A tolonidine derivative, its preparation method and antibacterial application

Abstract

The application discloses a peachwood phenol derivative, a preparation method and antibacterial application thereof. The peachwood phenol derivative is prepared by chemically modifying the para-phenolic hydroxyl group of peachwood phenol. Compared with the peachwood phenol, the peachwood phenol derivative has improved water solubility and antibacterial activity, can enhance the chemical stability, has good water solubility, and has better antibacterial effect, and the minimum inhibitory concentration (MIC) is significantly lower than that of the peachwood phenol, and can be used for preparing more antibacterial products. Meanwhile, the peachwood phenol derivative is simple and fast in synthesis and preparation, high in yield, safe in operation, suitable for large-scale production and preparation, and provides more effective methods and products for replacing the peachwood phenol raw material.

Description

Technical Field

[0001] This invention relates to the fields of compound synthesis and biomedicine, and more specifically, to a tocopherol derivative, its preparation method, and its antibacterial applications. Background Technology

[0002] With the widespread use and overuse of antibiotics, bacterial resistance has evolved into a global public health crisis. Traditional antibiotics (such as β-lactams and quinolones) primarily exert their effects by inhibiting specific targets such as bacterial cell wall synthesis, protein synthesis, or nucleic acid replication. However, bacteria can easily modify or bypass these targets through gene mutations or the acquisition of resistance genes, leading to the emergence of multidrug-resistant bacteria and even "superbugs." Therefore, developing antibacterial agents with novel mechanisms of action is an urgent strategic need to overcome existing resistance and ensure the effectiveness of future anti-infective treatments.

[0003] Antimicrobial peptides are a class of natural defense molecules produced by the organism's innate immune system. Their core mechanism of action involves targeting negatively charged bacterial cell membranes through electrostatic interactions, disrupting membrane integrity, leading to leakage of cell contents and bacterial death. However, the development of natural antimicrobial peptides as drugs faces significant limitations: high production costs, susceptibility to protease hydrolysis in vivo, potential cytotoxicity, and low oral bioavailability. These drawbacks severely restrict their direct clinical application.

[0004] Pine is a natural diterpenoid compound isolated from plants of the Podocarpus genus. Its core antibacterial mechanism lies in targeting and destroying the bacterial cell membrane, significantly reducing membrane fluidity, and ultimately causing membrane perforation and leakage of contents, thereby rapidly killing bacteria. This physical "membrane destruction" mechanism is highly similar to the mechanism of action of antimicrobial peptides. It does not rely on traditional specific enzymes or receptor targets, so it is not easy to induce bacterial resistance, providing a new idea for solving the increasingly serious problem of antibiotic resistance. However, as a natural product, pine has the following inherent defects that seriously hinder its direct development into drugs or other products: (1) Extremely poor water solubility: Pine is a highly lipophilic crystal that is almost insoluble in water. This results in extremely low oral bioavailability, making it difficult to make into injections and limiting its distribution in the body, which greatly affects its drug-like properties. (2) Chemical stability and metabolic problems: Phenolic hydroxyl groups are easily oxidized in the air, affecting its activity and preservation. (3) Source and cost problems: It is mainly extracted from plants, with low content and complex extraction process, resulting in high cost and difficulty in large-scale production. Although the chemical total synthesis route has been established, the steps are cumbersome, the overall yield is not high, and the economic efficiency is still not ideal.

[0005] Existing research has focused on designing novel taurine derivatives (antimicrobial peptide mimics) based on their membrane disruption mechanisms through structural modification, aiming to develop antimicrobial drug candidates with higher activity and better drug-like properties. For example, chemical stability can be improved by preparing them as prodrugs such as sodium phosphate salts, water solubility can be enhanced through chemical modification of the phenolic hydroxyl groups, and water solubility can be further improved by introducing polar groups (amino, amide, sulfonic acid, glycosyl, etc.). Therefore, it is necessary to develop more taurine derivatives and their products for the preparation and research of antimicrobial drugs. This invention application is thus filed. Summary of the Invention

[0006] The technical problem to be solved by the present invention is to overcome the problems of poor water solubility and insufficient antibacterial activity of existing pyrrolidine. The present invention provides a pyrrolidine derivative, its preparation method and antibacterial application.

[0007] The first objective of this invention is to provide a taurine derivative or its hydrochloride salt.

[0008] A second objective of this invention is to provide a method for preparing taurine derivatives or their hydrochlorides.

[0009] A third objective of this invention is to provide applications of taurine derivatives or their hydrochlorides.

[0010] The above-mentioned objective of this invention is achieved through the following technical solution: This invention provides a pyruvic acid derivative or its hydrochloride salt, wherein the pyruvic acid derivative is a compound of formula (I) and its salt:

[0011] Equation (I) R1 is selected from one of C1~C6 alkylamino and aromatic heterocyclic amino groups; n=3~12; Or the taurine derivative is a compound of formula (II):

[0012] Formula (II) Where R2 is selected from one of C1~C4 alkylammonium, C1~C4 alkylphosphine-onium, and arylphosphonium; n=3~12; X - It is selected from one of the following: halide ions, trifluoromethanesulfonate ions, and nitrate ions.

[0013] The phenol derivative prepared by this invention exhibits better water solubility and antibacterial effect compared to phenol. Its minimum inhibitory concentration (MIC) is significantly lower than that of phenol, and it shows better antibacterial effects against Staphylococcus aureus, Bacillus subtilis, and Candida albicans, enabling the preparation of a wider range of antibacterial products. Furthermore, the phenol derivative provided by this invention can enhance its chemical stability through chemical modification of the phenolic hydroxyl groups. Its synthesis is simple, rapid, has a high yield, and is safe to operate, making it suitable for large-scale production.

[0014] Preferably, in the structural formula of the taurine derivative, X - Selected from iodide ions, bromide ions, and trifluoromethanesulfonate ions.

[0015] Preferably, the taurine derivative is a pharmaceutically acceptable salt of the compound shown in formula (I).

[0016] Preferably, the taurine derivative is selected from any one of the following compounds: .

[0017] More preferably, the taurine derivative is selected from any one of the following compounds: .

[0018] More preferably, the taurine derivative is selected from any one of the following compounds: .

[0019] More preferably, the taurine derivative is selected from any one of the following compounds: .

[0020] This invention provides a method for preparing a pine phenol derivative, comprising the following steps: S1. Preparation of pyrrolidine derivatives: Peach pyrrolidine compounds are dissolved in an organic solvent, and secondary amine compounds, thiomorpholine, or bis(2-pyridinemethyl)amine are added under an inert atmosphere. The mixture is stirred at 30℃-70℃ for 5-10 hours. After the reaction is completed, the reaction is quenched, extracted, the organic layers are combined, dried and filtered, the solvent is evaporated under reduced pressure, and purified to obtain pyrrolidine derivatives 1-9, 18. The secondary amine compound is selected from one of dimethylamine, dibutylamine, and diethylamine; The pyrrolidine compound is selected from one of the following structural formulas: .

[0021] Preferably, the method for preparing the hydrochloride salt of the taurine derivative is as follows: dissolve the product obtained in step S1 in ethyl acetate, slowly add 2 N hydrochloric acid solution dropwise until the solid precipitate is completely collected by filtration.

[0022] Or S2. Preparation of pyrrolidine derivatives: Pyrrolidine compounds are dissolved in an organic solvent, and triphenylphosphine or tributylphosphine is added under an inert atmosphere. The reaction is carried out at 60 ℃-90 ℃. After the reaction is completed, the solvent is removed, and the product is extracted, dried, and concentrated under reduced pressure to obtain pyrrolidine derivatives 16-17 and 19-26. The pyrrolidine compound is selected from one of the following structural formulas: .

[0023] Or S3. Preparation of pyrrolidine derivatives: Dissolve pyrrolidine compounds in an organic solvent, add iodomethane or MeOTf, stir and react at room temperature. After the reaction is complete, remove the organic solvent, extract, dry and filter to obtain pyrrolidine derivatives 10-15. The pyrrolidine compound is selected from one of the following structural formulas: .

[0024] Preferably, in step S1, the molar ratio of the taurine compound to the secondary amine compound, thiomorpholine, or bis(2-pyridinemethyl)amine is 1:(3-8).

[0025] More preferably, in step S1, the molar ratio of the taurine compound to the secondary amine compound, thiomorpholine, or bis(2-pyridinemethyl)amine is 1:6.

[0026] Preferably, in step S2, the molar ratio of the taurine compound to triphenylphosphine or tributylphosphine is 1:(1.5-3).

[0027] More preferably, in step S2, the molar ratio of the taurine compound to triphenylphosphine or tributylphosphine is 1:2.

[0028] Preferably, in step S3, the molar ratio of the taurine compound to iodomethane or MeOTf is 1:(70-120).

