Phenyl maleimide quaternary phosphonium salt derivative as well as preparation method and application thereof

Abstract

The invention discloses a phenol-based maleimide quaternary phosphonium salt derivative, the structural general formula of which is as shown in formula P. In the formula, R is selected from C1-C8 straight-chain or branched-chain alkyl with substituent groups and aryl with substituent groups, and the substituent groups in the C1-C8 straight-chain or branched-chain alkyl with substituent groups and aryl with substituent groups are at least one of hydrogen, halogen, trifluoromethyl and C1-C6 alkyl groups; x is selected from chlorine or bromine; n is equal to 0-10. The advantages of two antibacterial molecules are combined, the antibacterial performance is improved, the antibacterial spectrum is widened, the advantages of rapid sterilization and long-acting sterilization agents are achieved, and the efficient and broad-spectrum sterilization effect is achieved.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of organic synthesis, and relates to a phenol-based maleimide quaternary phosphonium salt derivative, a preparation method and application thereof. BACKGROUND

[0002] N-phenyl maleimide (NPMI) can be used as a marine antifouling agent on ships, warships, underwater pipelines and other equipment or fishing nets, which can effectively prevent the attachment and reproduction of harmful organisms in water, has low toxicity to fish, and has the characteristics of low pollution and low corrosion.

[0003]

[0004] The structure of 4-phenol maleimide molecule determines its unique function: the maleimide group: it is a highly reactive group that can undergo a rapid, high-selectivity Michael addition reaction with a sulfur group (-SH, also known as mercapto) under mild physiological conditions. This allows it to easily connect to proteins, polypeptides or other thiol-containing molecules. Phenol group: phenol and its derivatives have certain antibacterial properties and can destroy cell membrane structure and denature proteins. By combining the two, 4-phenol maleimide becomes a "bridge" that can be firmly connected to the surface of a material or a carrier on one end and covalently bonded to an antibacterial substance on the other end, while the phenol structure itself also contributes to certain antibacterial activity.

[0005] Maleimide structure compounds have a wide range of biological activities, including antifungal, antibacterial, herbicidal and insecticidal properties, and have excellent antibacterial activity and low cytotoxicity. In summary, the continuous development of new, stable and easy-to-prepare maleimide structure antibacterial agents will promote the development of safer and more effective treatment options for pathogenic microorganisms. Maleimide structure antibacterial agents have broad application prospects in the fields of antifungal, antibacterial, herbicidal and insecticidal, and their structural characteristics make them an important direction for future research and development of antibacterial drugs.

[0006] It is difficult for a single drug to deal with the complex microbial environment. The future trend is to be compounded with bactericides with different mechanisms of action to achieve synergistic effect, expand the antibacterial spectrum, and delay drug resistance. Triphenyl quaternary phosphonium is a kind of cationic bactericide, and quaternary phosphonium salt is a new type of cationic antibacterial agent. Because phosphorus is a third period element, the ionic radius is large, the polarization is strong, and the positive charge is strong, so the quaternary phosphonium salt has good antibacterial property, wide spectrum, low toxicity, high temperature resistance and high stability, and has the characteristics of low foam, strong mud stripping capacity and wide pH application range. In industrial circulating water and oilfield water injection system, it is used as a substitute and upgrading product of traditional bactericides. At the same time, triphenyl quaternary phosphonium salt can increase the cell membrane permeability of molecules, increase the penetration and mitochondrial enrichment capacity of molecules, has synergistic effect with phenolic maleimide, can make up the blank in the antibacterial spectrum of phenolic maleimide, reduce the occurrence of drug resistance, and make the product have a wider antibacterial spectrum. SUMMARY

[0007] In view of the problems existing in the prior art, the present application develops a phenolic maleimide quaternary phosphonium salt derivative, which has the characteristics of easy raw material, simple preparation method and low cost. At the same time, the target compound prepared by the method has the characteristics of good antibacterial property, wide antibacterial spectrum, low toxicity, high temperature resistance and high stability, which can overcome the shortcomings of weak antibacterial property and narrow antibacterial spectrum of phenolic maleimide.

