Quaternary phosphonium salt compound as well as preparation method and antibacterial application thereof

Abstract

The invention discloses a quaternary phosphonium salt compound and a preparation method thereof, and the preparation method comprises the following steps: (1) adding a compound 1 and a compound 2 into a reaction flask, carrying out a reflux reaction in a first solvent, and carrying out post-treatment to obtain an intermediate I; (2) sequentially adding a compound 3, a compound 5, a second solvent and paraformaldehyde into the reaction flask, and heating the reaction mixture to reflux; after the reaction is finished, performing post-treatment to obtain an intermediate II; and (3) sequentially adding the intermediate I, a carboxyl activation reagent, organic alkali and a third solvent into the reaction bottle, stirring for 30 minutes to 2 hours at room temperature, adding the intermediate II after the reaction is finished, continuously stirring for 2 to 24 hours at room temperature, and performing post-treatment to obtain a target compound after the reaction is finished. The compound has excellent inhibition performance on escherichia coli and staphylococcus aureus, and the preparation method is high in yield, cost-saving, easy to operate and beneficial to industrial production.

Description

Technical Field

[0001] The invention relates to the technical field of functional materials, and in particular to a quaternary phosphonium salt compound and a preparation method and antibacterial application thereof. Background Art

[0002] People are inevitably exposed to various microorganisms in their daily lives. Since the surfaces of textiles, furniture and other materials have a certain degree of roughness, bacteria are more likely to attach to them, causing the bacteria to be transmitted to the skin surface. Pathogenic bacteria multiply in large numbers and cause great harm to human health through the skin, respiratory tract, digestive tract and blood. Antibacterial treatment of materials is an important means to effectively prevent the growth and reproduction of various bacteria, kill bacteria and prevent bacterial transmission of infection.

[0003] Antibacterial materials are a development direction of functional materials. They refer to adding antibacterial agents to materials such as plastics to make plastics with bactericidal or bacteriostatic properties. During the time of contact with bacteria, the bacteria contaminated on the plastics will be killed or the bacterial reproduction will be inhibited. This kind of plastic can not only keep itself clean, but also reduce the cross-infection of bacteria caused by the use of plastic products. The core part of antibacterial plastics is the preparation of antibacterial agents, and the research and development of this type of product mainly focuses on the research and development of antibacterial agents.

[0004] Antimicrobial agents are mainly divided into three categories: inorganic antimicrobial agents, organic antimicrobial agents and natural antimicrobial agents. Although inorganic antimicrobial agents have a certain degree of heat resistance and strong antimicrobial ability, common inorganic antimicrobial agents contain heavy metals, are not safe for the human body, have a short-lasting antimicrobial effect, are prone to discoloration after long-term use, and are relatively expensive. Natural antimicrobial agents have low toxicity, but low antimicrobial efficiency, limited raw material sources, and a relatively limited range of uses. Organic antimicrobial agents are generally heat-resistant, but have low toxicity, are safer for the human body and the environment, have high antimicrobial efficacy, are easy to process, and have stable colors. They play an irreplaceable role in certain fields.

[0005] Quaternary phosphonium salt antimicrobial agents are a new type of antimicrobial agent introduced in the late 20th century. The structural characteristics of the quaternary phosphonium salt antimicrobial agent are that the phosphorus atom has a larger ionic radius than the nitrogen atom and has a stronger polarization effect, so it is easier to adsorb bacteria with negative ions. In addition, the molecular structure is stable and not easy to react with redox agents and acids and bases. The thermal stability is better than that of quaternary ammonium salt organic antimicrobial agents. With the increase of microbial resistance, quaternary phosphonium salt antimicrobial agents are expected to be used in more fields due to their high efficiency, broad spectrum and low toxicity. The most representative foreign research on quaternary phosphonium salts is the Japanese scholar Kanazawa. Starting in 1993, he synthesized a series of quaternary phosphonium salt antimicrobial agents. Future research may further explore its application in textiles, polymer materials, medicine and other fields to provide a wider range of antimicrobial solutions. In 2002, Rogers-Evans et al. synthesized quaternary phosphonium salts containing chlorine, bromine or iodine, and he improved the synthesis route to make it easier for industrial production. Ioconomopoulou et al. grafted quaternary phosphonium salts and triclosan onto polystyrene-divinylbenzene (PS-DVB) by suspension polymerization. The results showed that the release amount of the antibacterial agent was related to the amount of DVB grafted. Its release effect in water and saline directly affected its existence state, and thus affected the antibacterial effect. In 2006, Kenawy et al. formed a cross-linked copolymer of vinylbenzyl chloride, 2-chloroethyl vinyl ether and methyl methacrylate through divinylbenzene, and then modified the polymer with triethylamine, triphenylphosphine and tributylphosphine respectively. The results showed that the antibacterial effect of the polymer modified with triphenylphosphine was the best. In 2009, Liu Hongfang et al. used chloromethylstyrene as a carrier, and used the chloromethyl on the carrier to react with triphenylphosphine for quaternization to prepare a non-dissolving polytriphenyl quaternary phosphonium salt polymer antibacterial agent and a small molecule triphenyl quaternary phosphonium salt. In 2005, Jin Dong et al. used silica gel as a carrier, reacted γ-aminopropyl-triethoxysilane with halogenated alkyl triphenylphosphine bromide, and grafted quaternary phosphonium functional groups onto the surface of silica gel to obtain a water-insoluble antibacterial material. Liu Yuan et al. blended triphenylphosphonium chloride rubber, tributylphosphonium chloride rubber and low-density polyethylene, and prepared a new type of polymer quaternary phosphonium salt modified antibacterial plastic by melt extrusion, which has good antibacterial effects on Staphylococcus aureus and Escherichia coli. Quaternary phosphonium salts have great development space and potential in the field of antibacterial, and will also be the focus and hotspot of future antibacterial research.

[0006] Benzoxazine is a class of benzo-fused ring compounds containing nitrogen and oxygen six-membered heterocyclic rings. Its structure contains N and O six-membered oxazine rings and is mainly synthesized by Mannich reaction. Benzoxazine resin is a thermosetting resin. Compared with traditional phenolic resin, no small molecules are released during the curing process, the curing shrinkage is almost zero, the modulus is high, the strength is high, the heat resistance is good, the water absorption rate is low, and it has excellent thermal, chemical, electrical and mechanical properties. The cross-linked network of benzoxazine contains a large number of hydrogen bonds, hydrogen bonds between hydroxyl groups and nitrogen in the molecule, and hydrogen bonds between ethyl hydroxyl groups and large π bonds. These hydrogen bonds ensure the excellent performance of polybenzoxazine materials, making them widely used in electronic engineering and aerospace fields. However, they also have the disadvantages of low cross-linking density, high curing temperature and high brittleness. Therefore, people have also conducted extensive research on its modification.