[0029] More preferably, in step S3, the molar ratio of the taurine compound to iodomethane or MeOTf is 1:95.

[0030] Furthermore, the present invention provides steps for preparing the above-mentioned pyrrolidine compound: S11. Preparation of intermediate products: Porphyrin was dissolved in acetonitrile, and then added to a solution of 1,3-dibromopropane under an inert atmosphere. The reaction was carried out at 50-80 °C. After the reaction was completed, the reaction was quenched, extracted, and the organic layers were combined, dried, filtered, and the solvent was evaporated under reduced pressure. Chromatographic separation was then performed to obtain porphyrin compound S1. Based on the substitution of the α,ω-dibromoalkane chain length, porphyrin compounds S1-S6 were obtained, with the following structural formulas: .

[0031] Or S12. Preparation of intermediate products: Dissolve taurine compound S1 or S2 in N,N-dimethylformamide, add diethylamine, di-n-butylamine, or dimethylamine under an inert atmosphere, and react at 50 °C. After the reaction is completed, quench the reaction, extract, combine the organic layers, wash, dry and filter, evaporate the solvent under reduced pressure, and purify to obtain taurine compounds S7-S10, with the following structural formulas: .

[0032] Preferably, the organic solvent is selected from N,N-dimethylformamide and anhydrous acetonitrile.

[0033] Preferably, in step S1, the molar ratio of taurine to 1,3-dibromopropane is 1:(1-3).

[0034] This invention provides the application of the above-mentioned taurine derivative in the preparation of antibacterial products.

[0035] Preferably, the bacteria inhibited by the antibacterial product are Escherichia coli, Staphylococcus aureus, Bacillus subtilis, and Candida albicans.

[0036] In particular, the pyrrolidine derivatives provided by this invention for in vitro inhibition of pathogens have a lower minimum inhibitory concentration (MIC) and can be used to prepare more antibacterial products.

[0037] The present invention also provides an antibacterial product containing the above-mentioned taurine derivative.

[0038] The present invention has the following beneficial effects: This invention provides a phenol derivative obtained through chemical synthesis. Compared to phenol, this derivative exhibits improved water solubility and antibacterial activity. Chemical modification of the phenolic hydroxyl groups enhances its chemical stability, resulting in good water solubility and superior antibacterial effects. Its minimum inhibitory concentration (MIC) is significantly lower than that of phenol, enabling the preparation of a wider range of antibacterial products. Furthermore, the synthesis of this phenol derivative is simple, rapid, and yield-efficient, with safe operation, making it suitable for large-scale production and providing more effective methods and products to replace phenol as a raw material. Attached Figure Description

[0039] Figure 1 For the toxicity test of taurine.

[0040] Figure 2 Toxicity test of 5-pyrrolidine derivative.

[0041] Figure 3 Toxicity test of 11-tocopherol derivative.

[0042] Figure 4 Toxicity test of 17-tocopherol derivative.

[0043] Figure 5 Toxicity test of 19-tocopherol derivative. Detailed Implementation

[0044] The present invention will be further described below with reference to the accompanying drawings and specific embodiments, but the embodiments do not limit the present invention in any way. Unless otherwise specified, the reagents, methods and equipment used in the present invention are conventional reagents, methods and equipment in this technical field.

[0045] Unless otherwise specified, all reagents and materials used in the following examples are commercially available.

[0046] Example 1 Synthesis of precursors (1) Synthesis of intermediate S1: Tocopherol (200 mg, 0.7 mmol) was placed in a 50 mL round-bottom flask, and 6 mL of acetonitrile was added and stirred to dissolve. Sodium hydride (25 mg, 1.05 mmol) was added under ice bath and stirred for 30 min. Under nitrogen atmosphere, the reaction solution was slowly added dropwise to a solution of 1,3-dibromopropane (709 uL, 8 mmol) in 10 mL of acetonitrile. The reaction system was stirred at 60 °C. When the reaction was completed by TLC monitoring, 10 mL of ice water was added to quench the reaction. The aqueous layer was extracted with ethyl acetate (5 mL × 3), the organic layers were combined, anhydrous sodium sulfate was added to dry the organic layer, filtered, the solvent was evaporated under reduced pressure, and 132.6 mg of intermediate S1 (white solid, yield 46.6%) was obtained by silica gel column chromatography.

[0047] The synthetic route is as follows: .

[0048] (2) Synthesis of intermediate S2: Tocopherol (200 mg, 0.7 mmol) was placed in a 50 mL round-bottom flask, and 6 mL of acetonitrile was added and stirred to dissolve. Sodium hydride (25 mg, 1.05 mmol) was added under ice bath and stirred for 30 min. Under nitrogen atmosphere, the reaction solution was slowly added dropwise to a solution of 1,4-dibromobutane (955 uL, 8 mmol) in 10 mL of acetonitrile. The reaction system was stirred at 60 °C. When the reaction was completed by TLC monitoring, 10 mL of ice water was added to quench the reaction. The aqueous layer was extracted with ethyl acetate (5 mL × 3), the organic layers were combined, anhydrous sodium sulfate was added to dry the organic layer, filtered, the solvent was evaporated under reduced pressure, and the intermediate S2 (white solid, yield 83.3%) was obtained by silica gel column chromatography.

[0049] The synthetic route is as follows: .

[0050] (3) Synthesis of intermediate S3: 200 mg (0.7 mmol) of tocopherol was placed in a 50 mL round-bottom flask, and 6 mL of acetonitrile was added and stirred to dissolve. Sodium hydride (25 mg, 1.05 mmol) was added under ice bath conditions and stirred for 30 min. Under nitrogen atmosphere, the reaction mixture was slowly added dropwise to a solution of 1,6-dibromohexane (1.077 mL, 8 mmol) in 10 mL of acetonitrile. The reaction system was stirred at 60 °C. After TLC monitoring, the reaction was quenched with 10 mL of ice water. The aqueous layer was extracted with ethyl acetate (5 mL × 3), the organic layers were combined, and anhydrous sodium sulfate was added to dry the organic layer. The mixture was filtered, the solvent was evaporated under reduced pressure, and the product was separated by silica gel column chromatography to obtain 178.4 mg of intermediate S3 (white solid, yield 56.7%).

[0051] The synthetic route is as follows: .

[0052] (4) Synthesis of intermediate S4: 200 mg (0.7 mmol) of tocopherol was placed in a 50 mL round-bottom flask, and 6 mL of acetonitrile was added and stirred to dissolve. Sodium hydride (25 mg, 1.05 mmol) was added under ice bath conditions and stirred for 30 min. Under nitrogen atmosphere, the reaction mixture was slowly added dropwise to a solution of 1,8-dibromooctane (1.289 mL, 8 mmol) in 10 mL of acetonitrile. The reaction system was stirred at 60 °C. After TLC monitoring, the reaction was quenched with 10 mL of ice water. The aqueous layer was extracted with ethyl acetate (5 mL × 3), the organic layers were combined, and anhydrous sodium sulfate was added to dry the organic layer. The mixture was filtered, the solvent was evaporated under reduced pressure, and the product was separated by silica gel column chromatography to obtain 208.3 mg of intermediate S4 (white solid, yield 62.3%).

[0053] The synthetic route is as follows: .

[0054] (5) Synthesis of intermediate S5: 200 mg (0.7 mmol) of tocopherol was placed in a 50 mL round-bottom flask, and 6 mL of acetonitrile was added and stirred to dissolve. Sodium hydride (25 mg, 1.05 mmol) was added under ice bath conditions and stirred for 30 min. Under nitrogen atmosphere, the reaction mixture was slowly added dropwise to a solution of 1,10-dibromodecane (1.573 mL, 8 mmol) in 10 mL of acetonitrile. The reaction system was stirred at 60 °C. After TLC monitoring, the reaction was quenched with 10 mL of ice water. The aqueous layer was extracted with ethyl acetate (5 mL × 3), the organic layers were combined, and anhydrous sodium sulfate was added to dry the organic layer. The mixture was filtered, the solvent was evaporated under reduced pressure, and the product was separated by silica gel column chromatography to obtain 241.4 mg of intermediate S5 (white solid, yield 68.2%).

[0055] The synthetic route is as follows: .

[0056] (6) Synthesis of intermediate S6: 200 mg (0.7 mmol) of tocopherol was placed in a 50 mL round-bottom flask, and 6 mL of acetonitrile was added and stirred to dissolve. Sodium hydride (25 mg, 1.05 mmol) was added under ice bath conditions and stirred for 30 min. Under nitrogen atmosphere, the reaction mixture was slowly added dropwise to a solution of 1,12-dibromododecane (2.02 mL, 8 mmol) in 10 mL of acetonitrile. The reaction system was stirred at 60 °C. After TLC monitoring, the reaction was quenched with 10 mL of ice water. The aqueous layer was extracted with ethyl acetate (5 mL × 3), the organic layers were combined, and anhydrous sodium sulfate was added to dry the organic layer. The mixture was filtered, the solvent was evaporated under reduced pressure, and the product was separated by silica gel column chromatography to obtain 196.1 mg of intermediate S6 (white solid, yield 52.5%).

