PIC polymer with thermal response solid-liquid phase change property and preparation method thereof

Abstract

The invention discloses a PIC polymer with a thermal response solid-liquid phase change property and a preparation method thereof.The preparation method comprises the steps that firstly, a tyrosine derivative serves as a raw material and is subjected to phosphate esterification, activation, coupling with methoxypolyethylene glycol, condensation with chiral dipeptide and dehydration, and a chiral monomer containing isocyano groups is synthesized; then, under the action of a nickel catalyst, polymerizing the chiral monomer at 70 DEG C, and finally, dialyzing and purifying to obtain the material. The material is formed by polymerizing chiral thermal response monomers, contains a right-handed spiral skeleton and a temperature-sensitive oligomeric ethylene glycol branched chain, can adjust the cloud point temperature interval to 30-80 DEG C in different modes, is fast in phase change collaboration, narrow in interval and small in hysteresis phenomenon, and can be circulated for more than ten times by heating and cooling; a thermal response chain segment of the polymer contains ester bonds and peptide bonds, and the material can be degraded into small molecules and safely removed under physiological conditions after completing functions, so that the bottleneck problem of biological safety is solved.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of intelligent polymer materials and functional phase change materials, and relates to a preparation method of a heat-responsive solid-liquid phase change material. BACKGROUND

[0002] Thermoresponsive phase change materials, especially those with low critical solution temperature (LCST) properties, are a hot spot in the research of smart materials. Such materials dissolve in solvents (usually water) at low temperatures to form a homogeneous solution. When the temperature rises above the critical phase change temperature LCST, the balance of hydrophilic and hydrophobic levels in the material is disrupted, the polymer chains undergo dehydration and aggregation, causing the solution to become turbid macroscopically, resulting in phase separation. This property makes it have great application potential in drug controlled release systems, intelligent tissue engineering scaffolds, chemical / biological sensors, optical switches, and intelligent catalysis, etc. Since the aqueous solution of poly (N-isopropylacrylamide) (PNIPAM) was found to have an LCST behavior of about 32°C in the 1960s, researchers have been committed to developing new, more optimized thermoresponsive materials to meet the higher requirements for phase transition temperature, biocompatibility, response rate and stability in different application scenarios.

[0003] PNIPAM is the most widely studied and classic thermoresponsive polymer to date. The isopropylamide groups on its molecular chain interact with water molecules through hydrogen bonds at low temperatures, causing the polymer chain to stretch and dissolve in water. When the temperature rises to the vicinity of the LCST (about 32°C), the hydrogen bonds are broken and the hydrophobic isopropyl groups become more active, causing the molecular chain to collapse and aggregate, forming an aggregate that is insoluble in water, causing the solution to become turbid. However, the phase transition temperature of PNIPAM homopolymer is limited by its chemical structure, and the phase transition temperature is fixed and difficult to accurately control over a wide range, fixed at about 32°C. Although fine tuning can be achieved by copolymerization with other monomers, the adjustment range is limited, and often accompanied by problems such as widening of the phase transition interval and decrease in response sensitivity. This limits its application in applications requiring specific phase transition temperatures (such as precise body temperature 37°C or higher industrial temperature).

[0004] In addition, PNIPAM has a significant phase transition hysteresis: there is a significant difference between the cloud point temperature and the dissolution temperature during heating and cooling cycles, i.e. thermal hysteresis. This hysteresis is due to the asymmetry of the aggregation and disaggregation kinetics of the polymer chain, affecting its performance in applications requiring high precision and rapid reversible switching (such as high-precision sensors, optical devices).

[0005] Its biocompatibility and degradability are controversial and limited: PNIPAM itself has relatively good biocompatibility, but its monomer NIPAM has certain cytotoxicity. More importantly, the PNIPAM backbone is composed of non-degradable carbon-carbon bonds, which cannot be metabolized and cleared in vivo, potentially leading to long-term retention and safety risks, severely restricting its application in clinical medicine.

