WO2020083180A1 - METHOD FOR PREPARING POLY(γ-BUTYROLACTONE) WITH HIGH MOLECULAR WEIGHT - Google Patents

METHOD FOR PREPARING POLY(γ-BUTYROLACTONE) WITH HIGH MOLECULAR WEIGHT Download PDF

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WO2020083180A1
WO2020083180A1 PCT/CN2019/112181 CN2019112181W WO2020083180A1 WO 2020083180 A1 WO2020083180 A1 WO 2020083180A1 CN 2019112181 W CN2019112181 W CN 2019112181W WO 2020083180 A1 WO2020083180 A1 WO 2020083180A1
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butyrolactone
urea
poly
catalyst
catalytic system
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PCT/CN2019/112181
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French (fr)
Chinese (zh)
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李志波
沈勇
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青岛科技大学
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    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G63/00—Macromolecular compounds obtained by reactions forming a carboxylic ester link in the main chain of the macromolecule
    • C08G63/78—Preparation processes
    • C08G63/82—Preparation processes characterised by the catalyst used
    • C08G63/823—Preparation processes characterised by the catalyst used for the preparation of polylactones or polylactides
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G63/00—Macromolecular compounds obtained by reactions forming a carboxylic ester link in the main chain of the macromolecule
    • C08G63/02—Polyesters derived from hydroxycarboxylic acids or from polycarboxylic acids and polyhydroxy compounds
    • C08G63/06—Polyesters derived from hydroxycarboxylic acids or from polycarboxylic acids and polyhydroxy compounds derived from hydroxycarboxylic acids
    • C08G63/08—Lactones or lactides

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  • the present invention relates to the field of polymer materials. Specifically, the present invention relates to a method for preparing high molecular weight poly ( ⁇ -butyrolactone), and poly ( ⁇ -butyrolactone) prepared by the method.
  • Poly ( ⁇ -butyrolactone) is an important class of aliphatic polyester, with good biocompatibility and biodegradability, and has broad application prospects in the field of biomedicine.
  • Poly ( ⁇ -butyrolactone) has a suitable degradation rate in the body, between polyglycolide and polylactic acid, and compared with existing biological materials, poly ( ⁇ -butyrolactone) does not It will cause the accumulation of acidic substances in the tissues, which is not easy to cause inflammation.
  • Poly ( ⁇ -butyrolactone) can be obtained by two methods: biological fermentation and chemical synthesis.
  • the poly ( ⁇ -butyrolactone) obtained by the biological fermentation method has been approved by the US Food and Drug Administration (FDA) and can be used clinically as a surgical suture and a hernia patch.
  • FDA US Food and Drug Administration
  • the biological fermentation method has the disadvantages of complicated process flow, difficulty in purification of the resulting product, and residual biological substances that easily cause the body's immune reaction.
  • Poly ( ⁇ -butyrolactone) can also be obtained by chemical synthesis using ring-opening polymerization of ⁇ -butyrolactone.
  • ⁇ -Butyrolactone is a bio-based monomer with a wide range of sources and low prices. It can be obtained from biomass raw materials, such as corn and wheat, and is a renewable raw material.
  • the poly ( ⁇ -butyrolactone) obtained by chemical synthesis method can be modified with functional groups, and there is no residue of biological substances, so it is more suitable for applications in biomedicine such as tissue engineering scaffolds.
  • ⁇ -butyrolactone has a five-membered ring structure, and the ring tension is very small.
  • the catalysts reported in the literature that can synthesize poly include metal organic catalysts, organic phosphazene base catalysts and N-heterocyclic ethylene catalysts (Nature Chemistry, 2016, 8 (1), 42-49; Polymer Chemistry, 2018, 9 (26), 3674-3683.)
  • metal-organic catalysts are not suitable for applications in the field of biomedicine due to their high toxicity and their tendency to remain in the resulting product poly ( ⁇ -butyrolactone).
  • Organic phosphazene base catalysts and N-heterocyclic ethylene catalysts have low activity. According to reports in the literature, it is difficult to prepare high molecular weight poly ( ⁇ -butyrolactone). The resulting products have poor mechanical properties and cannot meet the requirements of biomedicine. Requirements for practical applications.
  • an object of the present invention is to propose a method for preparing high molecular weight poly ( ⁇ -butyrolactone) and the poly ( ⁇ -butyrolactone) obtained by this method.
  • the method for preparing poly ( ⁇ -butyrolactone) can prepare high molecular weight poly ( ⁇ -butyrolactone) products that meet the application requirements in the field of biomedicine.
  • the invention proposes a method for preparing poly ( ⁇ -butyrolactone). According to an embodiment of the invention, the method includes:
  • ⁇ -butyrolactone is polymerized in a catalytic system to obtain poly ( ⁇ -butyrolactone);
  • the catalytic system includes: an initiator, a catalyst and urea, and the catalyst is an alkali metal, an alkali metal compound and an organic phosphorus At least one of the nitrile compounds.
  • the method for preparing poly ( ⁇ -butyrolactone) according to the embodiment of the present invention, at least one of an alkali metal, an alkali metal compound and an organic phosphazene compound, an initiator, and urea form a catalytic system, and the used catalyst and urea It has low toxicity and can be easily removed from the product; at the same time, the catalytic system has high activity, and the prepared poly ( ⁇ -butyrolactone) product has high molecular weight and good mechanical properties.
  • the method for preparing poly ( ⁇ -butyrolactone) according to the above embodiments of the present invention may also have the following additional technical features:
  • the method for preparing poly ( ⁇ -butyrolactone) includes: (1) mixing the initiator, the catalyst, and the urea in an organic solvent to obtain the catalyst System; (2) adding the ⁇ -butyrolactone to the catalytic system for polymerization reaction to obtain the poly ( ⁇ -butyrolactone).
  • the initiator is a monohydric alcohol or a polyhydric alcohol.
  • the monohydric alcohol is selected from methanol, ethanol, isopropanol, tert-butanol, benzyl alcohol, phenylethanol, phenylpropanol, diphenylmethanol, 2,2-diphenylethanol , At least one of hydroxyl-terminated oligoethylene glycol monomethyl ether;
  • the polyol is selected from 2,2-diphenylethanol, ethylene glycol, 1,2-propanediol, 1,3-propanediol, 1, At least one of 4-butanediol, 1,2-benzenedimethanol, 1,3-benzenedimethanol, 1,4-benzenedimethanol, 2,2'-biphenyldimethanol, glycerin, and pentaerythritol.
  • the alkali metal is selected from at least one of lithium, sodium and potassium.
  • the alkali metal compound is selected from at least one of potassium hydride, sodium hydride, sodium naphthalene, potassium naphthalene, biphenyl sodium, benzhydryl sodium, and benzhydryl potassium.
  • the organic phosphazene compound is selected from hexa [tris (dimethylamine) phosphazene] triphosphazene, phosphazene ligand P4-tert-butyl and phosphazene ligand P2 -At least one of t-butyl.
  • the organic solvent is selected from at least one of toluene, tetrahydrofuran, dichloromethane, chloroform, dioxane, acetonitrile, and N, N-dimethylformamide.
  • the urea is a compound represented by formula (I),
  • R 1 and R 2 are independently methyl, ethyl, propyl, isopropyl, cyclohexyl, phenyl, 4-chlorophenyl, 4-methoxyphenyl, 4-tris Fluoromethylphenyl, 2,6-dimethylphenyl, 2,4-dimethoxyphenyl or 2,4,6-trimethoxyphenyl.
  • the urea has a structure shown in one of the following:
  • the molar ratio of the catalyst to the initiator is (1-60): 3, and the molar ratio of the catalyst to the urea is 1: (1-10), the The molar ratio of urea to the ⁇ -butyrolactone is 1: (10-3000).
  • the initiator, the catalyst, and the urea are mixed in an organic solvent, and stirred at -70 to -10 ° C for 10 to 30 minutes to obtain the catalytic system.
  • the polymerization reaction is completed at -70 to -20 ° C for 0.5 to 48 hours.
  • the molar concentration of ⁇ -butyrolactone in the catalytic system is 4-13 mol / L.
  • step (2) includes: after adding the ⁇ -butyrolactone to the catalytic system for polymerization, adding a compound containing an active functional group to the reaction system to terminate the reaction, and using Methanol is precipitated to obtain the poly ( ⁇ -butyrolactone).
  • the active functional group-containing compound is selected from at least one of acid, acid chloride, acid anhydride, thioisocyanate, isocyanate, and halogenated hydrocarbon; preferably, the active functional group-containing compound is selected From acetic acid, benzoic acid, acryloyl chloride, methacryloyl chloride, acetic anhydride, succinic anhydride, maleimidobutyryl chloride, epichlorohydrin, 3-chloropropene, 3-chloropropyne, 4-methoxy At least one of phenylphenyl thioisocyanate and 4-methoxybenzyl isocyanate.
  • the molar ratio of the active functional group-containing compound to the urea is (1-10): 1.
  • the present invention proposes a poly ( ⁇ -butyrolactone) product prepared by the method for preparing poly ( ⁇ -butyrolactone) of the above examples.
  • the residual amount of catalyst and urea in the poly ( ⁇ -butyrolactone) product is very low or no residue, which can meet the application requirements in the field of biomedicine, and has high molecular weight and good mechanical properties.
  • Example 2 is a 13 C NMR spectrum of the poly ( ⁇ -butyrolactone) prepared in Example 2;
  • FIG. 3 is a comparison of GPC spectra of the poly ( ⁇ -butyrolactone) prepared in Comparative Example 2 and Example 2;
  • Example 5 is a drawing curve of poly ( ⁇ -butyrolactone) prepared in Example 3 and Example 4;
  • Example 6 is a GPC spectrum of poly ( ⁇ -butyrolactone) prepared in Example 6;
  • Example 7 is a GPC spectrum of poly ( ⁇ -butyrolactone) prepared in Example 7;
  • Example 8 is a GPC spectrum of poly ( ⁇ -butyrolactone) prepared in Example 8.
  • the invention proposes a method for preparing poly ( ⁇ -butyrolactone).
  • the method includes: polymerizing ⁇ -butyrolactone in a catalytic system to obtain poly ( ⁇ -butyrolactone);
  • the catalytic system includes: an initiator, a catalyst, and a urea, and the catalyst is an alkali At least one of metal, alkali metal compound and organic phosphazene compound.
  • the method comprises at least one of an alkali metal, an alkali metal compound, and an organic phosphazene compound, an initiator, and urea to form a catalytic system.
  • the catalyst at least one of alkali metal, alkali metal compound and organic phosphazene compound
  • the catalyst in the catalytic system can interact with urea to deprotonate it to form urea anion, and urea anion interacts through hydrogen bonding
  • urea anion interacts through hydrogen bonding
  • it activates the polymer growth chain ends and monomers, so that the catalytic system shows a high polymerization activity.
  • the hydrogen bonding of the urea anion to the growing chain end reduces the basicity of the growing chain end functional group and increases the steric hindrance of the growing chain end, thereby reducing the possibility of transesterification and chain end biting.
  • the controllability of the polymerization reaction is improved, which facilitates the preparation of high molecular weight poly ( ⁇ -butyrolactone).
  • alkali metal is a strong electron donor, and it is easy to capture proton hydrogen in the urea group in the catalytic system, making it a urea anion.
  • the alkali metal compound itself exhibits strong basicity, and it can also capture proton hydrogen in the urea group to make it a urea anion.
  • the organic phosphazene compound can capture proton hydrogen in the urea group and make it a urea anion.
  • the solubility of the organic phosphazene compound in organic solvents is better than that of inorganic bases.
  • the catalytic system has a very high catalytic activity and can catalyze the polymerization of ⁇ -butyrolactone at a high conversion rate to obtain a high molecular weight poly ( ⁇ -butyrolactone).