[0057] The synthetic route is as follows: .

[0058] (7) Synthesis of intermediate S7: S2 (377.8 mg, 0.89 mmol) was placed in a dry 25 mL round-bottom flask, and 10 mL of N,N-dimethylformamide was added. Under nitrogen atmosphere, diethylamine (1 mL) was added to the reaction system. The mixture was heated to 50 °C and stirred for 24 hours. After the reaction was completed, 10 mL of water was added to quench the reaction, and the aqueous layer was extracted with ethyl acetate (10 mL × 3). The organic phases were combined and washed once with saturated sodium bicarbonate aqueous solution (10 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. 274.7 mg of intermediate S7 (pale yellow oil, yield 72%) was obtained by silica gel column chromatography.

[0059] The synthetic route is as follows: .

[0060] (8) Synthesis of intermediate S8: S2 (336 mg, 0.79 mmol) was placed in a dry 25 mL round-bottom flask, and 10 mL of N,N-dimethylformamide was added. Under nitrogen atmosphere, di-n-butylamine (1 mL) was added to the reaction system. The mixture was heated to 50 °C and stirred for 24 hours. After the reaction was completed, 10 mL of water was added to quench the reaction, and the aqueous layer was extracted with ethyl acetate (10 mL × 3). The organic phases were combined and washed once with saturated sodium bicarbonate aqueous solution (10 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. 264 mg of intermediate S8 (pale yellow oil, yield 68%) was obtained by silica gel column chromatography.

[0061] The synthetic route is as follows: .

[0062] (9) Synthesis of intermediate S9: S1 (96.6 mg, 0.24 mmol) was placed in a dry 25 mL round-bottom flask, and 10 mL of N,N-dimethylformamide was added. Under nitrogen atmosphere, dimethylamine (1 mL) was added to the reaction system. The mixture was heated to 50 °C and stirred for 24 hours. After the reaction was completed, 10 mL of water was added to quench the reaction, and the aqueous layer was extracted with ethyl acetate (10 mL × 3). The organic phases were combined and washed once with saturated sodium bicarbonate aqueous solution (10 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. 62.8 mg of intermediate S9 (pale yellow oil, yield 72%) was obtained by silica gel column chromatography.

[0063] The synthetic route is as follows: .

[0064] (10) Synthesis of intermediate S10: S1 (134 mg, 0.33 mmol) was placed in a dry 25 mL round-bottom flask, and 10 mL of N,N-dimethylformamide was added. Under nitrogen atmosphere, di-n-butylamine (1 mL) was added to the reaction system. The mixture was heated to 50 °C and stirred for 24 hours. After the reaction was completed, 10 mL of water was added to quench the reaction, and the aqueous layer was extracted with ethyl acetate (10 mL × 3). The organic phases were combined and washed once with saturated sodium bicarbonate aqueous solution (10 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. 127 mg of intermediate S10 (pale yellow oil, yield 85.1%) was obtained by silica gel column chromatography.

[0065] The synthetic route is as follows: .

[0066] Example 2 Preparation of pyrrolidine derivatives (1) Synthesis of Product 1: S3 (50 mg, 0.11 mmol) was placed in a dry 25 mL round-bottom flask, and 2 mL of N,N-dimethylformamide was added. Under nitrogen atmosphere, diethylamine (0.5 mL) was added to the reaction system, and the reaction system was stirred at 50 °C. The reaction was monitored by TLC. After the reaction was completed, 10 mL of water was added to quench the reaction, and the aqueous layer was extracted with ethyl acetate (10 mL × 3). The organic phases were combined and washed once with saturated sodium bicarbonate aqueous solution (10 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, the solvent was evaporated under reduced pressure, and purified by silica gel column chromatography. The obtained product was dissolved in 1 mL of ethyl acetate and 2 N hydrochloric acid solution was slowly added dropwise until the solid precipitate was completely collected. The solid was collected by filtration to give 47.9 mg of Product 1 (yellow solid, yield 91.3%).

[0067] Synthesis route: .

[0068] Peach phenol derivative 1 1 The H NMR characterization results are as follows: 1 H NMR (600 MHz, Chloroform-d) δ 7.11 – 7.02 (m, 1H), 6.68 (d, J =8.8 Hz, 1H), 3.97 – 3.85 (m, 2H), 3.26 (s, 1H), 2.94 (dd, J = 17.0, 6.6 Hz,1H), 2.83 – 2.70 (m, 4H), 2.64 (s, 2H), 2.24 (t, J = 10.9 Hz, 2H), 2.12 –2.02(m, J = 13.1, 6.5 Hz, 1H), 1.90 (dd, J = 13.3, 7.8 Hz, 1H), 1.94 –1.81 (m,2H), 1.67 – 1.61 (m, 4H), 1.53 –1.48 (m, 2H), 1.48 – 1.36 (m, 4H), 1.31 –1.28 (m, 5H), 1.20 – 1.16 (m, 6H), 0.94 (s, 3H), 0.91 (s, 3H).

[0069] (2) Synthesis of Product 2: S4 (383 mg, 0.8 mmol) was placed in a dry 50 mL round-bottom flask, and 10 mL of N,N-dimethylformamide was added. Under nitrogen atmosphere, diethylamine (1 mL) was added to the reaction system, and the reaction system was stirred at 50 °C. The reaction was monitored by TLC. After the reaction was completed, 10 mL of water was added to quench the reaction, and the aqueous layer was extracted with ethyl acetate (10 mL × 3). The organic phases were combined and washed once with saturated sodium bicarbonate aqueous solution (10 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, the solvent was evaporated under reduced pressure, and purified by silica gel column chromatography. The obtained product was dissolved in 4 mL of ethyl acetate and 2 N hydrochloric acid solution was slowly added dropwise until the solid precipitate was completely collected. The solid was collected by filtration to give 329 mg of product 2 (yellow solid, yield 81.3%).

[0070] Synthesis route: .

[0071] Peach phenol derivative 2 1 The H NMR characterization results are as follows: 1 H NMR (600 MHz, Chloroform-d)δ7.07 (d, J = 9.3 Hz, 1H), 6.69 (d, J =9.0 Hz, 1H), 3.93–3.88 (m, 2H), 2.95 (dd, J = 17.0, 6.8 Hz, 1H), 2.82–2.72(m, 1H), 2.54 –2.49 (m, 4H), 2.42 (t, J = 8.0 Hz, 2H), 2.25 (d, J = 12.6 Hz,1H), 1.97–1.88 (m, 2H), 1.79 –1.70 (m, 2H), 1.73 (dd, J = 13.8, 3.4 Hz, 1H),1.67 (dd, J = 12.4, 5.8 Hz, 1H), 1.63–1.56 (m, 1H), 1.47 – 1.42(m, 6H), 1.39–1.26 (m, 18H), 1.19 (d, J = 7.0 Hz, 5H), 1.03 (t, J = 7.2 Hz, 6H), 0.94 (s,3H), 0.92 (s, 4H).

[0072] (3) Synthesis of Product 3: S5 (230 mg, 0.45 mmol) was placed in a dry 50 mL round-bottom flask, and 10 mL of N,N-dimethylformamide was added. Under nitrogen atmosphere, diethylamine (1 mL) was added to the reaction system, and the reaction system was stirred at 50 °C. The reaction was monitored by TLC. After the reaction was completed, 10 mL of water was added to quench the reaction, and the aqueous layer was extracted with ethyl acetate (10 mL × 3). The organic phases were combined and washed once with saturated sodium bicarbonate aqueous solution (10 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, the solvent was evaporated under reduced pressure, and purified by silica gel column chromatography. The obtained product was dissolved in 4 mL of ethyl acetate and 2 N hydrochloric acid solution was slowly added dropwise until the solid precipitate was completely collected. The solid was collected by filtration to give 222.3 mg of product 3 (yellow solid, yield 92.5%).

[0073] Synthesis route: .

[0074] Peach phenol derivative 3 1 The H NMR characterization results are as follows: 1 H NMR (600 MHz, Chloroform-d)δ7.07 (d, J = 8.8 Hz, 1H), 6.69 (d, J =9.1 Hz, 1H), 3.90 –3.82 (m, 2H), 2.95 (dd, J = 17.0, 6.8 Hz, 1H), 2.79–2.56(m, 7H), 2.48 (t, J = 8.0 Hz, 2H), 2.25 (d, J = 12.8 Hz, 1H), 1.96–1.89 (m,1H), 1.85–1.57 (m, 6H), 1.48 –1.42 (m, 5H), 1.30 –1.24 (m, 27H), 1.19 (s,5H), 1.07–1.02 (m, 7H), 0.94 (s, 3H), 0.92 (s, 5H).

