A polymeric peptoid containing pendant functionalized diphenylamine groups and methods for making the same

Abstract

The application provides a kind of poly-peptide containing functionalized diphenylamine group and its preparation method.The preparation method includes: N-thiocarboxylic anhydride containing bromine phenyl group is subjected to ring-opening polymerization under the action of initiator, and poly-peptide containing bromine phenyl group is obtained; in the presence of inorganic base, palladium catalyst and ligand, the raw material system including poly-peptide containing bromine phenyl group and aromatic amine derivative occurs amination coupling reaction, and poly-peptide containing functionalized diphenylamine group is obtained, as shown in formula (I), wherein R1 is any one of n-hexyl, benzyl, neopentyl, methoxy polyethylene glycol group;R2 is any one of hydrogen atom, alkyl, alkoxy, phenyl, triphenylvinyl, diazene phenyl;N is an integer between 10 and 100;X is 1 or 2.The preparation method is simple and easy to operate, with the advantages of high efficiency and strong universality, and is suitable for wide application.

Description

Technical Field

[0001] The present invention relates to the technical field of polymer synthesis, in particular to a polymerized peptide with a side group containing a functionalized diphenylamine group and a preparation method thereof. Background Art

[0002] Polypeptides are a new type of biopolymer material that mimics the structure of polypeptides. Its main chain is polyglycine, and the nitrogen atoms contain different substituents. Since the substituents of the polypeptides are located on the nitrogen atoms, there is no intramolecular and intermolecular hydrogen bonding. Therefore, polypeptides have the advantages of excellent biocompatibility, solubility and processability, and are widely used in nanoassembly and biomedical fields (Macromol. Rapid Commun. 2022, 441, 2200301; Eur. Polym. J. 2018, 109, 26-42). However, the side groups of the currently synthesized polypeptides are mainly alkyl and aromatic groups, and the performance is relatively single, which cannot meet the diversified and intelligent application requirements of polypeptide materials. Therefore, it is urgent to develop polypeptides with side group functionalization to meet market demand.

[0003] In the prior art, the synthesis of side-group functionalized polypeptides is usually achieved by the following method: designing and synthesizing N-carboxyanhydride (NCA) or N-thiocarboxylic anhydride (NTA) monomers containing functional side groups, and then ring-opening polymerization to obtain side-group functionalized polypeptides (Polym.C hem.2021, 1212, 1823-1829; Macromolecules 2020, 53 13, 5218-5226). However, this method requires the design of different monomer synthesis routes for different functional groups, which is relatively complicated and lacks universality.

[0004] Therefore, there is an urgent need to explore an efficient and universal method for preparing side-group functionalized peptides to meet market demand. Summary of the Invention

[0005] The present invention provides a preparation method of a polypeptide containing a functionalized diphenylamine group on a side group. The preparation method comprises the following steps: subjecting an N-thiocarboxylic anhydride containing a bromophenyl group to a ring-opening polymerization reaction under the action of an initiator to obtain a polypeptide containing a bromophenyl group on a side group; and then utilizing an amination coupling reaction catalyzed by a palladium-based catalyst to post-modify the side group of the polypeptide. The polypeptide containing a functionalized diphenylamine group on a side group can be efficiently prepared (with a yield of over 84%). The preparation method is simple and easy to perform, has the advantages of high efficiency and strong universality, and is suitable for wide promotion and application.

[0006] The present invention also provides a peptide having a side chain containing a functionalized diphenylamine group, which is prepared by the above preparation method. The synthetic route for preparing the peptide having a side chain containing a functionalized biphenyl group is simple, the raw materials are easily obtained, the cost is low, and the yield is high.

[0007] The first aspect of the present invention provides a method for preparing a peptide having a functionalized diphenylamine group as a side group, comprising: subjecting an N-thiocarboxylic anhydride containing a bromophenyl group to a ring-opening polymerization reaction under the action of an initiator to obtain a peptide having a bromophenyl group as a side group;

[0008] In the presence of an inorganic base, a palladium catalyst and a ligand, a raw material system including the polypeptide containing a bromophenyl group on the side group and an aromatic amine derivative undergoes an amination coupling reaction to obtain a polypeptide containing a functionalized diphenylamine group on the side group. The structural formula of the polypeptide containing a functionalized diphenylamine group on the side group is shown in formula (I):

[0009]

[0010] Wherein, R1 is any one of n-hexyl, benzyl, neopentyl, and methoxypolyethylene glycol; R2 is any one of hydrogen atom, alkyl, alkoxy, phenyl, triphenylvinyl, and diazenylphenyl; n is an integer between 10 and 100; and x is 1 or 2.

[0011] In the preparation method of the polypeptide containing a functionalized diphenylamine group as the side group, the molar ratio of the N-thiocarboxylic anhydride containing a bromophenyl group to the initiator is (10-100):1.

[0012] The method for preparing a polypeptide having a functionalized diphenylamine group as a side group, wherein the inorganic base is one of potassium phosphate and cesium carbonate, the palladium catalyst is one of tris(dibenzylideneacetone)dipalladium and palladium acetate, and the ligand is one of 2-(dicyclohexylphosphino)biphenyl and 2-(di-tert-butylphosphino)biphenyl;

[0013] The molar ratio of the bromophenyl group, aromatic amine derivative, inorganic base, palladium catalyst and ligand in the side group-containing bromophenyl group-containing peptide is 1: (1-2): (2-4): (0.1-0.2): (0.4-0.6).

[0014] In the above-mentioned method for preparing a peptide having a functionalized diphenylamine group as a side group, the reaction temperature for the amination coupling reaction is 90° C. to 120° C., and the reaction time is 12 h to 36 h.

[0015] In the above-mentioned method for preparing a peptide having a functionalized diphenylamine group as a side group, the reaction temperature for the ring-opening polymerization reaction is 50° C. to 80° C., and the reaction time is 24 h to 96 h.

[0016] The preparation method of the side group containing a functionalized diphenylamine group of the peptoid as described above, the N-thiocarboxylic anhydride containing a bromophenyl group is one of N-4-bromophenyl methyl glycine-N-thiocarboxylic anhydride and N-4-bromophenyl ethyl glycine-N-thiocarboxylic anhydride; the structural formula of the N-4-bromophenyl methyl glycine-N-thiocarboxylic anhydride is shown as formula (II), and the structural formula of the N-4-bromophenyl ethyl glycine-N-thiocarboxylic anhydride is shown as formula (III):

[0017]

[0018] The preparation method of the side group containing a functionalized diphenylamine group of the peptoid as described above, the structural formula of the aromatic amine derivative is any one of formula (IV), formula (V) or formula (VI):

[0019]

[0020] wherein, R3 is a hydrogen atom, an alkyl group, an alkoxy group or a phenyl group; R4-R6 are independently selected from one of a hydrogen atom, an alkyl group, an alkoxy group or a phenyl group; R7 is a hydrogen atom, an alkyl group, an alkoxy group, a sulfonic acid group or a dimethyl amino group.