  • the method for preparing poly ( ⁇ -butyrolactone) of the present invention includes: (1) mixing an initiator, a catalyst, and urea in an organic solvent to obtain a catalytic system. (2) ⁇ -butyrolactone is added to the catalytic system for polymerization reaction to obtain the poly ( ⁇ -butyrolactone). Specifically, the initiator, catalyst and urea can be dissolved in an organic solvent, after stirring at a low temperature for a period of time, ⁇ -butyrolactone is added to the above mixed solution, and reacted at a certain temperature for a period of time to obtain poly ( ⁇ - Butyrolactone).
  • the above initiator may be a monohydric alcohol or a polyhydric alcohol.
  • the monohydric alcohol may be selected from methanol, ethanol, isopropanol, tert-butanol, benzyl alcohol, phenylethanol, phenylpropanol, diphenylmethanol, 2,2-diphenylethanol, hydroxyl-terminated oligomer At least one of ethylene glycol monomethyl ether;
  • the above-mentioned polyol may be selected from 2,2-diphenylethanol, ethylene glycol, 1,2-propanediol, 1,3-propanediol, 1,4-butanediol At least one of alcohol, 1,2-benzenedimethanol, 1,3-benzenedimethanol, 1,4-benzenedimethanol, 2,2'-biphenyldimethanol, glycerin, and pentaerythritol.
  • the above alcohol initiators can efficiently initiate the ring-opening polymerization of ⁇ -butyrolactone, and the raw materials are widely available and cheap and easily available.
  • the method of the present invention can also be used to prepare poly ( ⁇ -butyrolactone) -containing block copolymers by using a hydroxyl-terminated macroalcohol as an initiator.
  • the above alkali metal may be at least one selected from lithium, sodium, and potassium.
  • the above-mentioned alkali metal compound may be at least one selected from potassium hydride, sodium hydride, sodium naphthalene, potassium naphthalene, biphenyl sodium, benzhydryl sodium, and benzhydryl potassium.
  • the above alkali metals and alkali metal compounds are super strong bases, which can effectively capture proton hydrogen of the urea group, and unlike alkali metal alkoxides, the reaction between the above alkali metal and alkali metal compounds and urea is irreversible, and above Alkali metals and alkali metal compounds are strong non-nucleophilic bases, and do not initiate ring-opening polymerization of ⁇ -butyrolactone by themselves, which is beneficial to obtain high molecular weight poly ( ⁇ -butyrolactone) with a clear structure.
  • the urea is a compound represented by formula (I),
  • R 1 and R 2 are independently methyl, ethyl, propyl, isopropyl, cyclohexyl, phenyl, 4-chlorophenyl, 4-methoxyphenyl, 4-tris Fluoromethylphenyl, 2,6-dimethylphenyl, 2,4-dimethoxyphenyl or 2,4,6-trimethoxyphenyl.
  • the above urea has a structure shown in one of the following:
  • the above organic solvent is selected from at least one of toluene, tetrahydrofuran, dichloromethane, chloroform, dioxane, acetonitrile, and N, N-dimethylformamide.
  • the above organic solvents can provide good solubility for initiators, catalysts and ⁇ -butyrolactone monomers, and the catalysts can exhibit strong basicity in the above organic solvents, improving the yield of poly ( ⁇ -butyrolactone).
  • due to the high solubility of catalyst and urea in methanol it is easy to separate the poly ( ⁇ -butyrolactone) product from the reaction system by precipitation. The catalyst and urea remain in the poly ( ⁇ -butyrolactone) product.
  • the amount is extremely low or no residue (as can be seen from Figure 1 and Figure 2), which can meet the application requirements in the field of biomedicine.
  • the molar ratio of the catalyst to the initiator in the polymerization reaction of ⁇ -butyrolactone, may be (1-60): 3, in other words, the molar ratio of the catalyst to the initiator may be 1/3 ⁇ 20/1, for example 1/3, 1/1, 3/1, 5/1, 10/1, 20/1.
  • the molar ratio of the catalyst to urea can be 1: (1-10), in other words, the molar ratio of the catalyst to urea can be 1/1 to 1/10, such as 1/1, 1/2, 1/3, 1/4 , 1/5, 1/6, 1/7, 1/8, 1/9 or 1/10.
  • the molar ratio of urea to ⁇ -butyrolactone can be 1: (10 to 3000), in other words, the molar ratio of urea to ⁇ -butyrolactone can be 1/10 to 1/3000, for example 1/10, 1/100 , 1/200, 1/300, 1/500, 1/1000, 1/1500, 1/2000, 1/2500, 1/3000, etc.
  • the molar concentration of ⁇ -butyrolactone in the catalytic system is 4-13 mol / L, such as 4 mol / L, 5 mol / L, 6 mol / L, 7 mol / L, 8 mol / L, 9 mol / L, 10mol / L, 11mol / L, 12mol / L or 13mol / L, etc.
  • the ⁇ -butyrolactone concentration here refers to the concentration of ⁇ -butyrolactone in the catalytic system of the initiator, catalyst, urea, and organic solvent. If the concentration of ⁇ -butyrolactone is too low, the polymerization rate is slow, the conversion rate is low, and the molecular weight of the resulting product is low.
  • the initiator, catalyst, and urea are mixed in an organic solvent, and stirred at -70 to -10 ° C for 10 to 30 minutes to obtain a catalytic system.
  • the reaction temperature may be -70 ° C, -60 ° C, -55 ° C, -50 ° C, -45 ° C, -40 ° C, -35 ° C, -30 ° C, -20 ° C, or -10 ° C.
  • the polymerization reaction of ⁇ -butyrolactone in the catalytic system is completed at -70 to -20 ° C for 0.5 to 48 hours.
  • the reaction temperature may be -60 ° C, -55 ° C, -50 ° C, -45 ° C, -40 ° C, -35 ° C, -30 ° C, or -20 ° C.
  • the reaction time can be 0.5h, 1h, 2h, 4h, 8h, 12h, 16h, 20h, 24h, 36h or 48h.
  • the above step (2) may include: after adding ⁇ -butyrolactone to the catalytic system to perform the polymerization reaction, adding a compound containing an active functional group to the reaction system to terminate the reaction, and using methanol precipitation, Poly ( ⁇ -butyrolactone) is obtained.
  • a poly ( ⁇ -butyrolactone) precipitate can be obtained simply by adding the reaction system to methanol.
  • unreacted initiators, catalysts, urea, etc. in the catalytic system can be left in the solvent, and the residual amount of catalyst and urea in the isolated poly ( ⁇ -butyrolactone) product is extremely low or no residue, which can meet the requirements of biomedicine Application requirements in the field.
  • the above-mentioned active functional group-containing compound may include at least one selected from the group consisting of acids, acid chlorides, acid anhydrides, thioisocyanates, isocyanates, and halogenated hydrocarbons; preferably, the above-mentioned active functional group-containing compound is selected from Acetic acid, benzoic acid, acryloyl chloride, methacryloyl chloride, acetic anhydride, succinic anhydride, maleimidobutyryl chloride, epichlorohydrin, 3-chloropropene, 3-chloropropyne, 4-methoxy At least one of phenylthioisocyanate and 4-methoxybenzyl isocyanate.
  • the molar ratio of the compound containing active functional groups to urea may be (1-10): 1.
  • the present invention proposes a poly ( ⁇ -butyrolactone) product prepared by the method for preparing poly ( ⁇ -butyrolactone) of the above examples.
  • the residual amount of catalyst and urea in the poly ( ⁇ -butyrolactone) product is very low or no residue, which can meet the application requirements in the field of biomedicine, and has high molecular weight and good mechanical properties.
  • the above poly ( ⁇ -butyrolactone) has a structure as shown in formula (A),
  • n is a natural number greater than or equal to 10
  • R a is hydroxy, methoxy, ethoxy, isopropoxy, t-butoxy, benzyloxy, phenylethoxy, diphenyl Methoxy, 2,2-diphenylethoxy or a substituted group represented by formula (B),
  • x is a natural number equal to or greater than 5.
  • R b is hydrogen or one of the following substituents
  • the molecular weights reported in the following examples are all measured in tetrahydrofuran phase gel permeation chromatography (GPC), and a narrow distribution polystyrene is used as a standard sample to calibrate the standard curve.
  • the number average molecular weight measured by GPC was 86.1 kg / mol, and the molecular weight distribution was 1.95.
  • the number average molecular weight measured by GPC was 16.3 kg / mol, and the molecular weight distribution was 1.80.
  • the nuclear magnetic hydrogen spectrum of the resulting product is shown in Figure 1, and the carbon spectrum is shown in Figure 2.
  • the GPC curve is shown in FIG. 3, and its molecular weight is significantly increased compared to Comparative Example 2 without urea addition.
  • the reaction was carried out under nitrogen protection for 12 h, and 0.1 mL of acryloyl chloride was added to terminate the reaction.
  • the reaction mixture was dissolved in 30 mL of dichloromethane, poured into 200 mL of methanol, and the precipitate was separated by centrifugation to obtain poly ( ⁇ -butyrolactone).
  • the number average molecular weight measured by GPC was 26.3 kg / mol, and the molecular weight distribution was 1.60.
  • the thermal weight loss (TGA) curve of the obtained product is shown in FIG. 4. Compared with the product obtained in Comparative Example 1, its thermal stability is greatly improved.
  • the tensile curve of the resulting product is shown in Figure 5.
  • the reaction was carried out under nitrogen protection for 12h, and 0.2g of acetic anhydride was added to terminate the reaction.
  • the reaction mixture was dissolved in 50 mL of dichloromethane, poured into 500 mL of methanol, and the precipitate was separated by centrifugation to obtain poly ( ⁇ -butyrolactone).
  • the number average molecular weight measured by GPC was 51.3 kg / mol, and the molecular weight distribution was 1.80.
  • the tensile curve of the resulting product is shown in Figure 5.
  • the number average molecular weight measured by GPC was 22.6 kg / mol, and the molecular weight distribution was 1.76.
  • the number average molecular weight measured by GPC was 61.3 kg / mol, and the molecular weight distribution was 2.17.
  • the GPC curve of the resulting product is shown in Figure 6.
  • the number average molecular weight measured by GPC was 71.4 kg / mol, and the molecular weight distribution was 1.99.
  • the GPC curve of the resulting product is shown in Figure 7.
  • the number average molecular weight measured by GPC was 88.3 kg / mol, and the molecular weight distribution was 2.19.
  • the GPC curve of the resulting product is shown in Figure 8.
  • the tensile curve of the resulting product is shown in Figure 9.
  • the number average molecular weight measured by GPC was 115.3 kg / mol, and the molecular weight distribution was 2.52.
  • the number average molecular weight measured by GPC was 12.1 kg / mol, and the molecular weight distribution was 1.59.
  • the number average molecular weight measured by GPC was 7.9 kg / mol, and the molecular weight distribution was 2.07.

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Abstract

Provided are a method for preparing poly(γ-butyrolactone) with a high molecular weight, and poly (γ-butyrolactone) prepared by the method. The method comprises: subjecting γ-butyrolactone to polymerization in a catalytic system to obtain the poly(γ-butyrolactone), wherein the catalytic system comprises: an initiator, a catalyst and urea, wherein the catalyst is at least one of an alkali metal, an alkali metal compound, and an organophosphazene compound.

Description

一种高分子量聚(γ-丁内酯)的制备方法Preparation method of high molecular weight poly (γ-butyrolactone) 技术领域Technical field
本发明涉及高分子材料领域，具体而言，本发明涉及一种高分子量聚(γ-丁内酯)的制备方法，以及通过该方法制备得到的聚(γ-丁内酯)。The present invention relates to the field of polymer materials. Specifically, the present invention relates to a method for preparing high molecular weight poly (γ-butyrolactone), and poly (γ-butyrolactone) prepared by the method.
