Isonitrile helical polymer with pH stimulation responsiveness as well as preparation method and application thereof

Abstract

The invention provides an isonitrile helical polymer with pH stimulation responsiveness and a preparation method and application thereof, and belongs to the technical field of polymer synthesis. One end of the isonitrile helical polymer contains an imidazolyl structure, and the other end of the isonitrile helical polymer contains a polyethylene glycol monomethyl ether chain segment. The synthesized polymer is of a spiral structure and can be protonated due to the fact that the polymer contains an imidazole group, and pH stimulation responsiveness is achieved. The polyisocyanide spiral polymer containing the imidazole structure can be used in the fields of chiral recognition, chiral separation, chiral signal amplification, controllable drug release, drug delivery, diagnosis and treatment, sensors, micromechanical systems, surface functionalization, catalysis and the like, and has a wide application prospect.

Description

Technical Field

[0001] The present application relates to the technical field of polymer synthesis, and in particular to an isonitrile helical polymer with pH stimulus responsiveness, and a preparation method and application thereof. Background Art

[0002] In the field of polymer materials, helical polymers have many excellent properties due to their unique helical structure and have broad application prospects in many fields. In recent years, stimulus-responsive polymers have become a research hotspot, among which pH stimulus-responsive polymers have attracted much attention in the fields of biomedicine and drug delivery because they can respond to changes in environmental pH.

[0003] Traditional drug delivery systems have some defects in the process of drug transportation and release. In particular, they face severe challenges in the delivery and release of chiral drugs. Different configurations of chiral drug enantiomers often have completely different physiological activities, so accurate delivery of chiral drugs is crucial. However, existing delivery systems find it difficult to achieve efficient and controlled release of chiral drugs at specific sites. Some conventional carriers have poor stability in the in vivo environment and are prone to premature drug release, resulting in side effects of drugs at non-target sites and reducing the effective concentration of drugs at target sites.

[0004] pH stimulus responsive materials are a type of smart materials that can change their chemical structure and molecular state as the pH of the environment changes. The response mechanism of this type of material is mainly based on the relationship between the pKa value of the weak electrolyte group and the degree of solution ionization. By changing the net charge, the osmotic pressure changes, thereby affecting the fluid properties and physicochemical properties of the material. pH stimulus responsive polymers provide a new approach to solving these problems. However, the existing pH stimulus responsive polymers still have deficiencies in structural design and performance optimization. For example, the response sensitivity of some polymers is not high enough, and they cannot respond to small pH changes in a timely and accurate manner; some polymers have poor biocompatibility and may trigger an immune response in the body.

[0005] Therefore, the development of a pH-stimuli-responsive helical polymer has important practical significance and potential application value for overcoming the defects of existing drug delivery systems, especially for solving the problems of precise delivery and release of chiral drugs. Summary of the invention

[0006] The purpose of the present application is to provide an isonitrile helical polymer with pH stimulus responsiveness, wherein the isonitrile helical polymer has good pH responsiveness and chiral characteristics.

[0007] Another object of the present application is to provide a method for preparing an isonitrile helical polymer with pH stimulus responsiveness, wherein the preparation conditions are mild and easy to control.

[0008] Another object of the present application is to provide the above-mentioned isonitrile helical polymer with pH-stimuli responsiveness for applications in the fields of chiral recognition, chiral separation, chiral signal amplification, controlled drug release, drug delivery, diagnosis and treatment, sensors, microelectromechanical systems, surface functionalization, and catalysis.

[0009] To solve the above technical problems, the technical solutions adopted in the present application are as follows:

[0010] On the one hand, the present application provides an isonitrile helical polymer with pH-stimuli responsiveness, wherein one end of the isonitrile helical polymer contains an imidazole group structure, and the other end contains a methoxypolyethylene glycol segment; its structural formula is shown in Formula I

[0011]

[0012] wherein, m is an integer from 0 to 20, and n is an integer greater than or equal to 10.