[0006] In summary, existing technologies have shortcomings in terms of the adjustability of phase transition temperature, the accuracy of response, and biocompatibility. Therefore, this invention proposes a novel method for synthesizing phase change materials that possesses all of these characteristics, along with a method for controlling their cloud point, providing new strategies and ideas for the design and application of thermally responsive materials. Summary of the Invention

[0007] To address the aforementioned technical problems, this invention aims to provide a PIC polymer with thermally responsive solid-liquid phase transition properties and its preparation method. The polymer is first synthesized from a tyrosine derivative via phosphorylation, activation, coupling with polyethylene glycol monomethyl ether, followed by condensation and dehydration with a chiral dipeptide to produce a chiral monomer containing isocyanates. Subsequently, under the action of a nickel catalyst, the chiral monomer is polymerized at 70°C, and finally purified by dialysis to obtain the material. This material, polymerized from a chiral thermally responsive monomer, contains a right-handed helical backbone and thermosensitive oligomeric polyethylene glycol branches. Its cloud point temperature range can be adjusted to 30-80°C through different methods. The phase transition is synergistic, rapid, and narrow, with minimal hysteresis, and can withstand more than ten heating and cooling cycles. The polymer's thermally responsive segments contain ester and peptide bonds. After fulfilling its function, the material can degrade into small molecules under physiological conditions and be safely eliminated, solving the bottleneck problem of biosafety.

[0008] To achieve the above objectives, the technical solution adopted by the present invention is as follows: A PIC polymer exhibiting thermally responsive solid-liquid phase transition properties has the following molecular structure: ; In the formula: R1 and R3 represent C1-C6 alkyl, halo-C1-C6 alkyl or C1-C6 alkoxy, respectively; m is an integer from 1 to 5; x is an integer from 2 to 4; n is an integer between 1000 and 10000.

[0009] The present invention also provides a method for preparing a PIC polymer with thermally responsive solid-liquid phase change properties, wherein the polymer is formed by polymerizing monomers and an initiator in a molar ratio of (1000-10000):1; wherein the initiator is nickel perchlorate hexahydrate.

[0010] As a limitation of the preparation method of the present invention, the monomer is prepared by dehydration condensation reaction of compound III and compound V to obtain compound VI, followed by ammonolysis of ethyl formate to obtain compound VII, and then by amide dehydration to nitrile to obtain monomer VIII. The specific preparation route is as follows: .

[0011] As a further limitation of the preparation method of the present invention, the dehydration condensation reaction uses a non-basic nucleophilic catalyst, ethyl 2-oxime cyanoacetate, and a condensing agent, diisopropylcarbodiimide, to activate the carboxylic acid of compound V, and then reacts with compound III to generate the target amide product.

[0012] As a further limitation of the preparation method of the present invention, the ammonolysis reaction of the ethyl formate is carried out in the presence of sodium formate, an alkaline substance.

[0013] As a further third limitation of the preparation method of the present invention, the amide dehydration to nitrile reaction is prepared by reacting compound of formula VII with phosphorus oxychloride in an alkaline solution in the presence of triethylamine under argon protection.

[0014] As a further fourth limitation of the preparation method of the present invention, the compound of formula III is obtained by phosphorylation of N-[tert-butyloxycarbonyl]-L-tyrosine tert-butyl ester and chlorophosphate to obtain compound I, followed by substitution of the tert-butyl group of compound I with tetraethylene glycol monomethyl ether, triethylene glycol monomethyl ether or diethylene glycol monomethyl ether to obtain compound II, and then reaction of compound II in ethyl acetate solution of hydrochloric acid. The specific preparation route is as follows: .

[0015] As a further fifth limitation of the preparation method of the present invention, the compound of formula V is obtained by reacting Boc-L-amino acid with D-amino acid methyl ester hydrochloride to obtain compound of formula IV, followed by hydrolysis with lithium hydroxide in methanol solution. The specific preparation route is as follows: .

[0016] The above-described technical solution of this invention, as a whole, involves interconnected and mutually influential steps that collectively determine the morphological characteristics and properties of the product. The polymers of this invention possess low critical solubility and cloud point temperatures in aqueous solutions. When their cloud point temperatures are reached, these polymers undergo entropy-driven dehydration, leading to polymer chain collapse and aggregation into spheres. The higher the temperature, the greater the number of spheres, transforming the solution into a suspension, and gradually reducing permeability. As the concentration increases, the number of polymer chains increases, and the number of spheres also increases accordingly, thus altering the cloud point temperature.