[0007] So far, there have been many studies on organic small molecule antibacterial agents. People have found that long-chain alkyl quaternary phosphonium salts have strong antibacterial properties, but these organic small molecule antibacterial agents have disadvantages such as easy volatility, easy residue, difficult processing, and poor stability. Therefore, the development of new antibacterial materials with these antibacterial groups is a recent research direction and hotspot. These new antibacterial materials can overcome these disadvantages, will not penetrate into human skin, are safer, and have better antibacterial properties. Summary of the invention

[0008] In view of the problems existing in the above-mentioned prior art, the present invention develops a quaternary phosphonium salt compound, and the present invention also provides a preparation method thereof, which has high yield, saves cost, is easy to operate, and is conducive to industrial production.

[0009] One of the technical problems to be solved by the present invention is to provide a quaternary phosphonium salt compound, the chemical structure of which is shown in III,

[0010] Among them, R 1 , R 2 and R 3 are C1-C18 fatty alkyl, phenyl, 3-methylphenyl, 4-methylphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-chlorophenyl, 4-chlorophenyl, 3-bromophenyl, 4-bromophenyl, 3-fluorophenyl, 4-fluorophenyl, benzyl, 3-methylbenzyl, 4-methylbenzyl, 3-methoxybenzyl, 4-methoxybenzyl, 3-chlorobenzyl, 4-chlorobenzyl, 3-bromobenzyl, 4-bromobenzyl, 3-fluorobenzyl, 4-fluorobenzyl; R 4 , R 5 and R 6 R is respectively hydrogen, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, amino, nitro, cyano, carboxyl, methoxycarbonyl, ethoxycarbonyl, benzyloxycarbonyl; 7is hydrogen, methyl, ethyl, C3-C18 fatty alkyl, phenyl, 3-methylphenyl, 4-methylphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-chlorophenyl, 4-chlorophenyl, 3-bromophenyl, 4-bromophenyl, 3-fluorophenyl, 4-fluorophenyl, 3-nitrophenyl, 4-nitrophenyl, 3-nitrilephenyl, 4-nitrilephenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 3-trifluoromethoxyphenyl, 4-trifluoromethoxyphenyl, benzyl and 3-methylbenzyl, 4-methylbenzyl, 3-methoxybenzyl, 4-methoxybenzyl, 3- chlorobenzyl, 4-chlorobenzyl, 3-bromobenzyl, 4-bromobenzyl, 3-fluorobenzyl, 4-fluorobenzyl, 3-nitrophenyl, 4-nitrophenyl, 3-nitrilephenyl, 4-nitrilephenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 3-trifluoromethoxyphenyl, 4-trifluoromethoxyphenyl, thiophene, furan, thiazole, pyrrole, pyrazole, imidazole, pyridine, pyrimidine, pyrazine, pyridazine, indole, quinoline; X is fluorine, chlorine, bromine, iodine, p-benzoyloxy, benzenesulfonyloxy, methanesulfonyloxy, trifluoromethanesulfonate, tetrafluoroborate, hexafluorophosphate; n=0-20.

[0011] The second technical problem to be solved by the present invention is to provide a method for preparing a quaternary phosphonium salt compound, comprising the following steps: Step (1) Compound 1 and Compound 2 are added to a reaction flask, refluxed in a first solvent, and post-treated to obtain an intermediate I, wherein the first reaction solvent is at least one of toluene, tetrahydrofuran, dioxane, N,N-dimethylformamide, methanol, ethanol, xylene, chlorobenzene, n-hexane and cyclohexane; Step (2) Compound 3 and Compound 5, a second solvent, and paraformaldehyde are added to a reaction flask in sequence, and the reaction mixture is heated to reflux; after the reaction is completed, intermediate II can be obtained by post-treatment, wherein the second reaction solvent is at least one of toluene, xylene, dioxane, ethanol, N,N-dimethylformamide and cyclohexane; Step (3) In the reaction flask, intermediate I, a carboxyl activation reagent, an organic base and a third solvent are added in sequence, and the mixture is stirred at room temperature for 30 min-2 h. After completion, intermediate II is added, and stirring is continued at room temperature for 2-24 h. After completion, post-treatment is performed to obtain the target compound, wherein the carboxyl activation reagent is at least one of DCC, DIC, EDC, HOAT, HOBT, CDI, HATU, HBTU, TBTU, PyBop and PyBop, the organic base is triethylamine or diisopropylethylamine, and the third solvent is at least one of chloroform, dichloromethane, tetrahydrofuran, acetonitrile, N,N-dimethylformamide and dimethyl sulfoxide. Among them, R 1 , R 2 and R 3are C1-C18 fatty alkyl, phenyl, 3-methylphenyl, 4-methylphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-chlorophenyl, 4-chlorophenyl, 3-bromophenyl, 4-bromophenyl, 3-fluorophenyl, 4-fluorophenyl, benzyl, 3-methylbenzyl, 4-methylbenzyl, 3-methoxybenzyl, 4-methoxybenzyl, 3-chlorobenzyl, 4-chlorobenzyl, 3-bromobenzyl, 4-bromobenzyl, 3-fluorobenzyl, 4-fluorobenzyl; R 4 , R 5 and R 6 R is respectively hydrogen, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, amino, nitro, cyano, carboxyl, methoxycarbonyl, ethoxycarbonyl, benzyloxycarbonyl; 7 is hydrogen, methyl, ethyl, C3-C18 fatty alkyl, phenyl, 3-methylphenyl, 4-methylphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-chlorophenyl, 4-chlorophenyl, 3-bromophenyl, 4-bromophenyl, 3-fluorophenyl, 4-fluorophenyl, 3-nitrophenyl, 4-nitrophenyl, 3-nitrilephenyl, 4-nitrilephenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 3-trifluoromethoxyphenyl, 4-trifluoromethoxyphenyl, benzyl and 3-methylbenzyl, 4-methylbenzyl, 3-methoxybenzyl, 4-methoxybenzyl, 3- chlorobenzyl, 4-chlorobenzyl, 3-bromobenzyl, 4-bromobenzyl, 3-fluorobenzyl, 4-fluorobenzyl, 3-nitrophenyl, 4-nitrophenyl, 3-nitrilephenyl, 4-nitrilephenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 3-trifluoromethoxyphenyl, 4-trifluoromethoxyphenyl, thiophene, furan, thiazole, pyrrole, pyrazole, imidazole, pyridine, pyrimidine, pyrazine, pyridazine, indole, quinoline; X is fluorine, chlorine, bromine, iodine, p-benzoyloxy, benzenesulfonyloxy, mesyloxy, trifluoromethanesulfonate, tetrafluoroborate, hexafluorophosphate; n=0-20, The chemical reaction equation is as follows: .

[0012] In a preferred embodiment of the present invention, in the above step (1), the molar ratio of compound 1 to compound 2 is 1:1.0-3.

[0013] In a preferred embodiment of the present invention, in the above step (1), the molar ratio of compound 1 to compound 2 is 1:1.0-1.2.

