Double-arm TPE (Thermoplastic Elastomer) derivative with side chain containing mannose molecule and norbornene as well as preparation and application of double-arm TPE derivative

Abstract

The invention relates to the technical field of synthesis of sugar-modified TPE derivatives connected with norbornene, in particular to a double-arm TPE derivative with a side chain containing mannose molecules and norbornene as well as preparation and application of the double-arm TPE derivative. The preparation method comprises the following steps: firstly, taking 4, 4 '-dibromo diphenyl ketone and benzophenone as raw materials to react to generate 4, 4-(2, 2-diphenylethyl-1, 1-diyl) bis (bromobenzene); the preparation method comprises the following steps: taking a TPE sugar-containing mother nucleus as a raw material, coupling and pulling out Br on one side by using Suzuki reaction, connecting a corresponding amino Boc fragment, pulling out Br on the other end by using Suzuki coupling reaction or Sonogashira coupling reaction, connecting a mannose derivative, and removing amino Boc by using trifluoroacetic acid to obtain a final key intermediate of the TPE sugar-containing mother nucleus; norbornene is introduced through nucleophilic substitution, the sugar-modified TPE derivative connected with the norbornene structure is finally obtained, and a foundation is laid for development of novel drug carrier materials.

Description

Technical Field

[0001] The present invention relates to the technical field of the synthesis of sugar-modified norbornene-linked TPE derivatives, and in particular to a dual-arm TPE derivative containing mannose molecules and norbornene in the side chain, and its preparation and application. Background Art

[0002] In the field of modern drug delivery and treatment, sugar-containing polymers have received great attention due to their special carbohydrate functional groups. Such polymers show great potential in drug delivery systems with their unique structural capabilities and specific recognition processes with biomolecules. At the same time, polyamino acids, as another important component of biomaterials, are increasingly widely used in the fields of medicine and materials science with their structural diversity, excellent biocompatibility and unique self-assembly characteristics. Biomaterials synthesized from amino acids have been successfully developed as drug carriers and show great development potential in the research of anti-tumor nano-drugs.

[0003] The aggregation-induced emission effect (AIE effect), as an emerging optical phenomenon, has gradually become an important direction in bioimaging and sensor design in recent years. The remarkable feature of AIE materials is that they exhibit excellent luminescence properties in the aggregated state. This property effectively solves the problem of the reduced luminescence efficiency of traditional organic fluorescent materials due to hydrophobicity in the aqueous environment, especially the technical bottleneck in solid-state or aggregated-state applications. The core mechanism of the AIE effect lies in the intermolecular aggregation behavior. When AIE molecules are in a dilute solution state, due to the high rotational and vibrational degrees of freedom between molecules, their luminescence efficiency is often low. However, under aggregated or solid-state conditions, the intermolecular interactions limit these degrees of freedom, resulting in a reduction in non-radiative transitions and thus significantly increasing the fluorescence emission intensity. This process not only enables AIE molecules to form aggregates under the induction of specific substrates, but also realizes a significant increase in fluorescence efficiency, even a transition from "dark" to "bright". AIE materials have great application potential in bioimaging and sensor design. First of all, AIE molecules can provide high-contrast imaging effects in bioimaging, especially in in vivo imaging, effectively overcoming the limitations of traditional fluorescent probes. Secondly, due to their high fluorescence efficiency in the aggregated state, AIE materials show superiority in the quantitative detection and qualitative analysis of stimuli. This makes AIE materials an ideal choice in the fields of environmental monitoring, disease diagnosis and biomarker detection. With the in-depth research, AIE materials are expected to provide a broader application prospect for the realization of high-quality in vivo imaging and high-sensitivity online sensing and monitoring.

[0004] Regarding a class of classic molecules of AIE materials - tetraphenylethylene (TPE), its unique structural design makes the luminescence performance of this molecule weak in the dispersed state. However, once it enters the aggregated state, the rotation of its benzene rings is restricted, and the radiative decay of excited-state electrons is enhanced, thus realizing the phenomenon of aggregation-induced emission. This phenomenon provides an opportunity for further research on molecular recombination and polymerization reactions.

[0005] Ring-Opening Metathesis Polymerization (ROMP) of cyclic olefins, as a unique polymerization method, is an effective way to prepare various functional polymer materials. The monomer of norbornene derivative (NBE) can prepare low-dispersity homopolymers and block copolymers with various special properties, functions, and topological structures through living ROMP under mild conditions. The flexibility of ROMP provides a broad design space for scientific researchers, enabling the regulation of the properties of polymers according to application requirements. By selecting different monomers and their combinations, scientists can synthesize polymer materials with specific biocompatibility and biological functions. Their applications in drug delivery systems are particularly worthy of attention. Their controllable release characteristics and adaptability to the biological environment make the drug delivery process more efficient and safe.

[0006] In recent years, with the continuous deepening of the theory and application of AIE materials, on the one hand, existing defects have also been found in AIE materials: 1) In terms of biocompatibility and toxicity, many AIE molecules (such as TPE derivatives) are highly hydrophobic and prone to aggregation in the body, which may trigger immune responses or long-term retention toxicity. 2) Insufficient functionalization and targeting, AIE molecules lack specific targeting groups and rely on passive targeting, resulting in low efficiency. 3) Environmental sensitivity issues, some AIE materials are sensitive to pH and ionic strength, leading to poor signal stability. 4) Synthetic complexity, multi-step synthesis leads to low yields and high costs. On the other hand, there are few reports on the combination of AIE and sugar polymers. Research has found that the hydrophilic modification of AIE materials can be improved by sugar polymers. Using sugar groups (such as mannose targeting macrophages) to enhance the active targeting ability, sugar polymer-coated AIE nanoparticles can also be designed to buffer environmental interference. On the other hand, modular synthesis strategies can be developed to enhance the binding force using the multivalent sugar cluster effect and combine the AIE signal amplification to detect sensitivity. Therefore, how to develop new TPE materials has become a new topic with challenges and potential. Summary of the Invention

[0007] To solve the above problems, the object of the present invention is to provide a double-arm TPE derivative with mannose molecules and norbornene in the side chain, and its preparation and application. The developed novel TPE materials will not be limited to traditional polymer synthesis methods, and are more likely to utilize modern molecular design and synthesis strategies, such as modular synthesis, functional modification, and regulation of interactions with other biomolecules, to provide more options for AIE research. This will inject new vitality into the further promotion of innovation in drug delivery technology and the development of bioimaging technology. The combination of sugar-containing polymers and AIE materials in the present invention provides a new perspective and idea for the development of modern drug delivery and imaging technology. Through in-depth research on polyamino acids and AIE materials, not only can the design of novel drug carriers be explored, but also the application of biomaterials in the medical field can be promoted; in the future, more emphasis will be placed on the multifunctionality of these materials and their feasibility in practical applications, to promote their wide application in the fields of medicine and biotechnology.