[0008] The present application discloses a phenolic maleimide quaternary phosphonium salt derivative, the structure general formula is as shown in formula P, In the formula, R is selected from substituted C1-C8 straight chain or branched alkyl, substituted aryl, wherein the substituents in the substituted C1-C8 straight chain or branched alkyl, substituted aryl are at least one hydrogen, halogen, trifluoromethyl, C1-C6 alkyl; X is selected from chlorine or bromine; n=0-10.

[0009] In a preferred embodiment of the present application, the structure general formula is as shown in formula P-02, In the formula, X is selected from chlorine or bromine; n=1-6.

[0010] In a preferred embodiment of the present application, the representative compound structure is as follows:

[0011] .

[0012] The present application also discloses a preparation method of a phenolic maleimide quaternary phosphonium salt derivative, comprising the following steps, The chemical reaction equation is as follows:

[0013] (1) in the reaction vessel, compound S01 and compound S02 are added in turn, in the first reaction solvent ethyl acetate or toluene, the reaction temperature is 0-120℃, the reaction time is 8h-24h, after the reaction is completed, cooling, concentration, recrystallization are carried out to obtain compound M1; (2) in the reaction vessel, compound M1 and compound S03 are condensed in the second reaction solvent under the action of condensing agent, the reaction temperature is 0-50℃, the reaction time is 8h-24h, after the reaction is completed, cooling, concentration, recrystallization are carried out to obtain compound phenolic maleimide ester base derivative, the second reaction solvent is selected from one or more mixtures of dichloromethane, tetrahydrofuran, DMF, DMSO, 1,4-dioxane, ethyl acetate and 1,2-dichloroethane;The condensing agent is selected from one or more mixtures of DCC, DIC, EDC, EDCI, HATU, HBTU, TBTU, CDI and EEDQ; In the formula, R is selected from substituted C1-C8 straight chain or branched alkyl, substituted aryl, wherein the substituent group of substituted C1-C8 straight chain or branched alkyl, substituted aryl is at least one hydrogen, halogen, trifluoromethyl, C1-C6 alkyl;X is selected from chlorine or bromine;n=0-10.

[0014] In a preferred embodiment of the present application, in step (2), the amount of substance ratio of compound M and compound S03 is 1:0.3-3.

[0015] In a preferred embodiment of the present application, in step (1), the compound S01 is triphenylphosphine, and the compound prepared in step (2) is triphenylphenolic maleimide quaternary phosphonium salt derivative, wherein X is selected from chlorine or bromine;n=1-6.

[0016] The present application also discloses a preparation method of phenolic maleimide quaternary phosphonium salt derivative, comprising the following steps, The chemical reaction equation is as follows:

[0017] (1) in the reaction vessel, compound S02 and compound S03 are added in turn in the second reaction solvent, and condensation reaction occurs under the action of condensing agent, the reaction temperature is 0-80℃, the reaction time is 1h-24h, after the reaction is completed, cooling, concentration, recrystallization are carried out to obtain compound phenolic maleimide ester base derivative, the second reaction solvent is selected from one or more mixtures of dichloromethane, tetrahydrofuran, DMF, DMSO, 1,4-dioxane, ethyl acetate and 1,2-dichloroethane;The condensing agent is selected from one or more mixtures of DCC, DIC, EDC, EDCI, HATU, HBTU, TBTU, CDI and EEDQ; (2) In a reaction vessel, compound M2 and compound SO1 are reacted in the first reaction solvent, ethyl acetate or toluene, at a temperature of 0℃-150℃ for 8h-36h. After the reaction is complete, the mixture is cooled, concentrated, and recrystallized to obtain compound P. In the formula, R is selected from C1-C8 straight-chain or branched alkyl groups with substituents, and aryl groups with substituents, wherein the substituents in the C1-C8 straight-chain or branched alkyl groups with substituents are at least one hydrogen, halogen, trifluoromethyl, or C1-C6 alkyl; X is selected from chlorine or bromine; n=0-10.

