for dehydration, for example, in the case of toluene; or using a vacuum-evacuation-nitrogen filling cycle for deoxygenation, for example, in the case of Sn(Oct)2. Water and oxygen can interfere with the polymerization reaction, leading to side reactions or polymer chain termination, and reducing the molecular weight and quality of the polymer. The present invention utilizes the Schlenk technique for anhydrous and oxygen-free treatment to ensure the purity and stability of the reaction system.

[0025] In some preferred embodiments of the present invention, the mixing in step b is to mix toluene, ε-CL, Sn(Oct)2 and mPEG that have been treated to be anhydrous and oxygen-free, and then repeat the vacuum-nitrogen filling cycle three times to remove oxygen and moisture from the reaction system through nitrogen replacement, thereby further ensuring anhydrous and oxygen-free reaction conditions.

[0026] In some preferred embodiments of the present invention, the stannous octoate Sn(Oct)2 is used as a catalyst, and its catalytic mechanism belongs to a typical coordination-insertion ring-opening polymerization (Coordination-Insertion ROP). Its catalytic process is highly selective and is the key to achieving controllable polymerization.

[0027] Traditional methods for preparing PCL-PEG diblock copolymers involve a single addition of raw materials, including ε-CL, mPEG, and a catalyst. However, when adding all the raw materials all at once, mPEG can simultaneously trigger the growth of multiple ε-CL chains, potentially leading to the formation of PCL-PEG~PCL triblock copolymers (initiated by dihydroxylated PEG). This broadens the molecular weight distribution, and long PEG chains tend to form crystalline regions, resulting in decreased solubility. The present invention, however, adds a portion of mPEG during the initial reaction in the first stage. At this point, the reaction is initiated solely by the initial mPEG, forming a well-defined, one-terminal PCL chain. Subsequently, after 5-7 hours of the second stage reaction, mPEG is added again to react with the remaining ε-CL, forming a gradient block structure and avoiding crosslinking. By adding mPEG in stages, the present invention dynamically regulates the length and structure of the PEG blocks within the polymer chain, optimizes the distribution and interactions of the PEG segments, and balances the flexibility and rigidity of the polymer chain, significantly improving the solubility and biocompatibility of the PCL-PEG diblock copolymer.

[0028] The present invention regulates the hydrophobicity, hydrophilicity, and mechanical properties of the polymer by precisely controlling the mass ratio of mPEG and ε-CL, the temperature of the constant-temperature oil bath, the reaction time, the time of re-addition of mPEG during the reaction, and the molecular weight of mPEG, thereby ensuring efficient polymerization. Optimizing these conditions can reduce the occurrence of side reactions and increase the molecular weight and quality of the polymer. The synthesis method of the present invention can significantly improve the efficiency and repeatability of the polymerization reaction, making the polymer synthesis more stable and suitable for large-scale production.

[0029] The present invention avoids the use of organic solvents such as dichloromethane, instead employing the safer solvent toluene. After the reaction, the polymer product is dissolved in chloroform, then coagulated in methanol, and finally dried under vacuum at room temperature for 24 hours to obtain a PCL-PEG diblock copolymer. This post-processing step effectively removes residual solvent, improving the biosafety of the product, and the post-processing step reduces production costs.

[0030] The present invention will be further described in detail below with reference to specific embodiments.

[0031] 1. The influence of constant temperature oil bath temperature on the product Example 1: A method for dynamically regulating the synthesis of a PCL-PEG diblock copolymer comprises the following steps: Phase 1: a. First, place toluene, ε-CL, Sn(Oct)2, and mPEG into a 200 mL round-bottom Schlenk flask for anhydrous and oxygen-free treatment. The toluene content is 10 mL, the Sn(Oct)2 content is 0.01 mL, and the mass ratio of ε-CL to mPEG (M~2000) is 2.5:1. Phase 2: b. The four reactants were then mixed together, and the vacuum-nitrogen filling cycle was repeated three times. The mixed reaction system was placed in a constant temperature oil bath at 85° C. for 12 hours. c. After the constant temperature oil bath reaction in step b was carried out for 6 hours, 1.8 g of mPEG (Mn~2000) was added again and the reaction was continued for 6 hours to form a polymer product; Phase 3: d. After the reaction is completed, the polymer product is dissolved in chloroform and then coagulated in methanol. Finally, the polymer product is placed in vacuum drying at room temperature for 24 hours to obtain a PCL-PEG diblock copolymer.