[0008] The present invention first constructs the TPE core using the McMurry reaction. Using 4,4'-dibromobenzophenone and benzophenone as raw materials, 4,4-(2,2-diphenylethylene-1,1-diyl)bis(bromobenzene) is generated; then, the Suzuki reaction is used to couple and remove one side of the Br and connect the corresponding amino Boc fragment. Subsequently, the other end of the Br is removed by the Suzuki coupling reaction or the Sonogashira coupling reaction and a mannose derivative is connected to obtain a single-arm tetraphenylethylene sugar-containing compound with a protecting group. Subsequently, the amino Boc is removed with trifluoroacetic acid to obtain the key intermediate of the final TPE sugar-containing core; then, norbornene is introduced through nucleophilic substitution to obtain a TPE derivative with a sugar modification and a norbornene structure attached. The present invention innovatively combines the ROMP effect of norbornene, the aggregation-induced emission enhancement effect of TPE, and important functional substances in vivo such as glycopeptides and glycoproteins, opening up a new approach. This method not only provides a feasible solution for the glycosylation modification of polymers such as polypeptides, but also provides an effective means for the determination of the distribution and content of glycopeptide polymers, thus providing a new monitoring method for detecting biological processes in animals. In addition, the application of this technology also provides new options for the development of a variety of functional polymer materials, with good application prospects.

[0009] The object of the present invention can be achieved by the following technical solutions:

[0010] The first object of the present invention is to provide a double-arm TPE derivative with mannose molecules and norbornene in the side chain, and its chemical structural formula is shown as formula (VIII-1) or formula (VIII-2):

[0011]

[0012] The second object of the present invention is to provide a method for preparing a bis-arm TPE derivative with a side chain containing a mannose molecule and a norbornene, comprising the following steps:

[0013] (S1) Mix 4,4'-dibromobenzophenone and benzophenone and carry out the McMurry reaction, and perform post-treatment to obtain a first compound (constructing the TPE nucleus by the McMurry reaction);

[0014] (S2) Mix N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester with the first compound prepared in step (S1) and carry out the Suzuki coupling reaction, and perform post-treatment to obtain a second compound;

[0015] (S3) Mix the mannose derivative with the second compound prepared in step (S2) and react, and perform post-treatment to obtain a third compound;

[0016] (S4) Mix trifluoroacetic acid with the third compound prepared in step (S3) and carry out a substitution reaction, and perform post-treatment to obtain a fourth compound;

[0017] (S5) Mix norbornene dianhydride and ethanolamine and carry out a substitution reaction, and perform post-treatment to obtain a fifth compound;

[0018] (S6) Mix p-toluenesulfonyl chloride with the fifth compound prepared in step (S5) and carry out a substitution reaction, and perform post-treatment to obtain a sixth compound;

[0019] (S7) Mix triethylamine, the fourth compound prepared in step (S4) and the sixth compound prepared in step (S6) and carry out a substitution reaction, and perform post-treatment to obtain a bis-arm TPE derivative with a side chain containing a mannose molecule and a norbornene;

[0020] Among them, the chemical structural formula of the first compound is shown as formula (I); the chemical structural formula of the second compound is shown as formula (II); the chemical structural formula of the fifth compound is shown as formula (VI); the chemical structural formula of the sixth compound is shown as formula (VII); the chemical structural formula of the mannose derivative is shown as formula (III-1) or formula (III-2); when the chemical structural formula of the mannose derivative is shown as formula (III-1), the chemical structural formula of the third compound is shown as formula (IV-1), the chemical structural formula of the fourth compound is shown as formula (V-1), and the chemical structural formula of the seventh compound is shown as formula (VIII-1); when the chemical structural formula of the mannose derivative is shown as formula (III-2), the chemical structural formula of the third compound is shown as formula (IV-2), the chemical structural formula of the fourth compound is shown as formula (V-2), and the chemical structural formula of the seventh compound is shown as formula (VIII-2);

[0021]

[0022] In the present invention, the preparation process of the double-arm TPE derivative containing mannose molecules and norbornene in the side chain is as follows:

[0023]

[0024] In one embodiment of the present invention, in step (S1), anhydrous titanium tetrachloride is used as the catalyst and zinc powder is used as the initiator;

[0025] The molar ratio of 4,4'-dibromobenzophenone, benzophenone, anhydrous titanium tetrachloride, and zinc powder is 1:1.2 - 1.3:4.5 - 5:9.5 - 10;

[0026] During the McMurry reaction, the temperature is 0°C - 90°C and the time is 16 h - 20 h.

[0027] In one embodiment of the present invention, in step (S1), the post-treatment is adsorption, filtration, washing, drying, and purification.

[0028] In one embodiment of the present invention, in step (S2), 1,1'-bis(diphenylphosphino)ferrocene dichloropalladium(II) is used as the catalyst, and Na 2 CO 3 is used to create an alkaline environment;

[0029] The molar ratio of N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester, the first compound, 1,1'-bis(diphenylphosphino)ferrocene dichloropalladium(II), and Na 2 CO 3 is 1 - 1.2:1:0.1 - 0.2:2 - 2.5;

[0030] During the Suzuki coupling reaction, the temperature is 105°C - 120°C and the time is 16 h - 24 h.

[0031] In one embodiment of the present invention, in step (S2), the post-treatment is washing, drying, filtration, and purification.

[0032] In one embodiment of the present invention, in step (S3), 1,1'-bis(diphenylphosphino)ferrocene dichloropalladium(II) is used as the catalyst and CuI is used as the catalyst, and Na 2 CO 3 is used to create an alkaline environment;

[0033] When the chemical structural formula of the mannose derivative is as shown in formula (III-1), the second compound, the mannose derivative, 1,1'-bis(diphenylphosphino)ferrocene dichloropalladium(II), and Na 2 CO3 The molar ratio is 1:1 to 1.5:0.1 to 0.2:2 to 2.5;

[0034] The Suzuki coupling reaction occurs. During the Suzuki coupling reaction, the temperature is 105 °C to 120 °C, and the reaction time is 16 h to 24 h;

[0035] When the chemical structural formula of the mannose derivative is as shown in formula (III-2), the molar ratio of the second compound, the mannose derivative, dichloropalladium(II) bis(diphenylphosphino)ferrocene, and CuI is 1:1.5 to 2:0.1 to 0.2:0.2 to 0.4;

[0036] The Sonogashira coupling reaction occurs. During the Sonogashira coupling reaction, the temperature is 80 °C to 100 °C, and the reaction time is 24 h to 36 h.

[0037] In one embodiment of the present invention, in step (S3), the post-treatment is washing, drying, and purification.

[0038] In one embodiment of the present invention, in step (S4), the dosage ratio of trifluoroacetic acid to the third compound is 2 to 4 mL:1.02 mmol;

[0039] During the substitution reaction, the temperature is 0 °C to 25 °C, and the time is 5 h to 8 h.

[0040] In one embodiment of the present invention, in step (S4), the post-treatment is neutralization, washing, drying, and purification.