[0017] Introducing different salts into polymers can also adjust their cloud point temperature. Polymer macromolecules have numerous polar groups on their surface, which can form hydrogen bonds with water molecules, while anions in salt solutions (such as...) (e.g., sodium sulfate) has a high charge density and a strong hydration capacity. It can attract and firmly "hold" a large number of water molecules through strong ion-dipole interactions, forming a stable hydration layer around them. When a large amount of sodium sulfate is added... Like a sponge absorbing water, it "steals" a large number of free water molecules from the solution for its own hydration. This leads to a sharp reduction in the number of water molecules available for solubilizing polymer chains. The hydration shell on the surface of the polymer chain is destroyed or weakened. Without the protection of the hydration shell, hydrophobic interactions or cohesive forces such as van der Waals forces between polymer chains begin to dominate. In order to achieve a more stable state, the polymer chains will move closer to each other, aggregate, and curl up, eventually separating from the solution. Macroscopically, this manifests as a decrease in solubility and a decrease in cloud point temperature.

[0018] Conversely, salt-soluble ions ( (etc.) will disrupt the hydrogen bond network between water molecules, making water more "disordered", thereby weakening hydrophobic interactions and promoting dissolution. It is an ion with a large surface area and low charge density. It is hydrophobic and tends to migrate to the hydrophobic interface, that is, directly adsorbed on the hydrophobic surface of the polymer. This adsorption behavior is equivalent to covering the surface of the hydrophobic group with an "ionic coating", which shields the attraction between the hydrophobic groups. At the same time, it can cause the hydrophobic cross-linking points between polymer chains to be destroyed, allowing the chains to stretch out and be more easily solubilized by water molecules, thereby increasing the solubility and increasing the cloud point temperature.

[0019] The above technical solution has the following advantages or beneficial effects: This invention synthesizes a chiral, thermoresponsive monomer and further polymerizes it into a two-part helical polymer. Specifically, the polymer comprises a stable helical backbone (a right-handed helical supramolecular structure formed by the chiral centers of amino acids during polymerization of isonitrile monomers modified with chiral amino acids) and thermosensitive polyethylene glycol branches (the cloud point temperature can be changed by altering the length of the branches). The block structure of this invention endows the molecule with clear polarization, the helical backbone ensures the thermal stability and biocompatibility of the material, and the thermoresponsive segments act as independent, functionally defined "switch" units. This structure makes the phase transition process more coordinated, rapid, and sharp (with a narrower phase transition range), significantly reducing hysteresis. The thermally responsive chain segment of the present invention introduces hydrolyzable ester bonds and enzymatically degradable peptide bonds during the polymerization process. These degradable chemical bonds ensure that after the material has completed its function (such as drug delivery), it can be degraded into small molecules under physiological conditions and safely cleared by the body, fundamentally solving the bottleneck problem of biosafety.

[0020] This invention is applicable to the preparation of thermally responsive phase change materials.

[0021] The technical solution of the present invention will be further described in detail below with reference to the accompanying drawings and specific embodiments. Attached Figure Description

[0022] Figure 1 This is a synthesis route diagram of the thermally responsive phase change material obtained in Example 1 of the present invention; Figure 2 The above is the 1H NMR spectrum of compound VIII in Example 1 of this invention; Figure 3 Fourier transform infrared spectra of the thermally responsive phase change material and 4OEG methyl monomer prepared in Example 1 of this invention; Figure 4 The images show the UV-Vis spectra of aqueous solutions of the PIC polymer (thermal-responsive phase change material) prepared in Example 1 of this invention at different concentrations. Figure 5 The UV-Vis spectrum of the mixture obtained by adding sodium sulfate solution to a 10 mg / mL solution of the PIC polymer prepared in Example 1 of this invention; Figure 6 This is the UV-Vis spectrum of the PIC polymer prepared in Example 2 of the present invention at a concentration of 1 mg / mL. Detailed Implementation

[0023] The following embodiments are merely some, not all, of the embodiments of the present invention. Therefore, the detailed descriptions of the embodiments provided below are not intended to limit the scope of the claimed invention, but merely to illustrate selected embodiments. All other embodiments obtained by those skilled in the art based on the embodiments of the present invention without inventive effort are within the scope of protection of the present invention.

[0024] In this invention, unless otherwise specified, all equipment and raw materials are commercially available or commonly used in the industry. The methods described in the following embodiments are conventional methods in the art, unless otherwise specified.