[0013] On the other hand, the present application provides a method for preparing an isonitrile helical polymer with pH-stimuli responsiveness, comprising the following steps:

[0014] S1. React 4-aminobenzoic acid with freshly prepared acetic anhydride to obtain 4-formylaminobenzoic acid, then add it to pentafluorophenol, add an additive and react to obtain pentafluorophenyl-4-formylaminobenzoate, and dehydrate the product under the action of a dehydrating agent to prepare pentafluorophenyl-4-isocyanatobenzoate;

[0015] S2. React chiral L / D-histidine with (Boc)2O to prepare N,N'-bis-Boc-L / D-histidine; dissolve N,N'-bis-Boc-L / D-histidine in anhydrous ethyl acetate, heat under reflux to obtain N-Boc-L / D-histidine, and react this product with a monomethyl ether containing ethylene glycol repeating units to obtain an N-Boc-protected histidine ester;

[0016] S3. Remove the Boc protecting group of the N-Boc-protected histidine ester obtained in Step S2 under acidic conditions to obtain a pale yellow oil, then add the pentafluorophenyl-4-isocyanatobenzoate prepared in Step S1, and react under basic conditions to obtain N-(4-isocyanatophenyl)histidine ester;

[0017] S4. Polymerize the N-(4-isocyanatophenyl)histidine ester monomer prepared in Step S3 under the action of a catalyst to obtain the isonitrile helical polymer.

[0018] Compared with the prior art, the embodiments of the present application have at least the following advantages or beneficial effects:

[0019] For the first aspect, the present application discloses a novel isocyanide helical polymer, with an imidazole group structure at one end and a methoxypolyethylene glycol chain segment at the other end; this isocyanide helical polymer has good pH responsiveness and chiral characteristics, and is applicable to fields such as chiral recognition, chiral separation, chiral signal amplification, controlled drug release, drug delivery, diagnosis and treatment, sensors, microelectromechanical systems, surface functionalization, and catalysis.

[0020] For the second aspect, the present application discloses a method for preparing the above-mentioned isocyanide helical polymer, which has the following characteristics: 1. Mild polymerization conditions to ensure the stability of the product structure; 2. Achieving precise pH responsiveness through a reversible protonation / deprotonation process; 3. The product has good biocompatibility and environmental friendliness; 4. The preparation process is easy to control and suitable for large-scale production. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] To more clearly illustrate the technical solutions of the embodiments of the present application, the following will briefly introduce the drawings required for the embodiments. It should be understood that the following drawings only show some embodiments of the present application, and therefore should not be regarded as limiting the scope. For those of ordinary skill in the art, without creative efforts, other related drawings can also be obtained based on these drawings.

[0022] Figure 1 2-(2-(2-Methoxyethoxy)ethoxy)ethyl (4-isocyanatobenzoyl)-L / D-histidinate in the embodiments of the present application 1 H NMR;

[0023] Figure 2 2-(2-(2-Methoxyethoxy)ethoxy)ethyl (4-isocyanatobenzoyl)-L / D-histidinate in the embodiments of the present application 13 C NMR spectrum;

[0024] Figure 3 For the 2-(2-(2-methoxyethoxy)ethoxy)ethyl (4-isocyanatobenzoyl)-L / D-histidinate polymer in the embodiments of the present application 1 H NMR spectrum;

[0025] Figure 4 GPC spectrum of the 2-(2-(2-methoxyethoxy)ethoxy)ethyl (4-isocyanatobenzoyl)-L / D-histidinate polymer in the embodiments of the present application;

[0026] Figure 5 UV spectra of the 2-(2-(2-methoxyethoxy)ethoxy)ethyl (4-isocyanatobenzoyl)-L / D-histidinate polymer under different pH conditions in the embodiments of the present application;

[0027] Figure 6 This is the circular dichroism spectrum of 2-(2-(2-methoxyethoxy)ethoxy)ethyl (4-isocyanatobenzoyl)-L / D-histidine ester polymer under different pH conditions in Example 1 of this application. Detailed implementation mode

[0028] To make the objectives, technical solutions, and advantages of the embodiments of this application clearer, the technical solutions in the embodiments of this application will be clearly and completely described below. For those conditions not specified in the examples, they are carried out according to conventional conditions or the conditions recommended by the manufacturer. For reagents or instruments without indicating the manufacturer, they are all conventional products that can be obtained through commercial purchase.

[0029] It should be noted that, without conflict, the embodiments in this application and the features in the embodiments can be combined with each other. This application will be described in detail with reference to specific embodiments below.

[0030] An isocyanide helical polymer with pH-stimuli responsiveness, one end of the isocyanide helical polymer contains an imidazole group structure, and the other end contains a methoxypolyethylene glycol chain segment; its structural formula is shown in Formula I

[0031]

[0032] Among them, m is an integer from 0 to 20, and n is an integer greater than or equal to 10.