[0041] In one embodiment of the present invention, in step (S5), triethylamine is used to create a basic environment;

[0042] The molar ratio of norbornene dianhydride, ethanolamine, and triethylamine is 1:1.1 to 1.3:9 to 10;

[0043] During the substitution reaction, the temperature is 120 °C to 125 °C, and the time is 15 h to 20 h.

[0044] In one embodiment of the present invention, in step (S5), the post-treatment is concentration, crystallization, drying, and purification.

[0045] In one embodiment of the present invention, in step (S6), the molar ratio of p-toluenesulfonyl chloride, the fifth compound, and pyridine is 0.9 to 1.1:1:2.2 to 2.57;

[0046] During the substitution reaction, the temperature is 15 °C to 25 °C, and the time is 20 h to 24 h.

[0047] In one embodiment of the present invention, in step (S6), the post-treatment is neutralization, filtration, washing, and drying.

[0048] In one embodiment of the present invention, in step (S7), the molar ratio of triethylamine, the fourth compound, and the sixth compound is 4.5 - 8.5:1:2 - 3.5;

[0049] During the substitution reaction, the temperature is 100°C - 105°C, and the time is 16 h - 20 h.

[0050] In one embodiment of the present invention, in step (S7), the post-treatment is concentration, washing, drying, and purification.

[0051] The third object of the present invention is to provide an application of a double-armed TPE derivative containing a mannose molecule and a norbornene in a drug delivery system.

[0052] Compared with the prior art, the present invention has the following beneficial effects:

[0053] With the development of biomaterials science and nanotechnology, polymers with specific structures and functions have received increasing attention in the fields of human health and biomedicine. Especially in the aspect of drug carriers, how to prepare intelligent materials that can achieve specific recognition and effective drug release has become one of the hotspots in scientific research. In response to this need, the present invention uses the McMurry reaction, Suzuki reaction, and Sonogashira reaction to synthesize an acetyl-protected sugar-containing compound of double-armed tetraphenylethylene, and further realizes the connection with the norbornene fragment, laying a foundation for the development of new drug carrier materials.

[0054] (1) The present invention synthesizes a double-armed TPE sugar-containing derivative with high efficiency and stability through the McMurry reaction, Suzuki reaction, and Sonogashira reaction. During the synthesis process, first, the acetyl-protected form of TPE is synthesized by the McMurry reaction. Due to the special structure and biocompatibility of the sugar-containing molecule, this synthesis method has significant advantages. This step effectively improves the hydrolysis resistance and chemical stability of the synthesized compound. Subsequently, the norbornene fragment is further introduced into the molecular structure; the finally obtained compound not only has the optical properties of TPE but also enhances the interaction ability with biological macromolecules through the introduction of norbornene.

[0055] (2) The TPE sugar derivatives synthesized in the present invention can effectively bind norbornene. Its design goal is to create a material that can achieve various functions through post-polymerization modification. The tunability of this compound provides broad prospects for its application in the biomedical field. Compared with traditional drug carrier materials, the compound designed in the present invention can not only achieve specific recognition of biological proteins, but also its drug release ability after polymerization increases the practicality of the material.

[0056] (3) When the sugar-containing polymer in the present invention performs molecular recognition with specific types of proteins, due to its multivalent interaction characteristics, it can significantly improve the affinity and specificity. This characteristic makes it have great application potential in drug carriers. By regulating the structure of the polymer, researchers can achieve the recognition of different target proteins, thus achieving the goal of personalized drug release.

[0057] (4) The TPE structure in the present invention also has the aggregation-induced emission effect, which also has important scientific potential in bioimaging and tracer analysis. Description of the Drawings

[0058] Figure 1 It is the 1H NMR spectrum of the first compound in Example 1 of the present invention.

[0059] Figure 2 It is the 13C NMR spectrum of the first compound in Example 1 of the present invention.

[0060] Figure 3 It is the 1H NMR spectrum of the second compound in Example 1 of the present invention.

[0061] Figure 4 It is the 13C NMR spectrum of the second compound in Example 1 of the present invention.

[0062] Figure 5 It is the 1H NMR spectrum of the third compound in Example 1 of the present invention.

[0063] Figure 6 It is the 13C NMR spectrum of the third compound in Example 1 of the present invention.

[0064] Figure 7 It is the 1H NMR spectrum of the fourth compound in Example 1 of the present invention.

[0065] Figure 8 It is the 13C NMR spectrum of the fourth compound in Example 1 of the present invention.

[0066] Figure 9 It is the 1H NMR spectrum of the fifth compound in Example 1 of the present invention.

[0067] Figure 10 It is the 13C NMR spectrum of the fifth compound in Example 1 of the present invention.

[0068] Figure 11 1H NMR spectrum of the sixth compound in Example 1 of the present invention.

[0069] Figure 12 13C NMR spectrum of the sixth compound in Example 1 of the present invention.

[0070] Figure 13 1H NMR spectrum of the seventh compound in Example 1 of the present invention.

[0071] Figure 14 13C NMR spectrum of the seventh compound in Example 1 of the present invention.

[0072] Figure 15 1H NMR spectrum of the third compound in Example 2 of the present invention.

[0073] Figure 16 13C NMR spectrum of the third compound in Example 2 of the present invention.

[0074] Figure 17 1H NMR spectrum of the fourth compound in Example 2 of the present invention.

[0075] Figure 18 13C NMR spectrum of the fourth compound in Example 2 of the present invention.

[0076] Figure 19 1H NMR spectrum of the seventh compound in Example 2 of the present invention.

[0077] Figure 20 13C NMR spectrum of the seventh compound in Example 2 of the present invention. Detailed implementation mode

[0078] The present invention will be described in detail below with reference to the accompanying drawings and specific embodiments.

[0079] In the following examples, the sources of the reagents used are as follows: Mannose derivative B was synthesized according to the second method for preparing intermediate B in the synthesis method in the experimental details section of Example 1 in Patent WO2014100158A1, and mannose derivative F was synthesized according to the sixth method for preparing intermediate F in the synthesis method in the experimental details section of Example 1 in Patent WO2014100158A1; 1,4-dioxane (≥99.5%), acetone (≥99.5%), dichloromethane (≥99.5%), methanol (≥99.5%), zinc powder (≥95%), toluene (≥99.5%) were purchased from Sinopharm Chemical Reagent Co., Ltd.; 4,4'-dibromobenzophenone, benzophenone, N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester, X-Phos-Pd-G3 were purchased from Shanghai Shaoyuan Reagent Co., Ltd.; anhydrous potassium phosphate (≥98%) was purchased from Shanghai Haohong Biopharmaceutical Technology Co., Ltd.; anhydrous titanium tetrachloride, trifluoroacetic acid, ultra-dry acetonitrile (≥99.9%), ultra-dry triethylamine (≥99.5%) were purchased from Anajie Chemical; S-PHOS was purchased from Bidepharm; ultra-dry tetrahydrofuran (≥99.9%) was purchased from Beijing Innochem Science & Technology Co., Ltd.; ethanolamine (99%) was purchased from Shanghai Aladdin Biochemical Technology Co., Ltd.; other reagents not mentioned such as anhydrous potassium carbonate (>99%) and sodium bicarbonate (>99.5%) were all purchased from Shanghai Tansuo Technology Co., Ltd.

