CN113980257B - Crown ether lactone polymer and preparation method and application thereof - Google Patents
Crown ether lactone polymer and preparation method and application thereof Download PDFInfo
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Abstract
The invention provides a preparation method of crown ether lactone, which comprises the following steps: s1, mixing a monomer, a catalyst, a metal salt and an initiator in a solvent in an inert atmosphere, and carrying out a polymerization reaction at-50-40 ℃; s2, adding a polymerization inhibitor to terminate the polymerization reaction, and separating to obtain the crown ether lactone polymer; wherein, the catalyst is one or a combination of several of organic alkali or phosphonitrile ligand; the monomer is lactone crown ether or a mixed monomer consisting of lactone crown ether and aliphatic lactone ring monomers. According to the invention, the organic base or the phosphazene ligand is used as the catalyst, so that the polymerization reaction can be initiated at a lower temperature, the one-pot method preparation is realized, the industrialization is facilitated, and the crown ether lactone polymer with narrow molecular weight distribution (as low as 1.17) can be prepared; meanwhile, other molecular chain segments can be introduced, so that the controllable tail end of the crown ether lactone polymer is realized, and the application of the crown ether lactone polymer is further widened.
Description
Technical Field
The invention belongs to the technical field of biomedical high molecular materials, and particularly relates to a crown ether lactone polymer and a preparation method and application thereof.
Background
Polyethylene glycol (PEG) is a popular material in the field of biological medicine, and its wide use has brought about many health problems, for example, PEG can generate anti-PEG antibodies after entering human body, and when PEG drugs enter human body again, it can accelerate the human body to remove PEG, so that the PEG-entrapped drug bioavailability is reduced and the PEG-resistant antibodies are difficult to degrade.
Aliphatic polyester materials are one of the currently important biodegradable materials, but the degradation rate of the polyester materials in a natural state or in a living body is slow due to the hydrophobic property of the polyester materials, so the development and the use of the polyester materials are limited by the degradation rate of the polyester materials.
In order to solve the problem that PEG cannot be degraded, scientists polymerize PEG and aliphatic polyester to synthesize a class of crown ether lactone polymers, and the class of crown ether lactone polymers contains PEG chain segments and ester chains, can be degraded in organisms, and cannot generate anti-PEG antibodies. However, the synthesis methods of the crown ether lactone Polymers reported at present, such as the polymerization methods in Unconvent, amphilic Polymers Based on Chiral Poly (ethylene oxide) Polymers, synthesis and Characterisation 1 reported by Meijer et al, have high polymerization temperature and uncontrollable polymerization reaction (i.e., the molecular weight is difficult to control and the molecular weight distribution of the prepared polymer is wide). The harsh preparation conditions and the uncontrollable nature of the reaction limit the widespread use of such polymers.
Therefore, there is an urgent need to develop a method for preparing a crown ether lactone polymer having a controllable molecular weight, which can be carried out at a relatively low temperature.
Disclosure of Invention
The invention provides a preparation method of a crown ether lactone polymer with controllable molecular weight, which can be carried out at a lower temperature, and aims to overcome the problems of harsh preparation conditions, uncontrollable reaction and the like of the crown ether lactone polymer in the prior art.
Another object of the present invention is to provide a crown ether lactone polymer produced by the above production method.
Another object of the present invention is to provide the use of the above-mentioned crown ether lactone polymers for the preparation of pharmaceutical carriers.
In order to solve the technical problems, the technical scheme adopted by the invention is as follows:
a preparation method of a crown ether lactone polymer comprises the following steps:
s1, mixing a monomer, a catalyst, a metal salt and an initiator in a solvent in an inert atmosphere, and carrying out a polymerization reaction at-50-40 ℃;
s2, adding a polymerization inhibitor to terminate polymerization reaction, and separating to obtain the crown ether lactone polymer;
wherein, the catalyst is one or a combination of several of organic alkali or phosphonitrile ligand; the monomer is lactone crown ether or a mixed monomer consisting of lactone crown ether and aliphatic lactone ring monomers.
Among the catalysts for preparing the crown ether lactone polymers reported in the prior art, tin catalysts are the main catalysts. The inventor creatively discovers that the polymerization reaction can be initiated at a lower temperature (-50-40 ℃) by taking the organic base or the phosphazene ligand as a catalyst, the polymerization reaction is controllable, and the crown ether lactone polymer with narrower molecular weight distribution can be prepared.