背景技术Background technique
聚(γ-丁内酯)是一类重要的脂肪族聚酯，具有良好的生物相容性和生物可降解性，在生物医药领域具有广阔的应用前景。聚(γ-丁内酯)在体内具有合适的降解速率，介于聚乙交酯和聚乳酸之间，并且与现有的生物材料相比，聚(γ-丁内酯)在降解时不会造成酸性物质在组织中的积累，不易引发炎症。聚(γ-丁内酯)可以通过生物发酵法和化学合成法两种方法得到。其中，生物发酵法得到的聚(γ-丁内酯)目前已经获得美国食品药品监督管理局(FDA)的批准，可以作为手术缝合线和疝气补片在临床上使用。但是，生物发酵法具有工艺流程复杂，所得产物纯化困难，残留生物物质易引起机体免疫反应等缺点。Poly (γ-butyrolactone) is an important class of aliphatic polyester, with good biocompatibility and biodegradability, and has broad application prospects in the field of biomedicine. Poly (γ-butyrolactone) has a suitable degradation rate in the body, between polyglycolide and polylactic acid, and compared with existing biological materials, poly (γ-butyrolactone) does not It will cause the accumulation of acidic substances in the tissues, which is not easy to cause inflammation. Poly (γ-butyrolactone) can be obtained by two methods: biological fermentation and chemical synthesis. Among them, the poly (γ-butyrolactone) obtained by the biological fermentation method has been approved by the US Food and Drug Administration (FDA) and can be used clinically as a surgical suture and a hernia patch. However, the biological fermentation method has the disadvantages of complicated process flow, difficulty in purification of the resulting product, and residual biological substances that easily cause the body's immune reaction.
聚(γ-丁内酯)也可以通过化学合成法，利用γ-丁内酯的开环聚合反应得到。γ-丁内酯是一种来源广泛、价格低廉的生物基单体，可以从生物质原料，如玉米、小麦等作物得到，是一种可再生原材料。利用化学合成法得到的聚(γ-丁内酯)可以对其进行官能团修饰，并且没有生物物质残留，更加适合在组织工程支架等生物医药方面的应用。但γ-丁内酯具有五元环结构，环张力很小，长期以来被认为是一种不可聚合的单体，目前也仅有少数文献报道其化学合成。文献报道的能够合成聚(γ-丁内酯)的催化剂包括金属有机催化剂、有机磷腈碱催化剂以及N-杂环乙烯催化剂三种(Nature Chemistry,2016,8(1),42-49；Polymer Chemistry,2018,9(26),3674-3683.)其中，金属有机催化剂由于毒性较大，并且容易残留在所得产物聚(γ-丁内酯)中，因此不适合在生物医药领域应用。而有机磷腈碱催化剂和N-杂环乙烯催化剂则由于其活性较低，根据文献报道，难以制备得到高分子量的聚(γ-丁内酯)，所得产物机械性能较差，不能满足生物医药方面实际应用的要求。Poly (γ-butyrolactone) can also be obtained by chemical synthesis using ring-opening polymerization of γ-butyrolactone. γ-Butyrolactone is a bio-based monomer with a wide range of sources and low prices. It can be obtained from biomass raw materials, such as corn and wheat, and is a renewable raw material. The poly (γ-butyrolactone) obtained by chemical synthesis method can be modified with functional groups, and there is no residue of biological substances, so it is more suitable for applications in biomedicine such as tissue engineering scaffolds. However, γ-butyrolactone has a five-membered ring structure, and the ring tension is very small. It has been considered as a non-polymerizable monomer for a long time, and only a few literatures report its chemical synthesis. The catalysts reported in the literature that can synthesize poly (γ-butyrolactone) include metal organic catalysts, organic phosphazene base catalysts and N-heterocyclic ethylene catalysts (Nature Chemistry, 2016, 8 (1), 42-49; Polymer Chemistry, 2018, 9 (26), 3674-3683.) Among them, metal-organic catalysts are not suitable for applications in the field of biomedicine due to their high toxicity and their tendency to remain in the resulting product poly (γ-butyrolactone). Organic phosphazene base catalysts and N-heterocyclic ethylene catalysts have low activity. According to reports in the literature, it is difficult to prepare high molecular weight poly (γ-butyrolactone). The resulting products have poor mechanical properties and cannot meet the requirements of biomedicine. Requirements for practical applications.
发明内容Summary of the invention
本发明旨在至少在一定程度上解决相关技术问题之一。为此，本发明的一个目的在于提出一种高分子量聚(γ-丁内酯)的制备方法，以及通过该方法制备得到的聚(γ-丁内 酯)。该制备聚(γ-丁内酯)的方法可制备得到满足生物医药领域应用要求的高分子量聚(γ-丁内酯)产品。The present invention aims to solve one of the related technical problems at least to a certain extent. To this end, an object of the present invention is to propose a method for preparing high molecular weight poly (γ-butyrolactone) and the poly (γ-butyrolactone) obtained by this method. The method for preparing poly (γ-butyrolactone) can prepare high molecular weight poly (γ-butyrolactone) products that meet the application requirements in the field of biomedicine.
在本发明的一个方面，本发明提出了一种制备聚(γ-丁内酯)的方法。根据本发明的实施例，该方法包括：In one aspect of the invention, the invention proposes a method for preparing poly (γ-butyrolactone). According to an embodiment of the invention, the method includes:
使γ-丁内酯在催化体系中进行聚合反应，得到聚(γ-丁内酯)；所述催化体系包括：引发剂、催化剂和脲，所述催化剂为碱金属、碱金属化合物和有机磷腈化合物中的至少之一。Γ-butyrolactone is polymerized in a catalytic system to obtain poly (γ-butyrolactone); the catalytic system includes: an initiator, a catalyst and urea, and the catalyst is an alkali metal, an alkali metal compound and an organic phosphorus At least one of the nitrile compounds.
根据本发明实施例的制备聚(γ-丁内酯)的方法，以碱金属、碱金属化合物和有机磷腈化合物中的至少之一和引发剂、脲组成催化体系，所使用的催化剂和脲毒性低，很容易从产物中除去；同时，催化体系活性高，制备得到的聚(γ-丁内酯)产品分子量高，具有良好的机械性能。According to the method for preparing poly (γ-butyrolactone) according to the embodiment of the present invention, at least one of an alkali metal, an alkali metal compound and an organic phosphazene compound, an initiator, and urea form a catalytic system, and the used catalyst and urea It has low toxicity and can be easily removed from the product; at the same time, the catalytic system has high activity, and the prepared poly (γ-butyrolactone) product has high molecular weight and good mechanical properties.
另外，根据本发明上述实施例的制备聚(γ-丁内酯)的方法还可以具有如下附加的技术特征：In addition, the method for preparing poly (γ-butyrolactone) according to the above embodiments of the present invention may also have the following additional technical features:
在本发明的一些实施例中，所述制备聚(γ-丁内酯)的方法包括：(1)将所述引发剂、所述催化剂和所述脲在有机溶剂中混合，得到所述催化体系；(2)将所述γ-丁内酯加入到所述催化体系中进行聚合反应，得到所述聚(γ-丁内酯)。In some embodiments of the present invention, the method for preparing poly (γ-butyrolactone) includes: (1) mixing the initiator, the catalyst, and the urea in an organic solvent to obtain the catalyst System; (2) adding the γ-butyrolactone to the catalytic system for polymerization reaction to obtain the poly (γ-butyrolactone).
在本发明的一些实施例中，所述引发剂为一元醇或多元醇。In some embodiments of the present invention, the initiator is a monohydric alcohol or a polyhydric alcohol.
在本发明的一些实施例中，所述一元醇选自甲醇、乙醇、异丙醇、叔丁醇、苄醇、苯乙醇、苯丙醇、二苯基甲醇、2,2-二苯基乙醇、端羟基寡聚乙二醇单甲醚中的至少之一；所述多元醇选自2,2-二苯基乙醇、乙二醇、1,2-丙二醇、1,3-丙二醇，1,4-丁二醇、1,2-苯二甲醇、1,3-苯二甲醇、1,4-苯二甲醇、2,2’-联苯二甲醇、丙三醇和季戊四醇中的至少之一。In some embodiments of the present invention, the monohydric alcohol is selected from methanol, ethanol, isopropanol, tert-butanol, benzyl alcohol, phenylethanol, phenylpropanol, diphenylmethanol, 2,2-diphenylethanol , At least one of hydroxyl-terminated oligoethylene glycol monomethyl ether; the polyol is selected from 2,2-diphenylethanol, ethylene glycol, 1,2-propanediol, 1,3-propanediol, 1, At least one of 4-butanediol, 1,2-benzenedimethanol, 1,3-benzenedimethanol, 1,4-benzenedimethanol, 2,2'-biphenyldimethanol, glycerin, and pentaerythritol.
在本发明的一些实施例中，所述碱金属选自锂、钠和钾中的至少之一。In some embodiments of the invention, the alkali metal is selected from at least one of lithium, sodium and potassium.
在本发明的一些实施例中，所述碱金属化合物选自氢化钾、氢化钠、萘钠、萘钾、联苯钠，二苯甲基钠和二苯甲基钾中的至少之一。In some embodiments of the present invention, the alkali metal compound is selected from at least one of potassium hydride, sodium hydride, sodium naphthalene, potassium naphthalene, biphenyl sodium, benzhydryl sodium, and benzhydryl potassium.
在本发明的一些实施例中，所述有机磷腈化合物选自六[三(二甲基胺)磷氮烯]三聚磷腈、磷腈配体P4-叔丁基和磷腈配体P2-叔丁基中的至少之一。In some embodiments of the present invention, the organic phosphazene compound is selected from hexa [tris (dimethylamine) phosphazene] triphosphazene, phosphazene ligand P4-tert-butyl and phosphazene ligand P2 -At least one of t-butyl.
在本发明的一些实施例中，所述有机溶剂选自甲苯、四氢呋喃、二氯甲烷、三氯甲烷、二氧六环、乙腈和N,N-二甲基甲酰胺中的至少之一。In some embodiments of the present invention, the organic solvent is selected from at least one of toluene, tetrahydrofuran, dichloromethane, chloroform, dioxane, acetonitrile, and N, N-dimethylformamide.
在本发明的一些实施例中，所述脲为式(I)所示化合物，In some embodiments of the present invention, the urea is a compound represented by formula (I),
Figure PCTCN2019112181-appb-000001
Figure PCTCN2019112181-appb-000001
式(I)中，R 1和R 2分别独立为甲基、乙基、丙基、异丙基、环己基、苯基、4-氯苯基、4-甲氧基苯基、4-三氟甲基苯基、2,6-二甲基苯基、2,4-二甲氧基苯基或2,4,6-三甲氧基苯基。 In formula (I), R 1 and R 2 are independently methyl, ethyl, propyl, isopropyl, cyclohexyl, phenyl, 4-chlorophenyl, 4-methoxyphenyl, 4-tris Fluoromethylphenyl, 2,6-dimethylphenyl, 2,4-dimethoxyphenyl or 2,4,6-trimethoxyphenyl.
在本发明的一些实施例中，所述脲具有以下其中之一所示的结构：In some embodiments of the present invention, the urea has a structure shown in one of the following:
Figure PCTCN2019112181-appb-000002
Figure PCTCN2019112181-appb-000002
在本发明的一些实施例中，所述催化剂与所述引发剂的摩尔比例为(1～60):3，所述催化剂与所述脲的摩尔比例为1:(1～10)，所述脲与所述γ-丁内酯的摩尔比例为1:(10～3000)。In some embodiments of the present invention, the molar ratio of the catalyst to the initiator is (1-60): 3, and the molar ratio of the catalyst to the urea is 1: (1-10), the The molar ratio of urea to the γ-butyrolactone is 1: (10-3000).