[0080] Unless otherwise specified, all reagents used are commercially available reagents, and all detection means and methods used are conventional detection means and methods in the art.

[0081] Example 1

[0082] This example provides a method for preparing a double-armed TPE derivative containing a mannose molecule and norbornene in the side chain, which specifically includes the following steps:

[0083] (S1) Preparation of the first compound

[0084] 4,4'-Dibromobenzophenone (4.1 g, 12.06 mmol), benzophenone (2.64 g, 14.48 mmol) and zinc powder (7.5 g, 114.6 mmol) were added to a 250 mL dry three-necked flask. After sealing, the flask was purged with nitrogen three times. 150 mL of anhydrous tetrahydrofuran was slowly injected into the reaction system through a syringe. After stirring in an ice bath for 30 min, anhydrous titanium tetrachloride (6.3 mL, 57.5 mmol) was slowly added dropwise through a syringe, and the mixture was stirred at 0 °C for 30 min, followed by reaction at 85 °C for 20 h. After the reaction was completed, the reaction solution was poured into 100 mL of saturated potassium carbonate solution, stirred for 30 min, then diatomaceous earth was added to adsorb the titanium salt, and the mixture was washed 4 times with ethyl acetate. The organic phases were combined, the solvent was evaporated, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated again. The crude product was dried and separated by column chromatography to obtain 1.6 g of a white solid, which was the first compound with a yield of 32%.

[0085] The 1H NMR spectrum and 13C NMR spectrum of the first compound are shown respectively as Figure 1 and Figure 2 shown below.

[0086] The NMR data of the first compound are as follows:[[]]END]]

[0087] 1 H NMR (401 MHz, CDCl 3 ) δ 7.35 - 7.22 (m, 1H), 7.16 (d, J = 3.1 Hz, 2H), 7.04 (d, J = 3.6 Hz, 1H), 6.91 (d, J = 7.1 Hz, 1H).

[0088] 13 C NMR (101 MHz, CDCl 3 ) δ = 143.03, 142.12, 132.99, 131.20, 131.06, 127.98, 126.50, 77.39, 77.07, 76.75.

[0089] (S2) Preparation of the second compound

[0090] The first compound (4.0 g, 8.16 mmol) prepared in step (S1) was dissolved in 20 mL of 1,4-dioxane and stirred until dissolved. N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (2.53 g, 8.16 mmol), 1,1'-bis(diphenylphosphino)ferrocene dichloropalladium(II) (0.6 g, 0.82 mmol), and Na 2 CO 3(1.73 g, 16.32 mmol), and then replaced with nitrogen three times, and reacted at 105 °C for 20 h. After the reaction, the solvent was evaporated, and the crude product was extracted twice with ethyl acetate and saturated brine. After drying with anhydrous sodium sulfate and filtering, the product was separated by silica gel column chromatography to obtain 0.85 g of an off-white solid, which was the second compound with a yield of 25%.

[0091] The 1H NMR spectrum and 13C NMR spectrum of the second compound are shown respectively as Figure 3 and Figure 4 shown.

[0092] The NMR data of the second compound are as follows:

[0093] 1 H NMR (400 MHz, CDCl 3 ) δ 9.32 (s, 2H), 7.20 (d, J = 8.0 Hz, 2H), 7.15 - 7.03 (m, 3H), 6.91 (dd, J = 16.2, 7.6 Hz, 4H), 6.73 (dd, J = 12.7, 8.4 Hz, 4H), 6.49 (t, J = 9.0 Hz, 4H), 6.11 (s, 1H), 3.96 (s, 2H), 3.49 (s, 2H), 2.39 (s, 2H), 1.41 (s, 9H).

[0094] 13 C NMR (101 MHz, CDCl 3 ) δ = 133.22, 131.30, 130.92, 127.83, 124.11, 77.38, 77.07, 76.75, 28.54.

[0095] (S3) Preparation of the third compound

[0096] The second compound (1 g, 1.68 mmol) prepared in step (S2) was dissolved in 6 mL of 1,4-dioxane, stirred until dissolved, and then mannose derivative sugar B (0.52 g, 1.68 mmol), 1,1'-bis(diphenylphosphino)ferrocene dichloropalladium(II) (0.13 g, 0.17 mmol), and Na 2 CO 3 (0.36 g, 3.36 mmol) were added successively. Then, it was replaced with nitrogen three times and reacted at 105 °C for 21 h. After the reaction, the solvent was evaporated, and the crude product was extracted three times with ethyl acetate and saturated brine. After drying with anhydrous sodium sulfate and filtering, the product was separated by silica gel column chromatography to obtain 0.49 g of a white solid, which was the third compound with a yield of 52%.

[0097] The 1H NMR spectrum and 13C NMR spectrum of the third compound are shown respectively asFigure 5 and Figure 6 as shown

[0098] The NMR data of the third compound are as follows:

[0099] 1 H NMR(400MHz,CDCl 3 )δ8.46(d,J = 5.6Hz,2H),7.23(d,J = 8.3Hz,2H),7.12(dd,J = 13.2,7.2Hz,3H),7.01 - 6.92(m,4H),6.91 - 6.85(m,4H),6.84 - 6.78(m,4H),6.29(d,J = 9.2Hz,2H),6.15(s,1H),5.62(t,J = 9.6Hz,2H),5.47(dd,J = 10.1,3.4Hz,2H),5.43(d,J = 3.0Hz,2H),5.07(d,J = 2.0Hz,4H),4.60(t,J = 6.1Hz,2H),4.14(dd,J = 11.6,4.9Hz,2H),4.03(dd,J = 11.5,7.3Hz,2H),3.97(s,2H),3.49(d,J = 5.3Hz,2H),2.39(s,2H),2.19(s,6H),1.99(s,6H),1.95(s,6H),1.80(s,6H),1.41(s,9H).

[0100] 13 C NMR(101MHz,CDCl 3 )δ = 170.20,154.30,141.00,140.00,139.20,138.00,132.50,129.20,128.60,128.50,127.70,127.55,127.11,126.30,115.10,80.70,79.80,74.10,73.10,72.40,70.70,63.00,46.60,44.30,29.80,28.40,20.70.

[0101] (S4) Preparation of the fourth compound

[0102] The third compound (1 g, 1.20 mmol) prepared in step (S3) was dissolved in a mixed solution of 2 mL of anhydrous methanol and anhydrous dichloromethane (MeOH:DCM = 1:1 (volume ratio)). 1.05 mL of trifluoroacetic acid was added dropwise at 0 °C and stirred for 35 min, and then reacted at 25 °C for 8 h. After the reaction, the reaction solution was diluted with ethyl acetate, neutralized to pH = 8.3 with cold saturated sodium bicarbonate solution, then washed with saturated brine, dried over anhydrous sodium sulfate, and the product was separated by silica gel column chromatography to obtain 520 mg of a pale yellow powdery product, which is the fourth compound, with a yield of 56%.