[0014] In a preferred embodiment of the present invention, in the above step (2), the molar ratio of compound 3, compound 4 and paraformaldehyde is 1:0.8-1.5:2-10.

[0015] In a preferred embodiment of the present invention, in the above step (2), the molar ratio of compound 3, compound 4 and paraformaldehyde is 1:0.8-1.2:3-5.

[0016] In a preferred embodiment of the present invention, in the above step (3), the molar ratio of the intermediate I, intermediate II, carboxyl activation reagent and organic base is 1:1-1.5:1-1.2:1-5.

[0017] The third technical problem to be solved by the present invention is to provide an antibacterial agent, comprising the above-mentioned quaternary phosphonium salt compound or the quaternary phosphonium salt compound prepared by the above-mentioned preparation method.

[0018] In a preferred embodiment of the present invention, the above-mentioned antibacterial agent is used against Staphylococcus aureus and Escherichia coli.

[0019] The fourth technical problem to be solved by the present invention is an antibacterial plastic, comprising the above-mentioned quaternary phosphonium salt compound or the quaternary phosphonium salt compound prepared by the above-mentioned preparation method. Beneficial Effects

[0020] (1) Based on the characteristics of benzoxazine structure and reaction, the present invention introduces some shortcomings of organic small molecule antibacterial agents into the structural design of quaternary phosphonium salt antibacterial agents, and develops a quaternary phosphonium salt antibacterial agent to reduce the harm caused by pathogenic microorganisms to people. It not only has theoretical significance, but also has important application development value. The present invention can be used in the fields of sterilization and disinfection of leather, textiles, daily hygiene products, and medical instruments.

[0021] (2) Compared with the existing preparation methods of antibacterial compounds, the present invention is simple to operate, has convenient raw material sources, is environmentally friendly, is suitable for industrial production, and has good application prospects. DETAILED DESCRIPTION

[0022] The technical solutions in the embodiments of the present invention are described clearly and completely below. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative work are within the scope of protection of the present invention. Example 1

[0023] (3-Oxo-3-((3-phenyl-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)methoxy)propyl)triphenylphosphonium bromide

[0024] (1) Preparation of 2-carboxyethyltriphenylphosphonium bromide Add 40.8g (155.43mmol, 1eq) of triphenylphosphine and 300ml of acetonitrile to a 500ml three-necked flask, stir until dissolved, slowly add 26.2g (170.97mmol, 1.1eq) of 3-bromopropionic acid, heat to reflux, react for 70h, monitor by TLC until the reaction is complete, cool to room temperature, concentrate under reduced pressure to remove acetonitrile, add 100ml of ether to the residue, stir, filter, and vacuum dry to obtain 52g of white solid product. 1H NMR (400 MHz, CDCl3): δ= 10.34 (s, 1H), 7.89-7.61 (m, 15 H),3.82-3.63 (m, 2H), 3.02-2.82 (m, 2H).

[0025] (2) Preparation of (3-phenyl-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)methanol A 2L three-necked flask was added with aniline 750g (0.81mol, 1eq), 4-hydroxybenzyl alcohol 100g (0.81mol, 1eq), paraformaldehyde 73.0g (2.4mol, 3eq), and toluene 1L in sequence, and the temperature was raised to reflux for reaction for 8h. The reaction was monitored by TLC to be complete. The reaction solution was cooled to room temperature, concentrated, and the residue was added with anhydrous ether 1L and stirred, filtered, and the filtrate was concentrated under reduced pressure. The residue was recrystallized with 250ml chloroform, filtered, and vacuum dried to obtain 103g of the target product. 1H NMR (400 MHz, CDCl3):δ= 6.80−7.28 (m,8H),5.36 (s, 2H), 4.62 (s, 2H),4.55 (s, 2H).

[0026] (3) Preparation of (3-oxo-3-((3-phenyl-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)methoxy)propyl)triphenylphosphonium bromide In a 1L three-necked flask, 71.0 g (170.1 mmol, 1 eq) of 2-carboxyethyltriphenylphosphonium bromide, 54.0 g (188.6 mmol, 1.1 eq) of (3-phenyl-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)methanol, 54.6 g (170.1 mmol, 1 eq) of TBTU, 22.0 g (170.1 mmol, 1 eq) of diisopropylethylamine, and 500 ml of dichloromethane were added in sequence and stirred at room temperature for 6 h. After completion, 200 ml of deionized water was added, the liquid was separated, and the organic phase was separated. The phase was washed with 200 ml of deionized water and 200 ml of saturated brine in sequence, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The obtained solid was crystallized from ethyl acetate / dichloromethane and dried in vacuo to obtain 80 g of the product. 1H NMR (500 MHz, DMSO-d6): δ=7.91 (m,3H),7.85–7.78 (m,6H),7.77 (m,5H),7.23 (d,J = 9.7 Hz,2H),7.17–7.05 (m, 5H), 6.88 (s, 1H), 6.72 (s, 2H), 5.46 (s, 2H), 4.93 (s, 2H), 4.65 (s, 2H), 3.86 (m, 2H), 2.71 (m, 2H). Example 2

[0027] (3-((3-(4-nitrophenyl)-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)methoxy)-3-oxopropyl)triphenylphosphonium bromide

[0028] (1) Preparation of 2-carboxyethyltriphenylphosphonium bromide To three 2L bottles, add 1L of toluene, 202.5g of triphenylphosphine (0.77mol, 1eq), and 124.0g of 3-bromopropionic acid (0.81mol, 1.05eq). After the addition is completed, reflux for 60h and monitor the reaction by TLC until it is complete. Cool to room temperature and concentrate under reduced pressure to remove acetonitrile. Add 500ml of ethyl acetate to the residue, stir, filter, and vacuum dry to obtain 250g of a white solid product.

[0029] (2) Preparation of (3-(4-nitrophenyl)-3,4-dihydro-2H-benzo[e][1,3]oxazine-6-yl)methanol Toluene 3000ml, dioxane 600ml, p-nitroaniline 111.2g (0.8mol, 1eq), p-hydroxybenzyl alcohol 100.0g (0.8mol, 1eq), paraformaldehyde 60.0g (2.0mol, 2.5eq) were added to a 5L three-necked flask in sequence, and the temperature was raised to reflux for 8h. The reaction was monitored to be complete by TLC. The reaction solution was cooled to room temperature and concentrated in vacuo. The residue was dissolved in dichloromethane 500ml, and washed with deionized water 150ml and saturated brine 150ml in sequence. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was subjected to silica gel column chromatography to obtain 70g of a solid product. 1H NMR (500 MHz, CDCl3) δ 8.19 (d, J = 8.9 Hz,2H), 7.18 (d,J = 8.4 Hz,1H), 7.15–7.07 (m, 3H), 6.89 (d, J = 8.3 Hz, 1H), 5.44 (s, 2H),4.77 (s, 2H), 4.64 (s, 2H).