The crown ether lactone polymer can be polymerized between crown ether lactones, and can be copolymerized with aliphatic lactone ring monomers to obtain a crown ether lactone copolymer, and other molecular chain segments are introduced into the crown ether lactone polymer to realize the controllable tail end of the crown ether lactone polymer and further widen the application of the crown ether lactone polymer.
Preferably, the aliphatic lactone ring type monomer is 4-17 membered ring lactone.
Further preferably, the aliphatic lactone ring monomer is caprolactone.
The molar ratio of the lactone-type crown ether to the aliphatic lactone ring-type monomer is preferably 1.
Preferably, the organic base is one or a combination of TBD or DBU.
Preferably, the phosphazene ligand is P 1 -tert-butyltris (tetramethylene), P 1 -t-Bu、P 1 -tert-octyl radical, P 2 -Et、P 2 -t-Bu、P 4 -t-Bu or P 4 -tert-octyl or combinations of several thereof.
In order to obtain a narrower molecular weight distribution of the prepared crown ether lactone polymer, the phosphazene ligand is further preferably P 2 -t-Bu or P 4 -t-Bu, or a combination of both.
Preferably, the temperature of the polymerization reaction in step S1. Is from 0 to 25 ℃.
Preferably, the metal salt is one or a combination of several of lithium salt, sodium salt, potassium salt or rubidium salt; more preferably one or a combination of more of lithium bromide, sodium iodide, potassium iodide and rubidium iodide. The metal salt is used as a template agent and is cooperated with a catalyst to prepare the crown ether lactone polymer.
Preferably, the initiator is one or a combination of more of benzyl alcohol, hydroxyl of polyethylene glycol or ethylene glycol.
Preferably, the polymerization inhibitor is one or a combination of more of benzoic acid, acetic acid or hydrochloric acid.
Preferably, the solvent I is one or a combination of several of dichloromethane, dichloroethane, tetrahydrofuran, toluene or anisole.
Preferably, the molar ratio of the monomer, the initiator, the catalyst and the metal salt is 100 (0.1-20) to (0.01-50).
Preferably, the inert atmosphere is an atmosphere composed of one or more gases of nitrogen, helium or argon.
In the present invention, the time of the polymerization reaction can be selected depending on the molecular weight of the desired crown ether lactone polymer. Preferably, the time of the polymerization reaction is 0.1 to 12 hours; more preferably 0.3 to 0.6 hour.
Preferably, the crown ether lactone polymer is obtained by separating and purifying by adding a poor solvent to precipitate, and washing the precipitate, wherein the poor solvent is an ether/n-hexane mixed solvent.
Conventional lactone-type crown ethers may be used in the present invention.
Preferably, the lactone-type crown ether is
The invention uses the series of lactone crown ethers to carry out polymerization research.
Preferably, the preparation method of the lactone-type crown ether comprises the following steps:
monodisperse polyethylene glycol
Uniformly mixing catalyst metal hydride in a solvent II, then dropwise adding tert-butyl bromoacetate, reacting for 0.5-12 h at 25-100 ℃ (the reaction equation is shown as below), and separating to obtain the lactone type crown ether; wherein m is an integer of 1 to 10. />
Further preferably, m =3.
Preferably, the solvent II is one or a combination of several of toluene, tetrahydrofuran or acetonitrile.
Preferably, the metal hydride is one or a combination of lithium hydride, sodium hydride or potassium hydride.
Preferably, the lactone-type crown ether is isolated in the following manner: cooling the reaction system to room temperature, filtering by using diatomite to remove solid insoluble substances, concentrating the solution, and purifying by column chromatography by using ethyl acetate to obtain the lactone crown ether.
The invention also protects the crown ether lactone polymer prepared by the preparation method.
Preferably, the number average molecular weight of the crown ether lactone polymer is 6000 to 13000, and the dispersity (PDI) is 1.17 to 1.6.
Further preferably, the crown ether lactone polymer has a structure as shown in formula (I):
the application of the crown ether lactone polymer in the preparation of the drug carrier is also within the protection scope of the invention.
Compared with the prior art, the invention has the beneficial effects that:
according to the invention, the organic base or the phosphazene ligand is used as the catalyst, and the polymerization reaction can be initiated at a lower temperature (-50-40 ℃), so that the one-pot method preparation is realized, the industrialization is facilitated, the crown ether lactone polymer with narrow molecular weight distribution can be prepared, and the dispersion degree of the crown ether lactone polymer can be as low as 1.17; meanwhile, other molecular chain segments can be introduced, so that the controllable tail end of the crown ether lactone polymer is realized, and the application of the crown ether lactone polymer is further widened.