[0075] (4) Synthesis of Product 4: S1 (200 mg, 0.49 mmol) was placed in a dry 50 mL round-bottom flask, and 10 mL of N,N-dimethylformamide was added. Under nitrogen atmosphere, diethylamine (1 mL) was added to the reaction system, and the reaction system was stirred at 50 °C. The reaction was monitored by TLC. After the reaction was completed, 10 mL of water was added to quench the reaction, and the aqueous layer was extracted with ethyl acetate (10 mL × 3). The organic phases were combined and washed once with saturated sodium bicarbonate aqueous solution (10 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, the solvent was evaporated under reduced pressure, and 146.6 mg of product 4 (pale yellow oil, yield 92.5%) was obtained by silica gel column chromatography.

[0076] Synthesis route: .

[0077] Peach phenol derivative 4 1 The H NMR characterization results are as follows: 1 H NMR (600 MHz, Chloroform-d) δ 7.08 (d, J = 8.8 Hz, 1H), 6.68 (d, J= 8.7 Hz, 1H), 4.05 – 3.96 (m, 2H), 3.01 – 2.69 (m, 9H), 2.24 (d, J = 12.9Hz, 1H), 2.15 –2.08 (m, 2H), 2.05 – 1.87 (m, 1H), 1.66 (m, 3H), 1.46 (d, J =13.3 Hz, 1H), 1.41 – 1.11 (m, 25H), 1.02 – 0.94 (m, 3H), 0.92 – 0.81 (m,5H).

[0078] (5) Synthesis of Product 5: S2 (200 mg, 0.47 mmol) was placed in a dry 50 mL round-bottom flask, and 10 mL of N,N-dimethylformamide was added. Under nitrogen atmosphere, dimethylamine (1 mL) was added to the reaction system, and the reaction system was stirred at 50 °C. The reaction was monitored by TLC. After the reaction was completed, 10 mL of water was added to quench the reaction, and the aqueous layer was extracted with ethyl acetate (10 mL × 3). The organic phases were combined and washed once with saturated sodium bicarbonate aqueous solution (10 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, the solvent was evaporated under reduced pressure, and purified by silica gel column chromatography. The obtained product was dissolved in 4 mL of ethyl acetate and 2 N hydrochloric acid solution was slowly added dropwise until the solid precipitate was completely collected. The solid was collected by filtration to give 121 mg of product 5 (yellow solid, yield 61%).

[0079] Synthesis route: .

[0080] Peach phenol derivative 5 1 The H NMR characterization results are as follows: 1 H NMR (600 MHz, Chloroform-d) δ 7.07 (d, J = 8.7 Hz, 1H), 6.69 (d, J= 8.7 Hz, 1H), 3.93 (t, J = 5.3 Hz, 2H), 2.94 (dd, J = 16.9, 6.7 Hz, 1H), 2.84 – 2.71 (m, 1H), 2.41 (t, J = 7.5 Hz, 2H), 2.29 (s, 6H), 2.22 –2.17 (m,1H), 1.95 – 1.87 (m, 3H), 1.83 –1.78 (m, 3H), 1.69 –1.62 (m, 4H), 1.62 – 1.54(m, 1H), 1.46 (d, J = 13.2 Hz, 1H), 1.39 – 1.28 (m, 8H), 1.26 (d, J = 10.8Hz, 4H), 1.18 (s, 4H), 0.94 (s, 3H), 0.91 (s, 3H).

[0081] (6) Synthesis of Product 6: S2 (200 mg, 0.47 mmol) was placed in a dry 50 mL round-bottom flask, and 10 mL of N,N-dimethylformamide was added. Under nitrogen atmosphere, dibutylamine (1 mL) was added to the reaction system, and the reaction system was stirred at 50 °C. The reaction was monitored by TLC. After the reaction was completed, 10 mL of water was added to quench the reaction, and the aqueous layer was extracted with ethyl acetate (10 mL × 3). The organic phases were combined and washed once with saturated sodium bicarbonate aqueous solution (10 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, the solvent was evaporated under reduced pressure, and 153.8 mg of product 6 (pale yellow oil, yield 69%) was obtained by silica gel column chromatography.

[0082] Synthesis route: .

[0083] Peach phenol derivative 6 1 The H NMR characterization results are as follows: 1H NMR (400 MHz, Chloroform-d) δ 7.08 (d, J = 8.8 Hz, 1H), 6.69 (d, J= 8.8 Hz, 1H), 3.93 (t, J = 6.2 Hz, 2H), 2.95 (dd, J = 17.1, 6.5 Hz, 1H), 2.82 – 2.56 (m, 1H), 2.49 –2.42 (m, 6H), 2.25 (d, J = 13.0 Hz, 1H), 1.91 (dd,J = 13.3, 7.9 Hz, 1H), 1.87 – 1.73 (m, 3H), 1.73 – 1.54 (m, 5H), 1.45-1.38(m, 5H), 1.37 (dd, J = 13.2, 4.2 Hz, 1H), 1.34 – 1.27 (m, 11H), 1.22 (d, J =28.5 Hz, 5H), 0.95 – 0.92 (m, 8H), 0.91 (d, J = 7.4 Hz, 4H).

[0084] (7) Synthesis of Product 7: S2 (150 mg, 0.36 mmol) was placed in a dry 50 mL round-bottom flask, and 10 mL of N,N-dimethylformamide was added. Thiomorpholine (1 mL) was added to the reaction system under nitrogen atmosphere, and the reaction system was stirred at 50 °C. The reaction was monitored by TLC. After the reaction was completed, 10 mL of water was added to quench the reaction, and the aqueous layer was extracted with ethyl acetate (10 mL × 3). The organic phases were combined and washed once with saturated sodium bicarbonate aqueous solution (10 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, the solvent was evaporated under reduced pressure, and purified by silica gel column chromatography. The obtained product was dissolved in 4 mL of ethyl acetate and 2 N hydrochloric acid solution was slowly added dropwise until the solid precipitate was completely collected. The solid was collected by filtration to give 124 mg of product 7 (yellow solid, yield 72.2%).

[0085] Synthesis route: .

[0086] Peach phenol derivative 7 1 The H NMR characterization results are as follows: 1H NMR (500 MHz, Chloroform-d) δ 7.08 (d, J = 8.8 Hz, 1H), 6.69 (d, J= 8.8 Hz, 1H), 3.93 –3.87 (m, 2H), 2.95 (dd, J = 17.0, 6.5 Hz, 1H), 2.81 –2.73 (m, 1H), 2.73 – 2.67 (m, 8H), 2.46 – 2.41 (m, 2H), 2.25 (dd, J = 12.7,1.5 Hz, 1H), 1.91 (dd, J = 13.3, 8.0 Hz, 1H), 1.85 – 1.76 (m, 2H), 1.74 (t, J= 3.4 Hz, 1H), 1.71 (dd, J = 7.6, 2.5 Hz, 1H), 1.70 – 1.63 (m, 2H), 1.63 –1.56 (m, 1H), 1.47 (dd, J = 13.1, 1.5 Hz, 1H), 1.37 (dd, J = 13.3, 3.7 Hz,1H), 1.34 – 1.30 (m, 5H), 1.30 – 1.25 (m, 3H), 1.24 – 1.18 (m, 4H), 0.95 (s,3H), 0.92 (s, 3H).

[0087] (8) Synthesis of Product 8: S2 (200 mg, 0.47 mmol) was placed in a dry 50 mL round-bottom flask, and 10 mL of N,N-dimethylformamide was added. Under nitrogen atmosphere, dibutylamine (1 mL) was added to the reaction system, and the reaction system was stirred at 50 °C. The reaction was monitored by TLC. After the reaction was completed, 10 mL of water was added to quench the reaction, and the aqueous layer was extracted with ethyl acetate (10 mL × 3). The organic phases were combined and washed once with saturated sodium bicarbonate aqueous solution (10 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, the solvent was evaporated under reduced pressure, and purified by silica gel column chromatography. The obtained product was dissolved in 4 mL of ethyl acetate and 2 N hydrochloric acid solution was slowly added dropwise until the solid precipitate was completely collected. The solid was collected by filtration to give 169.6 mg of product 8 (yellow solid, yield 71.3%).

[0088] Synthesis route: .