[0025] Example 1 This embodiment prepares a PIC polymer with thermally responsive solid-liquid phase change properties. The preparation process and steps are as follows: Synthesis of S1, tert-butyl 2-((tert-butoxycarbonyl)amino)-3-(4-((dimethoxyphosphoryl)oxy)phenyl)propionate 29.6 mmol of N-(tert-butyloxycarbonyl)-L-tyrosine tert-butyl ester and 59.2 mmol of triethylamine were dissolved in 100 mL of dichloromethane in an ice bath. 59.2 mmol of dimethyl chlorophosphate was added dropwise under stirring. The solution temperature was raised to room temperature, and the mixture was stirred at room temperature for 20 h. The reaction was then terminated by pouring the reaction solution into 100 mL of deionized water. The mixture was extracted three times with dichloromethane, with 150 mL of dichloromethane added each time. After extraction, the mixture was dried over anhydrous magnesium sulfate. After filtration and removal of the solvent under reduced pressure, the residue was purified by silica gel column chromatography by elution with petroleum ether and ethyl acetate at a volume ratio of 3:1 to 1:1 to obtain a light yellow oily substance, namely tert-butyl 2-((tert-butyloxycarbonyl)amino)-3-(4-((dimethoxyphosphoryl)oxy)phenyl)propionate, denoted as compound I. The structure of the product was characterized by 1H NMR spectroscopy, and the data are as follows: 1H NMR (CDCl3, 600 MHz): 7.13 (s, 4H), 4.99 (d, J=8.1 Hz, 1H), 4.42 (q, J=6.6 Hz, 1H), 3.85 (d, J=11.3 Hz, 6H), 3.07–2.97 (m, 2H), 1.41 (d, J=13.1 Hz, 18H). The spectral data are consistent with the structure of the target compound, confirming the successful synthesis of compound I.