[0018] The present invention also discloses a resin, wherein the above-mentioned phenol-based maleimide quaternary phosphine salt derivative is added or the phenol-based maleimide quaternary phosphine salt derivative is prepared by the above-mentioned preparation method of the phenol-based maleimide quaternary phosphine salt derivative.

[0019] This invention also discloses the application of phenol-based maleimide quaternary phosphine salt derivatives as antibacterial agents or antimicrobial drugs.

[0020] The present invention also discloses the application of the above-mentioned phenol-based maleimide quaternary phosphine salt derivative or the phenol-based maleimide quaternary phosphine salt derivative prepared by the above-mentioned preparation method, or the above-mentioned resin as an antibacterial agent or antibacterial drug.

[0021] In a preferred embodiment of the present invention, the above-mentioned application as an antibacterial agent or antimicrobial drug includes its application against Escherichia coli, Candida albicans, Staphylococcus aureus, Salmonella, Pseudomonas aeruginosa, or Aspergillus niger.

[0022] Maleimide compounds possess a wide range of biological activities, including antifungal, antibacterial, herbicidal, and insecticidal properties. They exhibit excellent antibacterial activity and low cytotoxicity, and their structural characteristics make them an important direction for future antibacterial drug development. This invention comprises synergistic bactericidal effects from two functional groups: phenolic maleimide and quaternary phosphine salt. This enhances antibacterial performance, broadens the antibacterial spectrum, and provides the advantages of long-acting bactericides. It has broad application prospects and development potential, particularly in the marine antifouling, biomedical, healthcare, and food packaging industries, demonstrating highly efficient and broad-spectrum bactericidal effects. Attached Figure Description

[0023] Figure 1 This is the hydrogen NMR spectrum of compound P1.

[0024] Figure 2 The images show high-performance liquid chromatograms of compound P1 at different wavelengths. Detailed Implementation

[0025] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only a part of the embodiments of the present invention, and not all of them. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention. All raw materials used in this invention are purchased from the market.

[0026] I. Synthesis of compounds P1-P9 Example 1

[0027]

[0028] Synthesis of compound P1: (1) Synthesis of compound M-1: Under magnetic stirring, ω-bromocarboxylic acid (64 g, 383 mmol, 1.0 eq) and triphenylphosphine (100 g, 381 mmol, 1.0 eq) were dissolved in 500 mL of ethyl acetate in a 1 L four-necked flask, and the mixture was refluxed under nitrogen protection for 24 hours. After the mixture cooled to room temperature, it was concentrated under vacuum. The residue was crystallized from ethyl acetate, slurried, washed, and dried to give 150 g of the corresponding 3-(carboxypropyl)triphenylphosphine bromide as a white solid, with a yield of 92% and a purity of 98%.

[0029] 1H NMR (400 MHz, DMSO-d6) δ 12.36 (s, 1H), 8.04-7.55 (m, 15H), 3.61 (m, 2H), 2.58-2.36 (m, 2H), 1.72 (m, 2H) ppm. ESI-HRMS (m / z): 349.2 [M-Br] + ; (2) Synthesis of compound P1 Under magnetic stirring, 4-maleiminophenol (30 g, 159 mmol, 1.0 eq) and 3-(propylcarboxy)triphenylphosphine bromide (71.5 g, 167 mmol, 1.05 eq) were dissolved in CH2Cl2 (500 mL) in a 1 L four-necked flask. N,N'-diisopropylcarbodiimide (DIC, 24 g, 190 mmol, 1.2 eq) was slowly added at room temperature. After reacting for 12 h at room temperature, the reaction was monitored by TLC and HPLC. The solvent was directly evaporated by rotary evaporation and concentrated to obtain a yellow viscous semi-solid. Ethanol (300 mL) was added, and the mixture was mechanically stirred, cooled in an ice bath, and slurried for 1 h. The mixture was then filtered, and the filter cake was washed with ethanol (100 mL). The filter cake was dried to obtain 75 g of white solid. Yield: 79%, Purity: 93%.