[0033] A preparation method of an isocyanide helical polymer with pH-stimuli responsiveness, comprising the following steps:

[0034] S1. React 4-aminobenzoic acid with freshly prepared acetic anhydride to obtain 4-formylaminobenzoic acid, then add it to pentafluorophenol, add an additive and react to obtain pentafluorophenyl-4-formylaminobenzoate, and the product is dehydrated under the action of a dehydrating agent to prepare pentafluorophenyl-4-isocyanatobenzoate;

[0035] S2. React chiral L / D-histidine with (Boc)2O to prepare N,N'-bisBoc-L / D-histidine; dissolve N,N'-bisBoc-L / D-histidine in anhydrous ethyl acetate, heat under reflux to obtain N-Boc-L / D-histidine, and this product reacts with a monomethyl ether containing ethylene glycol repeating units to obtain an N-Boc-protected histidine ester;

[0036] S3. Remove the Boc protecting group from the N-Boc-protected histidine ester obtained in step S2 under acidic conditions to obtain a pale yellow oil, and then add the pentafluorophenyl-4-isocyanatobenzoate prepared in step S1, and react under basic conditions to obtain N-(4-isocyanatophenyl)histidine ester;

[0037] S4. Polymerize the N-(4-isocyanatophenyl)histidine ester monomer prepared in step S3 under the action of a catalyst to obtain the isocyanide helical polymer.

[0038] In some embodiments of the present application, in the above step S1, the ratio of 4-aminobenzoic acid to freshly prepared acetic anhydride is 1 g∶(1 - 3) mL, and the freshly prepared acetic anhydride is stirred at room temperature for 1 - 3 h; the reaction condition is under argon protection. The specific steps for preparing 4-formylaminobenzoic acid are as follows: Under argon protection, dissolve 4-aminobenzoic acid in anhydrous ethyl acetate, slowly drop in freshly prepared acetic anhydride under ice bath conditions. After dropping, continue stirring for 30 min, then heat to reflux and react until complete. Cool, filter by suction, wash the solid 3 times with ethyl acetate and distilled water, and dry to obtain white solid 4-formylaminobenzoic acid.

[0039] In some embodiments of the present application, in the above step S1, the additives are EDCI, DMAP, anhydrous CH2Cl2, and Et3N; the molar ratio of 4-formylaminobenzoic acid, EDCI, DMAP, Et3N, and pentafluorophenol is 1∶(1 - 1.5)∶(0.1 - 0.3)∶(1 - 3)∶(1 - 3). The specific steps for preparing pentafluorophenyl-4-formylaminobenzoate are as follows: Under nitrogen protection, add 4-formylaminobenzoic acid, EDCI, DMAP, and anhydrous dichloromethane respectively, slowly drop in Et3N, and finally add pentafluorophenol and continue to react until complete. Quench the reaction with distilled water, and wash the obtained filter cake 3 times with water and acetone in sequence. Recrystallize the obtained crude product with ethanol to obtain pentafluorophenyl-4-formylaminobenzoate.

[0040] In some embodiments of the present application, in the above step S1, the dehydrating agent is triphosgene or phosphorus oxychloride, and the system temperature is 0 - 4 °C when adding the dehydrating agent. The specific steps for preparing pentafluorophenyl-4-isocyanatobenzoate are as follows: Under nitrogen protection, dissolve pentafluorophenyl-4-formylaminobenzoate in anhydrous CH2Cl2, slowly drop in ET3N at 0 °C. After dropping, stir at 0 °C for 20 min, then slowly drop in the anhydrous CH2Cl2 solution of triphosgene. After dropping, continue to react at 0 °C until complete. Wash successively with saturated sodium bicarbonate, water, and saturated brine, and dry with anhydrous sodium sulfate. Column chromatography gives a white solid.

[0041] In some embodiments of the present application, the ratio of L / D-histidine to (Boc)2O in the above step S2 is 1∶(1 - 3). The specific steps for preparing N,N'-bisBoc-L / D-histidine are as follows: Under an argon atmosphere, add L / D-histidine (1.5 g, 10.0 mmol) at 0 °C. After dissolving with anhydrous methanol, add Et3N, and slowly dropwise add (Boc)2O. After dropping, transfer to room temperature and stir until the reaction is complete. The reaction is quenched with a saturated NH4Cl solution, rotary evaporated, extracted with ethyl acetate, the organic layer is collected, dried over anhydrous sodium sulfate, filtered, and the organic layer is concentrated to obtain the target compound N,N'-bisBoc-L / D-histidine.

[0042] The specific steps for preparing N-Boc-L / D-histidine are as follows: Under an argon atmosphere, add N,N'-bisBoc-L / D-histidine at 0 °C. After dissolving with anhydrous ethyl acetate, heat the solution to reflux, stir and react for 6 h, filter, and wash the solid residue with anhydrous ethyl acetate to obtain white solid N-Boc-L / D-histidine.