[0030] (3) Preparation of (3-((3-(4-nitrophenyl)-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)methoxy)-3-oxypropyl)triphenylphosphonium bromide 2-carboxyethyltriphenylphosphonium bromide 60.0g (144mmol, 1eq), dichloromethane 400ml, TBTU 46.4g (144mmol, 1eq), diisopropylethylamine 18.6g (144mmol, 1eq) were added to a 1L four-necked bottle in sequence, and the mixture was stirred at room temperature for 1h. (3-(4-nitrophenyl)-3,4-dihydro-2H-benzo[e][1,3]oxazine-6-yl)methanol 45.0g (157mmol, 1.1eq) was added, and the mixture was stirred for 4h. The reaction was monitored by TLC to be complete. 200ml of deionized water was added, and the organic phase was separated. The mixture was washed with 150ml of deionized water and 150ml of saturated brine in sequence, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The obtained solid was subjected to silica gel column chromatography to obtain 24g of the product. 1H NMR (500 MHz, CDCl3): δ= 8.16 (dd, J1 = 9.7, J2=4.4 Hz, 2H), 7.82 (t, J = 5.9 Hz, 3H), 7.73 (m, 12H), 7.28 (dd, J1= 17.3, J2=4.0 Hz, 2H),7.14 (dd, J1= 9.6, J2=4.1 Hz, 2H), 7.02 (d, J = 7.8 Hz, 1H), 5.44 (s, 2H),4.94 (s, 2H), 4.84 (s, 2H), 3.72 (dt, J1 =13.0, J2=6.7 Hz, 2H), 2.85 (dt, J =13.5, 6.9 Hz, 2H). Example 3

[0031] (3-Oxo-3-((3-(p-tolyl)-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)methoxy)propyl)triphenylphosphonium bromide

[0032] (1) Preparation of 2-carboxyethyltriphenylphosphonium bromide To three 2L bottles, add 1L of toluene, 202.5g of triphenylphosphine (0.77mol, 1eq), and 124.0g of bromopropionic acid (0.81mol, 1.05eq). After the addition is completed, reflux for 60h and monitor the reaction by TLC until it is complete. Cool to room temperature and concentrate under reduced pressure to remove acetonitrile. Add 500ml of ethyl acetate to the residue, stir, filter, and vacuum dry to obtain 250g of a white solid product.

[0033] (2) Preparation of (3-(p-methylphenyl)-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)methanol A 2L three-necked flask was added with 35.0g aniline (327mmol, 1eq), 40.6g 4-hydroxybenzyl alcohol (327mol, 1eq), 10.0g paraformaldehyde (981mmol, 3eq), and 350ml toluene in sequence. The temperature was raised to reflux for reaction for 10h. The reaction was monitored by TLC until complete. The temperature was lowered to room temperature, the reaction solution was concentrated, the residue was dissolved in 500ml DCM, washed with 100ml saturated sodium bicarbonate and 100ml deionized water, the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was recrystallized from toluene to obtain 38.7g of a white solid product. 1H NMR (400 MHz, CDCl3): δ= 7.25-6.74 (m, 7H), 5.30 (s, 2H), 4.56 (s,2H), 4.53 (s, 2H), 2.24 (s, 3H).

[0034] (3) Preparation of (3-oxo-3-((3-(p-tolyl)-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)methoxy)propyl)triphenylphosphonium bromide In a 1L three-necked flask, 35.5 g of 2-carboxyethyltriphenylphosphonium bromide (85 mmol, 1 eq), 24.1 g (94.3 mmol, 1.1 eq) of (3-(p-methylphenyl)-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)methanol (94.3 mmol, 1.1 eq), 27.3 g (85 mmol, 1 eq) of TBTU, 16.5 g (127.5 mmol, 1.5 eq) of diisopropylethylamine and 250 ml of dichloromethane were added in sequence and stirred at room temperature for 6 h. After completion, 100 ml of deionized water was added, the liquid was separated, and the organic phase was separated. The mixture was washed with 100 ml of deionized water and 100 ml of saturated brine in sequence, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography to obtain 11.2 g of the product. 1H NMR (500 MHz,Chloroform-d) δ 7.78- 7.61 (m, 15H), 7.30 (m, 1H), 7.20-7.13 (m, 3H), 6.86 –6.76 (m, 3H), 5.28 (s, 2H), 4.90 (s, 2H), 4.52 (s, 2H), 3.91 (m, 2H), 2.71 (m, 2H), 2.24 (s, 3H). Example 4

[0035] (4-oxo-4-((3-(4-(trifluoromethyl)-3,4-dihydro-2 H -Benzo[e][1,3]oxazin-6-yl)methoxy)butyl)triphenylphosphonium bromide

[0036] (1) Preparation of (3-carboxypropyl)triphenylphosphonium bromide Add 300ml toluene, 142.8g (0.55mol, 1eq) of triphenylphosphine, and 100g (0.60mol, 1.1eq) of 4-bromobutyric acid to a 1L three-necked flask. After the addition is complete, the reaction solution is refluxed for 51h and monitored by TLC until the reaction is complete. Filter while hot and wash the filter cake with 200ml of hot toluene. After completion, slurry the filter cake with 150ml of ethyl acetate, filter, and vacuum dry the filter cake to obtain 184g of the product. 1H NMR (400 MHz, CDCl3): δ=7.91 -7.66 (m, 15H), 3.31 - 3.22 (m, 2H), 2.57 (t, J = 6.3 Hz, 2H), 1.82(m, 2H).

[0037] (2) Preparation of (3-(4-(trifluoromethyl)phenyl)-3,4-hydrogen-2H-benzo[e][1,3]oxazin-6-yl)methanol In a 500ml three-necked flask, 32.2g (0.2mol, 1eq) of trifluoromethylaniline, 24.8g (0.2mol, 1eq) of 4-hydroxybenzyl alcohol, 18.3g (0.2mol, 3eq) of paraformaldehyde, and 200ml of toluene were added in sequence, and the temperature was raised to reflux for reaction for 6h, then cooled to room temperature, the reaction solution was concentrated, the residue was dissolved in 250ml of dichloromethane, and washed with 100ml of 0.2N sodium bicarbonate, deionized water, and saturated brine in sequence, the organic phase was concentrated, the residue was purified by flash column chromatography, and vacuum dried to obtain 21.4g of the target product. 1H NMR (400MHz, CDCl3): δ=7.36-7.44 (m, 2H), 6.96−7.30 (m, 5H), 5.39 (s, 2H), 4.65 (s, 2H), 4.57 (s, 2H).