Drawings
FIG. 1 is a nuclear magnetic diagram of the hydrogen spectrum of lactone-type crown ethers used in the present invention in deuterated chloroform;
FIG. 2 is a nuclear magnetic diagram of the hydrogen spectrum of the crown ether lactone polymer prepared in example 1 in deuterated chloroform;
FIG. 3 is a gel exclusion chromatogram of a crown ether lactone polymer prepared in example 1;
FIG. 4 is a time-of-flight mass spectrum of the crown ether lactone polymer prepared in example 1;
FIG. 5 is a kinetic profile of the crown ether lactone polymer of example 1 during polymerization;
FIG. 6 is a nuclear magnetic diagram of the block-type crown ether lactone polymer prepared in example 7 in deuterated chloroform;
FIG. 7 is a gel exclusion chromatogram of a block-type crown ether lactone polymer prepared in example 7;
FIG. 8 is a nuclear magnetic diagram of the hydrogen spectrum of the random copoly-crown lactone polymer prepared in example 8 in deuterated chloroform;
FIG. 9 is a gel exclusion chromatogram of a random copolyprown lactone polymer prepared in example 8;
FIG. 10 is a graph showing the hydrolysis curves of the crown ether lactone polymers prepared in example 1 in aqueous solutions at different pH conditions;
FIG. 11 is a nuclear magnetic diagram of the hydrogen spectrum of the recovered crown ether lactone polymer prepared in example 1 in deuterated chloroform.
Detailed Description
The present invention will be further described with reference to the following specific examples and drawings, which are not intended to limit the invention in any manner. Reagents, methods and apparatus used in the present invention are conventional in the art unless otherwise indicated.
Unless otherwise indicated, reagents and materials used in the present invention are commercially available.
The lactone-type crown ether of the present invention is obtained by reacting tetraethylene glycol with t-butyl bromoacetate (the reaction equation is shown below):
the preparation method comprises the following specific steps:
1) Adding 9g of tetraethylene glycol into a 1000mL round-bottom flask, then adding 800mL of toluene solvent, then adding 3g of sodium hydride solid, stirring and mixing at 80 ℃ for 30min, then dropwise adding 10g of tert-butyl bromoacetate into the reaction system, and then continuing to react at 80 ℃ for 5h;
2) After the reaction, the reaction mixture was cooled to room temperature, and the insoluble solid matter was removed by filtration, and the mixture was concentrated and purified by column chromatography (ethyl acetate as mobile phase) to obtain lactone-type crown ether (designated as O-15C 5), wherein the nuclear magnetic spectrum diagram of O-15C5 is shown in FIG. 1.
Example 1
This example provides a crown ether lactone polymer, the preparation method of which includes the following steps:
s1, in a nitrogen atmosphere, adding 10mmol of lactone type crown ether O-15C5, 0.5mmol of initiator benzyl alcohol and 0.25mmol of metal salt template sodium iodide into 6mL of solvent dichloromethane, fully and uniformly mixing, then adding 0.25mmol of organic base catalyst DBU, and stirring at room temperature (25 ℃) to carry out polymerization reaction (a reaction equation is shown below);
s2, after reacting for 30min, adding polymerization inhibitor benzoic acid to terminate polymerization reaction, then precipitating and purifying for three times by using a mixed solvent of diethyl ether/n-hexane (volume ratio is 1.
Wherein, the hydrogen spectrum nuclear magnetism diagram of the prepared crown ether lactone polymer is shown in figure 2, and the peak positions in figure 2 show that the prepared polymer is a pure crown ether lactone polymer and contains the structure of initiator benzyl alcohol.
The molecular weight and dispersion of the prepared crown ether lactone polymer were further analyzed by SEC, as shown in fig. 3, indicating that the number average molecular weight of the crown ether lactone polymer was 6900 (PEO as a standard sample) and the dispersion was 1.18.
The characterization of the time-of-flight mass spectrum of the crown ether lactone polymer is shown in FIG. 4, which shows that the polymer structure is initiated only by benzyl alcohol to obtain a linear polymer chain, and a mass spectrum with normal distribution also indirectly shows that the molecular weight distribution of the crown ether lactone is controllable.