[0043] In some embodiments of the present application, the molar ratio of N-Boc-L / D-histidine to the monomethyl ether containing ethylene glycol repeating units in the above step S2 is (0.8 - 0.95)∶1. After the reaction is completed and rotary evaporated, column chromatography is carried out. The specific steps for preparing N-Boc-protected histidine ester are as follows: Under nitrogen protection, add N-Boc-L / D-His, EDCI, DMAP, and monomethyl triethylene glycol ether in sequence, dissolve with anhydrous CH2Cl2, stir vigorously at room temperature for 16 h, and monitor the reaction of raw materials to completion by TLC. Rotary evaporate, without washing and drying, and purify and separate by silica gel chromatography column to obtain a colorless oil N-Boc-L / D-His-TEM.

[0044] In some embodiments of the present application, the acidic condition in the above-mentioned step S3 is provided by anhydrous trifluoroacetic acid. The reaction for removing the Boc protecting group is specifically as follows: first, react at -5°C to -30°C (preferably -20°C) for 30 to 60 minutes (preferably 30 minutes), and then stir and react at room temperature for 2 to 8 hours (preferably 4 hours). The specific steps are as follows: Under argon protection, N-Boc-L / D-His-TEM is dissolved in anhydrous CH2Cl2. At -20°C, anhydrous trifluoroacetic acid is slowly added dropwise. After the addition is complete, react at -20°C for 30 minutes, and then transfer to room temperature and stir for 4 hours until the reaction is complete. After the reaction solution is rotary evaporated, the target compound L / D-His-TEM trifluoroacetate is obtained. Under an argon atmosphere, L / D-His-TEM trifluoroacetate, anhydrous CH2Cl2, and anhydrous Et3N are added, and it is slightly heated and stirred for 30 minutes. The reaction is monitored by TLC until it is complete. Cool to room temperature, and successively add DMAP and pentafluorophenyl 4-isocyanobenzoate, and stir at room temperature overnight. The reaction of the raw materials is monitored by TLC until it is complete. Wash once with distilled water, saturated sodium bicarbonate, and saturated sodium chloride successively, dry with anhydrous sodium sulfate, and purify by silica gel chromatography column to obtain the monomer.

[0045] In some embodiments of the present application, the catalyst in the above-mentioned step S4 is NiCl2·6H2O or Ni(dppp)Cl2. The specific steps of the polymerization are as follows: Add the obtained monomer 2-(2-(2-methoxyethoxy)ethoxy)ethyl (4-isocyanobenzoyl)-L / D-histidine ester (L / D-HisPI) to the reaction flask, evacuate and displace the gas 3 times under an oil pump, and add freshly distilled anhydrous THF to dissolve it under an argon atmosphere. Then add the initiator Ni(dppp)Cl2 or NiCl2·6H2O to the reaction system under an argon atmosphere, heat the oil bath to 55°C and continue stirring for 2 hours. Cool to room temperature, add a large amount of methanol to the reaction flask, and a large amount of precipitate will be generated instantly. Centrifuge, wash, and repeat the operation 3 times. Dry to obtain poly-L / D-HisPI in the form of a solid powder.

[0046] The application of an isocyanide helical polymer with pH-stimuli responsiveness in the fields of chiral recognition, chiral separation, chiral signal amplification, controlled drug release, drug delivery, diagnosis and treatment, sensors, microelectromechanical systems, surface functionalization, and catalysis.

[0047] The characteristics and properties of the present application are further described in detail below in combination with examples.

[0048] Example

[0049] An isocyanide helical polymer with pH-stimuli responsiveness, including steps S1-S4, wherein the reaction equations of steps S1-S3 are shown in Formula II:

[0050]

[0051] The preparation method is as follows:

[0052] S1-1. Synthesis of 4-formamidobenzoic acid (1):

[0053] Under argon protection, 4-aminobenzoic acid (0.72 g, 0.73 mmol) and 10 mL of anhydrous ethyl acetate were added to a 250 mL two-necked flask. Under ice bath conditions, 1.80 mL of freshly prepared acetic formic anhydride (V 无水甲酸 ∶V 乙酸酐 = 2∶1, stirred at room temperature for 2 h) was slowly added dropwise. After the addition was complete, stirring was continued for 30 min, then the temperature was raised to reflux and the reaction was carried out for 10 h. The reaction of the raw materials was monitored by TLC until it was complete. After cooling, suction filtration was carried out, and the solid was washed 3 times with 10 mL of ethyl acetate and 10 mL of distilled water, and then dried to obtain 0.79 g of the target product 1.