[0089] Peach phenol derivative 8 1 The H NMR characterization results are as follows: 1H NMR (600 MHz, Chloroform-d) δ 7.07 (d, J = 8.7 Hz, 1H), 6.69 (d, J= 8.7 Hz, 1H), 4.06 – 3.89 (m, 2H), 2.94 (dd, J = 17.1, 6.7 Hz, 1H), 2.83 –2.74 (m, 2H), 2.74 – 2.64 (m, 2H), 2.58 – 2.41 (m, 4H), 2.24 (d, J = 12.9 Hz,1H), 1.98 (d, J = 9.3 Hz, 2H), 1.90 (dd, J = 13.5, 7.7 Hz, 2H), 1.75 – 1.55(m, 4H), 1.52 – 1.43 (m, 5H), 1.37 (s, 3H), 1.31 (t, J = 8.3 Hz, 10H), 1.26(s, 2H), 1.18 (s, 3H), 0.93 (d, J = 8.1 Hz, 7H), 0.91 (s, 6H).

[0090] (9) Synthesis of Product 9: S2 (150 mg, 0.36 mmol) was placed in a dry 50 mL round-bottom flask, and 10 mL of N,N-dimethylformamide was added. Under nitrogen atmosphere, bis(2-pyridinemethyl)amine (1 mL) was added to the reaction system, and the reaction system was stirred at 50 °C. The reaction was monitored by TLC. After the reaction was completed, 10 mL of water was added to quench the reaction, and the aqueous layer was extracted with ethyl acetate (10 mL × 3). The organic phases were combined and washed once with saturated sodium bicarbonate aqueous solution (10 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, the solvent was evaporated under reduced pressure, and 140.4 mg of product 9 (pale yellow oil, yield 72.2%) was obtained by silica gel column chromatography.

[0091] Synthesis route: .

[0092] Peach phenol derivative 9 1 The H NMR characterization results are as follows: 1H NMR (600 MHz, Chloroform-d) δ 8.57 – 8.46 (m, 2H), 7.63 (td, J =7.7, 1.9 Hz, 2H), 7.54 (d, J = 7.8 Hz, 2H), 7.13 (dd, J = 7.6, 4.8 Hz, 2H),7.05 (d, J = 8.7 Hz, 1H), 6.62 (d, J = 8.7 Hz, 1H), 3.83 (s, 6H), 3.28 – 3.19(m, 1H), 2.93 (dd, J = 17.0, 6.7 Hz, 1H), 2.79 – 2.70 (m, 1H), 2.62 (t, J =6.8 Hz, 2H), 2.24 –2.19 (m, 2H), 1.90 (dd, J = 13.4, 7.8 Hz, 1H), 1.83 – 1.63(m, 7H), 1.59 –1.51 (m, 1H), 1.46–1.41 (m, 1H), 1.38 – 1.31 (m, 2H), 1.31 –1.26 (m, 6H), 1.26 (s, 4H), 1.18 (s, 4H), 0.94 (s, 3H), 0.91 (s, 3H).

[0093] (10) Synthesis of Product 10: Intermediate S7 (274.7 mg, 0.66 mmol) was placed in a dry 50 mL round-bottom flask, dissolved in 10 mL of anhydrous methanol, and iodomethane (1 mL) was slowly added dropwise under ice bath conditions. The reaction system was stirred at room temperature, and the reaction was monitored by TLC. After the reaction was completed, methanol was removed by rotary evaporation under reduced pressure, 10 mL of water was added, and the mixture was extracted with dichloromethane (10 mL × 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. Product 10 (brown solid, 90.2%) was obtained by silica gel column chromatography.

[0094] Synthesis route: .

[0095] Peach phenol derivative 10 1 The H NMR characterization results are as follows: 1H NMR (600 MHz, Chloroform-d) δ 7.19–6.95 (m, 1H), 6.78–6.47 (m,1H), 4.13–3.88 (m, 2H), 3.88–3.60 (m, 2H), 3.45 (s, 8H), 2.93 (dd, J = 17.5,6.2 Hz, 1H), 2.84–2.67 (m, 1H), 2.37–1.82 (m, 6H), 1.82–1.59 (m, 7H), 1.52–1.01 (m, 20H), 1.01–0.46 (m, 9H).

[0096] (11) Synthesis of Product 11: Product 5 (78.5 mg, 0.2 mmol) was placed in a dry 50 mL round-bottom flask, dissolved in 10 mL of anhydrous methanol, and iodomethane (1 mL) was slowly added dropwise under ice bath conditions. The reaction system was stirred at room temperature, and the reaction was monitored by TLC. After the reaction was completed, methanol was removed by rotary evaporation under reduced pressure, 10 mL of water was added, and the mixture was extracted with dichloromethane (10 mL × 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. 100 mg of product 11 (yellow solid, 93.8%) was obtained by silica gel column chromatography.

[0097] Synthesis route: .

[0098] Peach phenol derivative 11 1 The H NMR characterization results are as follows: 1 H NMR (600 MHz, Chloroform-d) δ 7.06 (d, J = 8.8 Hz, 1H), 6.69 (d, J= 8.8 Hz, 1H), 3.99 (t, J = 4.8 Hz, 2H), 3.73 – 3.45 (m, 6H), 3.25 (s, 5H),2.91 (dd, J = 17.1, 6.4 Hz, 1H), 2.80 – 2.62 (m, 1H), 2.22 (d, J = 12.8 Hz,1H), 2.08 – 1.85 (m, 6H), 1.79 (s, 2H), 1.74 – 1.51 (m, 4H), 1.51 – 1.36 (m, 9H), 1.26 (dd, J = 10.6, 7.0 Hz, 10H), 1.15 (s, 5H), 0.91 (d, J = 18.1 Hz, 7H).

[0099] (12) Synthesis of Product 12: Intermediate S8 (264 mg, 0.56 mmol) was placed in a dry 50 mL round-bottom flask, dissolved in 10 mL of anhydrous methanol, and iodomethane (1 mL) was slowly added dropwise under ice bath conditions. The reaction system was stirred at room temperature, and the reaction was monitored by TLC. After the reaction was completed, methanol was removed by rotary evaporation under reduced pressure, 10 mL of water was added, and the mixture was extracted with dichloromethane (10 mL × 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. Product 12 (brown solid, 49%) was obtained by silica gel column chromatography.

[0100] Synthesis route: .

[0101] Peach phenol derivative 12 1 The characterization results of H NMR are as follows: 1 H NMR (600 MHz, Chloroform-d) δ 7.07 (d, J = 8.7 Hz, 1H), 6.69 (d, J= 8.6 Hz, 1H), 4.24 – 3.80 (m, 2H), 3.80 – 3.55 (m, 2H), 3.55 – 3.39 (m, 4H),3.32 (s, 4H), 3.11 – 2.83 (m, 1H), 2.83 – 2.61 (m, 1H), 2.23 (d, J = 12.6 Hz,1H), 2.10 – 1.83 (m, 6H), 1.83 – 1.54 (m, 10H), 1.54 – 1.06 (m, 21H), 1.06 –0.71 (m, 14H).

[0102] (13) Synthesis of Product 13: Product 4 (40 mg, 0.1 mmol) was placed in a dry 50 mL round-bottom flask, dissolved in 10 mL of anhydrous methanol, and iodomethane (1 mL) was slowly added dropwise under ice bath conditions. The reaction system was stirred at room temperature, and the reaction was monitored by TLC. After the reaction was completed, methanol was removed by rotary evaporation under reduced pressure, 10 mL of water was added, and the mixture was extracted with dichloromethane (10 mL × 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. 39 mg of product 13 (yellow solid, 52%) was obtained by silica gel column chromatography.

[0103] Synthesis route: .

[0104] Peach phenol derivative 131 The H NMR characterization results are as follows: 1 H NMR (500 MHz, Chloroform-d) δ 7.08 (d, J = 8.8 Hz, 1H), 6.69 (d, J= 8.7 Hz, 1H), 4.24 – 3.98 (m, 2H), 3.67 (d, J = 8.9 Hz, 6H), 3.35 (d, J =20.1 Hz, 4H), 2.91 (dd, J = 17.2, 6.7 Hz, 1H), 2.73 –2.67 (m, J = 8.9 Hz,1H), 2.38 – 2.28 (m, 2H), 2.23 (d, J = 12.7 Hz, 1H), 1.90 (dd, J = 13.4, 7.6Hz, 1H), 1.73 (s, 5H), 1.67 – 1.54 (m, 2H), 1.44 –1.41 (m, 7H), 1.35 – 1.21(m, 9H), 1.17 (d, J = 13.6 Hz, 4H), 0.93 (s, 3H), 0.90 (s, 3H).

[0105] (14) Synthesis of Product 14: Intermediate S9 (62.8 mg, 0.17 mmol) was placed in a dry 50 mL round-bottom flask, dissolved in 10 mL of anhydrous methanol, and iodomethane (1 mL) was slowly added dropwise under ice bath conditions. The reaction system was stirred at room temperature, and the reaction was monitored by TLC. After the reaction was completed, methanol was removed by rotary evaporation under reduced pressure, 10 mL of water was added, and the mixture was extracted with dichloromethane (10 mL × 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. 39 mg of product 14 (brown oil, 42%) was obtained by silica gel column chromatography.