[0032] Figure 1 1H NMR spectrum of the PCL-PEG diblock copolymer in Example 1, Figure 2 This is a GPC chart of the PCL-PEG diblock copolymer in Example 1. As shown, the PCL-PEG diblock copolymer obtained using the technical solution described in Example 1 appears white and clean. The 1H NMR spectrum shows the absence of free PEG or PCL, and the diffusion coefficients of all groups are consistent, indicating that PCL-PEG was successfully synthesized and has a high molecular weight (weight-average molecular weight of 8127). This indicates a relatively complete reaction, a high success rate, and stable results.

[0033] Comparative Example 1: The method of Example 1 was followed, except that the temperature of the constant temperature oil bath in step b was 130°C.

[0034] Figure 3 1H NMR spectrum of PCL-PEG diblock copolymer in Comparative Example 1, Figure 4This is the GPC chart of the PCL-PEG diblock copolymer in Comparative Example 1. As can be seen from the figure, the product obtained using the technical solution described in Comparative Example 1 is light yellow or yellow, indicating a low probability of successful PCL-PEG synthesis. The weight-average molecular weight is 5924, with a large molecular weight difference and incomplete reaction, indicating that the temperature is too high for polymer synthesis.

[0035] 2. The effect of mPEG addition time on PCL-PEG diblock copolymer.

[0036] Example 2: A method for dynamically regulating the synthesis of a PCL-PEG diblock copolymer comprises the following steps: a. First, place toluene, ε-CL, Sn(Oct)2, and mPEG into a 200 mL round-bottom Schlenk flask for anhydrous and oxygen-free treatment. The toluene content is 10 mL, the Sn(Oct)2 content is 0.03 mL, and the mass ratio of ε-CL to mPEG (M~2000) is 2.5:1. b. The four reactants were then mixed together, and the vacuum-nitrogen filling cycle was repeated three times. The mixed reaction system was placed in a constant temperature oil bath at 85° C. for 12 hours. c. After the constant temperature oil bath reaction in step b was carried out for 6 hours, 1.8 g of mPEG (Mn~1000) was added again and the reaction was continued for 6 hours to form a polymer product; d. After the reaction is completed, the polymer product is dissolved in chloroform and then coagulated in methanol. Finally, the polymer product is placed in vacuum drying at room temperature for 24 hours to obtain a PCL-PEG diblock copolymer.

[0037] Comparative Example 2: The method of Example 2 was followed, except that, in step c, after the constant temperature oil bath reaction in step b was carried out for 4 hours, 1.8 g of mPEG (Mn~1000) was added again, and the reaction was continued for 8 hours to form a polymer product.

[0038] Comparative Example 3: The method of Example 2 was followed, except that, in step c, after the constant temperature oil bath reaction in step b was carried out for 8 hours, 1.8 g of mPEG (Mn~1000) was added again, and the reaction was continued for 4 hours to form a polymer product.

[0039] Conclusion: In Comparative Example 2, after the reaction system was reacted in a constant temperature oil bath at 85°C for 4 hours, mPEG monomer was added and the reaction was continued for 8 hours. At this time, the front-end reaction of the polymer was not complete and the experimental environment was damaged (such as Figure 3); In Comparative Example 3, after the reaction system was reacted in a constant temperature oil bath at 85° C. for 8 hours, mPEG monomer was added and the reaction was continued for 4 hours. At this time, the second half of the reaction was not completed, more raw materials remained, and the conversion rate was low (such as Figure 4 ). In Example 2 of the present invention, after the reaction system was reacted in a constant temperature oil bath at 85° C. for 6 hours, mPEG monomer was added and the reaction was continued for 6 hours. At this time, the reaction was relatively complete.