[0021] The preparation method of the side group containing a functionalized diphenylamine group of the peptoid as described above, the specific step of performing ring-opening polymerization reaction is: dissolving the N-thiocarboxylic anhydride containing a bromophenyl group in a first organic solvent to obtain a mixed solution, then adding an initiator to the mixed solution, so that the N-thiocarboxylic anhydride containing a bromophenyl group performs ring-opening polymerization reaction under the action of the initiator to obtain a peptoid containing a bromophenyl group on the side group, or dissolving the N-thiocarboxylic anhydride containing a bromophenyl group and the initiator in a first organic solvent, so that the N-thiocarboxylic anhydride containing a bromophenyl group performs ring-opening polymerization reaction under the action of the initiator to obtain a peptoid containing a bromophenyl group on the side group;

[0022] The initiator is one of n-hexylamine, benzylamine, neopentylamine, methoxy polyethylene glycol amine;

[0023] The first organic solvent is at least one of tetrahydrofuran, dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl pyrrolidone, dimethyl sulfoxide, tetramethyl urea, acetonitrile, benzonitrile, toluene, chloroform.

[0024] The method for preparing the polypeptide having a functionalized diphenylamine group as a side group, wherein the specific steps of the amination coupling reaction are as follows: dissolving the polypeptide having a bromophenyl group as a side group, an aromatic amine derivative, an inorganic base, a palladium catalyst and a ligand in a second organic solvent; and in the presence of the inorganic base, the palladium catalyst and the ligand, subjecting the raw material system including the polypeptide having a bromophenyl group as a side group and the aromatic amine derivative to an amination coupling reaction to obtain the polypeptide having a functionalized diphenylamine group as a side group;

[0025] The second organic solvent includes N,N-dimethylformamide.

[0026] The second aspect of the present invention provides a polymeric peptide having a side group containing a functionalized diphenylamine group, which is prepared by the above-mentioned method for preparing a polymeric peptide having a side group containing a functionalized diphenylamine group.

[0027] The present invention provides a method for preparing a peptide having a functionalized diphenylamine group as a side group. The method comprises the following steps: subjecting an N-thiocarboxylic anhydride containing a bromophenyl group to a ring-opening polymerization reaction under the action of an initiator to obtain a peptide having a bromophenyl group as a side group; and then subjecting a raw material system comprising the peptide having a bromophenyl group as a side group and an aromatic amine derivative to an amination coupling reaction in the presence of a palladium catalyst, an inorganic base, and a ligand to obtain a peptide having a functionalized diphenylamine group as a side group. The present invention utilizes an amination coupling reaction catalyzed by a palladium catalyst to post-modify the side groups of the peptide having a bromophenyl group as a side group. On the basis of forming the diphenylamine group, alkyl, alkoxy, phenyl, triphenylvinyl, and other groups are simultaneously introduced, thereby efficiently preparing a peptide having a functionalized diphenylamine group as a side group (with a yield of over 84%). The present invention uses an amination coupling reaction for post-modification of the peptide, and is a novel method for preparing a peptide having functionalized side groups. The raw materials for the preparation method provided by the present invention are widely available from existing commercial channels and are low-cost. In addition, the preparation method is simple and easy to perform, the conditions for the ring-opening polymerization reaction and the amination coupling reaction are mild, and there is no need to design different monomer synthesis routes for different functional groups. The method has the advantages of high efficiency and strong universality, and is suitable for wide promotion and application.

[0028] The present invention provides a peptide having a functionalized diphenylamine side chain, prepared by the aforementioned preparation method. The peptide has a simple synthetic route, readily available raw materials, low cost, and high yield. The structure and properties of the peptide having a functionalized diphenylamine side chain are easily regulated and can be modulated via the functional groups on the aromatic amine derivative. The peptide has broad application prospects in liquid crystals, fluorescence, nanoassembly, intelligent response, and other fields. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] Figure 1 This is the H NMR spectrum of the α1-clustered peptide provided in Example 1 of the present invention;

[0030] Figure 2 The hydrogen spectrum nuclear magnetic chart of the α2-cluster peptide provided for the embodiment 2 of the present application;

[0031] Figure 3 The hydrogen spectrum nuclear magnetic chart of the α3-cluster peptide provided for the embodiment 3 of the present application;

[0032] Figure 4 The fluorescence spectrum chart of the α3-cluster peptide provided for the embodiment 3 of the present application in the tetrahydrofuran / water mixed solution;

[0033] Figure 5 The hydrogen spectrum nuclear magnetic chart of the α4-cluster peptide provided for the embodiment 4 of the present application;

[0034] Figure 6 The ultraviolet-visible light absorption spectrum of the α4-cluster peptide provided for the embodiment 4 of the present application under different wavelength conditions; wherein, Figure 6 a is under the light irradiation condition with the wavelength of 450 nm; b is under the light irradiation condition with the wavelength of 530 nm;

[0035] Figure 7 The hydrogen spectrum nuclear magnetic chart of the α5-cluster peptide provided for the embodiment 5 of the present application;

[0036] Figure 8 The hydrogen spectrum nuclear magnetic chart of the α6-cluster peptide provided for the embodiment 6 of the present application;

[0037] Figure 9 The hydrogen spectrum nuclear magnetic chart of the α7-cluster peptide provided for the embodiment 7 of the present application. DETAILED DESCRIPTION

[0038] In order to make the objects, technical solutions and advantages of the present application clearer, the following will combine the embodiments of the present application to make a clear and complete description of the technical solutions in the embodiments of the present application. Obviously, the described embodiments are some embodiments of the present application, but not all the embodiments of the present application. Based on the embodiments in the present application, all the other embodiments obtained by those skilled in the art without creative labor fall within the protection scope of the present application.

[0039] The raw materials and reagents used in the following embodiments can be obtained from commercial channels if no special description is made, and the processes used adopt the conventional processes in the art if no special description is made.

[0040] It should be noted that the description of “first”, “second” and the like in the present application is only for the purpose of description, and therefore should not be understood as a limitation on the present application.

[0041] The terminology used herein is for the purpose of describing embodiments only and is not intended to be limiting of the application as a whole.

[0042] As used herein, the term “N-thiocarboxyanhydride of bromobenzene-containing phenyl group” refers to N-4-bromobenzylglycine-N-thiocarboxyanhydride or N-4-bromophenethylglycine-N-thiocarboxyanhydride. The N-4-bromobenzylglycine-N-thiocarboxyanhydride, N-4-bromophenethylglycine-N-thiocarboxyanhydride used in the embodiments of the present application are synthesized according to the method in the reference (European Polymer Journal, 2018, 109, 26-42; Acta Polym. Sin. 2022, 53 12, 1475-1483).