在本发明的一些实施例中，将所述引发剂、所述催化剂和所述脲在有机溶剂中混合，并在-70～-10℃下搅拌10～30min，得到所述催化体系。In some embodiments of the present invention, the initiator, the catalyst, and the urea are mixed in an organic solvent, and stirred at -70 to -10 ° C for 10 to 30 minutes to obtain the catalytic system.
在本发明的一些实施例中，所述聚合反应在-70～-20℃进行0.5～48h完成。In some embodiments of the present invention, the polymerization reaction is completed at -70 to -20 ° C for 0.5 to 48 hours.
在本发明的一些实施例中，所述γ-丁内酯在所述催化体系中的摩尔浓度为4～13mol/L。In some embodiments of the present invention, the molar concentration of γ-butyrolactone in the catalytic system is 4-13 mol / L.
在本发明的一些实施例中，步骤(2)包括：将所述γ-丁内酯加入到所述催化体系中进行聚合反应后，向反应体系中加入含活性官能团的化合物终止反应，并利用甲醇沉淀，得到所述聚(γ-丁内酯)。In some embodiments of the present invention, step (2) includes: after adding the γ-butyrolactone to the catalytic system for polymerization, adding a compound containing an active functional group to the reaction system to terminate the reaction, and using Methanol is precipitated to obtain the poly (γ-butyrolactone).
在本发明的一些实施例中，所述含活性官能团的化合物选自酸、酰氯、酸酐、硫代异氰酸酯、异氰酸酯和卤代烃中的至少之一；优选地，所述含活性官能团的化合物选自 乙酸、苯甲酸、丙烯酰氯、甲基丙烯酰氯、醋酸酐、丁二酸酐、马来酰亚胺基丁酰氯、环氧氯丙烷、3-氯丙烯、3-氯丙炔、4-甲氧基苯基硫代异氰酸酯和4-甲氧苄基异氰酸酯中的至少之一。In some embodiments of the present invention, the active functional group-containing compound is selected from at least one of acid, acid chloride, acid anhydride, thioisocyanate, isocyanate, and halogenated hydrocarbon; preferably, the active functional group-containing compound is selected From acetic acid, benzoic acid, acryloyl chloride, methacryloyl chloride, acetic anhydride, succinic anhydride, maleimidobutyryl chloride, epichlorohydrin, 3-chloropropene, 3-chloropropyne, 4-methoxy At least one of phenylphenyl thioisocyanate and 4-methoxybenzyl isocyanate.
在本发明的一些实施例中，所述含活性官能团的化合物与所述脲的摩尔比例为(1～10):1。In some embodiments of the present invention, the molar ratio of the active functional group-containing compound to the urea is (1-10): 1.
在本发明的另一方面，本发明提出了通过上述实施例的制备聚(γ-丁内酯)的方法制备得到的聚(γ-丁内酯)产品。该聚(γ-丁内酯)产品中催化剂和脲的残留量极低或无残留，能够满足生物医药领域的应用要求，且分子量高、具有良好的机械性能。In another aspect of the present invention, the present invention proposes a poly (γ-butyrolactone) product prepared by the method for preparing poly (γ-butyrolactone) of the above examples. The residual amount of catalyst and urea in the poly (γ-butyrolactone) product is very low or no residue, which can meet the application requirements in the field of biomedicine, and has high molecular weight and good mechanical properties.
本发明的附加方面和优点将在下面的描述中部分给出，部分将从下面的描述中变得明显，或通过本发明的实践了解到。Additional aspects and advantages of the present invention will be partially given in the following description, and some will become apparent from the following description, or be learned through the practice of the present invention.
附图说明BRIEF DESCRIPTION
附图是用来提供对本发明的进一步理解，并且构成说明书的一部分，与下面的具体实施方式一起用于解释本发明，但并不构成对本发明的限制。在附图中：The drawings are used to provide a further understanding of the present invention, and constitute a part of the specification, together with the following specific embodiments to explain the present invention, but do not constitute a limitation of the present invention. In the drawings:
图1为实施例2中制得的聚(γ-丁内酯)的 1H NMR谱图； 1 is a 1 H NMR spectrum of poly (γ-butyrolactone) prepared in Example 2;
图2为实施例2中制得的聚(γ-丁内酯)的 13C NMR谱图； 2 is a 13 C NMR spectrum of the poly (γ-butyrolactone) prepared in Example 2;
图3为对比实施例2和实施例2制得的聚(γ-丁内酯)的GPC谱图对比；FIG. 3 is a comparison of GPC spectra of the poly (γ-butyrolactone) prepared in Comparative Example 2 and Example 2;
图4为对比实施例1和实施例3制得的聚(γ-丁内酯)的TGA谱图对比；4 is a comparison of TGA spectra of poly (γ-butyrolactone) prepared in Comparative Example 1 and Example 3;
图5为实施例3和实施例4制得的聚(γ-丁内酯)的拉伸曲线；5 is a drawing curve of poly (γ-butyrolactone) prepared in Example 3 and Example 4;
图6为实施例6制得的聚(γ-丁内酯)的GPC谱图；6 is a GPC spectrum of poly (γ-butyrolactone) prepared in Example 6;
图7为实施例7制得的聚(γ-丁内酯)的GPC谱图；7 is a GPC spectrum of poly (γ-butyrolactone) prepared in Example 7;
图8为实施例8制得的聚(γ-丁内酯)的GPC谱图；8 is a GPC spectrum of poly (γ-butyrolactone) prepared in Example 8;
图9为实施例8制得的聚(γ-丁内酯)的拉伸曲线；9 is a drawing curve of poly (γ-butyrolactone) prepared in Example 8;
具体实施方式detailed description
下面详细描述本发明的实施例。下面描述的实施例是示例性的，仅用于解释本发明，而不能理解为对本发明的限制。实施例中未注明具体技术或条件的，按照本领域内的文献所描述的技术或条件或者按照产品说明书进行。所用试剂或仪器未注明生产厂商者，均为可以通过市购获得的常规产品。The embodiments of the present invention are described in detail below. The embodiments described below are exemplary and are only used to explain the present invention, and cannot be construed as limiting the present invention. If no specific technology or conditions are indicated in the examples, the technology or conditions described in the literature in the art or the product specification shall be followed. The reagents or instruments used do not indicate the manufacturer, and are all conventional products that are commercially available.
在本发明的一个方面，本发明提出了一种制备聚(γ-丁内酯)的方法。根据本发明的实施例，该方法包括：使γ-丁内酯在催化体系中进行聚合反应，得到聚(γ-丁内酯)；该 催化体系包括：引发剂、催化剂和脲，催化剂为碱金属、碱金属化合物和有机磷腈化合物中的至少之一。In one aspect of the invention, the invention proposes a method for preparing poly (γ-butyrolactone). According to an embodiment of the present invention, the method includes: polymerizing γ-butyrolactone in a catalytic system to obtain poly (γ-butyrolactone); the catalytic system includes: an initiator, a catalyst, and a urea, and the catalyst is an alkali At least one of metal, alkali metal compound and organic phosphazene compound.
下面对根据本发明实施例的制备聚(γ-丁内酯)的方法进行进一步的详细描述。The method for preparing poly (γ-butyrolactone) according to the embodiment of the present invention will be described in further detail below.
根据本发明的实施例，该方法以碱金属、碱金属化合物和有机磷腈化合物中的至少之一和引发剂、脲组成催化体系。总的来说，催化体系中催化剂(碱金属、碱金属化合物和有机磷腈化合物中的至少之一)可以和脲发生相互作用将其脱质子化形成脲阴离子，而脲阴离子通过氢键相互作用同时活化聚合物增长链末端和单体，从而使催化体系表现出很高的聚合活性。另一方面，脲阴离子与增长链末端通过氢键结合后降低了增长链末端官能团的碱性，增大了增长链末端的空间位阻，从而降低了酯交换和链末端回咬的可能性，提高了聚合反应的可控性，利于制备得到高分子量的聚(γ-丁内酯)。具体而言，碱金属是一种强电子给体，在催化体系中很容易夺取脲基团中的质子氢，使其成为脲阴离子。碱金属化合物本身呈现强碱性，也可以夺取脲基团中的质子氢，使其成为脲阴离子。有机磷腈化合物除了本身是一种有机超强碱，可以夺取脲基团中的质子氢，使其成为脲阴离子外，有机磷腈化合物在有机溶剂中的溶解性比无机碱好，易于和脲形成均相催化体系。由此，该催化体系具有很高的催化活性，可以催化γ-丁内酯高转化率地聚合得到高分子量的聚(γ-丁内酯)。According to an embodiment of the present invention, the method comprises at least one of an alkali metal, an alkali metal compound, and an organic phosphazene compound, an initiator, and urea to form a catalytic system. In general, the catalyst (at least one of alkali metal, alkali metal compound and organic phosphazene compound) in the catalytic system can interact with urea to deprotonate it to form urea anion, and urea anion interacts through hydrogen bonding At the same time, it activates the polymer growth chain ends and monomers, so that the catalytic system shows a high polymerization activity. On the other hand, the hydrogen bonding of the urea anion to the growing chain end reduces the basicity of the growing chain end functional group and increases the steric hindrance of the growing chain end, thereby reducing the possibility of transesterification and chain end biting. The controllability of the polymerization reaction is improved, which facilitates the preparation of high molecular weight poly (γ-butyrolactone). Specifically, alkali metal is a strong electron donor, and it is easy to capture proton hydrogen in the urea group in the catalytic system, making it a urea anion. The alkali metal compound itself exhibits strong basicity, and it can also capture proton hydrogen in the urea group to make it a urea anion. In addition to being an organic superbase, the organic phosphazene compound can capture proton hydrogen in the urea group and make it a urea anion. The solubility of the organic phosphazene compound in organic solvents is better than that of inorganic bases. Form a homogeneous catalytic system. Thus, the catalytic system has a very high catalytic activity and can catalyze the polymerization of γ-butyrolactone at a high conversion rate to obtain a high molecular weight poly (γ-butyrolactone).
另外，发明人在研究中发现，现有技术中虽然有涉及有机磷腈化合物与脲的催化体系制备聚酯的技术方案。但由于γ-丁内酯具有五元环结构、环张力很小，聚合过程中在热力学上是不利的，因而γ-丁内酯在聚合上与己内酯、戊内酯、丙交酯等常见环状内酯单体具有本质的不同，采用有机磷腈化合物与脲的催化体系通过γ-丁内酯开环聚合制备聚(γ-丁内酯)的研究未见报道。In addition, the inventor discovered in the research that although there are technical solutions in the prior art that involve a catalytic system of an organic phosphazene compound and urea to prepare polyester. However, because γ-butyrolactone has a five-membered ring structure and a small ring tension, it is thermodynamically disadvantageous during the polymerization process, so γ-butyrolactone is polymerized with caprolactone, valerolactone, lactide, etc. Common cyclic lactone monomers are essentially different. Studies on the preparation of poly (γ-butyrolactone) by ring-opening polymerization of γ-butyrolactone using a catalytic system of organic phosphazene compound and urea have not been reported.
根据本发明的一些实施例，本发明的制备聚(γ-丁内酯)的方法包括：(1)将引发剂、催化剂和脲在有机溶剂中混合，得到催化体系。(2)将γ-丁内酯加入到所述催化体系中进行聚合反应，得到所述聚(γ-丁内酯)。具体地，可以将引发剂、催化剂和脲溶于有机溶剂中，在低温下搅拌一段时间后，将γ-丁内酯加入上述混合溶液中，在一定温度下反应一段时间，得到聚(γ-丁内酯)。According to some embodiments of the present invention, the method for preparing poly (γ-butyrolactone) of the present invention includes: (1) mixing an initiator, a catalyst, and urea in an organic solvent to obtain a catalytic system. (2) γ-butyrolactone is added to the catalytic system for polymerization reaction to obtain the poly (γ-butyrolactone). Specifically, the initiator, catalyst and urea can be dissolved in an organic solvent, after stirring at a low temperature for a period of time, γ-butyrolactone is added to the above mixed solution, and reacted at a certain temperature for a period of time to obtain poly (γ- Butyrolactone).