[0103] The 1H NMR spectrum and 13C NMR spectrum of the fourth compound are as Figure 7 and Figure 8 shown.

[0104] The NMR data of the fourth compound are as follows:[[]]END]]

[0105] 1 H NMR (400 MHz, CDCl 3 ) δ 8.48 (d, J = 7.6 Hz, 2H), 7.26 (d, J = 8.3 Hz, 2H), 7.13 (dd, J = 13.0, 7.2 Hz, 3H), 6.94 (dd, J = 11.3, 7.6 Hz, 4H), 6.89 (dd, J = 12.0, 8.8 Hz, 4H), 6.81 (dd, J = 11.0, 9.0 Hz, 4H), 6.30 (d, J = 9.2 Hz, 2H), 6.18 (s, 1H), 5.62 (t, J = 9.6 Hz, 2H), 5.48 (dd, J = 10.1, 3.4 Hz, 2H), 5.43 (d, J = 3.1 Hz, 2H), 5.07 (s, 4H), 4.61 (t, J = 6.1 Hz, 2H), 4.14 (dd, J = 11.5, 4.9 Hz, 2H), 4.04 - 4.01 (m, 2H), 3.58 (s, 2H), 3.13 (t, J = 5.4 Hz, 2H), 2.44 (s, 2H), 2.19 (s, 6H), 2.00 (s, 6H), 1.95 (s, 6H), 1.80 (s, 6H).

[0106] 13 C NMR (101 MHz, CDCl 3)δ = 170.20, 141.00, 140.00, 139.20, 138.00, 132.50, 129.20, 128.60, 128.50, 127.70, 127.55, 127.11, 126.30, 115.10, 80.70, 74.10, 73.10, 72.40, 70.70, 63.00, 48.50, 43.20, 32.90, 20.70.

[0107] (S5) Preparation of the Fifth Compound

[0108] Take 4 g (24.4 mmol) of norbornene dianhydride and dissolve it in 100 mL of anhydrous toluene. Add ethanolamine (1.6 mL, 26.8 mmol) and triethylamine (34 mL, 244 mmol) at 0 °C. After replacing nitrogen, stir for 30 min, and then react at 120 °C for 15 h. After the reaction, evaporate the solvent. Extract with dichloromethane and water, dry with anhydrous sodium sulfate, and concentrate to obtain the crude product. Dissolve the crude product in 4 mL of dichloromethane and slowly drip it into 150 mL of petroleum ether to precipitate. Stir for 1 h, filter, and wash three times with a mixed solution of dichloromethane and petroleum ether (dichloromethane:petroleum ether = 1:100 (volume ratio)) to obtain 3.8 g of a white solid product, which is the fifth compound, with a yield of 76%.

[0109] The 1H NMR spectrum and 13C NMR spectrum of the fifth compound are as Figure 9 and Figure 10 shown.

[0110] The NMR data of the fifth compound are as follows:[[]]END]]

[0111] 1 H NMR (400 MHz, CDCl 3 ) δ 6.30 (s, 3H), 4.74 (s, 1H), 3.48 (dd, J = 6.5, 3.6 Hz, 2H), 3.44 (d, J = 4.8 Hz, 2H), 3.09 (s, 2H), 2.67 (s, 2H), 1.34 (d, J = 9.7 Hz, 1H), 1.27 (d, J = 9.6 Hz, 1H).

[0112] 13 C NMR (101 MHz, CDCl 3 ) δ = 178.16, 138.10, 57.57, 47.72, 44.99, 42.83, 40.99.

[0113] (S6) Preparation of the Sixth Compound

[0114] Dissolve the fifth compound (3 g, 14.48 mmol) prepared in step (S5) in 40 mL of anhydrous dichloromethane. Add pyridine (5 mL, 43.44 mmol) at 0 °C, and then dropwise add p-toluenesulfonyl chloride (1.5 mL, 16.0 mmol). React at 0 °C for 5 h. After the reaction is completed, dilute the reaction solution with dichloromethane, wash it successively three times with cold saturated sodium bicarbonate solution and saturated brine, dry it over anhydrous sodium sulfate, and concentrate to obtain 2 g of a pale yellow powdery product, which is the sixth compound, with a yield of 92%.

[0115] The 1H NMR spectrum and 13C NMR spectrum of the sixth compound are shown in Figure 11 and Figure 12 as shown below.

[0116] The NMR data of the sixth compound are as follows:[[]]END]

[0117] 1 H NMR (400 MHz, CDCl 3 ) δ 6.30 (s, 2H), 4.40 (t, J = 5.3 Hz, 2H), 3.84 (t, J = 5.3 Hz, 2H), 3.29 (s, 2H), 3.03 (s, 3H), 2.74 (s, 2H), 1.54 (d, J = 9.9 Hz, 1H), 1.30 (d, J = 9.9 Hz, 1H).

[0118] 13 C NMR (101 MHz, CDCl 3 ) δ = 170.46, 170.42, 160.95, 160.04, 137.03, 136.99, 144.16, 143.70, 143.41, 140.22, 139.06, 137.40, 136.51, 134.02, 132.52, 131.25, 131.24, 128.28, 126.32, 124.60, 124.27, 119.74, 114.45, 114.37, 84.71, 73.41, 70.33, 68.16, 67.79, 62.07, 61.11, 60.24, 21.22, 20.96, 20.87, 20.79, 20.46.

[0119] (S7) Preparation of the seventh compound

[0120] The fourth compound (300 mg, 0.276 mmol) prepared in step (S4) and the sixth compound (230 mg, 0.828 mmol) prepared in step (S6) were placed in a 5 mL microwave tube, dissolved in 1 mL of ultradry acetonitrile, and then ultradry triethylamine (0.29 mL, 2.2 mmol) was added. After purging with nitrogen three times, the reaction was carried out at 110 °C for 20 h. After the reaction was completed, the solvent was rotary evaporated and the product was separated by silica gel column chromatography to obtain 175 mg of a pale yellow powdery product, namely the seventh compound, with a yield of 44%.

[0121] The 1H NMR spectrum and 13C NMR spectrum of the seventh compound are shown in Figure 13 and Figure 14 as follows.

[0122] The NMR data of the seventh compound are as follows:[[]]

[0123] 1 H NMR (400 MHz, CDCl 3 ) δ 7.86 (d, J = 11.2 Hz, 2H), 7.14 - 7.08 (m, 5H), 7.03 - 7.00 (m, 2H), 6.95 (t, J = 9.5 Hz, 6H), 6.72 (t, J = 8.2 Hz, 4H), 6.26 (s, 2H), 6.01 (s, 1H), 5.91 (dd, J = 8.6, 4.8 Hz, 2H), 5.49 - 5.42 (m, 4H), 5.25 (t, J = 9.5 Hz, 2H), 5.11 (d, J = 3.3 Hz, 4H), 4.31 (dd, J = 12.6, 4.9 Hz, 2H), 4.16 (d, J = 11.6 Hz, 2H), 4.07 - 4.00 (m, 2H), 3.68 (t, J = 6.1 Hz, 2H), 3.21 (d, J = 17.8 Hz, 4H), 2.71 (d, J = 27.4 Hz, 6H), 2.44 (s, 2H), 2.09 (s, 6H), 2.06 (s, 6H), 2.04 (s, 6H), 1.86 (s, 6H), 1.50 (d, J = 9.6 Hz, 1H), 1.41 (d, J = 9.9 Hz, 1H).