[0054] White solid, yield: 91.1%. 1 HNMR(400MHz, DMSO-d6)δ12.73(s, 2H), 10.77(s, 1H), 8.32(s, 1H), 7.89(d, J = 8.5Hz, 2H), 7.71(d, J = 8.5Hz, 2H). 13 CNMR(100MHz, DMSO-d6)δ166.76, 159.98, 142.07, 130.43, 125.57, 118.52.

[0055] S1-2. Synthesis of pentafluorophenyl 4-formamidobenzoate (2):

[0056] Under nitrogen protection, 4-formamidobenzoic acid (0.81 g, 5 mmol), EDCI (1.05 g, 5.5 mmol), and DMAP (0.122 g, 1 mmol) were added to a 100 mL two-necked flask. 40 mL of anhydrous CH2Cl2 was added, and Et3N (0.56 g, 5.5 mmol) was slowly added dropwise. After stirring at room temperature for 1 h, pentafluorophenol (0.92 g, 5 mmol) was added and the reaction was continued for 10 h. The reaction of the raw materials was monitored by TLC until it was complete. The reaction was quenched with 10 mL of distilled water, and the solid residue obtained by filtration was washed 3 times with water and acetone in sequence, and then recrystallized by heating with ethanol and dried to obtain 1.30 g of the target product 2.

[0057] White solid, yield: 80.18%. 1 H NMR(400MHz, DMSO-d6)δ10.73(s, 1H), 8.41(s, 1H), 8.15(d, J = 8.6Hz, 2H), 7.85(d, J = 8.6Hz, 2H). 1313C NMR (100 MHz, DMSO-d6) δ 161.57, 160.38, 144.29, 141.96, 139.49, 138.70, 137.73, 131.88, 120.16, 119.04.

[0058] Synthesis of 4-isocyanatophenyl pentafluorobenzoate (3):

[0059] Under nitrogen protection, add pentafluorophenyl 4-carbamoylbenzoate (1.00 g, 3.02 mmol) to a 100 mL single-necked flask, add 20 mL of anhydrous CH2Cl2, stir and mix evenly, and slowly add ET3N (1.22 g, 12.06 mmol) dropwise at 0 °C. After dropping, stir at 0 °C for 20 min. Slowly add triphosgene (0.89 g, 3.03 mmol) dissolved in 15 mL of anhydrous CH2Cl2 dropwise. After dropping, continue to react at 0 °C for 2 h, and monitor the reaction of the raw materials to completion by TLC. Wash successively with 10 mL of saturated sodium bicarbonate, 10 mL of water, and 10 mL of saturated brine, and dry over anhydrous sodium sulfate. Purify by silica gel chromatography column (V 乙酸乙酯 ∶V 石油醚 = 1∶8). 0.328 g of the target product 3 was obtained.

[0060] White solid, with a yield of 72.2%. 1 1H NMR (400 MHz, Chloroform-d) δ 8.26 (d, J = 8.6 Hz, 2H), 7.56 (d, J = 8.5 Hz, 2H). 13 13C NMR (100 MHz, Chloroform-d) δ 169.19, 161.28, 142.76, 141.28, 140.24, 139.47, 133.26, 132.20, 127.96, 127.16.

[0061] Synthesis of N,N'-bis-Boc-L / D-histidine (4):

[0062] Under an argon atmosphere, add L / D-histidine (1.5 g, 10.0 mmol) to a 100 mL two-necked flask at 0 °C. After dissolving with 40 mL of anhydrous methanol, add Et3N (2.7 mL, 19.3 mmol). The mixture is cooled to 0 °C, and (Boc)2O (4.6 g, 21.2 mmol) is slowly added dropwise. After dropping, transfer to room temperature and stir for 4 h, and monitor the reaction of the raw materials to completion by TLC. The reaction is quenched with 15 mL of saturated NH4Cl solution, the organic solvent is rotary evaporated, extracted 3 times with 10 mL of ethyl acetate, the organic layer is collected, dried over anhydrous sodium sulfate, filtered, and the organic layer is concentrated to obtain 3.0 g of the target compound 4.

[0063] White solid, yield: 85.7%. 1 H NMR (400 MHz, Chloroform-d) δ 8.15 (s, 1H), 7.20 (s, 1H), 5.48 (s, 1H), 4.48 (s, 1H), 3.31–3.11 (dd, J = 3.0 Hz, J = 14.6 Hz 2H), 1.60 (s, 9H), 1.46 (s, 9H).