根据本发明的实施例，上述引发剂可以为一元醇或多元醇。具体的，上述一元醇可以为选自甲醇、乙醇、异丙醇、叔丁醇、苄醇、苯乙醇、苯丙醇、二苯基甲醇、2,2-二苯基乙醇、端羟基寡聚乙二醇单甲醚中的至少之一；上述多元醇可以为选自2,2-二苯基乙醇、乙二醇、1,2-丙二醇、1,3-丙二醇，1,4-丁二醇、1,2-苯二甲醇、1,3-苯二甲醇、1,4-苯二甲醇、2,2’-联苯二甲醇、丙三醇和季戊四醇中的至少之一。以上醇类引发剂可以高 效地引发γ-丁内酯的开环聚合反应，且原料来源广泛、廉价易得。另外，通过利用含端羟基的大分子醇作为引发剂，本发明的方法还可以用于制备含聚(γ-丁内酯)的嵌段共聚物。According to an embodiment of the present invention, the above initiator may be a monohydric alcohol or a polyhydric alcohol. Specifically, the monohydric alcohol may be selected from methanol, ethanol, isopropanol, tert-butanol, benzyl alcohol, phenylethanol, phenylpropanol, diphenylmethanol, 2,2-diphenylethanol, hydroxyl-terminated oligomer At least one of ethylene glycol monomethyl ether; the above-mentioned polyol may be selected from 2,2-diphenylethanol, ethylene glycol, 1,2-propanediol, 1,3-propanediol, 1,4-butanediol At least one of alcohol, 1,2-benzenedimethanol, 1,3-benzenedimethanol, 1,4-benzenedimethanol, 2,2'-biphenyldimethanol, glycerin, and pentaerythritol. The above alcohol initiators can efficiently initiate the ring-opening polymerization of γ-butyrolactone, and the raw materials are widely available and cheap and easily available. In addition, the method of the present invention can also be used to prepare poly (γ-butyrolactone) -containing block copolymers by using a hydroxyl-terminated macroalcohol as an initiator.
根据本发明的实施例，上述碱金属可以为选自锂、钠和钾中的至少之一。根据本发明的实施例，上述碱金属化合物可以为选自氢化钾、氢化钠、萘钠、萘钾、联苯钠，二苯甲基钠和二苯甲基钾中的至少之一。以上碱金属和碱金属化合物均为超强碱，能够有效夺取脲基团的质子氢，且与碱金属醇盐不同，以上碱金属和碱金属化合物和脲之间的反应为不可逆反应，并且以上碱金属和碱金属化合物为非亲核性强碱，自身不会引发γ-丁内酯开环聚合，利于得到具有明确结构的高分子量聚(γ-丁内酯)。According to an embodiment of the present invention, the above alkali metal may be at least one selected from lithium, sodium, and potassium. According to an embodiment of the present invention, the above-mentioned alkali metal compound may be at least one selected from potassium hydride, sodium hydride, sodium naphthalene, potassium naphthalene, biphenyl sodium, benzhydryl sodium, and benzhydryl potassium. The above alkali metals and alkali metal compounds are super strong bases, which can effectively capture proton hydrogen of the urea group, and unlike alkali metal alkoxides, the reaction between the above alkali metal and alkali metal compounds and urea is irreversible, and above Alkali metals and alkali metal compounds are strong non-nucleophilic bases, and do not initiate ring-opening polymerization of γ-butyrolactone by themselves, which is beneficial to obtain high molecular weight poly (γ-butyrolactone) with a clear structure.
根据本发明的实施例，上述有机磷腈化合物可以为选自六[三(二甲基胺)磷氮烯]三聚磷腈({[(NMe 2) 3P＝N] 2P＝N} 3)、磷腈配体P4-叔丁基([(NMe 2) 3P＝N] 3P＝NtBu，tert-Bu-P 4)和磷腈配体P2-叔丁基([(NMe 2) 3P＝N](NMe 2) 2P＝NtBu，tert-Bu-P 2)中的至少之一。 According to an embodiment of the present invention, the organic phosphazene compound may be selected from hexa [tris (dimethylamine) phosphazene] triphosphazene ({[(NMe 2 ) 3 P = N] 2 P = N} 3 ), phosphazene ligand P4-tert-butyl ([(NMe 2 ) 3 P = N] 3 P = NtBu, tert-Bu-P 4 ) and phosphazene ligand P2-tert-butyl ([(NMe 2 ) 3 P = N] (NMe 2 ) 2 P = NtBu, at least one of tert-Bu-P 2 ).
在本发明的一些实施例中，所述脲为式(I)所示化合物，In some embodiments of the present invention, the urea is a compound represented by formula (I),
Figure PCTCN2019112181-appb-000003
Figure PCTCN2019112181-appb-000003
式(I)中，R 1和R 2分别独立为甲基、乙基、丙基、异丙基、环己基、苯基、4-氯苯基、4-甲氧基苯基、4-三氟甲基苯基、2,6-二甲基苯基、2,4-二甲氧基苯基或2,4,6-三甲氧基苯基。 In formula (I), R 1 and R 2 are independently methyl, ethyl, propyl, isopropyl, cyclohexyl, phenyl, 4-chlorophenyl, 4-methoxyphenyl, 4-tris Fluoromethylphenyl, 2,6-dimethylphenyl, 2,4-dimethoxyphenyl or 2,4,6-trimethoxyphenyl.
根据本发明的实施例，上述脲具有以下其中之一所示的结构：According to an embodiment of the present invention, the above urea has a structure shown in one of the following:
Figure PCTCN2019112181-appb-000004
Figure PCTCN2019112181-appb-000004
根据本发明的实施例，上述有机溶剂选自甲苯、四氢呋喃、二氯甲烷、三氯甲烷、二氧六环、乙腈和N,N-二甲基甲酰胺中的至少之一。以上有机溶剂可以为引发剂、催化剂和γ-丁内酯单体提供良好的溶解性，且催化剂在以上有机溶剂中可以表现出强碱性，提高聚(γ-丁内酯)的收率。另外，由于催化剂和脲在甲醇中溶解性大，很容易将聚(γ-丁内酯)产品通过沉淀的方式从反应体系中分离出来，聚(γ-丁内酯)产品中催化剂和脲残留量极低或无残留(从图1和图2中可以看出)，能够满足生物医药领域的应用要求。According to an embodiment of the present invention, the above organic solvent is selected from at least one of toluene, tetrahydrofuran, dichloromethane, chloroform, dioxane, acetonitrile, and N, N-dimethylformamide. The above organic solvents can provide good solubility for initiators, catalysts and γ-butyrolactone monomers, and the catalysts can exhibit strong basicity in the above organic solvents, improving the yield of poly (γ-butyrolactone). In addition, due to the high solubility of catalyst and urea in methanol, it is easy to separate the poly (γ-butyrolactone) product from the reaction system by precipitation. The catalyst and urea remain in the poly (γ-butyrolactone) product. The amount is extremely low or no residue (as can be seen from Figure 1 and Figure 2), which can meet the application requirements in the field of biomedicine.
根据本发明的一些实施例，在γ-丁内酯的聚合反应中，催化剂与引发剂的摩尔比例可以为(1～60):3，换言之，催化剂与引发剂的摩尔比例可以为1/3～20/1，例如1/3、1/1、3/1、5/1、10/1、20/1。催化剂与脲的摩尔比例可以为1:(1～10)，换言之，催化剂与脲的摩尔比例可以为1/1～1/10，例如1/1、1/2、1/3、1/4、1/5、1/6、1/7、1/8、1/9或是1/10。脲与γ-丁内酯的摩尔比例可以为1:(10～3000)，换言之，脲与γ-丁内酯的摩尔比例可以为1/10～1/3000，例如1/10、1/100、1/200、1/300、1/500、1/1000、1/1500、1/2000、1/2500或是1/3000等。According to some embodiments of the present invention, in the polymerization reaction of γ-butyrolactone, the molar ratio of the catalyst to the initiator may be (1-60): 3, in other words, the molar ratio of the catalyst to the initiator may be 1/3 ~ 20/1, for example 1/3, 1/1, 3/1, 5/1, 10/1, 20/1. The molar ratio of the catalyst to urea can be 1: (1-10), in other words, the molar ratio of the catalyst to urea can be 1/1 to 1/10, such as 1/1, 1/2, 1/3, 1/4 , 1/5, 1/6, 1/7, 1/8, 1/9 or 1/10. The molar ratio of urea to γ-butyrolactone can be 1: (10 to 3000), in other words, the molar ratio of urea to γ-butyrolactone can be 1/10 to 1/3000, for example 1/10, 1/100 , 1/200, 1/300, 1/500, 1/1000, 1/1500, 1/2000, 1/2500, 1/3000, etc.
根据本发明的一些实施例，γ-丁内酯在催化体系中的摩尔浓度为4～13mol/L，例如4mol/L、5mol/L、6mol/L、7mol/L、8mol/L、9mol/L、10mol/L、11mol/L、12mol/L或是13mol/L等。需要说明的是，这里的γ-丁内酯浓度是指γ-丁内酯在引发剂、催化剂、脲和有机溶剂的催化体系中的浓度。如果γ-丁内酯的浓度过低，则聚合速率较慢，转化率较低，所得产物分子量较低。According to some embodiments of the present invention, the molar concentration of γ-butyrolactone in the catalytic system is 4-13 mol / L, such as 4 mol / L, 5 mol / L, 6 mol / L, 7 mol / L, 8 mol / L, 9 mol / L, 10mol / L, 11mol / L, 12mol / L or 13mol / L, etc. It should be noted that the γ-butyrolactone concentration here refers to the concentration of γ-butyrolactone in the catalytic system of the initiator, catalyst, urea, and organic solvent. If the concentration of γ-butyrolactone is too low, the polymerization rate is slow, the conversion rate is low, and the molecular weight of the resulting product is low.
根据本发明的一些实施例，将引发剂、催化剂和脲在有机溶剂中混合，并在-70～-10℃下搅拌10～30min，得到催化体系。其中，反应温度可以为-70℃、-60℃、-55℃、-50℃、-45℃、-40℃、-35℃、-30℃、-20℃或是-10℃等。相对于直接将单体与引发剂、催化剂和脲混合进行反应，通过在上述条件下首先获得催化体系，再加入单体，可以进一步提高γ-丁内酯的转化率和所得聚(γ-丁内酯)的分子量。According to some embodiments of the present invention, the initiator, catalyst, and urea are mixed in an organic solvent, and stirred at -70 to -10 ° C for 10 to 30 minutes to obtain a catalytic system. The reaction temperature may be -70 ° C, -60 ° C, -55 ° C, -50 ° C, -45 ° C, -40 ° C, -35 ° C, -30 ° C, -20 ° C, or -10 ° C. Relative to directly mixing the monomer with the initiator, catalyst and urea to react, by first obtaining the catalytic system under the above conditions, and then adding the monomer, the conversion rate of γ-butyrolactone and the resulting poly (γ-butyrolactone Lactone) molecular weight.