[0043] As used herein, the term “poly-peptide with side groups of bromobenzene-containing phenyl group” refers to a synthetic poly-peptide, the main chain of which is poly-glycine, and the substituent on the nitrogen atom is 4-bromobenzyl or 4-bromophenethyl. In other words, this term is used to represent a polymer prepared from N-thiocarboxyanhydride of bromobenzene-containing phenyl group monomer source. Such as poly(N-4-bromobenzylglycine), poly(N-4-bromophenethylglycine), poly(ethylene glycol)-b-poly(N-4-bromophenethylglycine) in the embodiments of the present application.

[0044] As used herein, the term “aromatic amine derivative” refers to a compound in which an amino group (-NH2) is attached to a benzene ring, and other atoms or groups are attached to the benzene ring.

[0045] The first aspect of the present application provides a method for preparing a poly-peptide with side groups of functionalized diphenylamine group, comprising: ring-opening polymerization of N-thiocarboxyanhydride of bromobenzene-containing phenyl group in the presence of an initiator to obtain a poly-peptide with side groups of bromobenzene-containing phenyl group;

[0046] In the presence of an inorganic base, a palladium-based catalyst and a ligand, an amine coupling reaction occurs in a raw material system comprising the poly-peptide with side groups of bromobenzene-containing phenyl group and an aromatic amine derivative, to obtain a poly-peptide with side groups of functionalized diphenylamine group, the structure of which is shown in formula (I):

[0047]

[0048] wherein R1 is any one of n-hexyl, benzyl, neopentyl, methoxy polyethylene glycol group; R2 is any one of hydrogen atom, alkyl group, alkoxy group, phenyl group, triphenylvinyl group, diazene phenyl group; n is an integer between 10 and 100; x is 1 or 2.

[0049] The object of the present invention is to prepare a polypeptide containing a functionalized diphenylamine group on a side group. Specifically, in the presence of an initiator, an amino group in the initiator nucleophilically attacks the carbonyl group at position 5 of an N-thiocarboxylic anhydride containing a bromophenyl group to cause a ring-opening polymerization reaction. The thiocarbamic acid group formed by the reaction is unstable and, after removing a molecule of carbonyl sulfide (COS), forms a new secondary amino group, which continues to nucleophilically attack the N-thiocarboxylic anhydride to open the ring for chain growth, thereby obtaining a polypeptide containing a bromophenyl group on a side group; a palladium-based catalyst and a ligand form a palladium compound, and then the bromophenyl group in the polypeptide containing a bromophenyl group on a side group undergoes an oxidative addition reaction with the palladium compound to obtain an addition product; the addition product is coordinated with an aromatic amine derivative to obtain an intermediate; and then the intermediate is deprotonated and eliminated under the action of an inorganic base to obtain a polypeptide containing a functionalized diphenylamine group on a side group.

[0050] The present invention uses a ring-opening polymerization reaction of N-thiocarboxylic anhydride containing a bromophenyl group to obtain a polypeptide containing a bromophenyl group on the side group, and then uses an amination coupling reaction catalyzed by a palladium-based catalyst to post-modify the side group of the polypeptide, which can efficiently prepare a polypeptide containing a functionalized diphenylamine group on the side group (with a yield of more than 84%). The present invention uses an amination coupling reaction for the post-modification of polypeptides, which is a new method for preparing polypeptides with functionalized side groups. The raw materials of the preparation method provided by the present invention are widely available and can be obtained from existing commercial channels at low cost. In addition, the preparation method is simple and easy to perform, and the conditions for the ring-opening polymerization and amination coupling reaction are mild. It has the advantages of high efficiency and strong universality, and is suitable for wide promotion and application.

[0051] In a specific embodiment, the molar ratio of the N-thiocarboxylic anhydride containing a bromophenyl group to the initiator is (10-100):1.

[0052] When the molar ratio of the N-thiocarboxylic anhydride containing a bromophenyl group to the initiator is within the above range, the N-thiocarboxylic anhydride containing a bromophenyl group can fully undergo a ring-opening polymerization reaction under the action of the initiator, exhibiting better polymerization controllability, and obtaining a high-yield polypeptide containing a bromophenyl group on the side group.

[0053] For example, the molar ratio of the bromophenyl group-containing N-thiocarboxylic anhydride to the initiator can be any one of 10:1, 20:1, 30:1, 40:1, 50:1, 60:1, 70:1, 80:1, 90:1 and 100:1, or a range consisting of any two of these.

[0054] In a specific embodiment, the inorganic base is one of potassium phosphate and cesium carbonate, the palladium catalyst is one of tris(dibenzylideneacetone)dipalladium and palladium acetate, and the ligand is one of 2-(dicyclohexylphosphino)biphenyl and 2-(di-tert-butylphosphino)biphenyl;

[0055] The molar ratio of the bromophenyl group in the side group bromophenyl group-containing peptoid, the aromatic amine derivative, the inorganic base, the palladium catalyst and the ligand is 1:(1-2):(2-4):(0.1-0.2):(0.4-0.6).

[0056] When the molar ratio of the bromophenyl group in the side group bromophenyl group-containing peptoid, the aromatic amine derivative, the inorganic base, the palladium catalyst and the ligand is within the above range, the starting material system of the side group bromophenyl group-containing peptoid and the aromatic amine derivative can be fully subjected to the amination coupling reaction, which is conducive to the preparation of the side group functionalized diphenylamine group-containing peptoid with high yield.

[0057] For example, the molar ratio of the bromophenyl group in the side group bromophenyl group-containing peptoid, the aromatic amine derivative, the inorganic base, the palladium catalyst and the ligand can be any one of 1:1:2:0.1:0.4, 1:2:4:0.2:0.6, 1:1:4:0.2:0.6, 1:1.5:3:0.1:0.5, 1:2:2:0.1:0.4, 1:1.5:3:0.1:0.5 and 1:1.5:2.5:0.1:0.5 and a range composed of any five thereof.

[0058] In one specific embodiment, the reaction temperature for the amination coupling reaction is 90-120°C, and the reaction time is 12-36h.

[0059] When the reaction temperature and the reaction time for the amination coupling reaction are within the above range, both the activity and the rate of the amination coupling reaction can be ensured, and the occurrence of side reactions can be reduced, while ensuring that the side group functionalized diphenylamine group-containing peptoid with high yield can be obtained.

[0060] For example, the reaction temperature for the amination coupling reaction can be any one of 90°C, 100°C, 110°C and 120°C and a range composed of any two thereof.

[0061] The reaction time can be any one of 12h, 14h, 16h, 18h, 20h, 22h, 24h, 26h, 28h, 30h, 32h, 34h and 36h and a range composed of any two thereof.

[0062] In one specific embodiment, the reaction temperature for the ring-opening polymerization reaction is 50-80°C, and the reaction time is 24-96h.