[0038] (3) Preparation of (4-oxo-4-((3-(4-(trifluoromethyl)-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)methoxy)butyl)triphenylphosphonium bromide Add 21.5g (50mmol, 1eq) of (3-carboxypropyl)triphenylphosphonium bromide, 200ml of dichloromethane, 16.8g (50mmol, 1eq) of TBTU, and 7.6g (75mmol, 1.5eq) of triethylamine to 1000ml of the solution, and stir at room temperature for 1h. After completion, dissolve 16.2g (52.5mmol, 1.05eq) of (3-(4-(trifluoromethyl)phenyl)-3,4-hydrogen-2H-benzo[e][1,3]oxazin-6-yl)methanol in 100ml of dichloromethane, add to the above solution, continue stirring for 4h, and monitor the reaction by TLC. After completion, add 200ml of deionized water, separate the liquids, separate the organic phase, wash with 100ml of deionized water and 100ml of saturated brine in turn, dry over anhydrous sodium sulfate, filter, concentrate the filtrate, and purify the residue by chromatography to obtain 21.6g of the product. 1H NMR (500 MHz, CD3Cl) 7.82 -7.70(m, 15H), δ=7.45-7.38 (m, 2H), 7.29-7.18 (m, 3H), 7.13-7.06 (m, 3H), 7.01 (m,1H), 5.45 (s, 2H), 4.93 (s, 2H), 4.74 (s, 2H), 3.79 (m, 2H), 2.79 (m, 2H), 1.96–1.84 (m, 2H). Example 5

[0039] (4-Oxo-4-((3-phenyl-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)methoxy)butyl)triphenylphosphonium chloride

[0040] (1) Preparation of (3-carboxypropyl)triphenylphosphonium chloride Add 250ml of xylene and 40.8g (155.43mmol, 1eq) of triphenylphosphine to a 500ml three-necked flask, stir and dissolve, add 20.0g (163.2mmol, 1.05eq) of chlorobutyric acid, heat to 150℃, react for 72h, and filter the reaction solution while hot, rinse with 100ml of hot xylene, and dry the filter cake at 60℃ under reduced pressure to constant weight to obtain a white solid product: 45.0g. 1H NMR (400 MHz, CDCl3): δ=7.60-8.10 (m, 15H), 3.34(m, 2 H), 2.86 (m,2 H), 2.19 (m, 2H).

[0041] (2) Preparation of (3-phenyl-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)methanol In a 1L three-necked flask, 56.0g (600mmol, 1eq) of aniline, 54g (2.5mol, 3eq) of paraformaldehyde, 74.4g (600mmol, 1eq) of p-hydroxybenzyl alcohol and 600ml of dioxane were added in sequence, and the mixture was stirred while the temperature was raised to reflux. The reaction was carried out for 8h. The reaction was completed after monitoring by TLC. The reaction solution was filtered and concentrated to dryness, and dichloromethane was added to dissolve until the solution was clear. The solution was washed three times with saturated NaHCO3 aqueous solution and once with deionized water. The solution was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography to obtain an off-white solid product: 24.7g.

[0042] (3) Preparation of (4-oxo-4-((3-phenyl-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)methoxy)butyl)triphenylphosphonium chloride 200 ml of dichloromethane, 17 g (22.0 mmol, 1.1 eq) of (3-carboxypropyl)triphenylphosphonium chloride, 14.2 g (22.0 mmol, 1.1 eq) of TBTU, and 5.6 g (22.0 mmol, 1.1 eq) of DIEA were added to a 500 ml three-necked flask in sequence, and the mixture was stirred at room temperature for 1 h. After completion, 9.74 g (20.0 mmol, 1 eq) of (3-phenyl-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)methanol were added, and the mixture was stirred for 3 h. The reaction was monitored by TLC to be complete. 100 ml of deionized water was added, and the organic phase was separated and washed with 50 ml of deionized water and 50 ml of saturated brine in sequence, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was chromatographed on a silica gel column to obtain 1.76 g of the product. 1H NMR (500 MHz, CDCl3): δ=7.81-7.72 (m, 16H), 7.31–7.29(m, 1H), 7.16–7.07 (m, 4H), 6.95 (s, 1H), 6.79 (s, 1H), 5.38 (d, J = 4.3 Hz,2H), 5.03 (s, 2H), 4.67 (s, 2H), 3.49 (m, 2H), 2.79 (m, 2H), 1.92 (m, 2H). Example 6

[0043] (11-Oxo-11-((3-phenyl-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)methoxy)undecyl)triphenylphosphonium bromide

[0044] (1) Preparation of (10-carboxydecyl)triphenylphosphonium bromide 11-Bromoundecanoic acid 40g (0.15 mol, 1 equiv), triphenylphosphine 43.4g (0.16 mol, 1.1eq), acetonitrile 280ml were added to a 500ml three-necked flask in sequence. After the addition was completed, the reaction solution was refluxed for 48h. The mixture was cooled to room temperature and concentrated in vacuo to remove the solvent. The residue was added with ethyl acetate 200ml, heated under reflux and stirred for 30min, filtered, and the filter cake was washed with ethyl acetate 50ml and dried in vacuo to obtain 72.4g of the product. 1H NMR (400 MHz, CDCl3): δ=7.78–7.84 (m,9H), 7.66–7.78 (m,6H), 3.70–3.81 (m,2H), 2.46 (t,J=7.0Hz,2H), 1.57–1.69 (m,6H), 1.19–1.35 (m,10H).

[0045] (2) Preparation of (3-phenyl-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)methanol According to the method in (2) of Example 5, 25.4 g of (3-phenyl-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)methanol was prepared.

[0046] (3) Preparation of (11-oxo-11-((3-phenyl-3,4-dihydro-2H-benzo[e][1,3]oxazine-6-yl)methoxy)undecyl)triphenylphosphonium bromide In a 500ml three-necked flask, 26.4g (50mmol, 1eq) of (10-carboxydecyl)triphenylphosphonium bromide, 250ml of dichloromethane, 16.9g (52.5mmol, 1.05eq) of TBTU and 7.8g (60mmol, 1.2eq) of diisopropylethylamine were added in sequence and the reaction was stirred at room temperature for 1h. After completion, 13.3g (55mmol, 1.1eq) of (3-phenyl-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)methanol was added to the above solution and the stirring was continued for 6h. After completion, 200ml of deionized water was added, the liquid was separated, the organic phase was separated, and the mixture was washed with 200ml of deionized water and 200ml of saturated brine in sequence, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was subjected to silica gel column chromatography to obtain 13.9g of the product. 1H NMR (400 MHz, CDCl3): δ= 7.80– 7.61 (m, 16H), 7.30 (d,J = 2.2 Hz, 1H), 7.26 – 7.17 (m, 4H), 6.92 (m, 1H), 6.79 (m, 1H), 5.40 (s,2H), 5.05 (s, 2H), 4.66 (s,2H), 3.65 (m, 2H), 2.76 (t, J = 8.5 Hz, 2H),1.67 –1.54 (m, 4H), 1.54 – 1.43 (m, 2H), 1.39 – 1.21 (m, 10H). Example 7

[0047] (4-((3-(4-nitrophenyl)-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)methoxy)-4-oxobutyl)triphenylphosphonium bromide

[0048] (1) Preparation of (3-carboxypropyl)triphenylphosphonium bromide Add 1000ml toluene, 428.4g (1.64mol, 1eq) of triphenylphosphine, and 300g (1.8mol, 1.1eq) of 4-bromobutyric acid to a 2L three-necked flask. After the addition is complete, the reaction solution is refluxed for 60h and monitored by TLC until the reaction is complete. Filter while hot and wash the filter cake with 200ml of hot toluene. After completion, slurry the filter cake with 500ml of ethyl acetate, filter, and vacuum dry the filter cake to obtain 561g of the product. 1H NMR (400 MHz, CDCl3): δ=7.91 -7.66 (m, 15H), 3.31 - 3.22 (m, 2H), 2.57(t, J = 6.3 Hz, 2H), 1.82(m, 2H).