[0064] Synthesis of S2-2, N-Boc-L / D-histidine (5):

[0065] Under an argon atmosphere, N,N'-bis-Boc-L / D-histidine (3.0 g, 8.45 mmol) was added to a 100 mL single-necked flask at 0 °C. After dissolving with 40 mL of anhydrous ethyl acetate, the solution was heated to reflux and stirred for 6 h. Then it was filtered, and the solid residue was washed with anhydrous ethyl acetate to obtain 2.1 g of the target product 5.

[0066] White solid, yield: 97.7%. 1 H NMR (400 MHz, DMSO-d6) δ 7.67 (s, 1H), 7.00 (d, J = 8.1 Hz, 1H), 6.84 (s, 1H), 4.14 (td, J = 8.1, 5.1 Hz, 1H), 2.86 (qd, J = 14.7, 6.7 Hz, 2H), 1.35 (s, 9H). 13 C NMR (100 MHz, DMSO-d6) δ 173.32, 155.20, 134.63, 116.60, 78.00, 53.59, 28.55, 28.11.

[0067] Synthesis of S2-3, 2.3.32-(2-(2-methoxyethoxy)ethoxy)ethyl (tert-butoxycarbonyl)-L / D-histidine ester (6):

[0068] Under nitrogen protection, N-Boc-L / D-His (0.51 g, 1.90 mmol), EDCI (0.41 g, 2.00 mmol), DMAP (0.11 g, 2.15 mmol), and triethylene glycol monomethyl ether (0.33 g, 2.00 mmol) were added to a 100 mL three-necked flask. After dissolving with 15 mL of anhydrous CH2Cl2, it was vigorously stirred at room temperature for 16 h. The reaction of the raw materials was monitored by TLC until it was complete. It was concentrated to dryness without washing and drying, and purified by silica gel column chromatography (V 二氯甲烷 ∶V 甲醇 = 15∶1) to obtain 0.55 g of the target product 6.

[0069] Colorless oil, yield: 69.7%. 11H NMR (400 MHz, Chloroform-d) δ 7.55 (s, 1H), 6.95 (s, 1H), 5.53 (s, 1H), 4.68–4.46 (m, 2H), 4.07 (d, J = 12.4 Hz, 1H), 3.97–3.49 (m, 10H), 3.35 (s, 3H), 3.29–3.21 (dd, J = 14.9, 3.7 Hz, 1H), 3.09 (dd, J = 14.8, 5.0 Hz, 1H), 1.44 (s, 9H). 13 13C NMR (100 MHz, Chloroform-d) δ 171.84, 155.62, 135.45, 120.16, 71.94, 70.63, 70.52, 70.50, 69.07, 64.16, 58.93, 53.64, 29.31, 28.44。

[0070] S3-1, Synthesis of Histidine-TEM Bis(trifluoroacetate) (7):

[0071] Under argon protection, N-Boc-L / D-His-TEM (0.32 g, 0.8 mmol) was dissolved in 3 mL of anhydrous CH2Cl2 in a 100 mL two-necked flask. At -20 °C, 1 mL of anhydrous trifluoroacetic acid was slowly added dropwise. After the addition was complete, the reaction was carried out at -20 °C for 30 min and then transferred to room temperature and stirred for 4 h. TLC was used to monitor the reaction until the raw materials were completely reacted. After the reaction solution was evaporated to dryness, 0.30 g of the target compound 7 was obtained. It was directly used in the next step without purification.

[0072] S3-2, Synthesis of 2-(2-(2-Methoxyethoxy)ethoxy)ethyl (4-Isocyanobenzoyl)-L / D-histidinate (L / D-HisPI) (8):

[0073] Under an argon atmosphere, 2-(2-(2-Methoxyethoxy)ethoxy)ethyl-L / D-histidinate trifluoroacetate (0.30 g, 2.2 mmol) was added to a single-necked flask, and 10 mL of anhydrous CH2Cl2 and Et3N (0.45 g, 13.5 mmol) were added. The mixture was stirred slightly heated for 30 min, and TLC was used to monitor the reaction until it was complete. After cooling to room temperature, DMAP (0.09 g, 2.2 mmol) and pentafluorophenyl 4-isocyanobenzoate (0.23 g, 2.2 mmol) were added in sequence, and the mixture was stirred overnight at room temperature. TLC was used to monitor the reaction until the raw materials were completely reacted. The mixture was washed once with 5 mL of distilled water, 5 mL of saturated sodium bicarbonate, and 5 mL of saturated sodium chloride, dried over anhydrous sodium sulfate, filtered by suction, and purified by silica gel chromatography column. (V 二氯甲烷 ∶V 甲醇 = 30∶1), and 0.15 g of the target product 8 was obtained.