[0063] When the reaction temperature and the reaction time for the ring-opening polymerization reaction are within the above range, both the activity and the rate of the ring-opening polymerization reaction can be ensured, and the occurrence of side reactions can be reduced, while ensuring that the side group bromophenyl group-containing peptoid with high yield can be obtained.

[0064] For example, the reaction temperature for the amination coupling reaction may be any one of 50°C, 55°C, 60°C, 65°C, 70°C, 75°C and 80°C, or a range consisting of any two thereof;

[0065] The reaction time can be any one of 24 h, 30 h, 34 h, 40 h, 44 h, 50 h, 54 h, 60 h, 64 h, 70 h, 74 h, 80 h, 84 h, 90 h and 96 h, or a range consisting of any two of them.

[0066] In a specific embodiment, the N-thiocarboxylic acid anhydride containing a bromophenyl group is one of N-4-bromophenylmethylglycine-N-thiocarboxylic acid anhydride and N-4-bromophenylethylglycine-N-thiocarboxylic acid anhydride; the structural formula of the N-4-bromophenylmethylglycine-N-thiocarboxylic acid anhydride is shown in formula (II), and the structural formula of the N-4-bromophenylethylglycine-N-thiocarboxylic acid anhydride is shown in formula (III):

[0067]

[0068] In the present invention, the specific method for synthesizing N-4-bromophenylmethylglycine-N-thiocarboxylic acid anhydride or N-4-bromophenylethylglycine-N-thiocarboxylic acid anhydride is not particularly limited, as long as the above structure is satisfied.

[0069] In a specific embodiment, the structural formula of the aromatic amine derivative is any one of formula (IV), formula (V), and formula (VI):

[0070]

[0071] Among them, R3 is a hydrogen atom, an alkyl group, an alkoxy group or a phenyl group; R4 to R6 are independently selected from one of a hydrogen atom, an alkyl group, an alkoxy group or a phenyl group; R7 is a hydrogen atom, an alkyl group, an alkoxy group, a sulfonic acid group or a dimethylamino group.

[0072] The present invention uses the aromatic amine derivative of the above structural formula to undergo an amination coupling reaction with a polypeptide containing a bromophenyl group on the side group, thereby obtaining a polypeptide containing a functionalized diphenylamine group on the side group with a high yield.

[0073] In a specific embodiment, the specific steps of performing the ring-opening polymerization reaction are: dissolving the N-thiocarboxylic anhydride containing a bromophenyl group in a first organic solvent to obtain a mixed solution, and then adding an initiator to the mixed solution, causing the N-thiocarboxylic anhydride containing a bromophenyl group to undergo a ring-opening polymerization reaction under the action of the initiator to obtain a polypeptide containing a bromophenyl group on the side group, or dissolving the N-thiocarboxylic anhydride containing a bromophenyl group and an initiator in a first organic solvent, causing the N-thiocarboxylic anhydride containing a bromophenyl group to undergo a ring-opening polymerization reaction under the action of the initiator to obtain a polypeptide containing a bromophenyl group on the side group;

[0074] The initiator is one of n-hexylamine, benzylamine, neopentylamine, and methoxypolyethylene glycol amine;

[0075] The first organic solvent is at least one of tetrahydrofuran, dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, tetramethylurea, acetonitrile, benzonitrile, toluene, and chloroform.

[0076] In a specific embodiment, the specific steps of the amination coupling reaction are: dissolving the polypeptide containing a bromophenyl group on the side group, an aromatic amine derivative, an inorganic base, a palladium catalyst and a ligand in a second organic solvent; in the presence of the inorganic base, the palladium catalyst and the ligand, the raw material system including the polypeptide containing a bromophenyl group on the side group and the aromatic amine derivative undergoes an amination coupling reaction to obtain the polypeptide containing a functionalized diphenylamine group on the side group;

[0077] The second organic solvent includes N,N-dimethylformamide.

[0078] The present invention does not particularly limit the specific inert gas atmosphere for the amination coupling reaction, and can be selected as needed. In some embodiments, the amination coupling reaction can be carried out under a nitrogen atmosphere.

[0079] In some embodiments, the obtained peptide cluster containing bromophenyl groups on the side groups is subjected to a first sedimentation, a first separation and a first drying treatment in sequence, which is conducive to obtaining a high yield of the peptide cluster containing bromophenyl groups on the side groups.

[0080] In some embodiments, the obtained peptides having functionalized diphenylamine groups on the side groups are subjected to a second sedimentation, a second separation and a second drying treatment in sequence, which is conducive to obtaining a high yield of peptides having functionalized diphenylamine groups on the side groups.

[0081] The second aspect of the present application provides a poly-peptide containing a functional diphenylamine group in the side chain, which is prepared by the above-mentioned method for preparing a poly-peptide containing a functional diphenylamine group in the side chain. The synthetic route for preparing the poly-peptide containing a functional diphenylamine group in the side chain is simple, the raw materials are easy to obtain, the cost is low, and the yield is high. The structure and performance of the poly-peptide containing a functional diphenylamine group in the side chain are easy to control, which can be adjusted by the functional groups on the aromatic amine derivative.

[0082] The present application will be further described below through specific examples.

[0083] The determination method of the obtained poly-peptide structure is 1 H NMR method, determined on a Bruker AVANCE III 400 superconducting nuclear magnetic resonance instrument, deuterated dimethyl sulfoxide (DMSO-d6) as the solvent, tetramethylsilane (TMS) as the internal standard, and the test temperature is 20℃; the polymerization degree is calculated by the integral ratio of the initiator group signal and the poly-peptide main chain signal; the relative molecular weight and molecular weight distribution of the polymer are determined by Agilent PL-50 gel permeation chromatograph, 0.02 mol / L LiBr-containing DMF as the mobile phase, the flow rate is 1.0 mL / min, the column temperature is 50℃, and monodisperse polystyrene is used as the standard sample.

[0084] The N-4-bromophenylmethylglycine-N-thiocarboxylic anhydride and N-4-bromophenyl ethyl glycine-N-thiocarboxylic anhydride used in the following examples are synthesized according to the method in the reference (European Polymer Journal, 2018, 109, 26-42; Acta Polym. Sin. 2022, 53 12, 1475-1483).