根据本发明的一些实施例，γ-丁内酯在催化体系中的聚合反应在-70～-20℃进行0.5～48h完成。反应温度可以是-60℃、-55℃、-50℃、-45℃、-40℃、-35℃、-30℃或是-20℃等。反应时间可以是0.5h、1h、2h、4h、8h、12h、16h、20h、24h、36h或是48h等。发明人在实验中发现，反应温度过高，则γ-丁内酯无法聚合；反应时间过短，则γ-丁内酯的转化率较低，所得聚(γ-丁内酯)的分子量较低；而过多地延长反应时间，并不能进一步有效地提高γ-丁内酯的转化率和产物的分子量。According to some embodiments of the present invention, the polymerization reaction of γ-butyrolactone in the catalytic system is completed at -70 to -20 ° C for 0.5 to 48 hours. The reaction temperature may be -60 ° C, -55 ° C, -50 ° C, -45 ° C, -40 ° C, -35 ° C, -30 ° C, or -20 ° C. The reaction time can be 0.5h, 1h, 2h, 4h, 8h, 12h, 16h, 20h, 24h, 36h or 48h. The inventor found in experiments that if the reaction temperature is too high, γ-butyrolactone cannot be polymerized; if the reaction time is too short, the conversion rate of γ-butyrolactone is low, and the molecular weight of the resulting poly (γ-butyrolactone) is relatively high. Low; and prolonging the reaction time too much can not further effectively increase the conversion rate of γ-butyrolactone and the molecular weight of the product.
根据本发明的一些实施例，上述步骤(2)可以包括：将γ-丁内酯加入到催化体系中进行聚合反应后，向反应体系中加入含活性官能团的化合物终止反应，并利用甲醇沉 淀，得到聚(γ-丁内酯)。根据本发明的实施例，终止反应后，可以简单地通过将反应体系加入到甲醇中来获得聚(γ-丁内酯)沉淀。由此，催化体系中未反应的引发剂、催化剂和脲等可留在溶剂中，分离得到的聚(γ-丁内酯)产品中催化剂和脲残留量极低或无残留，能够满足生物医药领域的应用要求。According to some embodiments of the present invention, the above step (2) may include: after adding γ-butyrolactone to the catalytic system to perform the polymerization reaction, adding a compound containing an active functional group to the reaction system to terminate the reaction, and using methanol precipitation, Poly (γ-butyrolactone) is obtained. According to an embodiment of the present invention, after terminating the reaction, a poly (γ-butyrolactone) precipitate can be obtained simply by adding the reaction system to methanol. As a result, unreacted initiators, catalysts, urea, etc. in the catalytic system can be left in the solvent, and the residual amount of catalyst and urea in the isolated poly (γ-butyrolactone) product is extremely low or no residue, which can meet the requirements of biomedicine Application requirements in the field.
根据本发明的一些实施例，上述含活性官能团的化合物可以包括选自酸、酰氯、酸酐、硫代异氰酸酯、异氰酸酯和卤代烃中的至少之一；优选地，上述含活性官能团的化合物选自乙酸、苯甲酸、丙烯酰氯、甲基丙烯酰氯、醋酸酐、丁二酸酐、马来酰亚胺基丁酰氯、环氧氯丙烷、3-氯丙烯、3-氯丙炔、4-甲氧基苯基硫代异氰酸酯和4-甲氧苄基异氰酸酯中的至少之一。According to some embodiments of the present invention, the above-mentioned active functional group-containing compound may include at least one selected from the group consisting of acids, acid chlorides, acid anhydrides, thioisocyanates, isocyanates, and halogenated hydrocarbons; preferably, the above-mentioned active functional group-containing compound is selected from Acetic acid, benzoic acid, acryloyl chloride, methacryloyl chloride, acetic anhydride, succinic anhydride, maleimidobutyryl chloride, epichlorohydrin, 3-chloropropene, 3-chloropropyne, 4-methoxy At least one of phenylthioisocyanate and 4-methoxybenzyl isocyanate.
根据本发明的一些实施例，含活性官能团的化合物与脲的摩尔比例可以为(1～10):1。According to some embodiments of the present invention, the molar ratio of the compound containing active functional groups to urea may be (1-10): 1.
在本发明的另一方面，本发明提出了通过上述实施例的制备聚(γ-丁内酯)的方法制备得到的聚(γ-丁内酯)产品。该聚(γ-丁内酯)产品中催化剂和脲的残留量极低或无残留，能够满足生物医药领域的应用要求，且分子量高、具有良好的机械性能。In another aspect of the present invention, the present invention proposes a poly (γ-butyrolactone) product prepared by the method for preparing poly (γ-butyrolactone) of the above examples. The residual amount of catalyst and urea in the poly (γ-butyrolactone) product is very low or no residue, which can meet the application requirements in the field of biomedicine, and has high molecular weight and good mechanical properties.
根据本发明的一些实施例，上述聚(γ-丁内酯)具有如式(A)所示的结构，According to some embodiments of the present invention, the above poly (γ-butyrolactone) has a structure as shown in formula (A),
Figure PCTCN2019112181-appb-000005
Figure PCTCN2019112181-appb-000005
式(A)中，n为大于等于10的自然数，R a为羟基、甲氧基、乙氧基、异丙氧基、叔丁氧基、苄氧基、苯基乙氧基、二苯基甲氧基、2,2-二苯基乙氧基或式(B)所示取代基团， Of formula (A), n is a natural number greater than or equal to 10, R a is hydroxy, methoxy, ethoxy, isopropoxy, t-butoxy, benzyloxy, phenylethoxy, diphenyl Methoxy, 2,2-diphenylethoxy or a substituted group represented by formula (B),
Figure PCTCN2019112181-appb-000006
Figure PCTCN2019112181-appb-000006
式(B)中，x为大于等于5的自然数。In formula (B), x is a natural number equal to or greater than 5.
R b为氢或以下之一的取代基团， R b is hydrogen or one of the following substituents,
Figure PCTCN2019112181-appb-000007
Figure PCTCN2019112181-appb-000007
另外，需要说明的是，前文针对“制备聚(γ-丁内酯)的方法”所描述的特征和优点同样适用于该聚(γ-丁内酯)产品，在此不再一一赘述。In addition, it should be noted that the features and advantages described above for the “method for preparing poly (γ-butyrolactone)” are also applicable to the poly (γ-butyrolactone) product, and will not be repeated here.
下面参考具体实施例，对本发明进行描述，需要说明的是，这些实施例仅仅是描述性的，而不以任何方式限制本发明。下述实施案例中所用的材料、试剂等，如无特殊说明，均可从商业途径得到。The present invention will be described below with reference to specific embodiments. It should be noted that these embodiments are merely descriptive and do not limit the present invention in any way. Unless otherwise specified, the materials and reagents used in the following examples can be obtained from commercial sources.
其中，六[三(二甲基胺)磷氮烯]三聚磷腈({[(NMe 2) 3P＝N] 2P＝N} 3)根据文献(Angewandte Chemie International Edition,2017,56(42),12987-12990)报道的方法合成。以下实施例中报道的分子量均在四氢呋喃相凝胶渗透色谱(GPC)中测得，以窄分布的聚苯乙烯作为标样标定标准曲线。 Among them, hexa [tris (dimethylamine) phosphazene] triphosphazene ({[(NMe 2 ) 3 P = N] 2 P = N} 3 ) according to the literature (Angewandte Chemie International Edition, 2017, 56 ( 42), 12987-12990) synthesis method. The molecular weights reported in the following examples are all measured in tetrahydrofuran phase gel permeation chromatography (GPC), and a narrow distribution polystyrene is used as a standard sample to calibrate the standard curve.
实施例1Example 1
将(1mmol,74.1mg)叔丁醇，(1mmol，151.2mg)萘钠、(3mmol，432.4mg)1,3-二异丙基脲和46mL四氢呋喃加入反应瓶中，置于-50℃低温冷浴中搅拌10min，用注射器将(2000mmol，154mL)γ-丁内酯加入反应管中。反应在氮气保护下进行10h，加入2mL丙烯酰氯终止反应。将反应混合物溶于1L二氯甲烷中，倒入5L甲醇中，离心分离沉淀得到聚(γ-丁内酯)。Add (1mmol, 74.1mg) tert-butanol, (1mmol, 151.2mg) sodium naphthalene, (3mmol, 432.4mg) 1,3-diisopropylurea and 46mL of tetrahydrofuran to the reaction flask, and cool at -50 ℃ Stir for 10 min in the bath and add (2000 mmol, 154 mL) γ-butyrolactone to the reaction tube with a syringe. The reaction was carried out under nitrogen protection for 10h, and 2mL of acryloyl chloride was added to terminate the reaction. The reaction mixture was dissolved in 1L of dichloromethane, poured into 5L of methanol, and the precipitate was separated by centrifugation to obtain poly (γ-butyrolactone).
GPC测得数均分子量为86.1kg/mol，分子量分布为1.95。The number average molecular weight measured by GPC was 86.1 kg / mol, and the molecular weight distribution was 1.95.
实施例2Example 2
将(0.15mmol，16.2mg)苄醇、(0.15mmol，179.7mg)六[三(二甲基胺)磷氮烯]三聚磷腈、(0.45mmol，111.75mg)1-环己基-3-(4-甲氧基苯基)脲和1mL四氢呋喃加入反应管中，置于-50℃低温冷浴中搅拌10min，用注射器将(45mmol，3.46mL)γ-丁内酯加入反应管中。反应在氮气保护下进行4h，加入10滴醋酸终止反应。将反应混合物溶于15mL二氯甲烷中，倒入100mL甲醇中，离心分离沉淀得到聚(γ-丁内酯)。(0.15mmol, 16.2mg) benzyl alcohol, (0.15mmol, 179.7mg) hexa [tris (dimethylamine) phosphazene] triphosphazene, (0.45mmol, 111.75mg) 1-cyclohexyl-3- (4-Methoxyphenyl) urea and 1 mL of tetrahydrofuran were added to the reaction tube, placed in a -50 ° C cold bath and stirred for 10 min, and (45 mmol, 3.46 mL) γ-butyrolactone was added to the reaction tube with a syringe. The reaction was carried out under nitrogen protection for 4h, and 10 drops of acetic acid was added to terminate the reaction. The reaction mixture was dissolved in 15 mL of dichloromethane, poured into 100 mL of methanol, and the precipitate was separated by centrifugation to obtain poly (γ-butyrolactone).
GPC测得数均分子量为16.3kg/mol，分子量分布为1.80。所得产物核磁氢谱如图1所示，碳谱如图2所示。GPC曲线如图3所示，与不加脲的对比实施例2相比，其分子量明显增大。The number average molecular weight measured by GPC was 16.3 kg / mol, and the molecular weight distribution was 1.80. The nuclear magnetic hydrogen spectrum of the resulting product is shown in Figure 1, and the carbon spectrum is shown in Figure 2. The GPC curve is shown in FIG. 3, and its molecular weight is significantly increased compared to Comparative Example 2 without urea addition.
实施例3Example 3
将(0.2mmol，21.6mg)苄醇、(0.8mmol，507mg)磷腈配体P4-叔丁基催化剂、 (2.4mmol，668mg)1-环己基-3-(2,6-二甲氧基苯基)脲和4.6mL四氢呋喃加入反应管中，置于-50℃低温冷浴中搅拌10min，用注射器将(200mmol，15.4mL)γ-丁内酯加入反应管中。反应在氮气保护下进行12h，加入0.1mL丙烯酰氯终止反应。将反应混合物溶于30mL二氯甲烷中，倒入200mL甲醇中，离心分离沉淀得到聚(γ-丁内酯)。(0.2 mmol, 21.6 mg) benzyl alcohol, (0.8 mmol, 507 mg) phosphazene ligand P4-tert-butyl catalyst, (2.4 mmol, 668 mg) 1-cyclohexyl-3- (2,6-dimethoxy Phenyl) urea and 4.6 mL of tetrahydrofuran were added to the reaction tube, placed in a -50 ° C low temperature cold bath and stirred for 10 min, and (200 mmol, 15.4 mL) γ-butyrolactone was added to the reaction tube with a syringe. The reaction was carried out under nitrogen protection for 12 h, and 0.1 mL of acryloyl chloride was added to terminate the reaction. The reaction mixture was dissolved in 30 mL of dichloromethane, poured into 200 mL of methanol, and the precipitate was separated by centrifugation to obtain poly (γ-butyrolactone).