[0074] Pale yellow oil, yield: 46.1%. 1 HNMR (400 MHz, Chloroform-d) δ 7.94 (d, J = 8.5 Hz, 2H), 7.57 (s, 1H), 7.45 (d, J = 8.5 Hz, 2H), 7.01 (s, 1H), 5.00 (dt, J = 7.7, 4.3 Hz, 1H), 4.48 (ddd, J = 12.4, 7.7, 2.2 Hz, 1H), 4.17–4.03 (m, 1H), 3.87–3.51 (m, 12H), 3.39 (s, 3H), 3.34 (dd, J = 14.7, 3.9 Hz, 1H), 3.16 (dd, J = 14.7, 4.7 Hz, 1H). 13 CNMR (150 MHz, Chloroform-d) δ 171.07, 166.25, 165.60, 135.26, 134.80, 128.76, 126.62, 117.73, 114.75, 71.88, 70.64, 70.40, 70.34, 69.03, 64.34, 58.89, 53.30, 28.68.

[0075] Its 1 HNMR is as Figure 1 shown. 13 CNMR is as Figure 2 shown.

[0076] S4. The synthetic route of the isocyanide helical polymer is shown in Formula III:

[0077]

[0078] Add the monomer L / D-HisPI (90.0 mg, 0.4 mmol) to a 25 mL polymerization tube, evacuate and replace the gas 3 times under an oil pump, add 2 mL of freshly distilled anhydrous THF to dissolve it under argon, and the solution is light yellow and transparent. Then add the initiator Ni(dppp)Cl2 (10.82 mg, 2.0 mmol) to the reaction system under argon. After the solution becomes briefly turbid, it turns brownish-yellow and transparent. Heat the oil bath to 55 °C and continue stirring for 2 h. Cool to room temperature, add a large amount of methanol to the reaction flask, and a large amount of precipitate is immediately produced. Place it in a centrifuge for centrifugation. After centrifugation, pour out the upper clear liquid, add methanol to the lower precipitate, shake and wash, and centrifuge. Repeat the operation 3 times. The lower solid is dried under reduced pressure to obtain 82.6 mg of the target compound as a green solid, yield: 93.6%.

[0079] 2-(2-(2-Methoxyethoxy)ethoxy)ethyl (4-isocyanobenzoyl)-L / D-histidine ester monomer and polymer 1 The H NMR spectrum is as Figure 3As shown. Starting from Figure 3 It can be seen from Figure 3 that the originally sharp peak shape has a decreased resolution and a broadened peak shape due to the overlap of many proton peaks with similar chemical shifts. The imidazole ring at 7.61 - 7.00 ppm stacks with the benzene ring, and the hydrogen of the amide bond originally at 7.87 ppm becomes passivated after polymerization, and its chemical shift moves to a higher field to 4.52 ppm. The chemical shifts of the peaks at other positions do not change significantly.

[0080] The GPC chart of 2-(2-(2-methoxyethoxy)ethoxy)ethyl (4-isocyanatobenzoyl)-L / D-histidine ester polymer is as Figure 4 shown. It can be seen that the determination of the polymer GPC is determined by gel permeation chromatography under the conditions of using a linear polymer standard polystyrene (prepared into a DMSO solution of 0.1 mg / mL), with DMSO as the mobile phase, a flow rate of 1.0 mL / minute, and a column temperature of 40 °C. The number average molecular weight Mn of the compound Poly-L-HisPI is 17.8 kDa, and its molecular weight distribution is Mw / Mn = 2.47. The number average molecular weight Mn of Poly-D-HisPI is 10.8 kDa, and its molecular weight distribution is Mw / Mn = 2.98.

[0081] pH responsiveness of the polymer: The obtained polymer is used to calibrate the pH meter by the two-point calibration method. Hydrochloric acid solutions and sodium hydroxide solutions with pH values of 1.0 - 14.0 are prepared. Weigh 1 mg of the sample to be tested and prepare a test solution of 1 mg / mL, shake it and let it stand overnight. Observe whether it dissolves. Prepare hydrochloric acid aqueous solutions with a gradient pH of 0.1 from pH = 3.0 - 4.0 in the same way and prepare test solutions of 1 mg / mL for testing.

[0082] Performance test: Data of monomers and polymers are measured using UV-vis and CD. The results are as Figure 5 and Figure 6 shown. It can be seen from the figure that the polymer exhibits obvious chiral signals. Through the pH stimulus responsiveness test, it is found that the polymer has a responsiveness to pH under the condition of pH = 3.0 - 4.0. The above results can fully demonstrate that the polymer containing an imidazole ring structure synthesized in this application is a helical structure and has pH stimulus responsiveness. Such polyisocyanide helical polymers can be used in fields such as chiral switches and chiral drug release.