[0085] Example 1

[0086] The present example provides a method for preparing a poly-peptide containing a functional diphenylamine group in the side chain represented by formula (VII):

[0087]

[0088] (1) Add 0.42 g (1.47 mmol) of N-4-bromophenylmethylglycine-N-thiocarboxylic anhydride to the reaction flask, and add 3.0 mL N,N-dimethylacetamide was added to dissolve the mixture to obtain a solution; 1.72 mL of a neopentylamine solution (a solution prepared by preparing neopentylamine and N,N-dimethylacetamide (0.0852 mmol / mL, 0.147 mmol)) was then added to the solution to obtain a reaction system 1, wherein the molar ratio of N-4-bromophenylmethylglycine-N-thiocarboxylic anhydride to neopentylamine in the reaction system 1 was 10:1. The reaction system 1 was reacted at 60° C. for 48 h to obtain a reaction product 1; the reaction product 1 was precipitated three times with diethyl ether and separated by centrifugation to obtain a precipitate 1; the precipitate 1 was dried in a vacuum drying oven at 40° C. to constant weight to obtain a white solid (0.334 g, yield 97%), which is poly(N-4-bromophenylmethylglycine). The degree of polymerization of the poly(N-4-bromophenylmethylglycine) was measured to be 10, and the number average molecular weight was 2.35 kg / mol. Gel permeation chromatography determined that the number average molecular weight of poly(N-4-bromophenylmethylglycine) was 3.2 kg / mol and the molecular weight distribution was 1.04.

[0089] (2) 96.0 mg (0.041 mmol, containing 0.41 mmol of bromophenyl group) of the white solid obtained in step (1) was placed in a Shrek flask filled with nitrogen, and aniline (38.2 mg, 0.41 mmol), potassium phosphate (348.1 mg, 1.64 mmol), tris(dibenzylideneacetone)dipalladium (75.1 mg, 0.082 mmol) and 2-(dicyclohexylphosphino)biphenyl (86.2 mg, 0.246 mmol) were added in sequence to obtain a reactant in which the molar ratio of bromophenyl group to aniline, potassium phosphate, tris(dibenzylideneacetone)dipalladium and 2-(dicyclohexylphosphino)biphenyl was 1:1:4:0.2:0.6; 3.5 mL of 4-nitropropane-2-nitropropane-3-nitropropane-4-nitropropane-5-nitropropane-6-nitropropane-7-nitropropane-8-nitropropane-9-nitropropane-10-nitropropane-11-nitropropane-12-nitropropane-13-nitropropane-14-nitropropane-15-nitropropane-1 The reactants were dissolved in N,N-dimethylformamide to obtain reaction system 2, and reaction system 2 was reacted at 100° C. for 24 h to obtain reaction product 2; reaction product 2 was centrifuged to remove impurities, and then precipitated three times in a methanol / ether (volume ratio 1:4) mixed solvent, centrifuged and separated to obtain precipitate 2; precipitate 2 was dried in a vacuum drying oven at a temperature of 40° C. to constant weight to obtain a light brown solid (86.9 mg, yield 86%), which is the polypeptide (α1-polypeptide) with a functionalized diphenylamine group on the side group shown in (VII), and its nuclear magnetic hydrogen spectrum is as follows: Figure 1 The number average molecular weight determined by gel permeation chromatography was 7.1 kg / mol, and the molecular weight distribution was 1.13.

[0090] Example 2

[0091] This example provides a method for preparing a peptide having a functionalized diphenylamine group as a side group represented by formula (VIII):

[0092]

[0093] Experimental procedure (1) is the same as in Example 1.

[0094] (2) 95.8 mg (0.041 mmol, containing 0.41 mmol of bromophenyl group) of the white solid obtained in step (1) was placed in a Shrek bottle filled with nitrogen, and 4-methoxyaniline (75.7 mg, 0.615 mmol), cesium carbonate (400.7 mg, 1.23 mmol), tris(dibenzylideneacetone)dipalladium (37.5 mg, 0.041 mmol) and 2-(dicyclohexylphosphino)biphenyl (71.9 mg, 0.205 mmol) were added in sequence to obtain a reactant, in which the molar ratio of the bromophenyl group to 4-methoxyaniline, cesium carbonate, tris(dibenzylideneacetone)dipalladium and 2-(dicyclohexylphosphino)biphenyl in the reactant was 1:1.5:3:0.1:0.5; then 3.5 mL of 4-methoxyaniline was added. The reactants were dissolved in N,N-dimethylformamide to obtain reaction system 2, and reaction system 2 was reacted at 110° C. for 24 h to obtain reaction product 2; the reaction product 2 was centrifuged to remove impurities, and then precipitated three times in a methanol / ether (volume ratio 1:4) mixed solvent, and separated after centrifugation to obtain precipitate 2; the precipitate 2 was dried in a vacuum drying oven at a temperature of 40° C. to constant weight to obtain a light brown solid (124.5 mg, yield 90%), which is the polypeptide (α2-polypeptide) with a functionalized diphenylamine group on the side group shown in (VIII), and its nuclear magnetic hydrogen spectrum is as follows Figure 2 The number average molecular weight determined by gel permeation chromatography was 7.9 kg / mol, and the molecular weight distribution was 1.06.

[0095] Example 3

[0096] This example provides a method for preparing a peptide having a functionalized diphenylamine group as a side group represented by formula (IX):

[0097]

[0098] Experimental procedure (1) is the same as in Example 1.

[0099] (2) The white solid obtained in step (1) 95.9 mg (0.041 mmol, containing 0.41 mmol of bromophenyl group) was placed in a Schlenk flask filled with nitrogen, and then 1-(4-aminophenyl)-1,2,2-triphenyl ethene (284.9 mg, 0.82 mmol), potassium phosphate (174.0 mg, 0.82 mmol), palladium acetate (9.2 mg, 0.041 mmol) and 2-(dicyclohexylphosphino)biphenyl (57.5 mg, 0.164 mmol) were added successively to obtain a reaction mixture, in which the molar ratio of bromophenyl group to 1-(4-aminophenyl)-1,2,2-triphenyl ethene, potassium phosphate, palladium acetate and 2-(dicyclohexylphosphino)biphenyl was 1:2:2:0.1:0.4; then 3.5 mL of N,N-dimethylformamide was added to dissolve the reaction mixture to obtain reaction system 2, and the reaction system 2 was reacted at 120°C for 12 h to obtain reaction product 2; the reaction product 2 was centrifuged to remove impurities, and then was precipitated in a mixture of methanol / ethyl ether (volume ratio 1:4) for three times, and was separated after centrifugation to obtain precipitate 2; the precipitate 2 was dried in a vacuum drying oven at a temperature of 40°C to constant weight to obtain a light brown solid (302.4 mg, yield 87%), which was a polymeric peptide containing functionalized diphenylamine group in side groups (α3-polymeric peptide) represented by (IX) and its proton nuclear magnetic resonance spectrum was shown in Figure 3 The number average molecular weight was 8.5 kg / mol and the molecular weight distribution was 1.10 determined by gel permeation chromatography.

[0100] The α3-polymeric peptide was dissolved in a tetrahydrofuran / water mixture solution, and fluorescence spectrum detection was performed, Figure 4 which was the fluorescence spectrum of the α3-polymeric peptide in the tetrahydrofuran / water mixture solution.