[0106] Synthesis route: .

[0107] Peach phenol derivative 14 1 The H NMR characterization results are as follows: 1H NMR (600 MHz, Chloroform-d) δ 7.12 – 7.06 (m, 1H), 6.68 (d, J =8.8 Hz, 1H), 4.10 –4.02 (m, 2H), 3.84 –3.79 (m, 2H), 3.51 (s, 10H), 3.19 –3.12 (m, 4H), 2.91 (dd, J = 17.1, 6.7 Hz, 1H), 2.73 –2.68 (m, 1H), 2.35 –2.29(m, 2H), 2.23 –2.19(m, 1H), 1.90 (dd, J = 13.4, 7.8 Hz, 1H), 1.80 – 1.70 (m,3H), 1.66 – 1.54 (m, 3H), 1.45 (t, J = 7.3 Hz, 6H), 1.36 (s, 2H), 1.27 –1.22(m, 17H), 1.16 (s, 4H), 0.93 (s, 3H), 0.90 (s, 4H).

[0108] (15) Synthesis of Product 15: Intermediate S10 (127 mg, 0.28 mmol) was placed in a dry 50 mL round-bottom flask, dissolved in 10 mL of anhydrous methanol, and MeOTf (1 mL) was slowly added dropwise under ice bath conditions. The reaction system was stirred at room temperature, and the reaction was monitored by TLC. After the reaction was completed, methanol was removed by rotary evaporation under reduced pressure, 10 mL of water was added, and the mixture was extracted with dichloromethane (10 mL × 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. Product 15 (brown oil, 64.4%) was obtained by silica gel column chromatography.

[0109] Synthesis route: .

[0110] Peach phenol derivative 15 1 The H NMR characterization results are as follows: 1H NMR (600 MHz, Chloroform-d) δ 7.09 (d, J = 8.7 Hz, 1H), 6.69 (d, J= 8.8 Hz, 1H), 4.25 – 3.97 (m, 4H), 3.74 –3.69 (m, 1H), 3.62 – 3.42 (m, 3H),3.38 – 3.10 (m, 16H), 2.93 (dd, J = 17.0, 6.7 Hz, 1H), 2.80 – 2.68 (m, 1H),2.56 (t, J = 7.7 Hz, 1H), 2.24 –2.19 (m, 3H), 2.07 (d, J = 27.8 Hz, 3H), 1.91(dd, J = 13.4, 7.9 Hz, 1H), 1.87 – 1.63 (m, 6H), 1.59 –1.52 (m, 1H), 1.44 –1.39 (m, 5H), 1.38 (t, J = 7.3 Hz, 4H), 1.27 –1.22 (m, 15H), 1.17 (s, 4H), 1.02-1.00 (m, 5H), 0.97 – 0.92 (m, 3H), 0.91 (s, 4H).

[0111] (16) Synthesis of product 16: S5 (202 mg, 0.4 mmol) and triphenylphosphine (209 mg, 0.8 mmol) were placed in a 50 mL round-bottom flask, and 30 mL of anhydrous acetonitrile was added and stirred to dissolve. The reaction system was heated to 85 °C under nitrogen and refluxed for 36 h. After the reaction was complete, the reaction solution was cooled to room temperature and concentrated under reduced pressure to remove the solvent. The solution was extracted with petroleum ether and methanol, the methanol layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 86.2 mg of product 16 (yellow oil, 34.9%).

[0112] Synthesis route: .

[0113] Peach phenol derivative 16 1 The H NMR characterization results are as follows: 1H NMR (500 MHz, Chloroform-d) δ 7.85 – 7.80 (m, 6H), 7.79 – 7.75 (m,3H), 7.69 –7.63 (m, 6H), 7.05 (d, J = 8.8 Hz, 1H), 6.67 (d, J = 8.8 Hz, 1H),3.86 –3.84 (m, 2H), 3.80 – 3.72 (m, 2H), 2.92 (dd, J = 17.0, 6.6 Hz, 1H),2.79 – 2.69 (m, 1H), 2.23 (d, J = 12.4 Hz, 1H), 1.89 (dd, J = 13.4, 8.3 Hz,2H), 1.78 – 1.54 (m, 10H), 1.47 – 1.38 (m, 4H), 1.34 (dd, J = 13.1, 3.8 Hz,1H), 1.29 (s, 2H), 1.27 (d, J = 7.7 Hz, 7H), 1.25 – 1.17 (m, 8H), 0.92 (s,3H), 0.89 (s,3H).

[0114] (17) Synthesis of product 17: S2 (168 mg, 0.4 mmol) and triphenylphosphine (209 mg, 0.8 mmol) were placed in a 50 mL round-bottom flask, and 30 mL of anhydrous acetonitrile was added and stirred to dissolve. The reaction system was heated to 85 °C under nitrogen and refluxed for 36 h. After the reaction was complete, the reaction solution was cooled to room temperature and concentrated under reduced pressure to remove the solvent. The solution was extracted with petroleum ether and methanol, the methanol layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 125.2 mg of product 17 (yellow oil, 46.2%).

[0115] Synthesis route: .

[0116] Peach phenol derivative 17 1 The H NMR characterization results are as follows: 1H NMR (500 MHz, Chloroform-d) δ 7.85 – 7.80 (m, 6H), 7.78 – 7.74 (m,3H), 7.65 –7.60 (m, 6H), 7.04 (d, J = 8.9 Hz, 1H), 6.66 (d, J = 8.8 Hz, 1H),4.00 – 3.91 (m, 4H), 2.86 (dd, J = 17.0, 6.6 Hz, 1H), 2.74 – 2.62 (m, 1H),2.21 (d, J = 12.4 Hz, 1H), 1.92 – 1.82 (m, 5H), 1.72 – 1.53 (m, 3H), 1.46 –1.41 (m, 2H), 1.34 – 1.13 (m, 7H), 1.03 (dd, J = 7.0, 4.5 Hz, 6H), 0.91 (s,3H), 0.89 (s, 3H).

[0117] (18) Synthesis of Product 18: S4 (76 mg, 0.16 mmol) was placed in a dry 50 mL round-bottom flask, and 5 mL of N,N-dimethylformamide was added. Under nitrogen atmosphere, 0.5 mL of thiomorpholine was added to the reaction system, and the reaction system was stirred at 50 °C. The reaction was monitored by TLC. After the reaction was completed, 5 mL of water was added to quench the reaction, and the aqueous layer was extracted with ethyl acetate (5 mL × 3). The organic phases were combined and washed once with saturated sodium bicarbonate aqueous solution (5 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. 30 mg of product 18 (pale yellow oil, yield 40%) was obtained by silica gel column chromatography.

[0118] Synthesis route: .

[0119] Peach phenol derivative 18 1 The H NMR characterization results are as follows: 1H NMR (500 MHz, Chloroform-d) δ 7.07 (d, J = 8.8 Hz, 1H), 6.69 (d, J= 8.8 Hz, 1H), 3.90 –3.84 (m, 2H), 2.95 (dd, J = 16.9, 6.5 Hz, 1H), 2.81 –2.68 (m, 9H), 2.68 (s, 2H), 2.38 – 2.32 (m, 2H), 2.25 (d, J = 12.8 Hz, 1H), 1.91 (dd, J = 13.3, 8.0 Hz, 1H), 1.83 – 1.55 (m, 6H), 1.52 – 1.41 (m, 6H),1.40 – 1.34 (m, 4H), 1.34 – 1.31 (m, 5H), 1.31 – 1.27 (m, 8H), 1.23 (d, J =27.2 Hz, 5H), 1.19 (s, 4H), 0.94 (s, 3H), 0.92 (s, 3H).

[0120] (19) Synthesis of Product 19: S6 (213 mg, 0.4 mmol) and triphenylphosphine (209 mg, 0.8 mmol) were placed in a 50 mL round-bottom flask, and 20 mL of anhydrous acetonitrile was added and stirred to dissolve. The reaction system was heated to 85 °C under nitrogen and refluxed for 36 h. After the reaction was complete, the reaction solution was cooled to room temperature and concentrated under reduced pressure to remove the solvent. The solution was extracted with petroleum ether and methanol, the methanol layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 168.6 mg of product 19 (yellow oil, 86.3%).

[0121] Synthesis route: .