[0049] (2) Preparation of (3-(4-nitrophenyl)-3,4-dihydro-2H-benzo[e][1,3]oxazine-6-yl)methanol According to the method in (2) of Example 5 (2), 24.9 g of (3-phenyl-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)methanol and 35 g of (3-(4-nitrophenyl)-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)methanol were prepared.

[0050] (3) Preparation of (4-((3-(4-nitrophenyl)-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)methoxy)-4-oxybutyl)triphenylphosphonium bromide In a 1000ml three-necked flask, 43.5g (105.0mmol, 1eq) of (3-carboxypropyl)triphenylphosphonium bromide, 200ml of dichloromethane, 33.6g (105.0mmol, 1eq) of TBTU, and 13.5g (105mmol, 1eq) of diisopropylethylamine were added in sequence, and the reaction was stirred at room temperature for 1h. After completion, 33.0g (115.2mmol, 1.1eq) of (3-(4-nitrophenyl)-3,4-dihydro-2H-benzo[e][1,3]oxazine-6-yl)methanol was dissolved in 200ml of dichloromethane and added to the above solution, and the stirring was continued for 4h. The reaction was monitored by TLC to be complete. After completion, 200ml of deionized water was added, and the organic phase was separated and washed with 100ml of deionized water and 100ml of saturated brine in sequence, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was chromatographed on a silica gel column to obtain 40g of the product. 1H NMR (500MHz, CDCl3) δ=8.17 (d, J = 8.1 Hz, 2H), 7.82 -7.70 (m, 16H), 7.29 (d, J = 3.3Hz, 2H), 7.25 (s, 1H), 7.15 – 7.10 (m, 1H), 5.44 (s, 2H), 5.07 (s, 2H), 4.84 (s, 2H), 3.50 (m, 2H), 2.83 (m, 2H), 1.91 (m, 2H). Example 8

[0051] (3-Oxo-3-((3-(pyridin-4-yl)-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)methoxy)propyl)triphenylphosphonium bromide

[0052] (1) Preparation of 2-carboxyethyltriphenylphosphonium bromide According to the method of Example 1, 58 g of 2-carboxyethyltriphenylphosphonium bromide was prepared.

[0053] (2) Preparation of (3-(pyridin-4-yl)-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)methanol 31.0 g (250 mmol, 1 eq) of 4-hydroxybenzyl alcohol, 23.5 g (250 mmol, 1 eq) of 4-aminopyridine, 15 g (250 mmol, 1 eq) of acetic acid, 67.5 g (750 mmol, 3 eq) of polyformaldehyde, 25 ml of ethylene glycol monomethyl ether and 130 ml of toluene were added to a 250 ml four-necked bottle and refluxed for 6 h; 67.5 g of polyformaldehyde was added and refluxed for 6 h, cooled to room temperature, 250 ml of 2N sodium hydroxide solution was added, stirred for 2 h, separated, the organic phase was extracted once with 100 ml of ethyl acetate, the organic phases were combined, washed with 100 ml of deionized water and 100 ml of saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography to obtain 24.8 g of the product. 1 H NMR (400 MHz, CDCl3) δ= 8.34 (m, 2H), 6.74-6.97 (m, 5H), 5.33 (s, 2H), 4.70 (m, 2H), 4.61 (s, 2H).

[0054] (3) Preparation of (3-oxo-3-((3-(pyridin-4-yl)-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)methoxy)propyl)triphenylphosphonium bromide In a 500 ml three-necked flask, 32.6 g of 2-carboxyethyltriphenylphosphonium bromide (78.5 mmol, 0.95 eq), 20 g of (3-(p-methylphenyl)-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)methanol (82.6 mmol, 1 eq), 25.2 g of TBTU (78.5 mmol, 0.9 eq), 20 g of triethylamine (196.3 mmol, 2.5 eq), and 250 ml of dichloromethane were added in sequence and stirred at room temperature for 4 h. After completion, 100 ml of deionized water was added, the liquid was separated, and the organic phase was separated, and washed with 100 ml of deionized water and 100 ml of saturated brine in sequence, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography to obtain 7.3 g of the product. 1 H NMR (400 MHz, CDCl3) δ=8.32 (m, 2H), 7.80-7.71 (m, 6H), 7.70-7.61 (m, 9H), 7.20-6.86 (m, 5H), 5.33 (s, 2H), 4.86 (m, 2H), 4.63 (s, 2H). Example 9

[0055] Preparation of 4-oxo-4-((3-phenyl-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)methoxy)butyl)triphenylphosphonium bromide

[0056] (1) Preparation of (3-carboxypropyl)triphenylphosphonium bromide According to the method of step (1) of Example 4, 45 g (50 g) of (3-carboxypropyl)triphenylphosphonium bromide was prepared.

[0057] (2) Preparation of (3-phenyl-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)methanol According to the method in (2) of Example 5, 32 g of (3-phenyl-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)methanol was prepared.

[0058] (3) Preparation of 4-oxo-4-((3-phenyl-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)methoxy)butyl)triphenylphosphonium bromide In a 1000ml four-necked flask, 50.8g (118.4mmol, 1eq) of (3-carboxypropyl)triphenylphosphonium bromide, 300ml of dichloromethane, 38.0g (118.4mmol, 1eq) of TBTU, and 15.3g (118.4mmol, 1eq) of diisopropylethylamine were added in sequence and stirred for 1h. 31.4g (130.2mmol, 1.1eq) of (3-phenyl-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)methanol was dissolved in 300ml of dichloromethane, and the solution was added to the above reaction solution and stirred for 2h. 100ml of deionized water was added to separate the mixture, and the organic phase was washed with 100ml of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography to obtain 21.5g of the product. 1H NMR (400 MHz, CDCl3): δ=7.81–7.72 (m, 4H), 7.75–7.62 (m, 11H), 7.28–7.20 (m, 2H), 7.13–7.03 (m, 4H), 6.90 (t, J = 7.3 Hz, 1H), 6.77 – 6.71 (m,1H), 5.34 (s, 2H), 4.99 (s, 2H), 4.62 (s, 2H), 3.51 – 3.36 (m, 2H), 2.80 –2.69 (m, 2H), 1.95–1.82 (m, 2H). Example 10

[0059] Tri-n-butyl(4-oxo-4-((3-phenyl-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)methoxy)butyl)phosphonium chloride

[0060] (1) Preparation of tri-n-butyl (carboxypropyl) phosphonium chloride 2g (9.89mmol, 1eq) of tributylphosphine and 1.17g (9.89mmol, 1eq) of chlorobutyric acid were mixed in a glove box and placed in a microwave tube, and then subjected to microwave reaction at 60°C and 250W for 20min. After completion, 50ml of anhydrous ether was added to the mixture, stirred for 15min, the ether was poured out, and the residue was dried in vacuo to obtain 3.1g of the product. 1 H NMR (CDCl3): δ 0.95 (t, 9H), 1.53 (m, 12H), 1.90 (m, 4H), 2.29-2.58 (m, 6H), 2.69 (t, 2H).