[0101] It can be seen from Figure 4 that the α3-polymeric peptide showed a fluorescence emission peak at 528 nm when excited by 415 nm light, which proved that the polymeric peptide containing functionalized diphenylamine group in side groups with aggregation-induced emission effect could be successfully prepared by the preparation method provided in the application, and indicated that the polymeric peptide containing functionalized diphenylamine group in side groups provided in the application could be applied in the field of fluorescence.

[0102] Example 4

[0103] The present example provides a preparation method of the polymeric peptide containing functionalized diphenylamine group in side groups represented by formula (X):

[0104]

[0105] The experimental step (1) was the same as that in Example 1.

[0106] (2) 95.5 mg (0.041 mmol, containing 0.41 mmol of bromophenyl group) of the white solid obtained in step (1) was placed in a Shrek flask filled with nitrogen, and 4-amino-4'-sulfonic acid azobenzene (170.5 mg, 0.615 mmol), potassium phosphate (261.2 mg, 1.23 mmol), tris(dibenzylideneacetone)dipalladium (37.6 mg, 0.041 mmol) and 2-(di-tert-butylphosphine)biphenyl (61.2 mg, 0.205 mmol) were added in sequence to obtain a reactant, in which the molar ratio of the bromophenyl group to 4-amino-4'-sulfonic acid azobenzene, potassium phosphate, tris(dibenzylideneacetone)dipalladium and 2-(di-tert-butylphosphine)biphenyl in the reactant was 1:1.5:3:0.1:0.5; then 3.5 mL of 4-amino-4'-sulfonic acid azobenzene, potassium phosphate, tris(dibenzylideneacetone)dipalladium and 2-(di-tert-butylphosphine)biphenyl was added. The reactants were dissolved in N,N-dimethylformamide to obtain reaction system 2, and reaction system 2 was reacted at 100° C. for 24 h to obtain reaction product 2; reaction product 2 was centrifuged to remove impurities, and then precipitated three times in a methanol / ether (volume ratio 1:4) mixed solvent, centrifuged and separated to obtain precipitate 2; precipitate 2 was dried in a vacuum drying oven at a temperature of 40° C. to constant weight to obtain a yellow solid (197.9 mg, yield 85%), which is the polypeptide (α4-polypeptide) with a functionalized diphenylamine group on the side group shown in (X), and its nuclear magnetic hydrogen spectrum is as follows: Figure 5 The number average molecular weight determined by gel permeation chromatography was 10.9 kg / mol, and the molecular weight distribution was 1.14.

[0107] Figure 6 is the UV-visible absorption spectrum of α4-clustered peptide under different wavelength conditions: Figure 6 a is under the condition of light with a wavelength of 450nm; Figure 6 b is under the condition of light with a wavelength of 530nm.

[0108] from Figure 6 The characteristic absorption peak of α4-clustered peptide was observed at around 425nm, which corresponds to the absorption peak of the trans configuration of the azobenzene group. Since there is an amino group on the azobenzene ring, the strong electron-donating effect of the amino group will cause the absorption band generated by the π-π* transition to red-shift, overlapping with the absorption band generated by the n-π* transition. Figure 6 As shown in a, when the α4-peptide is irradiated by 450nm blue light, the absorption peak at 425nm continues to decrease until it reaches a steady state after 60s. The azobenzene in the α4-peptide gradually changes from a trans configuration to a cis configuration; Figure 6As shown in b, under the irradiation of 530nm green light, the absorption peak of α4-clustered peptide was observed to rise continuously at 425nm. After 60s of continuous irradiation, the cis configuration returned to the more stable trans configuration, proving that the preparation method provided by the present invention can successfully prepare a clustered peptide with a side group containing a functionalized diphenylamine group and having photoresponsiveness, indicating that the clustered peptide with a side group containing a functionalized diphenylamine group provided by the present invention can be applied to the field of intelligent response.

[0109] Example 5

[0110] This embodiment provides a method for preparing a peptide having a functionalized diphenylamine group as a side group represented by formula (XI):

[0111]

[0112] (1) Add 0.45 g (1.50 mmol) of N-4-bromophenylethylglycine-N-thiocarboxylic anhydride to the reaction flask, and add 3.0 mL N,N-dimethylformamide was added to dissolve the mixture to obtain a solution; then, 0.82 mL of n-hexylamine solution (a solution prepared by configuring n-hexylamine and N,N-dimethylacetamide (0.0912 mmol / mL, 0.075 mmol)) was added to the solution to obtain reaction system 1, wherein the molar ratio of N-4-bromophenylethylglycine-N-thiocarboxylic anhydride to n-hexylamine in reaction system 1 was 20:1, and reaction system 1 was reacted at 70°C for 72 hours to obtain reaction product 1; reaction product 1 was precipitated with diethyl ether three times, centrifuged and separated to obtain precipitate 1; precipitate 1 was dried in a vacuum drying oven at 40°C to constant weight to obtain a white solid (0.341 g, yield 93%), which is poly(N-4-bromophenylethylglycine); the degree of polymerization of poly(N-4-bromophenylethylglycine) was measured to be 18, and the number average molecular weight was 4.42 kg / mol. Gel permeation chromatography determined that the number average molecular weight of poly(N-4-bromophenylethylglycine) was 7.1 kg / mol and the molecular weight distribution was 1.08.

[0113] (2) The white solid obtained in step (1) 120.0 mg (0.0271 mmol, containing bromophenyl group 0.488 mmol) was put into a Schlenk flask filled with nitrogen, and then 4-amino-4'-dimethylaminoazobenzene (175.9 mg, 0.732 mmol), potassium phosphate (310.0 mg, 1.46 mmol), tris(dibenzylideneacetone)dipalladium (44.7 mg, 0.0488 mmol) and 2-(dicyclohexylphosphino)biphenyl (85.5 mg, 0.244 mmol) were added successively to obtain a reaction mixture, in which the molar ratio of bromophenyl group to 4-amino-4'-dimethylaminoazobenzene, potassium phosphate, tris(dibenzylideneacetone)dipalladium, 2-(dicyclohexylphosphino)biphenyl was 1:1.5:3:0.1:0.5; then 4 mL of N,N-dimethylformamide was added to dissolve the reaction mixture to obtain reaction system 2, which was reacted at 90 °C for 36 h to obtain reaction product 2; the reaction product 2 was centrifuged to remove impurities, and then was precipitated in a mixture of methanol / ethyl ether (volume ratio 1:4) for three times, and then was separated after centrifugation to obtain precipitate 2; the precipitate 2 was dried in a vacuum drying oven at a temperature of 40 °C to constant weight to obtain a yellow solid (228.2 mg, yield 89%), which was a polyfolding peptide (a5-polyfolding peptide) containing a functionalized diphenylamine group in the side group represented by (XI), and the proton nuclear magnetic resonance spectrum thereof is shown in Figure 7 The number average molecular weight determined by gel permeation chromatography was 20.5 kg / mol, and the molecular weight distribution was 1.21.