[0124] 13 C NMR (101 MHz, CDCl 3)δ174.30,170.20,141.00,140.00,139.20,138.00,135.20,132.50,129.20,128.60,128.50,127.70,127.55,127.11,126.30,115.10,80.71,74.10,73.10,72.40,70.70,63.00,53.30,52.11,49.30,48.50,46.20,45.01,30.00,20.70.

[0125] Example 2

[0126] This example provides a method for preparing a double-arm TPE derivative containing a mannose molecule and a norbornene in the side chain, which specifically includes the following steps:

[0127] (S1) Preparation of the first compound

[0128] Take 4,4'-dibromobenzophenone (4.1 g, 12.06 mmol), benzophenone (2.64 g, 14.48 mmol) and zinc powder (7.5 g, 114.6 mmol) and add them to a 250 mL dry three-necked flask. After sealing, displace with nitrogen three times. Slowly inject 150 mL of anhydrous tetrahydrofuran into the reaction system through a syringe. After stirring in an ice bath for 30 min, slowly dropwise add anhydrous titanium tetrachloride (6.3 mL, 57.5 mmol) through a syringe, and stir at 0 °C for 30 min, and then react at 85 °C for 20 h. After the reaction is completed, pour the reaction solution into 100 mL of saturated potassium carbonate solution, stir for 30 min, then add diatomaceous earth to adsorb the titanium salt, wash with ethyl acetate 4 times, combine the organic phases, rotary evaporate the solvent, dry with anhydrous sodium sulfate, filter, rotary evaporate the solvent again, and dry the crude product by column chromatography to prepare the first compound.

[0129] (S2) Preparation of the second compound

[0130] Dissolve the first compound (4.0 g, 8.16 mmol) prepared in step (S1) in 20 mL of 1,4-dioxane, stir to dissolve, and successively add N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (2.53 g, 8.16 mmol), 1,1'-bis(diphenylphosphino)ferrocene dichloropalladium(II) (0.6 g, 0.82 mmol), Na 2 CO 3 (1.73 g, 16.32 mmol), then displace with nitrogen three times and react at 105 °C for 20 h. After the reaction is completed, rotary evaporate the solvent, extract the reaction solution twice with ethyl acetate and saturated brine, dry with anhydrous sodium sulfate, filter, and then separate the product by silica gel column chromatography to prepare the second compound.

[0131] (S3) Preparation of the third compound

[0132] Dissolve the second compound (1 g, 1.68 mmol) prepared in step (S2) in a mixed solvent of 6 mL of triethylamine and tetrahydrofuran (triethylamine:tetrahydrofuran = 1:2 (volume ratio)), stir to dissolve, and successively add mannose derivative sugar F (1.50 g, 3.37 mmol), 1,1'-bis(diphenylphosphino)ferrocene dichloropalladium(II) (0.38 g, 0.34 mmol), CuI (0.07 g, 0.34 mmol). Subsequently, displace with nitrogen three times and react at 100 °C for 36 h. After the reaction is completed, rotary evaporate the solvent, extract the reaction solution with ethyl acetate and saturated brine three times, dry with anhydrous sodium sulfate, and separate the product by silica gel column chromatography to obtain 0.40 g of a white solid, which is the third compound, with a yield of 51%.

[0133] The 1H NMR spectrum and 13C NMR spectrum of the third compound are respectively as Figure 15 and Figure 16 shown.

[0134] The NMR data of the third compound are as follows:[[]]END]]

[0135] 1 H NMR (400 MHz, CDCl 3 ) δ 8.42 (d, J = 1.9 Hz, 2H), 7.24 (d, J = 8.3 Hz, 2H), 7.14 (d, J = 7.4 Hz, 3H), 6.96 (dd, J = 13.2, 5.2 Hz, 4H), 6.91 - 6.87 (m, 4H), 6.83 (dd, J = 11.2, 8.9 Hz, 4H), 6.44 (d, J = 1.9 Hz, 2H), 6.19 - 6.08 (m, 1H), 5.82 (dd, J = 9.3, 3.9 Hz, 2H), 5.78 - 5.75 (m, 2H), 5.26 (t, J = 9.4 Hz, 2H), 5.12 (d, J = 3.0 Hz, 4H), 4.23 (dd, J = 12.6, 5.0 Hz, 2H), 4.03 (dd, J = 12.5, 2.2 Hz, 2H), 3.97 (s, 2H), 3.90 - 3.83 (m, 2H), 3.49 (d, J = 5.4 Hz, 2H), 2.40 (s, 2H), 2.16 (s, 6H), 2.04 (s, 6H), 2.00 (s, 6H), 1.99 (s, 6H), 1.42 (s, 9H).

[0136] 13 C NMR (101 MHz, CDCl 3)δ170.20,154.05,143.50,143.00,142.50,138.00,137.60,133.40,129.30,128.70,128.50,127.90,127.60,120.00,116.50,95.00,90.00,83.20,80.00,70.00,68.50,68.20,48.50,45.90,43.50,30.00,29.50,20.68.

[0137] (S4) Preparation of the fourth compound

[0138] Dissolve the third compound (1 g, 1.07 mmol) prepared in step (S3) in a mixed solution of 2 mL of anhydrous methanol and anhydrous dichloromethane (MeOH:DCM = 1:1 (volume ratio)). At 0 °C, add 1.08 mL of trifluoroacetic acid dropwise and stir for 35 min. Then react at 25 °C for 7 h. After the reaction is completed, dilute the reaction solution with ethyl acetate, neutralize the reaction solution to pH = 8.3 with cold saturated sodium bicarbonate solution, then wash with saturated brine, dry with anhydrous sodium sulfate, and then separate the product by silica gel column chromatography to obtain 490 mg of a pale yellow powdery product, which is the fourth compound, with a yield of 52%.

[0139] The 1H NMR spectrum and 13C NMR spectrum of the fourth compound are as Figure 17 and Figure 18 shown.

[0140] The NMR data of the fourth compound are as follows:

[0141] 1 H NMR(400MHz,CDCl 3)δ8.43(d, J = 4.7 Hz, 2H), 7.25(d, J = 8.3 Hz, 2H), 7.14(dt, J = 13.5, 6.9 Hz, 3H), 6.99 - 6.93(m, 4H), 6.91 - 6.87(m, 4H), 6.83(dd, J = 11.3, 8.9 Hz, 4H), 6.46(s, 2H), 6.18(s, 1H), 5.81(dd, J = 9.3, 3.9 Hz, 2H), 5.76(dd, J = 3.4, 2.1 Hz, 2H), 5.26(t, J = 9.4 Hz, 2H), 5.12(d, J = 1.9 Hz, 4H), 4.23(dd, J = 12.6, 5.0 Hz, 2H), 4.04 - 3.96(m, 2H), 3.86 - 3.83(m, 2H), 3.51(s, 2H), 3.07(s, 2H), 2.44(s, 2H), 2.16(s, 6H), 2.04(s, 6H), 2.00(s, 6H), 1.98(s, 6H).