[0061] (2) Preparation of (3-phenyl-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)methanol According to the method in (2) of Example 5, 25.8 g of (3-phenyl-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)methanol was prepared.

[0062] (3) Preparation of tri-n-butyl(4-oxo-4-((3-phenyl-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)methoxy)butyl)phosphonium chloride In a 100ml four-necked flask, 3.0g (9.23mmol, 1eq) of tri-n-butyl(carboxypropyl)phosphonium chloride, 25ml of dichloromethane, TBTU (9.23mmol, 1eq), and 2.41ml (9.23mmol, 1.5eq) of diisopropylethylamine were added in sequence and stirred for 1h. 4.04g (9.23mmol, 1eq) of p-(3-phenyl-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)methanol was dissolved in 25ml of dichloromethane, and this solution was added to the above reaction solution and continued to stir for 5h. 100ml of deionized water was added to separate the mixture, and the organic phase was washed with 25ml of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography to obtain 911mg of the product. 1H NMR (400 MHz, CDCl3): δ=7.30 (m, 1H), 7.26 – 7.17 (m, 3H), 6.92 (m, 1H), 6.79 (d,J = 8.9 Hz, 1H), 6.77 – 6.70 (m, 2H), 5.42 (s, 2H), 5.15 (s, 2H), 4.64 (m, 1H), 3.00 (m, 2H), 2.90 (m, 7H), 2.52 (m, 2H), 1.89 – 1.75 (m, 2H), 1.61-1.39(m,14H), 0.94 (t, J = 6.6 Hz, 10H). Embodiment 11

[0063] Preparation of (4-oxo-4-((3-phenyl-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)methoxy)butyl)triphenylphosphonium tetrafluoroborate

[0064] In a 250ml three-necked flask, add 10.0g (15.3mmol, 1eq) of (4-oxo-4-((3-phenyl-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)methoxy)butyl)triphenylphosphonium bromide and 100ml of dichloromethane, and stir to dissolve; dissolve 8.0g (77.0mmol, 5eq) of ammonium tetrafluoroborate in 50ml of water, add the above solution, stir to react for 24h, let stand, separate the layers, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain 9.8g of light yellow solid. 1H NMR (400 MHz, CD3Cl) δ=7.84–7.72 (m, 15H),7.29–7.20 (m, 2H), 7.14–7.03 (m, 4H), 6.97 –6.87 (m, 1H), 6.78–6.72 (m, 1H),5.35 (s, 2H), 5.00 (s, 2H), 4.63 (s, 2H), 3.51–3.39 (m, 2H), 2.82–2.71 (m,3H), 1.89 (m, 2H).19FNMR(376 MHz, CDCl3) δ=-152.02 (s, 0.98F), -152.07(s,3.02F). Example 12

[0065] Preparation of (3-oxo-3-((3-phenyl-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)methoxy)propyl)triphenylphosphonium tetrafluoroborate

[0066] In a 250ml three-necked flask, add 6.40g (10.0mmol, 1eq) of (3-oxo-3-((3-phenyl-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)methoxy)propyl)triphenylphosphonium bromide and 100ml of dichloromethane, and stir to dissolve; dissolve 1.95g (10.0mmol, 1eq) of silver tetrafluoroborate in 50ml of water, add the above solution, and stir to react for 3h. After completion, filter the reaction solution, let it stand to separate the liquids, dry the organic phase over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain 6.4g of light yellow solid. 1H NMR (500 MHz, CDCl3): δ=7.91 (m, 15H), 7.24 (m, 2H), 7.18–7.06 (m, 5H), 6.89 (s, 1H), 6.72 (s, 2H), 5.45 (s, 2H), 4.92 (s, 2H), 4.64 (s, 2H), 3.88 (m, 2H), 2.71 (m, 2H). Example 13

[0067] Preparation and antibacterial properties of antibacterial plastic test samples Take 100 parts of polystyrene, polyethylene or polypropylene powder and 1.5 parts, 2 parts or 3 parts of the product powder in each example, stir and mix evenly. Add into a micro twin-screw extruder, process at 170℃-230℃, melt blend and extrude into granules; then make a 50mm*50mm test sample at 190℃-210℃ injection molding temperature.

[0068] The test method is in accordance with the national standard of the People's Republic of China GB / T 31402-2015 / ISO 22916:2007. The samples are tested by the film method, and the test bacteria are Escherichia coli and Staphylococcus aureus.

[0069] The test results are as follows:

[0070] It can be seen that the plastic made by introducing the benzoxazine structure into the structure of the quaternary phosphonium salt antibacterial agent not only has excellent inhibitory performance against Escherichia coli and Staphylococcus aureus, but also overcomes the shortcomings of existing small molecule antibacterial agents such as easy volatility, easy residue, difficult processing, and poor stability, and has good application prospects.

[0071] The above examples are only for illustrating the technical concept and features of the present invention. Their purpose is to enable people familiar with this technology to understand the content of the present invention and implement it accordingly. They cannot be used to limit the protection scope of the present invention. Any equivalent changes or modifications made according to the spirit of the present invention should be included in the protection scope of the present invention.