[0114] Example 6

[0115] This example provides a method for preparing a polyfolding peptide containing a functionalized diphenylamine group in the side group represented by formula (XII):

[0116]

[0117] (1) 0.45 g (1.50 mmol) of N-4-bromophenyl ethyl glycine-N-thiocarboxylic anhydride and 0.113 g (0.15 mmol) of methoxy polyethylene glycol amine (mPEG-NH2) with a number average molecular weight of 750 (CAS No. 80506-64-5) were added to a reaction bottle to obtain a mixture, and 3.0 mL of N,N-dimethylformamide was added to dissolve the mixture to obtain reaction system 1, in which the molar ratio of N-4-bromophenyl ethyl glycine-N-thiocarboxylic anhydride to mPEG 15 -NH2) was 1:1; then the reaction system 1 was reacted at 40 °C for 24 h to obtain reaction product 1; the reaction product 1 was centrifuged to remove impurities, and then was precipitated in a mixture of methanol / ethyl ether (volume ratio 1:4) for three times, and then was separated after centrifugation to obtain precipitate 1; the precipitate 1 was dried in a vacuum drying oven at a temperature of 40 °C to constant weight to obtain a white solid (0.45 g, yield 100%), which was a polyfolding peptide containing a functionalized diphenylamine group in the side group represented by formula (XII). 15The molar ratio of -NH2 in the reaction system 1 is 10:1, the reaction system 1 is reacted at 50℃ for 96h to obtain a reaction product 1; the reaction product 1 is precipitated with ether for three times, and then separated after centrifugation to obtain a precipitate 1; the precipitate 1 is dried in a vacuum drying oven at a temperature of 40℃ until the weight is constant to obtain a white solid (0.449g, yield 95%), which is polyethylene glycol-b-poly(N-4-bromophenylethylglycine) A, the polymerization degree of the poly(N-4-bromophenylethylglycine) block is measured to be 10, and the number average molecular weight of the polyethylene glycol-b-poly(N-4-bromophenylethylglycine) is 3.15kg / mol. The number average molecular weight of the polyethylene glycol-b-poly(N-4-bromophenylethylglycine) is measured by gel permeation chromatography to be 7.6kg / mol, and the molecular weight distribution is 1.07.

[0118] (2) The white solid obtained in step (1) 119.7mg (0.038mmol, containing 0.38mmol of bromophenyl group) is placed in a Schlenk flask filled with nitrogen, and then 4-aminoazobenzene (112.4mg, 0.57mmol), potassium phosphate (201.7mg, 0.95mmol), tris(dibenzylideneacetone)dipalladium (34.8mg, 0.038mmol) and 2-(dicyclohexylphosphino)biphenyl (66.6mg, 0.19mmol) are added in sequence to obtain a reaction mixture, the molar ratio of bromophenyl group in the reaction mixture to 4-aminoazobenzene, potassium phosphate, tris(dibenzylideneacetone)dipalladium, 2-(dicyclohexylphosphino)biphenyl is 1:1.5:2.5:0.1:0.5; then 4mL of N,N-dimethylformamide is added to dissolve the reaction mixture to obtain a reaction system 2, the reaction system 2 is reacted at 100℃ for 24h to obtain a reaction product 2; the reaction product 2 is centrifuged to remove impurities, and then precipitated with ether for three times, and then separated after centrifugation to obtain a precipitate 2; the precipitate 2 is dried in a vacuum drying oven at a temperature of 40℃ until the weight is constant to obtain a yellow solid (173.2mg, yield 86%), which is a polymeric peptide containing functionalized diphenylamine group in side groups (α6-polymeric peptide) represented by (XII), the 1H NMR spectrum of which is shown in Figure 8

[0119] Example 7

[0120] The present example provides a preparation method of a polymeric peptide containing functionalized diphenylamine group in side groups represented by (XIII):

[0121]

[0122] ​(1) In a reaction bottle, 0.30 g (1.00 mmol) of N-4-bromophenylethylglycine-N- thioacid anhydride and 0.201 g (0.10 mmol) of methoxypolyethylene glycol amine (mPEG-NH2) with a number average molecular weight of 2000 were added to obtain a mixture, 4.0 mL of N-methylpyrrolidone was added to dissolve the mixture to obtain a reaction system 1, the molar ratio of N-4-bromophenylethylglycine-N-thioacid anhydride to mPEG-NH2 in the reaction system 1 was 10:1, the reaction system 1 was reacted at 80°C for 48 h to obtain a reaction product 1; the reaction product 1 was precipitated with ether for three times, and was separated after centrifugation to obtain a precipitate 1; the precipitate 1 was dried in a vacuum drying oven at a temperature of 40°C to constant weight to obtain a white solid (0.406 g, yield 92%), which was polyethylene glycol-b-poly(N-4-bromophenylethylglycine) B, the polymerization degree of the poly(N-4-bromophenylethylglycine) block was 8, and the number average molecular weight of the polyethylene glycol-b-poly(N-4-bromophenylethylglycine) was 3.92 kg / mol. The number average molecular weight of the polyethylene glycol-b-poly(N-4-bromophenylethylglycine) was 13.5 kg / mol, and the molecular weight distribution was 1.04, which was measured by gel permeation chromatography. 44 -NH2) (CAS No. 80506-64-5) to obtain a mixture, 4.0 mL of N-methylpyrrolidone was added to dissolve the mixture to obtain a reaction system 1, the molar ratio of N-4-bromophenylethylglycine-N-thioacid anhydride to mPEG 44 -NH2) (CAS No. 80506-64-5) to obtain a mixture, 4.0 mL of N-methylpyrrolidone was added to dissolve the mixture to obtain a reaction system 1, the molar ratio of N-4-bromophenylethylglycine-N-thioacid anhydride to mPEG

[0123] (2) The white solid obtained in step (1) was taken out, 141.1 mg (0.036 mmol, containing 0.288 mmol of bromophenyl group) was placed in a Schlenk bottle filled with nitrogen, and then 1-(4-aminophenyl)-1,2,2-triphenyl ethylene (150.1 mg, 0.432 mmol), potassium phosphate (183.4 mg, 0.864 mmol), tris(dibenzylideneacetone)dipalladium (26.4 mg, 0.0288 mmol) and 2-(dicyclohexylphosphino)biphenyl (50.5 mg, 0.144 mmol) were added in sequence to obtain a reaction, the molar ratio of bromophenyl group to 1-(4-aminophenyl)-1,2,2-triphenyl ethylene, potassium phosphate, tris(dibenzylideneacetone)dipalladium and 2-(dicyclohexylphosphino)biphenyl in the reaction was 1:1.5:3:0.1:0.5; then 4 mL of N,N-dimethylformamide was added to dissolve the reaction to obtain a reaction system 2, the reaction system 2 was reacted at 100°C for 24 h to obtain a reaction product 2; the reaction product 2 was centrifuged to remove impurities, and then was precipitated with ether for three times, and was separated after centrifugation to obtain a precipitate 2; the precipitate 2 was dried in a vacuum drying oven at a temperature of 40°C to constant weight to obtain a light brown solid (225.0 mg, yield 84%), which was a polymeric peptide with a functionalized diphenylamine group in the side group (α7-polymeric peptide) represented by (XIII), the proton nuclear magnetic resonance spectrum of which was as follows: Figure 9The number average molecular weight determined by gel permeation chromatography was 22.8 kg / mol, and the molecular weight distribution was 1.26.