In this example, the kinetics of the crown ether lactone polymer in the polymerization process was monitored, and the reaction was continued for 90min, the result of which is shown in fig. 5, and it can be seen from fig. 5 (a) that the monomer conversion rate and the polymerization time have a certain rule in the polymerization process of crown ether lactone; and as can be seen from fig. 5 (b), when the monomer conversion is not higher than 75%, a homopolymer of crown ether lactone having good controllability can be prepared.
Example 2
This example provides a crown ether lactone polymer, which was prepared by a method different from that of example 1 in that: the catalyst in step S1 was replaced with an organic base TBD.
The number average molecular weight of the prepared crown ether lactone polymer is 8000, and the dispersity is 1.3.
Example 3
This example provides a crown ether lactone polymer, which was prepared by a method different from that of example 1 in that: replacement of the catalyst in step S1 with P 2 -t-Bu。
The number average molecular weight of the prepared crown ether lactone polymer is 7500, and the dispersity is 1.2.
Example 4
This example provides a crown ether lactone polymer, which was prepared by a method different from that of example 1 in that: replacement of the catalyst in step S1 with P 4 -t-Bu。
The number average molecular weight of the prepared crown ether lactone polymer is 7000, and the dispersity is 1.3.
Example 5
This example provides a crown ether lactone polymer, which was prepared by a method different from that of example 1 in that: the temperature of the reaction in step S2 was replaced with 0 ℃.
The number average molecular weight of the prepared crown ether lactone polymer is 6500, and the dispersity is 1.3.
Example 6
This example provides a crown ether lactone polymer, which was prepared by a method different from that of example 1 in that: the metal salt in step S1 was replaced with potassium iodide.
The number average molecular weight of the prepared crown ether lactone polymer is 7000, and the dispersity is 1.2.
Example 7
This example provides a block copoly (crown ether lactone) polymer, which was prepared by a method different from that of example 1 in that: replacement of the initiator to polyethylene glycol hydroxy (mPEG) in step S1 n -OH, m is methyl terminated. n is molecular weight, n = 2000), the reaction time in step s2. Is 4h, the reaction equation is as follows:
the block-type crown ether lactone polymer obtained by the preparation is marked as PEG-b-p (O-15C 5).
Wherein, the hydrogen nuclear magnetic spectrum of the prepared block copolymerization crown ether lactone polymer is shown in fig. 6, and as can be seen from fig. 6, the hydrogen nuclear magnetic spectrum comprises a crown ether lactone repeating unit and a PEG repeating unit, and the ratio of the two repeating units is 41.
The molecular weight and dispersion degree of the prepared block copoly-crown lactone polymer were further analyzed by SEC, as shown in fig. 7, indicating that the number average molecular weight of the crown lactone polymer was 9300 (PEO was used as a standard sample) and the dispersion degree was 1.17.
Example 8
This example provides a random copolyprown lactone polymer prepared differently from example 1 in that: "10mmol lactone crown Ether
"replacement by" 5mmol lactone-type crown ether>
+ 5mmol caprolactone ", the reaction equation is as follows:
wherein, the hydrogen nuclear magnetic spectrum of the random copolymerization crown ether lactone polymer is shown in figure 8, as can be seen from figure 8, the hydrogen spectrogram can obviously distinguish two components of lactone type crown ether O-15C5 and caprolactone in the random copolymer, and the main peak positions corresponding to the caprolactone comprise a peak, b peak and two groups of peaks at the position of 1.5 ppm; the main peak position corresponding to lactone type crown ether O-15C5 is the peak of the remaining unlabeled positions, and the molar ratio O-15c5 cl =6 of the two components in the random copolymer can be calculated from the ratio of the peak areas.
The molecular weight and dispersion degree of the prepared random copolymerized crown lactone polymer were further analyzed by SEC, as shown in fig. 9, indicating that the number average molecular weight of the crown lactone polymer was 12500 (PEO was used as a standard sample) and the dispersion degree was 1.48.
The structure and properties of the crown ether lactone polymers prepared in the above examples were tested:
1. and (3) testing the structure:
the nuclear magnetic hydrogen spectrum is selected to determine the structures of the prepared lactone crown ether and crown ether lactone polymer; testing the molecular weight and the dispersity of the prepared polymer by selecting gel exclusion chromatography (SEC for short);
2. the hydrolysis behavior of the crown ether lactone polymers prepared in the above examples in aqueous solutions at different pH conditions was tested:
the specific test conditions were: taking the crown ether lactone polymer prepared in the example 1 as an example, the prepared crown ether lactone polymer is respectively added into PBS buffer solution with pH of 3, 5.2 and 7.4 and pure water and stirred uniformly, wherein the concentration of the crown ether lactone polymer in the buffer solution is 15mg/mL; a certain amount of the solution was taken out of the stirred solution at certain time intervals and subjected to lyophilization process, and the lyophilized sample was characterized for its change in molecular weight by SEC.