[0142] 13 C NMR(101 MHz, CDCl 3 )δ170.20, 143.50, 143.00, 142.50, 138.00, 137.60, 133.40, 129.30, 128.70, 128.50, 127.90, 127.60, 120.00, 116.50, 95.00, 90.00, 83.20, 70.00, 68.50, 68.20, 48.50, 47.90, 43.10, 31.90, 20.68.

[0143] (S5) Preparation of the Fifth Compound

[0144] Take 4 g (24.4 mmol) of norbornene dicarboxylic anhydride and dissolve it in 100 mL of anhydrous toluene. Add ethanolamine (1.6 mL, 26.8 mmol) and triethylamine (34 mL, 244 mmol) at 0 °C. After displacing nitrogen, stir for 30 min, and then react at 120 °C for 15 h. After the reaction is completed, evaporate the solvent under reduced pressure. Extract with dichloromethane and water, dry with anhydrous sodium sulfate, and concentrate to obtain the crude product. Dissolve the crude product in 4 mL of dichloromethane and slowly drip it into 150 mL of petroleum ether to precipitate. Stir for 1 h, filter, and wash three times with a mixed solution of dichloromethane and petroleum ether (dichloromethane:petroleum ether = 1:100 (volume ratio)) to prepare the fifth compound.

[0145] (S6) Preparation of the Sixth Compound

[0146] Dissolve the fifth compound (3 g, 14.48 mmol) prepared in step (S5) in 40 mL of anhydrous dichloromethane. Add pyridine (5 mL, 43.44 mmol) at 0 °C, and then dropwise add p-toluenesulfonyl chloride (1.5 mL, 16.0 mmol). React at 0 °C for 5 h. After the reaction is completed, dilute the reaction solution with dichloromethane, wash it three times successively with cold saturated sodium bicarbonate solution and saturated brine, dry it over anhydrous sodium sulfate, and concentrate to obtain the sixth compound.

[0147] (S7) Preparation of the seventh compound

[0148] Place the fourth compound (350 mg, 0.298 mmol) prepared in step (S4) and the sixth compound (230 mg, 0.828 mmol) prepared in step (S6) in a 5 mL microwave tube, dissolve them in 1 mL of ultradry acetonitrile, then add ultradry triethylamine (0.29 mL, 2.2 mmol). After displacing nitrogen three times, react at 110 °C for 20 h. After the reaction is completed, spin-dry the solvent and separate the product by silica gel column chromatography to obtain 180 mg of a yellow powdery product, which is the seventh compound, with a yield of 47%.

[0149] The 1H NMR spectrum and 13C NMR spectrum of the seventh compound are as Figure 19 and Figure 20 shown.

[0150] The NMR data of the seventh compound are as follows:

[0151] 1 H NMR (400 MHz, CDCl 3)δ 7.81 (d, J = 14.6 Hz, 2H), 7.11 (dd, J = 10.2, 7.8 Hz, 6H), 7.01 (dd, J = 7.4, 1.8 Hz, 2H), 6.95 (dd, J = 12.0, 8.5 Hz, 7H), 6.71 (t, J = 8.4 Hz, 5H), 6.26 (s, 2H), 6.01 (d, J = 3.7 Hz, 2H), 5.98 - 5.95 (m, 2H), 5.92 (ddd, J = 8.8, 3.6, 1.8 Hz, 2H), 5.39 (t, J = 8.9 Hz, 2H), 5.30 (s, 1H), 5.16 (d, J = 2.0 Hz, 5H), 4.42 - 4.32 (m, 2H), 4.06 (dd, J = 12.5, 1.9 Hz, 2H), 3.92 (dd, J = 6.8, 4.1 Hz, 2H), 3.67 (t, J = 6.3 Hz, 2H), 3.23 (s, 2H), 3.16 (s, 2H), 2.68 (d, J = 20.6 Hz, 6H), 2.42 (s, 2H), 2.19 (s, 6H), 2.08 (s, 6H), 2.07 (s, 6H), 2.06 (s, 6H), 1.51 (d, J = 9.7 Hz, 1H), 1.41 (d, J = 9.8 Hz, 1H).

[0152] 13 C NMR (101 MHz, CDCl 3 )δ 174.03, 170.20, 141.90, 140.00, 139.50, 139.00, 136.20, 134.30, 134.00, 129.00, 128.00, 127.00, 125.80, 123.30, 121.00, 116.50, 90.00, 82.40, 75.10, 74.20, 70.00, 69.10, 63.60, 54.30, 53.70, 49.60, 48.00, 46.30, 45.00, 30.69, 21.11, 20.68.

[0153] Lectins are a class of proteins that can specifically recognize and bind to carbohydrates. The interaction between polysaccharides and lectins is an important biomolecular recognition mechanism. Polysaccharides are composed of monosaccharides linked by glycosidic bonds, with high branching and structural diversity (such as linear, branched, cyclic), and may carry modification groups such as hydroxyl, carboxyl, and sulfate groups. Proteins form three-dimensional structures through the folding of amino acid sequences, and their surfaces may contain hydrophobic pockets, charged regions, or specific binding sites (such as the carbohydrate-binding domain of lectins). Because hydrogen bonds can form between the hydroxyl groups of sugars and the amino acid side chains of proteins. Based on hydrophobic interactions, some polysaccharides may have hydrophobic regions, and the hydrophobic residues of proteins may bind to them. In terms of electrostatic interactions, for example, the attraction between negatively charged sugars (such as sulfated polysaccharides) and positively charged protein regions. The recognition between polysaccharides and proteins is essentially the synergistic result of structural complementarity and multi-modal forces, and its specificity is jointly determined by the chemical modification, spatial conformation of the sugar chain, and the physicochemical properties of the protein binding site. However, the wide application of aggregation-induced emission (AIE) materials provides a new research perspective for this field. Although AIE probes can detect pH, temperature, and specific substances in various environments, they usually have excellent lipophilicity and certain biological toxicity, which limits their application in aqueous phases or in vivo. To overcome this defect, a sugar unit was combined with an AIE molecule by synthesizing a two-armed TPE derivative with mannose molecules and norbornene in the side chain, significantly improving the water solubility of the AIE molecule, reducing its biological toxicity, and improving its biocompatibility, providing a good basis for subsequent drug research.