[0124] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the above embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the above embodiments, or replace some or all of the technical features therein with equivalents. However, these modifications or replacements do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for preparing a peptide having a functionalized diphenylamine group as a side group, characterized in that: include: N-thiocarboxylic anhydride containing bromophenyl groups undergoes ring-opening polymerization under the action of an initiator to obtain a polypeptide containing bromophenyl groups on the side groups; In the presence of an inorganic base, a palladium catalyst and a ligand, a raw material system including the polypeptide containing a bromophenyl group on the side group and an aromatic amine derivative undergoes an amination coupling reaction to obtain a polypeptide containing a functionalized diphenylamine group on the side group. The polypeptide containing a functionalized diphenylamine group on the side group has a structural formula as shown in formula (I): Formula (I); Wherein, R1 is any one of n-hexyl, benzyl, neopentyl, and methoxypolyethylene glycol; R2 is any one of hydrogen atom, alkyl, alkoxy, phenyl, triphenylvinyl, and diazenylphenyl; n is an integer between 10 and 100; and x is 1 or 2.

2. The method for preparing a peptide having a functionalized diphenylamine group as a side group according to claim 1, wherein: The molar ratio of the N-thiocarboxylic anhydride containing a bromophenyl group to the initiator is (10-100):

1.

3. The method for preparing a peptide having a functionalized diphenylamine group as a side group according to claim 1, wherein: The inorganic base is one of potassium phosphate and cesium carbonate, the palladium catalyst is one of tris(dibenzylideneacetone)dipalladium and palladium acetate, and the ligand is one of 2-(dicyclohexylphosphino)biphenyl and 2-(di-tert-butylphosphino)biphenyl; The molar ratio of the bromophenyl group, aromatic amine derivative, inorganic base, palladium catalyst and ligand in the polypeptide containing bromophenyl group on the side group is 1: (1-2): (2-4): (0.1-0.2): (0.4-0.6).

4. The method for preparing a peptide having a functionalized diphenylamine group as a side group according to claim 1, wherein: The reaction temperature of the amination coupling reaction is 90 ° C to 120 ° C, and the reaction time is 12 h to 36 h.

5. The method for preparing a peptide having a functionalized diphenylamine group as a side group according to claim 1, wherein: The reaction temperature for the ring-opening polymerization reaction is 50°C to 80°C, and the reaction time is 24 h to 96 h.

6. The method for preparing a peptide having a functionalized diphenylamine group as a side group according to claim 1, wherein: The N-thiocarboxylic acid anhydride containing a bromophenyl group is one of N-4-bromophenylmethylglycine-N-thiocarboxylic acid anhydride and N-4-bromophenylethylglycine-N-thiocarboxylic acid anhydride; the structural formula of the N-4-bromophenylmethylglycine-N-thiocarboxylic acid anhydride is shown in formula (II), and the structural formula of the N-4-bromophenylethylglycine-N-thiocarboxylic acid anhydride is shown in formula (III): Formula (II); Formula (III).

7. A method for preparing a peptide having a functionalized diphenylamine group as a side group, characterized in that: include: N-thiocarboxylic anhydride containing bromophenyl groups undergoes ring-opening polymerization under the action of an initiator to obtain a polypeptide containing bromophenyl groups on the side groups; In the presence of an inorganic base, a palladium catalyst and a ligand, a raw material system including the polypeptide containing a bromophenyl group on the side group and an aromatic amine derivative undergoes an amination coupling reaction to obtain a polypeptide containing a functionalized diphenylamine group on the side group. The polypeptide containing a functionalized diphenylamine group on the side group has a structural formula as shown in formula (I): Formula (I); Wherein, R1 is any one of n-hexyl, benzyl, neopentyl, and methoxypolyethylene glycol; n is an integer between 10 and 100; x is 1 or 2; and R2 is obtained by amination coupling reaction of an aromatic amine derivative having the structural formula of formula (IV), formula (V), or formula (VI): Formula (IV), Formula (V), Formula (VI); Among them, R3 is a hydrogen atom, an alkyl group, an alkoxy group or a phenyl group; R4 to R6 are independently selected from one of a hydrogen atom, an alkyl group, an alkoxy group or a phenyl group; R7 is a hydrogen atom, an alkyl group, an alkoxy group, a sulfonic acid group or a dimethylamino group.

8. The method for preparing a peptide having a functionalized diphenylamine group as a side group according to claim 1, wherein: The specific steps of performing the ring-opening polymerization reaction are: dissolving the N-thiocarboxylic anhydride containing a bromophenyl group in a first organic solvent to obtain a mixed solution, then adding an initiator to the mixed solution, causing the N-thiocarboxylic anhydride containing a bromophenyl group to undergo a ring-opening polymerization reaction under the action of the initiator to obtain a polypeptide containing a bromophenyl group on the side group, or dissolving the N-thiocarboxylic anhydride containing a bromophenyl group and an initiator in a first organic solvent, causing the N-thiocarboxylic anhydride containing a bromophenyl group to undergo a ring-opening polymerization reaction under the action of the initiator to obtain a polypeptide containing a bromophenyl group on the side group; The initiator is one of n-hexylamine, benzylamine, neopentylamine, and methoxypolyethylene glycol amine; The first organic solvent is at least one of tetrahydrofuran, dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, tetramethylurea, acetonitrile, benzonitrile, toluene, and chloroform.

9. The method for preparing a peptide having a functionalized diphenylamine group as a side group according to claim 1, wherein: The specific steps of the amination coupling reaction are as follows: dissolving the polypeptide containing a bromophenyl group on the side group, an aromatic amine derivative, an inorganic base, a palladium catalyst and a ligand in a second organic solvent; and in the presence of the inorganic base, the palladium catalyst and the ligand, subjecting the raw material system including the polypeptide containing a bromophenyl group on the side group and the aromatic amine derivative to an amination coupling reaction to obtain the polypeptide containing a functionalized diphenylamine group on the side group; The second organic solvent includes N,N-dimethylformamide.

10. A peptide having a functionalized diphenylamine group as a side group, characterized in that: The peptide is prepared by the method for preparing a polymeric peptide having a side group containing a functionalized diphenylamine group according to any one of claims 1 to 9.

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