[0026] Synthesis of S2,2,5,8,11-tetraoxotridecane-13-yl 2-((tert-butoxycarbonyl)amino)-3-(4-((dimethoxyphosphoryl)oxy)phenyl)propionate S21. Dissolve 18.6 mmol of the above-synthesized compound I in 80 mL of dichloromethane, slowly add 40 mL of trifluoroacetic acid under stirring, stir for 4 h and remove the solvent under reduced pressure, then dissolve it in 32 mL of 2 M sodium bicarbonate solution, and slowly add 18.6 mmol of sodium carbonate to adjust the pH of the solution to 9 or 10. S22. Dissolve 22.3 mmol of di-tert-butyl dicarbonate in 13 mL of anhydrous 1,4-dioxane and slowly add it to the above reaction system S21. Stir for 1 h in an ice-water bath and then stir for 10 h at room temperature. Acidify with 2 mol / L dilute hydrochloric acid and extract three times with 100 mL of dichloromethane each time. After extraction, dry with anhydrous magnesium sulfate, filter and remove the solvent under reduced pressure. The residue is purified by silica gel column chromatography (ethyl acetate) to obtain yellow oil A. S23. Dissolve 14.4 mmol of the above-mentioned yellow oily substance A in 170 mL of ultra-dry dichloromethane. Then add 7.2 mmol of 4-dimethylaminopyridine and 21.6 mmol of tetraethylene glycol monomethyl ether to the system. Stir at room temperature until the solid dissolves. Cool the mixed solution to 0°C, add 14.4 mmol of N,N'-dicyclohexylcarboimide, and stir at 0°C for 1 h. Then react at room temperature for 10 h. Pour the reaction solution into 100 mL of water to terminate the reaction. Extract three times with dichloromethane, each time adding 200 mL of dichloromethane. After extraction, dry with anhydrous magnesium sulfate. The residue is purified by silica gel column chromatography by elution with petroleum ether / ethyl acetate at a volume ratio of 1:1 to give 2,5,8,11-tetraoxotridecane-13-yl 2-((tert-butoxycarbonyl)amino)-3-(4-((dimethoxyphosphoryl)oxy)phenyl)propionate, denoted as compound II. The structure of the product was characterized by 1H NMR spectroscopy, and the data are as follows: 1H NMR (CDCl3, 600 MHz): 7.13 (s, 4H), 5.03 (d, J=7.9 Hz, 1H), 4.58 (q, J=5.9 Hz, 1H), 4.26 (dt, J=16.9, 5.0 Hz, 2H), 3.85 (d, J=11.3 Hz, 6H), 3.67-3.61 (m, 14H), 3.54-3.52 (m, 2H), 3.36 (s, 3H), 3.17-3.07 (m, 2H), 1.41 (s, 9H). The spectral data are consistent with the structure of the target compound, confirming the successful synthesis of compound II. Synthesis of S3,2,5,8,11-tetraoxotridecane-13-yl-2-amino-3-(4-((dimethoxyphosphoryl)oxy)phenyl)propionate 9.5 mmol of the synthesized compound II was dissolved in 48 mL of 2 M ethyl hydrochloride solution at 0 °C and reacted at 0 °C for 6 h. The crude product was alkalized to pH 9-10 with saturated sodium hydroxide aqueous solution and extracted three times with 100 mL of dichloromethane each time. After extraction, the product was dried over anhydrous magnesium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography by elution with ethyl acetate / methanol at a volume ratio of 10:1 to give 2,5,8,11-tetraoxotridecane-13-yl2-amino-3-(4-((dimethoxyphosphoryl)oxy)phenyl)propionate, denoted as compound III. The structure of the product was characterized by 1H NMR spectroscopy, and the data are as follows: 1H NMR (CDCl3, 600 MHz): 7.13 (d, J=8.5 Hz, 2H), 7.07 (d, J=8.3 Hz, 2H), 4.19 (t, J=4.6 Hz, 1H), 3.78 (d, J=11.3 Hz, 6H), 3.57 (t, J=7.4 Hz, 16H), 3.48–3.44 (m, 2H), 3.29 (s, 3H), 2.99 (dd, J=13.7, 5.4 Hz, 1H), 2.82 (dd, J=13.7, 7.5 Hz, 1H), 2.43 (s, 2H). The spectral data are consistent with the structure of the target compound, confirming the successful synthesis of compound III. Synthesis of S4, methyl tert-butoxycarbonyl-L-alanyl-D-alanine ester 26.4 mmol Boc-L-alanine and 26.4 mmol D-alanine methyl ester hydrochloride were added to a round-bottom flask, and then 150 mL of dichloromethane was added to dissolve them. 39.6 mmol HOBt, 92.4 mmol TEA, and 31.7 mmol EDC were then added, and the mixture was stirred overnight at room temperature. The reaction solution was poured into 100 mL of water to terminate the reaction. The mixture was extracted three times with 200 mL of dichloromethane added each time. After extraction, the solution was dried over anhydrous magnesium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography by elution with petroleum ether / ethyl acetate at a volume ratio of 3:1 to 1:1 to obtain a white solid, namely methyl tert-butoxycarbonyl-L-alanyl-D-alanine ester, denoted as compound IV. The structure of the product was characterized by 1H NMR spectroscopy, and the data are as follows: 1H NMR (CDCl3, 600 MHz): 6.67 (s, 1H), 4.92 (s, 1H), 4.57 (s, 1H), 4.19 (s, 1H), 3.75 (s, 3H), 1.46 (s, 9H), 1.41 (d, J=7.2 Hz, 3H), 1.36 (d, J=7.1 Hz, 3H). The spectral data are consistent with the structure of the target compound, confirming the successful synthesis of compound IV. Synthesis of S5, tert-butoxycarbonyl-L-alanyl-D-alanine 21.2 mmol of the synthesized compound IV was dissolved in 80 mL of methanol, and then 42 mL of 5 M lithium hydroxide aqueous solution was added. The mixture was stirred overnight at room temperature, evaporated to dryness, dissolved in 10 mL of tetrahydrofuran, acidified with 2 mol / L dilute hydrochloric acid, and extracted with ethyl acetate (extracted 3 times, with 100 mL of ethyl acetate added each time). The mixture was dried over anhydrous magnesium sulfate, filtered, and the solvent was removed under reduced pressure to obtain tert-butoxycarbonyl-L-alanyl-D-alanine, denoted as compound V. Synthesis of S6, 2,5,8,11-tetraoxatridecane-13-yl(6R,9R,12S)-12-(4-((dimethoxyphosphoryl)oxy)benzyl)-2,2,6,9-tetramethyl-4,7,10-trioxo-3-oxa-5,8,11-triazatridecane-13-ester S61. Add 