[0122] Peach phenol derivative 19 1 The H NMR characterization results are as follows: 1H NMR (500 MHz, Chloroform-d) δ 7.85 – 7.80 (m, 6H), 7.80 – 7.76 (m,3H), 7.71 – 7.67 (m, 6H), 7.06 (d, J = 8.8 Hz, 1H), 6.68 (d, J = 8.7 Hz, 1H),3.90 – 3.86 (m, 2H), 3.73 –3.68 (m, 2H), 2.93 (dd, J = 17.0, 6.5 Hz, 1H),2.74 –2.68 (m, 1H), 2.27 – 2.20 (m, 1H), 1.93 – 1.85 (m, 2H), 1.80 – 1.70 (m, 3H), 1.62 –1.57 (m, 7H), 1.44 –1.37(m, 3H), 1.36 – 1.26 (m, 11H), 1.25 – 1.21(m, 5H), 1.21 – 1.14 (m, 11H), 0.93 (s, 3H), 0.90 (s, 3H).

[0123] (20) Synthesis of product 20: S6 (213 mg, 0.4 mmol) and tributylphosphine (162 mg, 0.8 mmol) were placed in a 50 mL round-bottom flask, and 20 mL of anhydrous acetonitrile was added and stirred to dissolve. The reaction system was heated to 85 °C under nitrogen and refluxed for 36 h. After the reaction was complete, the reaction solution was cooled to room temperature and concentrated under reduced pressure to remove the solvent. The solution was extracted with petroleum ether and methanol, the methanol layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 168.5 mg of product 20 (yellow oil, 93.3%).

[0124] Synthesis route: .

[0125] Peach phenol derivative 20 1 The H NMR characterization results are as follows: 1H NMR (500 MHz, Chloroform-d) δ 7.06 (d, J = 8.8 Hz, 1H), 6.68 (d, J= 8.8 Hz, 1H), 3.89 –3.82 (m, 2H), 2.93 (dd, J = 17.0, 6.7 Hz, 1H), 2.79 –2.69 (m, 1H), 2.47 – 2.42 (m, 9H), 2.23 (d, J = 12.8 Hz, 1H), 1.92 – 1.88 (m,1H), 1.85 – 1.80 (m, 2H), 1.77 (dd, J = 7.6, 5.7 Hz, 3H), 1.52 –1.46 (m,25H), 1.28 (dd, J = 16.3, 8.3 Hz, 21H), 0.98 – 0.95 (m, 13H), 0.92 (d, J =1.7 Hz, 10H), 0.91 (s, 3H), 0.90 (s, 3H).

[0126] (21) Synthesis of product 21: S5 (202 mg, 0.4 mmol) and tributylphosphine (162 mg, 0.8 mmol) were placed in a 50 mL round-bottom flask, and 20 mL of anhydrous acetonitrile was added and stirred to dissolve. The reaction system was heated to 85 °C under nitrogen and refluxed for 36 h. After the reaction was complete, the reaction solution was cooled to room temperature and concentrated under reduced pressure to remove the solvent. The solution was extracted with petroleum ether and methanol, the methanol layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 85.5 mg of product 21 (yellow oil, 31%).

[0127] Synthesis route: .

[0128] Peach phenol derivative 21 1 The H NMR characterization results are as follows: 1H NMR (500 MHz, Chloroform-d) δ 7.01 (d, J = 8.8 Hz, 1H), 6.63 (d, J= 8.7 Hz, 1H), 3.84 –3.78 (m, 2H), 2.88 (dd, J = 17.1, 6.5 Hz, 1H), 2.74 –2.64 (m, 1H), 2.42 – 2.32 (m, 9H), 2.18 (d, J = 12.8 Hz, 1H), 1.84 (dd, J =13.5, 7.9 Hz, 1H), 1.73 –1.68 (m, 2H), 1.69 – 1.56 (m, 3H), 1.54 – 1.42 (m,21H), 1.25 –1.20 (m, 17H), 0.91 –0.87 (m, 10H), 0.87 (s, 3H), 0.85 (s, 3H).

[0129] (22) Synthesis of product 22: S2 (168 mg, 0.4 mmol) and tributylphosphine (162 mg, 0.8 mmol) were placed in a 50 mL round-bottom flask, and 20 mL of anhydrous acetonitrile was added and stirred to dissolve. The reaction system was heated to 85 °C under nitrogen and refluxed for 36 h. After the reaction was complete, the reaction solution was cooled to room temperature and concentrated under reduced pressure to remove the solvent. The solution was extracted with petroleum ether and methanol, the methanol layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 86.2 mg of product 22 (yellow oil, 34.9%).

[0130] Synthesis route: .

[0131] Peach phenol derivative 22 1 The H NMR characterization results are as follows: 1H NMR (500 MHz, Chloroform-d) δ 7.07 (d, J = 8.8 Hz, 1H), 6.68 (d, J= 8.8 Hz, 1H), 4.03 – 3.92 (m, 2H), 2.91 (dd, J = 17.0, 6.6 Hz, 1H), 2.72 –2.68 (m, 1H), 2.62 –2.56 (m, 2H), 2.46 – 2.39 (m, 6H), 2.22 (dd, J = 12.6,3.6 Hz, 1H), 2.05 – 1.98 (m, 2H), 1.88 –1.80 (m, 1H), 1.82 –1.80 (m, 2H),1.75 (d, J = 7.8 Hz, 2H), 1.72 – 1.58 (m, 3H), 1.58 – 1.43 (m, 15H), 1.30 –1.23 (m, 8H), 1.15 (s, 4H), 0.97 – 0.88 (m, 16H).

[0132] (23) Synthesis of product 23: S3 (180 mg, 0.4 mmol) and triphenylphosphine (209 mg, 0.8 mmol) were placed in a 50 mL round-bottom flask, and 20 mL of anhydrous acetonitrile was added and stirred to dissolve. The reaction system was heated to 85 °C under nitrogen and refluxed for 36 h. After the reaction was complete, the reaction solution was cooled to room temperature and concentrated under reduced pressure to remove the solvent. The solution was extracted with petroleum ether and methanol, the methanol layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 163.6 mg of product 23 (yellow oil, 58.3%).

[0133] Synthesis route: .

[0134] Peach phenol derivative 23 1 The H NMR characterization results are as follows: 1H NMR (500 MHz, Chloroform-d) δ 7.84 (dd, J = 12.7, 7.8 Hz, 8H),7.76 –7.72 (m, J = 7.6 Hz, 4H), 7.67 –7.62 (m, 9H), 7.03 (d, J = 8.7 Hz, 1H),6.63 (d, J = 8.8 Hz, 1H), 3.84 –3.78 (m, 5H), 3.20 (s, 1H), 2.90 (dd, J =17.0, 6.6 Hz, 1H), 2.71 –2.66 (m, 1H), 2.22 (d, J = 12.7 Hz, 1H), 1.88 (dd, J= 13.4, 8.0 Hz, 1H), 1.77 – 1.60 (m, 15H), 1.57 (dd, J = 10.3, 7.0 Hz, 2H), 1.46 –1.40 (m, 4H), 1.36 – 1.26 (m, 2H), 1.21 –1.18 (m, 9H), 1.15 (s, 5H), 0.92 (s, 4H), 0.89 (s, 4H).

[0135] (24) Synthesis of product 24: S3 (180 mg, 0.4 mmol) and tributylphosphine (162 mg, 0.8 mmol) were placed in a 50 mL round-bottom flask, and 20 mL of anhydrous acetonitrile was added and stirred to dissolve. The reaction system was heated to 85 °C under nitrogen and refluxed for 36 h. After the reaction was complete, the reaction solution was cooled to room temperature and concentrated under reduced pressure to remove the solvent. The solution was extracted with petroleum ether and methanol, the methanol layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 100 mg of product 24 (yellow oil, 39.1%).

[0136] Synthesis route: .

[0137] Peach phenol derivative 24 1 The H NMR characterization results are as follows: 1H NMR (500 MHz, Chloroform-d) δ 7.06 (d, J = 8.8 Hz, 1H), 6.67 (d, J= 8.8 Hz, 1H), 3.88 –3.82 (m, 2H), 3.24 (s, 1H), 2.93 (dd, J = 17.0, 6.6 Hz,1H), 2.73 –2.68 (m, 1H), 2.44 –2.38 (m, 10H), 2.22 (dd, J = 10.1, 6.7 Hz,1H), 1.89 (dd, J = 13.3, 8.0 Hz, 2H), 1.81 – 1.73 (m, 5H), 1.73 – 1.61 (m,7H), 1.61 – 1.45 (m, 31H), 1.45 – 1.38 (m, 6H), 1.35 –1.30 (m, 6H), 1.29 (dd,J = 8.2, 7.0 Hz, 8H), 1.26 (d, J = 2.1 Hz, 1H), 1.23 (d, J = 2.4 Hz, 3H), 1.22 – 1.13 (m, 6H), 0.99 – 0.94 (m, 12H), 0.94 – 0.91 (m, 9H), 0.90 (d, J =4.8 Hz, 5H).