GPC测得数均分子量为26.3kg/mol，分子量分布为1.60。所得产物热失重(TGA)曲线如图4所示，与对比实施例1所得产物相比，其热稳定大大提高。所得产物拉伸曲线如图5所示。The number average molecular weight measured by GPC was 26.3 kg / mol, and the molecular weight distribution was 1.60. The thermal weight loss (TGA) curve of the obtained product is shown in FIG. 4. Compared with the product obtained in Comparative Example 1, its thermal stability is greatly improved. The tensile curve of the resulting product is shown in Figure 5.
实施例4Example 4
将(0.4mmol，54.5mg)苯丙醇、(1.6mmol，1.92g)六[三(二甲基胺)磷氮烯]三聚磷腈、(6.4mmol，1.97g)1-环己基-3-(2,6-二甲氧基苯基)脲和9.3mL四氢呋喃加入反应管中，置于-50℃低温冷浴中搅拌10min，用注射器将(400mmol，30.75mL)γ-丁内酯加入反应管中。反应在氮气保护下进行12h，加入0.2g醋酸酐终止反应。将反应混合物溶于50mL二氯甲烷中，倒入500mL甲醇中，离心分离沉淀得到聚(γ-丁内酯)。Combine (0.4 mmol, 54.5 mg) phenylpropanol, (1.6 mmol, 1.92 g) hexa [tris (dimethylamine) phosphazene] triphosphazene, (6.4 mmol, 1.97 g) 1-cyclohexyl-3 -(2,6-dimethoxyphenyl) urea and 9.3mL of tetrahydrofuran were added to the reaction tube, placed in a -50 ℃ low temperature cold bath and stirred for 10min, (400mmol, 30.75mL) γ-butyrolactone was added with a syringe Reaction tube. The reaction was carried out under nitrogen protection for 12h, and 0.2g of acetic anhydride was added to terminate the reaction. The reaction mixture was dissolved in 50 mL of dichloromethane, poured into 500 mL of methanol, and the precipitate was separated by centrifugation to obtain poly (γ-butyrolactone).
GPC测得数均分子量为51.3kg/mol，分子量分布为1.80。所得产物拉伸曲线如图5所示。The number average molecular weight measured by GPC was 51.3 kg / mol, and the molecular weight distribution was 1.80. The tensile curve of the resulting product is shown in Figure 5.
实施例5Example 5
将(1.5mmol，90.2mg)异丙醇、(1.5mmol，60mg)氢化钾、(6mmol，1.68g)1-苯基-3-(4-三氟甲基苯基)脲和10mL四氢呋喃加入反应管中，置于-60℃低温冷浴中搅拌10min，用注射器将(450mmol，34.6mL)γ-丁内酯加入反应管中。反应在氮气保护下进行12h，加入1mL丁二酸酐终止反应。将反应混合物溶于50mL二氯甲烷中，倒入500mL甲醇中，离心分离沉淀得到聚(γ-丁内酯)。(1.5mmol, 90.2mg) isopropanol, (1.5mmol, 60mg) potassium hydride, (6mmol, 1.68g) 1-phenyl-3- (4-trifluoromethylphenyl) urea and 10mL of tetrahydrofuran were added to the reaction Place the tube in a low temperature cold bath at -60 ° C and stir for 10 min. Add (450 mmol, 34.6 mL) γ-butyrolactone to the reaction tube with a syringe. The reaction was carried out under nitrogen protection for 12h, and 1mL of succinic anhydride was added to terminate the reaction. The reaction mixture was dissolved in 50 mL of dichloromethane, poured into 500 mL of methanol, and the precipitate was separated by centrifugation to obtain poly (γ-butyrolactone).
GPC测得数均分子量为22.6kg/mol，分子量分布为1.76。The number average molecular weight measured by GPC was 22.6 kg / mol, and the molecular weight distribution was 1.76.
实施例6Example 6
将(0.2mmol，21.6mg)苄醇、(0.6mmol，14.4mg)氢化钠、(0.6mmol，130.9mg)1-环己基-3-苯基脲和4.6mL四氢呋喃加入反应管中，置于-40℃低温冷浴中搅拌10min，用注射器将(200mmol，15.4mL)γ-丁内酯加入反应管中。反应在氮气保护下进行4h，加入0.1mL醋酸终止反应。将反应混合物溶于30mL二氯甲烷中，倒入 200mL甲醇中，离心分离沉淀得到聚(γ-丁内酯)。(0.2mmol, 21.6mg) benzyl alcohol, (0.6mmol, 14.4mg) sodium hydride, (0.6mmol, 130.9mg) 1-cyclohexyl-3-phenylurea and 4.6mL tetrahydrofuran were added to the reaction tube and placed in- Stir in a cold bath at 40 ° C for 10 min, and add (200 mmol, 15.4 mL) γ-butyrolactone to the reaction tube with a syringe. The reaction was carried out under nitrogen protection for 4h, and 0.1mL of acetic acid was added to terminate the reaction. The reaction mixture was dissolved in 30 mL of methylene chloride, poured into 200 mL of methanol, and the precipitate was separated by centrifugation to obtain poly (γ-butyrolactone).
GPC测得数均分子量为61.3kg/mol，分子量分布为2.17。所得产物GPC曲线如图6所示。The number average molecular weight measured by GPC was 61.3 kg / mol, and the molecular weight distribution was 2.17. The GPC curve of the resulting product is shown in Figure 6.
实施例7Example 7
将(0.2mmol，21.6mg)苄醇、(0.3mmol，6.9mg)钠、(0.6mmol，165.6mg)1-(4-氯苯基)-3-(4-甲氧基苯基)脲和2.53mL四氢呋喃加入反应管中，置于-50℃低温冷浴中搅拌10min，用注射器将(400mmol，30.8mL)γ-丁内酯加入反应管中。反应在氮气保护下进行4h，加入0.1mL醋酸酐终止反应。将反应混合物溶于100mL二氯甲烷中，倒入500mL甲醇中，离心分离沉淀得到聚(γ-丁内酯)。(0.2 mmol, 21.6 mg) benzyl alcohol, (0.3 mmol, 6.9 mg) sodium, (0.6 mmol, 165.6 mg) 1- (4-chlorophenyl) -3- (4-methoxyphenyl) urea and 2.53 mL of tetrahydrofuran was added to the reaction tube, placed in a -50 ° C cold bath and stirred for 10 min, and (400 mmol, 30.8 mL) γ-butyrolactone was added to the reaction tube with a syringe. The reaction was carried out under nitrogen protection for 4h, and 0.1mL of acetic anhydride was added to terminate the reaction. The reaction mixture was dissolved in 100 mL of dichloromethane, poured into 500 mL of methanol, and the precipitate was separated by centrifugation to obtain poly (γ-butyrolactone).
GPC测得数均分子量为71.4kg/mol，分子量分布为1.99。所得产物GPC曲线如图7所示。The number average molecular weight measured by GPC was 71.4 kg / mol, and the molecular weight distribution was 1.99. The GPC curve of the resulting product is shown in Figure 7.
实施例8Example 8
将(2mmol，216mg)苄醇、(4mmol，160mg)氢化钾、(8mmol，2.02g)1-(4-氯苯基)-3-环己基脲和102mL四氢呋喃加入反应管中，置于-40℃低温冷浴中搅拌10min，用注射器将(3000mmol，231mL)γ-丁内酯加入反应管中。反应在氮气保护下进行8h，加入3mL丁二酸酐终止反应。将反应混合物溶于1.5L二氯甲烷中，倒入6L甲醇中，离心分离沉淀得到聚(γ-丁内酯)。Add (2mmol, 216mg) benzyl alcohol, (4mmol, 160mg) potassium hydride, (8mmol, 2.02g) 1- (4-chlorophenyl) -3-cyclohexyl urea and 102mL of tetrahydrofuran to the reaction tube and place at -40 Stir for 10 min in a low temperature cold bath at ℃, and add (3000 mmol, 231 mL) γ-butyrolactone to the reaction tube with a syringe. The reaction was carried out under nitrogen protection for 8h, and 3mL of succinic anhydride was added to terminate the reaction. The reaction mixture was dissolved in 1.5 L of dichloromethane, poured into 6 L of methanol, and the precipitate was separated by centrifugation to obtain poly (γ-butyrolactone).
GPC测得数均分子量为88.3kg/mol，分子量分布为2.19。所得产物GPC曲线如图8所示。所得产物拉伸曲线如图9所示。The number average molecular weight measured by GPC was 88.3 kg / mol, and the molecular weight distribution was 2.19. The GPC curve of the resulting product is shown in Figure 8. The tensile curve of the resulting product is shown in Figure 9.
实施例9Example 9
将(0.1mmol，9.21mg)丙三醇、(0.3mmol，360mg)六[三(二甲基胺)磷氮烯]三聚磷腈、(0.9mmol，277mg)1-环己基-3-(2,6-二甲氧基苯基)脲和9.3mL四氢呋喃加入反应管中，置于-50℃低温冷浴中搅拌10min，用注射器将(400mmol，30.75mL)γ-丁内酯加入反应管中。反应在氮气保护下进行12h，加入0.2g甲基丙烯酰氯终止反应。将反应混合物溶于50mL二氯甲烷中，倒入500mL甲醇中，离心分离沉淀得到聚(γ-丁内酯)。Combine (0.1mmol, 9.21mg) glycerin, (0.3mmol, 360mg) hexa [tris (dimethylamine) phosphazene] triphosphazene, (0.9mmol, 277mg) 1-cyclohexyl-3- ( 2,6-Dimethoxyphenyl) urea and 9.3mL of tetrahydrofuran were added to the reaction tube, placed in a -50 ℃ low temperature cold bath and stirred for 10min, (400mmol, 30.75mL) γ-butyrolactone was added to the reaction tube in. The reaction was carried out under nitrogen protection for 12h, and 0.2g of methacryloyl chloride was added to terminate the reaction. The reaction mixture was dissolved in 50 mL of dichloromethane, poured into 500 mL of methanol, and the precipitate was separated by centrifugation to obtain poly (γ-butyrolactone).
GPC测得数均分子量为115.3kg/mol，分子量分布为2.52。The number average molecular weight measured by GPC was 115.3 kg / mol, and the molecular weight distribution was 2.52.
对比实施例1Comparative Example 1
将(0.15mmol，10.52mg)甲醇钾、(0.45mmol，98.24mg)1-环己基-3-苯基脲和1mL四氢呋喃加入反应管中，置于-50℃低温冷浴中搅拌10min，用注射器将(45mmol，3.46mL)γ-丁内酯加入反应管中。反应在氮气保护下进行4h，加入10滴醋酸终止反应。将反应混合物溶于10mL二氯甲烷中，倒入100mL甲醇中，离心分离沉淀得到聚(γ-丁内酯)。Add (0.15 mmol, 10.52 mg) potassium methoxide, (0.45 mmol, 98.24 mg) 1-cyclohexyl-3-phenylurea and 1 mL of tetrahydrofuran to the reaction tube, place in a -50 ° C cold bath and stir for 10 min, use a syringe (45 mmol, 3.46 mL) γ-butyrolactone was added to the reaction tube. The reaction was carried out under nitrogen protection for 4h, and 10 drops of acetic acid was added to terminate the reaction. The reaction mixture was dissolved in 10 mL of methylene chloride, poured into 100 mL of methanol, and the precipitate was separated by centrifugation to obtain poly (γ-butyrolactone).