[0030] 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.04 – 7.70 (m, 15H), 7.39 (d, J = 8.8 Hz, 2H), 7.28 (d, J = 8.8 Hz, 2H), 7.20 (s, 2H), 3.74 – 3.62 (m, 2H), 2.87 (t, J= 6.9 Hz, 2H), 1.99 – 1.81 (m, 2H) ppm. ESI-HRMS (m / z): 520.2 [M-Br] + The calculated value is 520.17 [M-Br]. + .

[0031] Melting point: 255.7-262.2 ℃. Example 2

[0032] Synthesis of compound P2

[0033] (1) Synthesis of compound 4-(butyroxyl)triphenylphosphine bromide: Under magnetic stirring, 5-bromopentanoic acid (50 g, 276 mmol, 1.0 eq) and triphenylphosphine (72.4 g, 276 mmol, 1.0 eq) were dissolved in 500 mL of ethyl acetate in a 1 L four-necked flask, and the mixture was refluxed under nitrogen protection for 24 hours. After the mixture cooled to room temperature, it was concentrated under vacuum. The residue was crystallized from ethyl acetate, slurried, washed, and dried to give 98 g of the corresponding 4-(butanocarboxy)triphenylphosphine bromide as a white solid, with a yield of 80% and a purity of 96%.

[0034] ESI-HRMS (m / z): 363.2 [M-Br] + The calculated value is 363.15 [M-Br]. + ; (2) Synthesis of compound P2 Under magnetic stirring, 4-maleiminophenol (30 g, 159 mmol, 1.0 eq) and 4-(butyricyl)triphenylphosphine bromide (76.3 g, 172 mmol, 1.05 eq) were dissolved in CH2Cl2 (500 mL) in a 1 L four-necked flask. N,N'-diisopropylcarbodiimide (DIC, 24.8 g, 197 mmol, 1.2 eq) was slowly added at room temperature. After reacting for 24 h at room temperature, the reaction was monitored by TLC and HPLC until complete. The solvent was directly evaporated by rotary evaporation and concentrated to obtain a yellow viscous semi-solid. Ethanol (300 mL) was added, and the mixture was mechanically stirred, cooled in an ice bath, and slurried for 1 h. The mixture was then filtered, and the filter cake was washed with ethanol (100 mL). The filter cake was dried to obtain 78 g of a white solid. Yield: 77%, Purity: 98%. 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.02 – 7.73 (m, 15H), 7.38 (d, J = 8.8 Hz, 2H), 7.26 (d, J = 8.8 Hz, 2H), 7.18 (s, 2H), 3.71 – 3.60 (m, 2H), 2.90 (t, J= 6.8 Hz, 2H), 1.92 – 1.75 (m, 2H), 1.38 – 1.26 (m, 2H)ppm. ESI-HRMS (m / z): 534.2 [M-Br] + The calculated value is 534.18 [M-Br]. + . Example 3

[0035] Synthesis of compound P3

[0036] (1) Synthesis of compound 5-(pentanoyl)triphenylphosphine bromide: Under magnetic stirring, 6-bromohexanoic acid (50 g, 256 mmol, 1.0 eq) and triphenylphosphine (67.2 g, 256 mmol, 1.0 eq) were dissolved in 500 mL of ethyl acetate in a 1 L four-necked flask, and the mixture was refluxed under nitrogen protection for 16 hours. After the mixture cooled to room temperature, it was concentrated under vacuum. The residue was crystallized from ethyl acetate, slurried, washed, and dried to give 100 g of the corresponding 5-(pentanocarboxyl)triphenylphosphine bromide as a white solid, with a yield of 85% and a purity of 97%.