[0138] (25) Synthesis of product 25: S4 (191 mg, 0.4 mmol) and triphenylphosphine (209 mg, 0.8 mmol) were placed in a 50 mL round-bottom flask, and 20 mL of anhydrous acetonitrile was added and stirred to dissolve. The reaction system was heated to 85 °C under nitrogen and refluxed for 36 h. After the reaction was complete, the reaction solution was cooled to room temperature and concentrated under reduced pressure to remove the solvent. The solution was extracted with petroleum ether and methanol, the methanol layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 136.2 mg of product 25 (yellow oil, 73.9%).

[0139] Synthesis route: .

[0140] Peach phenol derivative 25 1 The H NMR characterization results are as follows: 1H NMR (500 MHz, Chloroform-d) δ 7.07 (d, J = 8.8 Hz, 1H), 6.68 (d, J= 8.7 Hz, 1H), 3.91 –3.87 (m, 2H), 3.29 (d, J = 30.7 Hz, 1H), 3.12 –3.08 (m,1H), 2.93 (dd, J = 17.0, 6.6 Hz, 1H), 2.74 –2.68(m, 1H), 2.46 –2.38 (m, 13H),2.23 (dd, J = 14.1, 8.5 Hz, 1H), 2.10 (d, J = 13.4 Hz, 1H), 1.94 – 1.86 (m,1H), 1.79 –1.76 (m, 6H), 1.72 – 1.62 (m, 5H), 1.61 – 1.48 (m, 31H), 1.48 –1.38 (m, 4H), 1.38 – 1.22 (m, 12H), 1.17 (s, 5H), 1.00 – 0.95 (m, 16H), 0.95– 0.92 (m, 5H), 0.91 (d, J = 5.0 Hz, 4H).

[0141] (26) Synthesis of product 26: S4 (191 mg, 0.4 mmol) and tributylphosphine (162 mg, 0.8 mmol) were placed in a 50 mL round-bottom flask, and 20 mL of anhydrous acetonitrile was added and stirred to dissolve. The reaction system was heated to 85 °C under nitrogen and refluxed for 36 h. After the reaction was complete, the reaction solution was cooled to room temperature and concentrated under reduced pressure to remove the solvent. The solution was extracted with petroleum ether and methanol, the methanol layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 165.2 mg of product 26 (yellow oil, 82.1%).

[0142] Synthesis route: .

[0143] Peach phenol derivative 26 1 The H NMR characterization results are as follows: 1H NMR (500 MHz, Chloroform-d) δ 7.92 – 7.82 (m, 7H), 7.78 –7.72 (m,4H), 7.69 –7.62 (m, 8H), 7.06 (d, J = 8.8 Hz, 1H), 6.66 (d, J = 8.8 Hz, 1H),3.88 – 3.77 (m, 4H), 2.93 (dd, J = 17.0, 6.6 Hz, 1H), 2.80 – 2.66 (m, 1H),2.28 – 2.14 (m, 1H), 1.90 (dd, J = 13.4, 7.9 Hz, 1H), 1.78 – 1.69 (m, 3H),1.69 – 1.55 (m, 15H), 1.49 – 1.36 (m, 5H), 1.27 –1.22 (m, 19H), 1.17 (s, 6H), 0.93 (s, 4H), 0.91 (s, 3H).

[0144] Example 3: Water solubility test of taurine derivatives Weigh 10 mg of the taurine derivative 1-26 sample prepared in Example 2 and place it in a transparent glass bottle. Add a certain volume of ultrapure water. After each addition of ultrapure water, shake and dissolve the solution in a 37°C water bath for 2 hours. Observe and record the volume of water added when the solution in each glass bottle becomes clear and transparent.

[0145] The test results are shown in Table 1. Compared with pyruvic phenol, the water solubility of pyruvic phenol derivatives 1-26 prepared in Example 2 has been improved, from almost insoluble to slightly soluble. Among them, the water solubility of pyruvic phenol derivatives 11, 19, 23 and 26 has been significantly improved.

[0146] Table 1. Water solubility of pyruvic acid and its derivatives

[0147] Example 4: Antibacterial activity experiment of taurine derivatives The antibacterial activity of taurine derivatives was determined using the minimum inhibitory concentration (MIC) assay, employing commercially available pathogens: *Escherichia coli* (ATCC 25922), *Staphylococcus aureus* (ATCC 25923), *Bacillus subtilis* (ATCC 6633), and *Candida albicans* (ATCC 10231). The specific procedure was as follows: First, fresh bacterial suspensions were prepared, and the OD value of the suspensions was measured using a UV spectrophotometer. 600 Value, and according to OD 600 =1×10 8The standard CFU / mL is used to dilute the bacterial culture to 2×10⁻⁶. 5 CFU / mL. Then, 100 μL of culture medium was added to a sterile 96-well plate, and the test sample (tocopherol derivative 1-26) was added to the first well. This was followed by sequential two-fold dilutions, with 100 μL of a 2×10⁻⁶ concentration added to each well. 5 The bacterial culture was diluted with CFU / mL using a pipette. The 96-well plate was incubated overnight at 37°C. The next day, the absorbance of each well at 600 nm was measured using a microplate reader. The OD values ​​of different wells were compared. 600 The minimum inhibitory concentration (MIC) is determined by the concentration of bacteria that can completely inhibit bacterial growth.

[0148] The test results are shown in Table 2 below. It shows that pyritin and pyritin derivatives 1-26 had poor antibacterial effects against *Escherichia coli*; while pyritin derivatives 11, 12, 17, and 19 showed better antibacterial effects against *Staphylococcus aureus* than pyritin; pyritin derivatives 5, 9, 10, 11, 13, 17, and 19 showed better antibacterial effects against *Bacillus subtilis* than pyritin; and pyritin derivatives 1, 2, 3, 5, 8, 9, 10, 11, 12, 13, 15, 17, 19, 21, and 22 showed better antibacterial effects against *Candida albicans* than pyritin, with their MIC values ​​decreasing by 50% compared to pyritin, indicating a significant improvement in their antibacterial ability. In summary, pyritin derivatives 11, 17, and 19 showed better antibacterial effects against all three strains than pyritin, indicating that the pyritin derivatives prepared in this invention have improved antibacterial effects compared to pyritin and possess better antibacterial efficacy.

[0149] Table 2. MIC values ​​of pyruvic phenol and its derivatives against different strains

[0150] Example 5 Cytotoxicity test of taurine derivatives Cytotoxicity against mammalian cells was assessed using the MTT assay. HaCaT cells were seeded at a density of 8000 cells per well in 96-well plates using DMEM high-glucose medium supplemented with 10% fetal bovine serum. Before use, the plates were incubated at 37°C in a humidity-controlled incubator containing 5% CO2. The test compounds (tocopherol derivatives 5, 11, 17, and 19, which exhibited excellent antibacterial activity in Example 4) were serially diluted 2-fold in complete medium and further diluted with medium to achieve a concentration range of 0.5–32 μg / mL for each tocopherol derivative. The original medium in each well was replaced with 100 μL of drug-containing medium, and the plates were incubated at 37°C for 24 hours. After incubation, the cells were washed with PBS, and then 100 μL of fresh medium and 10 μL of 5 mg / mL MTT solution were added to each well. After incubation for another 2-4 hours, 100 μL of DMSO was added to each well as a dissolving solution, and the absorbance was measured at 570 nm using a microplate reader. Cell viability was calculated by dividing the absorbance of the sample (after background subtraction) by the absorbance of the untreated cells (after background subtraction).

[0151] The measurement results are as follows Figures 1-5 As shown, compared with pyrrolizine, pyrrolizine derivatives 5 and 17 exhibit significantly different cytotoxic effects, while pyrrolizine derivatives 11 and 19 show little difference in cytotoxicity. Pyrrolizine derivatives 5 and 17 demonstrate biocompatibility within the range of 0.5–2 μg / mL, while pyrrolizine derivatives 11 and 19 demonstrate biocompatibility within the range of 0.5–8 μg / mL. In summary, the pyrrolizine derivatives provided by this invention exhibit better water solubility and antibacterial activity than pyrrolizine, and possess greater potential for drug development.

[0152] The above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above embodiments. Any changes, modifications, substitutions, combinations, or simplifications made without departing from the spirit and principle of the present invention shall be considered equivalent substitutions and shall be included within the protection scope of the present invention.

Claims

1. A pine phenol derivative, characterized in that, The taurine derivative is selected from any one of the following compounds: 。 2. The pyrrolidine derivative according to claim 1, characterized in that, The taurine derivative is selected from any one of the following compounds: 。 3. The application of the taurine derivative according to claim 1 in the preparation of antibacterial products, characterized in that, The antibacterial product inhibits Staphylococcus aureus, Bacillus subtilis, and Candida albicans.

4. An antibacterial product, characterized in that, The product contains the taurine derivative as described in claim 1; the bacteria inhibited by the antibacterial product are Staphylococcus aureus, Bacillus subtilis, and Candida albicans.

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