10.5 mmol of the above-synthesized compound V and 11.6 mmol of ethyl 2-oxime cyanoacetate to 120 mL of anhydrous tetrahydrofuran, then add 11.6 mmol of N,N'-diisopropylcarbodiimide, and stir at room temperature for 5 min. S62. Dissolve 8.1 mmol of compound III synthesized in step S3 in 30 mL of anhydrous tetrahydrofuran, then add it to the above reaction solution. Stir for 1.5 h at room temperature. Pour the reaction solution into 150 mL of water to terminate the reaction. Extract three times with dichloromethane, each time adding 200 mL of dichloromethane. After extraction, dry with anhydrous magnesium sulfate, filter and remove the solvent under reduced pressure. Purify the residue by silica gel column chromatography with ethyl acetate / methanol at a volume ratio of 10:1 to give 2,5,8,11-tetraoxatridecane-13-yl(6R,9R,12S)-12-(4-((dimethoxyphosphoryl)oxy)benzyl)-2,2,6,9-tetramethyl-4,7,10-trioxo-3-oxa-5,8,11-triazatridecane-13-ester, denoted as compound VI. The structure of the product was characterized by 1H NMR spectroscopy, and the data are as follows: 1H NMR (CDCl3, 600 MHz): 7.12 (d, J=4.1 Hz, 4H), 4.78 (q, J=6.8 Hz, 1H), 4.45 (s, 1H), 4.32–4.26 (m, 1H), 4.24–4.18 (m, 1H), 4.11 (q, J=7.1 Hz, 2H), 3.84 (d, J=10.2 Hz, 6H), 3.71–3.60 (m, 12H), 3.54–3.50 (m, 2H), 3.35 (s, 3H), 3.15 (dd, J=14.1, 5.5 Hz, 1H), 3.04 (dd, J=14.0, 6.8 Hz, 1H). The spectral data (1 Hz, 1H), 1.42 (s, 9H), and 1.13 (d, J=6.5 Hz, 6H) are consistent with the structure of the target compound, confirming the successful synthesis of compound VI. Synthesis of S7,2,5,8,11-tetraoxotridecane-13-yl 3-(4-((dimethoxyphosphoryl)oxy)phenyl)-2-((R)-2-((R)-2-carboxamide propionamide)propionamide)propionate 7.2 mmol of the synthesized compound VI was dissolved in 36 mL of 2 M ethyl hydrochloride solution at 0 °C and reacted at 0 °C for 6 h. The crude product was alkalized to pH 9-10 with saturated sodium hydroxide aqueous solution and extracted three times with 100 mL of dichloromethane each time. After extraction, the product was dried with anhydrous magnesium sulfate, filtered, and the solvent was removed under reduced pressure to obtain a yellow oily substance B. 7.2 mmol of the above yellow oily substance was dissolved in 112 mL of ethyl formate, and then 72 mmol of sodium formate was added. The mixture was refluxed at 65 °C for 6 h under an argon atmosphere. After cooling to room temperature, the sodium formate was removed by filtration, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography by elution with ethyl acetate / methanol at a volume ratio of 4:1 to give 2,5,8,11-tetraoxotridecane-13-yl 3-(4-((dimethoxyphosphoryl)oxy)phenyl)-2-((R)-2-((R)-2-carboxamide propionamide)propionamide)propionate, denoted as compound VII. The structure of the product was characterized by 1H NMR spectroscopy, and the data are as follows: 1H NMR (CDCl3, 600 MHz): 7.78 (s, 1H), 7.35 (d, J=6.8 Hz, 1H), 7.21 (d, J=8.2 Hz, 1H), 7.14–6.99 (m, 4H), 6.80 (d, J=7.9 Hz, 1H), 4.82 (dt, J=8.1, 5.3 Hz, 1H), 4.59–4.37 (m, 2H), 4.26 (ddt, J=39.5, 12.2, 4.3 Hz, 2H), 3.85 (q, J=9.2, 7.4 Hz, 6H), 3.73–3.57 (m, 12H), 3.50 (dd, J=5.8, 3.2 Hz, 2H), 3.33 (d, J=2.4 Hz, 3H), 3.11 (qd, J=13.8, 5.0 Hz, 2H), 1.39-1.30 (m, 6H). The spectral data are consistent with the structure of the target compound, confirming the successful synthesis of compound VII. Synthesis of S8,2,5,8,11-tetraoxotridecane-13-yl 3-(4-((dimethoxyphosphoryl)oxy)phenyl)-2-((R)-2-((R)-2-isocyanopropamido)propamido)propionate 0.46 mmol of the synthesized compound VII and 1.84 mmol of triethylamine were added to 36 mL of dry dichloromethane. The mixture was cooled to 0°C, and then 0.46 mmol of phosphorus oxychloride was added. The mixture was stirred at 0°C for 2 h, and then stirred at room temperature for another 16 h. After the reaction was complete, the reaction solution was terminated with 10 mL of 10 wt.% sodium bicarbonate aqueous solution and washed with saturated sodium chloride aqueous solution. The mixture was extracted three times with dichloromethane, with 100 mL of dichloromethane added each time. After extraction, the mixture was dried over anhydrous magnesium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography by elution with ethyl acetate / methanol at a volume ratio of 10:1 to give 2,5,8,11-tetraoxotridecane-13-yl 3-(4-((dimethoxyphosphoryl)oxy)phenyl)-2-((R)-2-((R)-2-isocyanopropamido)propamido)propionate, denoted as compound VIII. The structure of the product was characterized by proton nuclear magnetic resonance spectroscopy (e.g.) Figure 2The data are as follows: 1H NMR (CDCl3, 600MHz): 7.13 (s, 4H), 4.85 (s, 1H), 4.43 (s, 1H), 4.37-4.16 (m, 3H), 3.85 (d, J=11.3 Hz, 6H), 3.64 (s, 14H), 3.53 (s, 2H), 3.36 (s, 3H), 3.12 (d, J=43.2 Hz, 2H), 1.60 (d, J=6.9 Hz, 3H), 1.32 (d, J=6.9 Hz, 3H). The spectral data are consistent with the structure of the target compound, confirming the successful synthesis of compound VIII. S9. Synthesis of thermally responsive phase change materials 53.2 μmol of the synthesized compound VIII was dissolved in 2 mL of a mixed solvent of methanol and toluene (volume ratio of methanol to toluene 3:1), and then 0.02 μmol of nickel perchlorate hexahydrate was added. The mixture was sealed in a flask and stirred at 70 °C for 120 h under argon protection. The solvent was then removed under vacuum, and the residue was dissolved in 1 mL of THF. The residue was then purified by dialysis using THF as the dialysate for 48 h. The resulting residual solution was concentrated to obtain the PIC polymer, i.e., the thermoresponsive phase change material. The synthesis route of this thermoresponsive phase change material is shown below. Figure 1 As shown.