[0040] 3. The effect of the molecular weight of mPEG added again on the PCL-PEG diblock copolymer.

[0041] Example 3: A method for dynamically regulating the synthesis of a PCL-PEG diblock copolymer comprises the following steps: a. First, place toluene, ε-CL, Sn(Oct)2, and mPEG into a 200 mL round-bottom Schlenk flask for anhydrous and oxygen-free treatment. The toluene content is 10 mL, the Sn(Oct)2 content is 0.01 mL, and the mass ratio of ε-CL to mPEG (M~2000) is 2:1. b. The four reactants were then mixed together, and the vacuum-nitrogen filling cycle was repeated three times. The mixed reaction system was placed in a constant temperature oil bath at 85° C. for 12 hours. c. After the constant temperature oil bath reaction in step b was carried out for 6 hours, 3.6 g of mPEG (Mn~1000) was added again and the reaction was continued for 6 hours to form a polymer product; d. After the reaction is completed, the polymer product is dissolved in chloroform and then coagulated in methanol. Finally, the polymer product is placed in vacuum drying at room temperature for 24 hours to obtain a PCL-PEG diblock copolymer.

[0042] Comparative Example 4: The method of Example 3 was followed, except that the molecular weight of the mPEG added again in step c was 4000.

[0043] Conclusion: The PCL-PEG diblock copolymer products obtained in Example 3 and Comparative Example 4 were subjected to subsequent treatment and sedimentation for about a month. It was found that the product in Example 3 had a good dispersion effect and no stratification; while the product in Comparative Example 4 had obvious stratification ( Figure 7b ), the dispersion effect is not good, indicating that the larger the molecular weight of the mPEG added again, the worse the dispersion effect. Figure 7a 7b is a schematic diagram of the PCL-PEG diblock copolymer in Example 3 and Comparative Example 4 after one month.

[0044] The preferred embodiments of the present invention have been described in detail above, but the present invention is not limited thereto. Within the technical concept of the present invention, various simple variations of the technical solution of the present invention may be made, including combining the various technical features in any other appropriate manner. These simple variations and combinations should also be regarded as disclosed in the present invention and fall within the scope of protection of the present invention.

Claims

1. A method for dynamically regulating the synthesis of PCL-PEG diblock copolymers, characterized in that: The synthesis method is divided into three stages, specifically comprising the following steps: Phase 1: a. First, toluene, ε-CL, Sn(Oct)2 and mPEG were placed in a Schlenk flask respectively for anhydrous and oxygen-free treatment, wherein the mass ratio of the ε-CL to mPEG was 1-3:1; Phase 2: b. Mixing, the mixture was replaced with nitrogen three times, and then placed in a constant temperature oil bath at 80°C-120°C to react for 12 hours; c. After the constant temperature oil bath reaction in step b is carried out for 5-7 hours, the same amount of mPEG as in the first stage is added again and the reaction is continued to form a polymer product; Phase 3: d. After the reaction is completed, the polymer product is dissolved in chloroform and then coagulated in methanol. Finally, the polymer product is placed in vacuum drying at room temperature for 24 hours to obtain a PCL-PEG diblock copolymer.

2. The method for synthesizing a dynamic control PCL-PEG diblock copolymer according to claim 1, wherein The molecular weight of mPEG in the first stage is 1000-2000, and the molecular weight of mPEG in the second stage is 1000-3000.

3. The method for synthesizing a dynamic control PCL-PEG diblock copolymer according to claim 1, wherein The toluene is 10 mL, and the Sn(Oct)2 is 0.01-0.1 mL.

4. Use of the PCL-PEG diblock copolymer according to claim 1 in the preparation of facial fillers, tissue repair materials, degradable hydrogels or tissue engineering materials.

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