GPC测得数均分子量为12.1kg/mol，分子量分布为1.59。The number average molecular weight measured by GPC was 12.1 kg / mol, and the molecular weight distribution was 1.59.
对比实施例2Comparative Example 2
将(0.15mmol，16.2mg)苄醇、(0.15mmol，179.7mg)六[三(二甲基胺)磷氮烯]三聚磷腈和1mL四氢呋喃加入反应管中，置于-50℃低温冷浴中搅拌10min，用注射器将(45mmol，3.46mL)γ-丁内酯加入反应管中。反应在氮气保护下进行4h，加入10滴醋酸终止反应。将反应混合物溶于15mL二氯甲烷中，倒入100mL甲醇中，离心分离沉淀得到聚(γ-丁内酯)。Add (0.15 mmol, 16.2 mg) benzyl alcohol, (0.15 mmol, 179.7 mg) hexa [tris (dimethylamine) phosphazene] triphosphazene and 1 mL of tetrahydrofuran to the reaction tube and place at -50 ° C and cool Stir in the bath for 10 min, and add (45 mmol, 3.46 mL) γ-butyrolactone to the reaction tube with a syringe. The reaction was carried out under nitrogen protection for 4h, and 10 drops of acetic acid was added to terminate the reaction. The reaction mixture was dissolved in 15 mL of dichloromethane, poured into 100 mL of methanol, and the precipitate was separated by centrifugation to obtain poly (γ-butyrolactone).
GPC测得数均分子量为7.9kg/mol，分子量分布为2.07。The number average molecular weight measured by GPC was 7.9 kg / mol, and the molecular weight distribution was 2.07.
在本说明书的描述中，参考术语“一个实施例”、“一些实施例”、“示例”、“具体示例”、或“一些示例”等的描述意指结合该实施例或示例描述的具体特征、结构、材料或者特点包含于本发明的至少一个实施例或示例中。在本说明书中，对上述术语的示意性表述不必须针对的是相同的实施例或示例。而且，描述的具体特征、结构、材料或者特点可以在任一个或多个实施例或示例中以合适的方式结合。此外，在不相互矛盾的情况下，本领域的技术人员可以将本说明书中描述的不同实施例或示例以及不同实施例或示例的特征进行结合和组合。In the description of this specification, the description referring to the terms "one embodiment", "some embodiments", "examples", "specific examples", or "some examples" means specific features described in conjunction with the embodiment or examples , Structure, material or characteristic is included in at least one embodiment or example of the present invention. In this specification, the schematic expression of the above terms does not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. In addition, without contradicting each other, those skilled in the art may combine and combine different embodiments or examples and features of the different embodiments or examples described in this specification.
尽管上面已经示出和描述了本发明的实施例，可以理解的是，上述实施例是示例性的，不能理解为对本发明的限制，本领域的普通技术人员在本发明的范围内可以对上述实施例进行变化、修改、替换和变型。Although the embodiments of the present invention have been shown and described above, it should be understood that the above-mentioned embodiments are exemplary and cannot be construed as limitations to the present invention, and those of ordinary skill in the art may understand the above within the scope of the present invention. The embodiments are changed, modified, replaced, and modified.

Claims (10)

  1. 一种制备聚(γ-丁内酯)的方法，其特征在于，包括：A method for preparing poly (γ-butyrolactone), which is characterized by comprising:
    使γ-丁内酯在催化体系中进行聚合反应，得到聚(γ-丁内酯)；Γ-butyrolactone is polymerized in a catalytic system to obtain poly (γ-butyrolactone);
    所述催化体系包括：引发剂、催化剂和脲，所述催化剂为碱金属、碱金属化合物和有机磷腈化合物中的至少之一。The catalytic system includes: an initiator, a catalyst, and urea, and the catalyst is at least one of an alkali metal, an alkali metal compound, and an organic phosphazene compound.
  2. 根据权利要求1所述的方法，其特征在于，包括：The method of claim 1, comprising:
    (1)将所述引发剂、所述催化剂和所述脲在有机溶剂中混合，得到所述催化体系；(1) Mix the initiator, the catalyst, and the urea in an organic solvent to obtain the catalytic system;
    (2)将所述γ-丁内酯加入到所述催化体系中进行聚合反应，得到所述聚(γ-丁内酯)。(2) The γ-butyrolactone is added to the catalytic system to perform a polymerization reaction to obtain the poly (γ-butyrolactone).
  3. 根据权利要求1或2所述的方法，其特征在于，所述引发剂为一元醇或多元醇；The method according to claim 1 or 2, wherein the initiator is a monohydric alcohol or a polyhydric alcohol;
    任选地，所述一元醇选自甲醇、乙醇、异丙醇、叔丁醇、苄醇、苯乙醇、苯丙醇、二苯基甲醇、2,2-二苯基乙醇、端羟基寡聚乙二醇单甲醚中的至少之一；所述多元醇选自2,2-二苯基乙醇、乙二醇、1,2-丙二醇、1,3-丙二醇，1,4-丁二醇、1,2-苯二甲醇、1,3-苯二甲醇、1,4-苯二甲醇、2,2’-联苯二甲醇、丙三醇和季戊四醇中的至少之一。Optionally, the monohydric alcohol is selected from methanol, ethanol, isopropanol, t-butanol, benzyl alcohol, phenylethanol, phenylpropanol, diphenylmethanol, 2,2-diphenylethanol, hydroxyl-terminated oligomer At least one of ethylene glycol monomethyl ether; the polyol is selected from 2,2-diphenylethanol, ethylene glycol, 1,2-propanediol, 1,3-propanediol, 1,4-butanediol At least one of 1,2-benzenedimethanol, 1,3-benzenedimethanol, 1,4-benzenedimethanol, 2,2'-biphenyldimethanol, glycerin, and pentaerythritol.
  4. 根据权利要求1或2所述的方法，其特征在于，所述碱金属选自锂、钠和钾中的至少之一；The method according to claim 1 or 2, wherein the alkali metal is selected from at least one of lithium, sodium and potassium;
    任选地，所述碱金属化合物选自氢化钾、氢化钠、萘钠、萘钾、联苯钠，二苯甲基钠和二苯甲基钾中的至少之一；Optionally, the alkali metal compound is selected from at least one of potassium hydride, sodium hydride, sodium naphthalene, potassium naphthalene, sodium biphenyl, sodium benzhydryl, and potassium benzhydryl;
    任选地，所述有机磷腈化合物选自六[三(二甲基胺)磷氮烯]三聚磷腈、磷腈配体P4-叔丁基和磷腈配体P2-叔丁基中的至少之一；Optionally, the organic phosphazene compound is selected from hexa [tris (dimethylamine) phosphazene] triphosphazene, phosphazene ligand P4-tert-butyl and phosphazene ligand P2-tert-butyl At least one of
    任选地，所述有机溶剂选自甲苯、四氢呋喃、二氯甲烷、三氯甲烷、二氧六环、乙腈和N,N-二甲基甲酰胺中的至少之一；Optionally, the organic solvent is selected from at least one of toluene, tetrahydrofuran, dichloromethane, chloroform, dioxane, acetonitrile, and N, N-dimethylformamide;
    任选地，所述脲为式(I)所示化合物，Optionally, the urea is a compound represented by formula (I),
    Figure PCTCN2019112181-appb-100001
    Figure PCTCN2019112181-appb-100001
    式(I)中，R 1和R 2分别独立为甲基、乙基、丙基、异丙基、环己基、苯基、4-氯苯基、4-甲氧基苯基、4-三氟甲基苯基、2,6-二甲基苯基、2,4-二甲氧基苯基或2,4,6-三甲氧基苯基； In formula (I), R 1 and R 2 are independently methyl, ethyl, propyl, isopropyl, cyclohexyl, phenyl, 4-chlorophenyl, 4-methoxyphenyl, 4-tris Fluoromethylphenyl, 2,6-dimethylphenyl, 2,4-dimethoxyphenyl or 2,4,6-trimethoxyphenyl;
    任选地，所述脲具有以下其中之一所示的结构：Optionally, the urea has a structure shown in one of the following:
    Figure PCTCN2019112181-appb-100002
    Figure PCTCN2019112181-appb-100002
    Figure PCTCN2019112181-appb-100003
    Figure PCTCN2019112181-appb-100003
  5. 根据权利要求1或2所述的方法，其特征在于，所述催化剂与所述引发剂的摩尔比例为(1～60):3，所述催化剂与所述脲的摩尔比例为1:(1～10)，所述脲与所述γ-丁内酯的摩尔比例为1:(10～3000)。The method according to claim 1 or 2, wherein the molar ratio of the catalyst to the initiator is (1-60): 3, and the molar ratio of the catalyst to the urea is 1: (1 ～ 10), the molar ratio of the urea to the γ-butyrolactone is 1: (10 ～ 3000).
  6. 根据权利要求1或2所述的方法，其特征在于，将所述引发剂、所述催化剂和所述脲在有机溶剂中混合，并在-70～-10℃下搅拌10～30min，得到所述催化体系；The method according to claim 1 or 2, characterized in that the initiator, the catalyst and the urea are mixed in an organic solvent and stirred at -70 to -10 ° C for 10 to 30 min to obtain Describe the catalytic system;
    任选地，所述聚合反应在-70～-20℃进行0.5～48h完成。Optionally, the polymerization reaction is completed at -70 to -20 ° C for 0.5 to 48 hours.
  7. 根据权利要求2所述的方法，其特征在于，所述γ-丁内酯在所述催化体系中的摩尔浓度为4～13mol/L。The method according to claim 2, wherein the molar concentration of the γ-butyrolactone in the catalytic system is 4-13 mol / L.
  8. 根据权利要求2所述的方法，其特征在于，步骤(2)包括：将所述γ-丁内酯加入到所述催化体系中进行聚合反应后，向反应体系中加入含活性官能团的化合物终止反应，并利用甲醇沉淀，得到所述聚(γ-丁内酯)。The method according to claim 2, characterized in that step (2) includes: after adding the γ-butyrolactone to the catalytic system for polymerization, adding a compound containing an active functional group to the reaction system to terminate Reaction and precipitation with methanol to obtain the poly (γ-butyrolactone).
  9. 根据权利要求8所述的方法，其特征在于，所述含活性官能团的化合物选自酸、酰氯、酸酐、硫代异氰酸酯、异氰酸酯和卤代烃中的至少之一；优选地，所述含活性官能团的化合物选自乙酸、苯甲酸、丙烯酰氯、甲基丙烯酰氯、醋酸酐、丁二酸酐、马来酰亚胺基丁酰氯、环氧氯丙烷、3-氯丙烯、3-氯丙炔、4-甲氧基苯基硫代异氰酸酯和4-甲氧苄基异氰酸酯中的至少之一；The method according to claim 8, wherein the active functional group-containing compound is at least one selected from the group consisting of acids, acid chlorides, acid anhydrides, thioisocyanates, isocyanates, and halogenated hydrocarbons; preferably, the active-containing compounds The functional group compound is selected from acetic acid, benzoic acid, acryloyl chloride, methacryloyl chloride, acetic anhydride, succinic anhydride, maleimidobutyryl chloride, epichlorohydrin, 3-chloropropene, 3-chloropropyne, At least one of 4-methoxyphenyl thioisocyanate and 4-methoxybenzyl isocyanate;
    任选地，所述含活性官能团的化合物与所述脲的摩尔比例为(1～10):1。Optionally, the molar ratio of the active functional group-containing compound to the urea is (1-10): 1.
  10. 权利要求1～9任一项所述的方法制备得到的聚(γ-丁内酯)。The poly (γ-butyrolactone) prepared by the method according to any one of claims 1 to 9.
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