[0027] like Figure 3 The figure shows the Fourier transform infrared spectra of the PIC polymer and 4OEG methyl monomer (compound VIII) prepared in Example 1. As can be seen from the figure, the infrared signal of the -C≡N- functional group with a wavelength near 2100 nm disappears, indicating that the material preparation is complete.

[0028] The PIC polymer (thermally responsive phase change material) prepared in this embodiment was dissolved in deionized water to obtain polymer solutions with concentrations of 10 mg / mL, 8 mg / mL, 6 mg / mL, 4 mg / mL, 2 mg / mL, and 1 mg / mL. The UV-Vis spectra of the polymer solutions at different concentrations are shown below. Figure 4 As shown in the figure, it can be seen that the cloud point temperature can be changed by altering the concentration of the polymer.

[0029] The polymer (thermally responsive phase change material) prepared according to this invention was dissolved in deionized water to obtain a polymer solution with a concentration of 10 mg / mL. Then, 2 mmol of sodium sulfate solution was added to 1 mL of the polymer solution to change its cloud point temperature. Figure 5The image shows the UV-Vis spectrum of the polymer solution after sodium sulfate solution was added to a polymer solution with a concentration of 10 mg / mL. As can be seen from the image, after adding sodium sulfate solution, the cloud point temperature of the polymer decreased from 52℃ to 37℃, and the thermal hysteresis was not obvious.

[0030] This invention grafts phosphate groups onto the original PIC and changes the polymer helix length, so the biocompatibility and degradability of the two are basically the same. Its excellent biocompatibility and degradability have been verified on the original PIC, and a large number of in vitro cell culture experiments, as well as in vitro drug loading and screening experiments have been carried out (publication numbers: CN113144282A, CN117986881A, CN119792187A, etc.).