[0037] ESI-HRMS (m / z): 377.2 [M-Br] +The calculated value is 377.17 [M-Br]. + ; (2) Synthesis of compound P3 Under magnetic stirring, 4-maleiminophenol (20 g, 106 mmol, 1.0 eq) and 5-(pentanocarboxy)triphenylphosphine bromide (50.8 g, 111 mmol, 1.05 eq) were dissolved in CH2Cl2 (500 mL) in a 1 L four-necked flask. N,N'-diisopropylcarbodiimide (DIC, 16 g, 127 mmol, 1.2 eq) was slowly added at room temperature. After reacting for 12 h at room temperature, the reaction was monitored by TLC and HPLC until complete. The solvent was directly evaporated by rotary evaporation and concentrated to obtain a yellow viscous semi-solid. Ethanol (300 mL) was added, and the mixture was mechanically stirred, cooled in an ice bath, and slurried for 2 h. The mixture was then filtered, and the filter cake was washed with ethanol (200 mL). The filter cake was dried to obtain 50 g of a white solid. Yield: 75%, Purity: 95%. ESI-HRMS (m / z): 548.1 [M-Br] + The calculated value is 548.2 [M-Br]. + . Example 4

[0038] Synthesis of compound P4

[0039] (1) Synthesis of compound 3-(propanoyl)triphenylphosphine bromide: Under magnetic stirring, ω-chlorocarboxylic acid (50 g, 408 mmol, 1.0 eq) and triphenylphosphine (107 g, 408 mmol, 1.0 eq) were dissolved in 500 mL of ethyl acetate in a 1 L four-necked flask, and the mixture was refluxed under nitrogen protection for 36 hours. After the mixture cooled to room temperature, it was concentrated under vacuum. The residue was crystallized from ethyl acetate, slurried, washed, and dried to give 88 g of the corresponding 3-(carboxypropyl)triphenylphosphine chloride as a white solid, with a yield of 62% and a purity of 96%.

[0040] ESI-HRMS (m / z): 349.2 [M-Cl] + The calculated value is 349.14 [M-Cl]. + ; (2) Synthesis of compound P4 Under magnetic stirring, 4-maleiminophenol (25 g, 132 mmol, 1.0 eq) and 3-(propylcarboxy)triphenylphosphine chloride (50.9 g, 132 mmol, 1.0 eq) were dissolved in CH2Cl2 (500 mL) in a 1 L four-necked flask. N,N'-diisopropylcarbodiimide (DIC, 20.9 g, 166 mmol, 1.25 eq) was slowly added at room temperature. After reacting at room temperature for 24 h, the reaction was monitored by TLC and HPLC. The solvent was directly evaporated by rotary evaporation and concentrated to obtain a yellow viscous semi-solid. Ethanol (200 mL) was added, and the mixture was mechanically stirred, cooled in an ice bath, and slurried for 1 h. The mixture was then filtered, and the filter cake was washed with ethanol (100 mL). The filter cake was dried to obtain 52 g of white solid. Yield: 71%, Purity: 96%.

[0041] ESI-HRMS (m / z): 520.3 [M-Cl] + The calculated value is 520.17 [M-Cl]. + . Example 5

[0042] Synthesis of compound P5

[0043] (1) Synthesis of compound 3-(carboxypropyl)tributylphosphine bromide: Under magnetic stirring, ω-bromocarboxylic acid (64 g, 383 mmol, 1.0 eq) and tributylphosphine (60.6 g, 299 mmol, 1.0 eq) were dissolved in 500 mL of ethyl acetate in a 1 L four-necked flask, and the mixture was refluxed under nitrogen protection for 24 hours. After the mixture cooled to room temperature, it was concentrated under vacuum. The residue was crystallized from ethyl acetate, slurried, washed, and dried to give 100 g of the corresponding 3-(carboxypropyl)tributylphosphine bromide as a white solid, with a yield of 90% and a purity of 96%.