[0083] The above-described embodiments are part of the embodiments of this application, rather than all of the embodiments. The detailed description of the embodiments of this application is not intended to limit the scope of this application that is claimed, but merely represents the selected embodiments of this application. All other embodiments obtained by those of ordinary skill in the art based on the embodiments in this application without creative efforts fall within the scope of protection of this application.

Claims

1. A pH-responsive isocyanide helical polymer, characterized in that, One end of the isocyanide helical polymer contains an imidazole group structure, and the other end contains a methoxy polyethylene glycol chain segment; its structural formula is shown in Formula I. Wherein, m is an integer from 0 to 20, and n is an integer greater than or equal to 10.

2. A method for preparing an isocyanide helical polymer having pH-stimuli responsiveness as described in claim 1, characterized in that, It includes the following steps: S1. React 4-aminobenzoic acid with freshly prepared acetic anhydride to obtain 4-formylaminobenzoic acid, then add it to pentafluorophenol, and react with an additive to obtain pentafluorophenyl 4-formylaminobenzoate. The product is dehydrated under the action of a dehydrating agent to prepare pentafluorophenyl 4-isocyanatobenzoate. S2. React chiral L / D-histidine with (Boc)2O to prepare N,N'-bisBoc-L / D-histidine; dissolve N,N'-bisBoc-L / D-histidine in anhydrous ethyl acetate, heat under reflux to obtain N-Boc-L / D-histidine, and react this product with a monomethyl ether containing ethylene glycol repeating units to obtain an N-Boc protected histidine ester. S3. Remove the Boc protecting group of the N-Boc protected histidine ester obtained in step S2 under acidic conditions to obtain a pale yellow oil, and then add the pentafluorophenyl 4-isocyanatobenzoate prepared in step S1, and react under basic conditions to obtain N-(4-isocyanatophenyl)histidine ester. S4. Polymerize the N-(4-isocyanatophenyl)histidine ester monomer prepared in step S3 under the action of a catalyst to obtain the isocyanide helical polymer.

3. The preparation method of an isocyanide helical polymer with pH stimulus responsiveness according to claim 2, characterized in that, In the step S1, the ratio of 4-aminobenzoic acid to freshly prepared acetic anhydride is 1 g∶(1 - 3) mL, and the freshly prepared acetic anhydride is stirred at room temperature for 1 - 3 h; the reaction conditions are under argon protection.

4. The preparation method of an isocyanide helical polymer with pH-stimuli responsiveness according to claim 2, characterized in that, In the step S1, the additive is EDCI, DMAP, anhydrous CH2Cl2 and Et3N; the molar ratio of 4-formylaminobenzoic acid, EDCI, DMAP, Et3N and pentafluorophenol is 1∶(1 - 1.5)∶(0.1 - 0.3)∶(1 - 3)∶(1 - 3).

5. The preparation method of an isocyanide helical polymer with pH stimulus responsiveness according to claim 2, characterized in that, In the step S1, the dehydrating agent is triphosgene or phosphorus oxychloride, and the system temperature is 0 - 4 °C when adding the dehydrating agent.

6. The preparation method of an isocyanide helical polymer with pH-stimuli responsiveness according to claim 2, wherein, In the step S2, the molar ratio of L / D-histidine to (Boc)2O is 1∶(1 - 3).

7. The preparation method of an isocyanide helical polymer with pH-stimuli responsiveness according to claim 2, characterized in that, In the step S2, the feeding molar ratio of N-Boc-L / D-histidine to the monomethyl ether containing ethylene glycol repeating units is (0.8 - 0.95)∶1, and after the reaction ends and is rotary evaporated, it is passed through a column.

8. The preparation method of an isocyanide helical polymer with pH-stimuli responsiveness according to claim 2, characterized in that, The acidic condition in the step S3 is provided by anhydrous trifluoroacetic acid. The reaction of removing the Boc protecting group is specifically to react at -5 °C to -30 °C for 30 - 60 min first, and then stir and react at room temperature for 2 - 8 h.

9. The preparation method of an isocyanide helical polymer with pH stimulus responsiveness according to claim 2, wherein, The catalyst in the step S4 is NiCl2·6H2O or Ni(dppp)Cl2.

10. Use of an isocyanide helical polymer with pH stimulus responsiveness as described in claim 1 in the fields of chiral recognition, chiral separation, chiral signal amplification, controlled drug release, drug delivery, diagnosis and treatment, sensors, microelectromechanical systems, surface functionalization and catalysis.

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