[0031] Example 2 This embodiment prepares a PIC polymer with thermally responsive solid-liquid phase change properties. The preparation process is similar to that of Example 1, except that in step S23, tetraethylene glycol monomethyl ether is replaced with triethylene glycol monomethyl ether.

[0032] The PIC polymer prepared in this embodiment was dissolved in deionized water to obtain a polymer solution with a concentration of 1 mg / mL. Figure 6 As can be seen from the UV-Vis spectrum, compared with Example 1, its cloud point temperature decreased from 67°C to 60°C, indicating that the cloud point temperature can be changed by changing the length of the branch chain.

[0033] Example 3 In this embodiment, a PIC polymer with thermally responsive solid-liquid phase change properties was prepared. The preparation process was similar to that in Example 1, except that in step S23, tetraethylene glycol monomethyl ether was replaced with diethylene glycol monomethyl ether.

[0034] Comparative Example To investigate the differences between the thermally responsive phase change material prepared in this invention and PNIPAM and ordinary PIC polymers, a comparative experiment was conducted. In this comparative example, a PIC polymer was prepared according to Chinese patent CN113144282A. Since the prepared PIC was in gel form, it did not have solid-liquid phase change characteristics.

[0035] Finally, it should be noted that the above descriptions are merely preferred embodiments of the present invention and are not intended to limit the present invention. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art can still modify the technical solutions described in the foregoing embodiments or make equivalent substitutions for some of the technical features. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the claims of the present invention.

Claims

1. A PIC polymer with thermally responsive solid-liquid phase change properties, characterized in that, Its molecular structural formula is: ； In the formula: R1 and R3 represent C1-C6 alkyl, halo-C1-C6 alkyl or C1-C6 alkoxy, respectively; m is an integer of 2-3; x is an integer of 2-4; n is an integer between 1000 and 10000.

2. The method for preparing a PIC polymer with thermally responsive solid-liquid phase change properties according to claim 1, characterized in that, The polymer is formed by polymerizing monomers and initiators in a molar ratio of (1000-10000):1; the initiator is nickel perchlorate hexahydrate.

3. The method for preparing a PIC polymer with thermally responsive solid-liquid phase change properties according to claim 2, characterized in that, The monomer is prepared by dehydration condensation reaction of compound III and compound V to obtain compound VI, followed by ammonolysis of ethyl formate to obtain compound VII, and then by amide dehydration to nitrile to obtain monomer VIII. The specific preparation route is as follows: 。 4. The method for preparing a PIC polymer with thermally responsive solid-liquid phase change properties according to claim 3, characterized in that, The dehydration condensation reaction uses a non-basic nucleophilic catalyst, ethyl 2-oxime cyanoacetate, and a condensing agent, diisopropylcarbodiimide, to activate the carboxylic acid of compound V, which then reacts with compound III to generate the target amide product.

5. The method for preparing a PIC polymer with thermally responsive solid-liquid phase change properties according to claim 3, characterized in that, The ammonolysis reaction of the ethyl formate is carried out in the presence of sodium formate, an alkaline substance.

6. The method for preparing a PIC polymer with thermally responsive solid-liquid phase change properties according to claim 3, characterized in that, The amide dehydration to nitrile reaction is prepared by reacting compound VII with phosphorus oxychloride in an alkaline solution containing triethylamine under argon protection.

7. The method for preparing a PIC polymer with thermally responsive solid-liquid phase change properties according to claim 3, characterized in that, The compound of formula III is prepared by phosphorylation of N-[tert-butyloxycarbonyl]-L-tyrosine tert-butyl ester with chlorophosphate to obtain compound I, followed by substitution of the tert-butyl group of compound I with tetraethylene glycol monomethyl ether, triethylene glycol monomethyl ether or diethylene glycol monomethyl ether to obtain compound II, and then reaction of compound II in ethyl acetate solution of hydrochloric acid. The specific preparation route is as follows: 。 8. The method for preparing a PIC polymer with thermally responsive solid-liquid phase change properties according to claim 3, characterized in that, The compound of formula V is obtained by reacting Boc-L-amino acid with D-amino acid methyl ester hydrochloride to obtain compound IV, followed by hydrolysis with lithium hydroxide in methanol solution. The specific preparation route is as follows: 。

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