Claims

1. A quaternary phosphonium salt compound, characterized in that: Its chemical structure is shown in III. , wherein R1, R2 and R3 are C1-C18 fatty alkyl, phenyl, 3-methylphenyl, 4-methylphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-chlorophenyl, 4-chlorophenyl, 3-bromophenyl, 4-bromophenyl, 3-fluorophenyl, 4-fluorophenyl, benzyl, 3-methylbenzyl, 4-methylbenzyl, 3-methoxybenzyl, 4-methoxybenzyl, 3-chlorobenzyl, 4-chlorobenzyl, 3-bromobenzyl, 4-bromobenzyl, 3-fluorobenzyl, 4-fluorobenzyl; R4, R5 and R6 are hydrogen, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, amino, nitro, cyano, carboxyl, methoxycarbonyl, ethoxycarbonyl, benzyloxycarbonyl; R7 is hydrogen, methyl, ethyl, C3-C18 fatty alkyl, phenyl, 3-methylphenyl, 4-methylphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-chlorophenyl, 4-chlorophenyl, 3-bromophenyl, 4-bromophenyl, 3-Fluorophenyl, 4-fluorophenyl, 3-nitrophenyl, 4-nitrophenyl, 3-nitrilephenyl, 4-nitrilephenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 3-trifluoromethoxyphenyl, 4-trifluoromethoxyphenyl, benzyl and 3-methylbenzyl, 4-methylbenzyl, 3-methoxybenzyl, 4-methoxybenzyl, 3-chlorobenzyl, 4-chlorobenzyl, 3-bromobenzyl, 4-bromobenzyl, 3-fluorobenzyl, 4-fluorobenzyl, 3-nitrobenzene phenyl, 4-nitrophenyl, 3-nitrilephenyl, 4-nitrilephenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 3-trifluoromethoxyphenyl, 4-trifluoromethoxyphenyl, thiophene, furan, thiazole, pyrrole, pyrazole, imidazole, pyridine, pyrimidine, pyrazine, pyridazine, indole, quinoline; X is fluorine, chlorine, bromine, iodine, p-benzoyloxy, benzenesulfonyloxy, methanesulfonyloxy, trifluoromethanesulfonate, tetrafluoroborate, hexafluorophosphate; n=0-20.

2. A method for preparing a quaternary phosphonium salt compound, characterized in that: The steps include: Step (1) Compound 1 and Compound 2 are added to a reaction flask, refluxed in a first solvent, and post-treated to obtain an intermediate I, wherein the first reaction solvent is at least one of toluene, tetrahydrofuran, dioxane, N,N-dimethylformamide, methanol, ethanol, xylene, chlorobenzene, n-hexane and cyclohexane; Step (2) Compound 3 and Compound 5, a second solvent, and paraformaldehyde are added to a reaction flask in sequence, and the reaction mixture is heated to reflux; after the reaction is completed, intermediate II can be obtained by post-treatment, wherein the second reaction solvent is at least one of toluene, xylene, dioxane, ethanol, N,N-dimethylformamide and cyclohexane; Step (3) In the reaction flask, intermediate I, carboxyl activation reagent, organic base and third solvent are added in sequence, stirred at room temperature for 30 min-2 h, and intermediate II is added after completion, and stirring is continued at room temperature for 2-24 h. After completion, post-treatment is performed to obtain the target compound, wherein the carboxyl activation reagent is at least one of DCC, DIC, EDC, HOAT, HOBT, CDI, HATU, HBTU, TBTU, PyBop and PyBop, the organic base is triethylamine or diisopropylethylamine, and the third solvent is chloroform, dichloromethane, tetrahydrofuran, acetonitrile, N,N-dimethylformamide and At least one of dimethyl sulfoxide, wherein R1, R2 and R3 are C1-C18 fatty alkyl, phenyl, 3-methylphenyl, 4-methylphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-chlorophenyl, 4-chlorophenyl, 3-bromophenyl, 4-bromophenyl, 3-fluorophenyl, 4-fluorophenyl, benzyl, 3-methylbenzyl, 4-methylbenzyl, 3-methoxybenzyl, 4-methoxybenzyl, 3-chlorobenzyl, 4-chlorobenzyl, 3-bromobenzyl, 4-bromobenzyl, 3-fluorobenzyl, 4-fluorobenzyl; R4, R5 and R6 are hydrogen, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy R7 is hydrogen, methyl, ethyl, C3-C18 fatty alkyl, phenyl, 3-methylphenyl, 4-methylphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-chlorophenyl, 4-chlorophenyl, 3-bromophenyl, 4-bromophenyl, 3-fluorophenyl, 4-fluorophenyl, 3-nitrophenyl, 4-nitrophenyl, 3-nitrilephenyl, 4-nitrilephenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 3-trifluoromethoxyphenyl, 4-trifluoromethoxyphenyl, benzyl and 3-methylbenzyl, 4-methylbenzyl, 3-methyl 4-(2-(4-nitrophenyl)-2-ol, 2-(2-nitrophenyl)-2-ol, 2-(2-nitrophenyl)-3-ol, 2-(2-nitrophenyl)-4-ol, 2-(2-nitrophenyl)-3-ol, 2-(2-nitrophenyl)-4-ol, 2-(2-nitrophenyl)-3-ol, 2-(2-nitrophenyl)-4-ol, 2-(2-nitrophenyl)-3-ol, 2-(2-nitrophenyl)-4-ol, 2-(2-nitrophenyl)-3-ol, 2-(2-nitrophenyl)-4-ol, 2-(2-nitrophenyl)-3-ol, 2-(2-nitrophenyl)-4-ol, 2-(2-nitrophenyl)-3-ol, 2-(2-nitrophenyl)-4-ol, 2-(2-nitrophenyl)-3-ol, 2-(2-nitrophenyl)-4-ol, 2-(2-nitrophenyl)-3-ol, 2-(2-nitrophenyl)-4-ol, 2-(2-nitrophenyl)-3-ol, 2-(2-nitrophenyl)-4-ol, 2-(2-nitrophenyl)-3-ol, 2-(2-nitrophenyl)-4-ol, 2-(2-nitrophenyl)-3-ol The chemical reaction equation is as follows: .

3. The method for preparing a quaternary phosphonium salt compound according to claim 2, wherein In step (1), the molar ratio of compound 1 to compound 2 is 1:1.0-3.

4. The method for preparing a quaternary phosphonium salt compound according to claim 3, characterized in that: In step (1), the molar ratio of compound 1 to compound 2 is 1:1.0-1.

2.

5. The method for preparing a quaternary phosphonium salt compound according to claim 2, wherein: In step (2), the molar ratio of compound 3, compound 4 and paraformaldehyde is 1:0.8-1.5:2-10.

6. The method for preparing a quaternary phosphonium salt compound according to claim 5, characterized in that: In step (2), the molar ratio of compound 3, compound 4 and paraformaldehyde is 1:0.8-1.2:3-5.

7. The method for preparing a quaternary phosphonium salt compound according to claim 2, characterized in that: In step (3), the molar ratio of the intermediate I, intermediate II, carboxyl activation reagent and organic base is 1:1-1.5:1-1.2:1-5.

8. An antibacterial agent, characterized in that The invention comprises the quaternary phosphonium salt compound as claimed in claim 1 or the quaternary phosphonium salt compound prepared by the preparation method as claimed in any one of claims 2 to 7.

9. Use of the antibacterial agent according to claim 8 in anti-Staphylococcus aureus and anti-Escherichia coli.

10. An antibacterial plastic, characterized in that: The invention comprises the quaternary phosphonium salt compound as claimed in claim 1 or the quaternary phosphonium salt compound prepared by the preparation method as claimed in any one of claims 2 to 7.

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