[0154] The above embodiments are only two specific cases, but within the following condition ranges, a two-armed TPE derivative with mannose molecules and norbornene in the side chain can be prepared by a preparation method of a two-armed TPE derivative with mannose molecules and norbornene in the side chain of the present invention, and only the product yield has a slight difference;

[0155] The specific condition ranges are as follows:

[0156] 1) In step (S1), the molar ratio of 4,4'-dibromobenzophenone to benzophenone is 1:1.2 - 1.3; during the McMurry reaction, the temperature is 0°C - 90°C, and the time is 16h - 20h;

[0157] 2) In step (S2), the molar ratio of N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester to the first compound is 1 - 1.2:1; during the Suzuki coupling reaction, the temperature is 105°C - 120°C, and the time is 16h - 24h;

[0158] 3) In step (S3), the molar ratio of the mannose derivative to the second compound is 1-2:1; during the reaction process, the temperature is 80°C - 120°C, and the time is 16 h - 36 h.

[0159] 4) In step (S4), the dosage ratio of trifluoroacetic acid to the third compound is 2-4 mL:1.02 mmol; during the substitution reaction process, the temperature is 0°C - 25°C, and the time is 5 h - 8 h.

[0160] 5) In step (S5), the molar ratio of norbornene dianhydride to ethanolamine is 1:1.1 - 1.3; during the substitution reaction process, the temperature is 120°C - 125°C, and the time is 15 h - 20 h.

[0161] 6) In step (S6), the molar ratio of p-toluenesulfonyl chloride to the fifth compound is 0.9 - 1.1:1; during the substitution reaction process, the temperature is 15°C - 25°C, and the time is 20 h - 24 h.

[0162] 7) In step (S7), the molar ratio of triethylamine, the fourth compound to the sixth compound is 4.5 - 8.5:1:2 - 3.5; during the substitution reaction process, the temperature is 100°C - 105°C, and the time is 16 h - 20 h.

[0163] The above description of the embodiments is for the convenience of those of ordinary skill in the art to understand and use the invention. It is obvious that those skilled in the art can easily make various modifications to these embodiments and apply the general principles described herein to other embodiments without creative efforts. Therefore, the present invention is not limited to the above embodiments, and the improvements and modifications made by those skilled in the art without departing from the scope of the present invention should be within the protection scope of the present invention.

Claims

1. A double-arm TPE derivative containing mannose molecules and norbornene in the side chain, characterized in that: Its chemical structure is shown in formula (VIII-1) or formula (VIII-2):

2. A method for preparing a double-arm TPE derivative having a side chain containing mannose molecules and norbornene as claimed in claim 1, characterized in that: The following steps are involved: (S1) mixing 4,4'-dibromophenyl ketone and benzophenone, performing a McMurry reaction, and post-treating to obtain a first compound (using the McMurry reaction to construct a TPE core); (S2) mixing N-Boc-1,2,5,6-tetrahydropyridine-4-boric acid pinacol ester with the first compound prepared in step (S1), performing a Suzuki coupling reaction, and post-treating to obtain a second compound; (S3) mixing the mannose derivative and the second compound prepared in step (S2) and reacting them, followed by post-treatment to obtain a third compound; (S4) mixing trifluoroacetic acid and the third compound prepared in step (S3) and performing a substitution reaction, followed by post-treatment to obtain a fourth compound; (S5) mixing nadic anhydride and ethanolamine, performing a substitution reaction, and post-treating to obtain a fifth compound; (S6) mixing p-toluenesulfonyl chloride and the fifth compound prepared in step (S5), performing a substitution reaction, and post-treating to obtain a sixth compound; (S7) mixing triethylamine, the fourth compound prepared in step (S4) and the sixth compound prepared in step (S6), and performing a substitution reaction, followed by post-treatment to obtain a two-arm TPE derivative having a mannose molecule and norbornene on the side chain; Wherein, the chemical structural formula of the first compound is as shown in formula (I); the chemical structural formula of the second compound is as shown in formula (II); the chemical structural formula of the fifth compound is as shown in formula (VI); the chemical structural formula of the sixth compound is as shown in formula (VII); the chemical structural formula of the mannose derivative is as shown in formula (III-1) or formula (III-2); when the chemical structural formula of the mannose derivative is as shown in formula (III-1), the chemical structural formula of the third compound is as shown in formula (IV-1), the chemical structural formula of the fourth compound is as shown in formula (V-1), and the chemical structural formula of the seventh compound is as shown in formula (VIII-1); when the chemical structural formula of the mannose derivative is as shown in formula (III-2), the chemical structural formula of the third compound is as shown in formula (IV-2), the chemical structural formula of the fourth compound is as shown in formula (V-2), and the chemical structural formula of the seventh compound is as shown in formula (VIII-2); 3. The method for preparing a double-arm TPE derivative having a side chain containing mannose molecules and norbornene according to claim 2, characterized in that: In step (S1), the molar ratio of 4,4'-dibromophenyl ketone to benzophenone is 1:1.2-1.3; During the McMurry reaction, the temperature is 0°C to 90°C and the time is 16h to 20h.

4. The method for preparing a double-arm TPE derivative having a side chain containing mannose molecules and norbornene according to claim 2, characterized in that: In step (S2), the molar ratio of N-Boc-1,2,5,6-tetrahydropyridine-4-boric acid pinacol ester to the first compound is 1 to 1.2:1; During the Suzuki coupling reaction, the temperature is 105°C to 120°C and the time is 16h to 24h.

5. The method for preparing a double-arm TPE derivative having a side chain containing mannose molecules and norbornene according to claim 2, characterized in that: In step (S3), the molar ratio of the mannose derivative to the second compound is 1 to 2:1; During the reaction, the temperature is 80°C to 120°C and the reaction time is 16h to 36h.

6. The method for preparing a double-arm TPE derivative having a side chain containing mannose molecules and norbornene according to claim 2, characterized in that: In step (S4), the ratio of trifluoroacetic acid to the third compound is 2-4 mL: 1.02 mmol; During the substitution reaction, the temperature is 0°C to 25°C and the time is 5h to 8h.

7. The method for preparing a double-arm TPE derivative having a side chain containing mannose molecules and norbornene according to claim 2, characterized in that: In step (S5), the molar ratio of nadic anhydride to ethanolamine is 1:1.1-1.3; During the substitution reaction, the temperature is 120°C to 125°C and the time is 15h to 20h.

8. The method for preparing a double-arm TPE derivative having a side chain containing mannose molecules and norbornene according to claim 2, characterized in that: In step (S6), the molar ratio of p-toluenesulfonyl chloride to the fifth compound is 0.9 to 1.1:1; During the substitution reaction, the temperature is 15°C to 25°C and the time is 20h to 24h.

9. The method for preparing a double-arm TPE derivative having a side chain containing mannose molecules and norbornene according to claim 2, characterized in that: In step (S7), the molar ratio of triethylamine, the fourth compound and the sixth compound is 4.5-8.5:1:2-3.5; During the substitution reaction, the temperature is 100°C to 105°C and the time is 16h to 20h.

10. Use of the double-arm TPE derivative containing mannose molecules and norbornene on the side chains as claimed in claim 1 in a drug delivery system.

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