The results are shown in detail in FIG. 10, from which it can be seen that the hydrolysis of the crown ether lactone polymers is well achieved in aqueous liquids. Wherein the degradation rate of the crown ether lactone polymer is slowest in a buffer solution system with the pH value of about 5, and the hydrolysis rate can be improved when the pH value of the buffer solution system is reduced or increased. The hydrolysis performance of the crown ether lactone polymer prepared in other examples was similar to that of example 1.
3. To the above fruitThe recovery performance of the crown ether lactone polymer prepared by the embodiment is tested, and the specific steps are as follows: taking the crown ether lactone polymer prepared in example 1 as an example, the prepared crown ether lactone polymer was added to toluene to perform a rotary evaporation azeotropic treatment at 50 ℃ until the solvent was removed, and then in an inert atmosphere (the inert atmosphere of the present invention is a nitrogen atmosphere), methylene chloride as a solvent was added to prepare a polymer solution having a concentration of 20mg/mL, and Na was added to the crown ether lactone polymer =1 + Adding a template agent NaI, finally adding 15mol% of a catalyst DBU, and carrying out depolymerization reaction for 2 hours at room temperature; finally adding benzoic acid to terminate the reaction, and leading the obtained product to pass through alkaline Al 2 O 3 The results of nuclear magnetic hydrogen spectroscopy analysis after the purification treatment are shown in FIG. 11. As can be seen from the figure by comparative analysis, the crown ether lactone polymer can be in Na + The depolymerization and recovery of the polymer can be smoothly realized under the template agent, and the recovery rate is as high as 93 percent.
The above-mentioned embodiments are intended to illustrate the objects, technical solutions and advantages of the present invention in further detail, and it should be understood that the above-mentioned embodiments are merely exemplary embodiments of the present invention, and are not intended to limit the scope of the present invention, and any modifications, equivalent substitutions, improvements and the like made within the spirit and principle of the present invention should be included in the scope of the present invention.
Claims (7)
1. A preparation method of a crown ether lactone polymer is characterized by comprising the following steps:
s1, mixing a monomer, a catalyst, a metal salt and an initiator in a solvent I in an inert atmosphere, and carrying out a polymerization reaction at a temperature of-50-40 ℃;
s2, adding a polymerization inhibitor to terminate the polymerization reaction, and separating to obtain the crown ether lactone polymer;
wherein, the catalyst is one or a combination of several of organic alkali or phosphonitrile ligand;
the monomer is lactone crown ether or a mixed monomer consisting of the lactone crown ether and an aliphatic lactone ring monomer;
the organic base is one or the combination of two of TBD or DBU;
the phosphazene ligand is P 1 -tert-butyltris (tetramethylene), P 1 -t-Bu、P 1 -tert-octyl radical, P 2 -Et、P 2 -t-Bu、P 4 -t-Bu or P 4 -tert-octyl groups;
the phosphazene ligand is P 2 -t-Bu or P 4 -t-Bu, alone or in combination;
the initiator is one or a combination of more of benzyl alcohol, polyethylene glycol hydroxyl or ethylene glycol; the metal salt is one or a combination of more of lithium salt, sodium salt, potassium salt or rubidium salt.
2. The method for producing a crown ether lactone polymer according to claim 1, wherein the temperature of the polymerization reaction in the step S1. Is 0 to 25 ℃.
3. The method for producing a crown ether lactone polymer according to claim 1, characterized in that the lactone-type crown ether is
Wherein m is an integer of 1 to 10.
4. The method for preparing the crown ether lactone polymer according to claim 1, wherein the polymerization inhibitor is one or a combination of benzoic acid, acetic acid or hydrochloric acid.
5. A crown ether lactone polymer produced by the production method according to any one of claims 1 to 4.
6. The crown ether lactone polymer of claim 5, which has a number average molecular weight of 6000 to 13000 and a dispersity of 1.17 to 1.6.
7. Use of a crown ether lactone polymer of any of claims 5 to 6 in the preparation of a pharmaceutical carrier.
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