[0044] ESI-HRMS (m / z): 289.2 [M-Br] + Calculated value: 289.2 [M-Br] + .

[0045] (2) Synthesis of compound P5 Under magnetic stirring, 4-maleiminophenol (30 g, 159 mmol, 1.0 eq) and 3-(carboxypropyl)tributylphosphine bromide (15 g, 79.3 mmol, 1.0 eq) were dissolved in CH2Cl2 (300 mL) in a 1 L four-necked flask. N,N'-diisopropylcarbodiimide (DIC, 12 g, 95 mmol, 1.2 eq) was slowly added at room temperature. After reacting for 16 h at room temperature, the reaction was monitored by TLC and HPLC. The solvent was directly evaporated by rotary evaporation and concentrated to obtain a yellow viscous semi-solid. Ethanol (200 mL) was added, and the mixture was mechanically stirred, cooled in an ice bath, and slurried for 1 h. The mixture was then filtered, and the filter cake was washed with ethanol (120 mL). The filter cake was dried to obtain 36 g of white solid. Yield: 84%, Purity: 95%.

[0046] ESI-HRMS (m / z): 460.2 [M-Br] + The calculated value is 460.3 [M-Br]. + . Example 6

[0047] Synthesis of compound P6

[0048] (1) Synthesis of compound 3-(propanoyl)diphenyltert-butylphosphine bromide: Under stirring, ω-bromocarboxylic acid (64 g, 383 mmol, 1.0 eq) and diphenyl tert-butylphosphine (60.6 g, 299 mmol, 1.0 eq) were dissolved in 500 mL of ethyl acetate in a 1 L four-necked flask, and the mixture was refluxed under nitrogen protection for 24 hours. After the mixture cooled to room temperature, it was concentrated under vacuum. The residue was crystallized from ethyl acetate, slurried, washed, and dried to give 100 g of the corresponding 3-(carboxypropyl)diphenyl tert-butylphosphine bromide, a white solid, with a yield of 90% and a purity of 96%.

[0049] ESI-HRMS (m / z): 329.2 [M-Br] + Calculated value: 329.17 [M-Br] + .

[0050] (2) Synthesis of compound P6 Under magnetic stirring, 4-maleiminophenol (10 g, 52.9 mmol, 1.0 eq) and 3-(propylcarboxy)diphenyl-tert-butylphosphine bromide (22.7 g, 55.5 mmol, 1.05 eq) were dissolved in CH2Cl2 (150 mL) in a 1 L four-necked flask. N,N'-diisopropylcarbodiimide (DIC, 8.4 g, 66 mmol, 1.2 eq) was slowly added at room temperature. After reacting for 16 h at room temperature, the reaction was monitored by TLC and HPLC. The solvent was directly evaporated by rotary evaporation and concentrated to obtain a yellow viscous semi-solid. Ethanol (300 mL) was added, and the mixture was mechanically stirred, cooled in an ice bath, and slurried for 1 h. The mixture was then filtered, and the filter cake was washed with ethanol (100 mL). The filter cake was dried to obtain 16 g of white solid. Yield: 60%, Purity: 96%.

[0051] ESI-HRMS (m / z): 500.3 [M-Br] + The calculated value is 500.20 [M-Br]. + . Example 7

[0052] Synthesis of compound P7

[0053] (1) Synthesis of compound 3-(propanoyl)tris(4-fluoro-phenyl)phosphine bromide: Under stirring, ω-bromocarboxylic acid (20 g, 120 mmol, 1.0 eq) and tris(4-fluoro-phenyl)phosphine (38.6 g, 122 mmol, 1.0 eq) were dissolved in 500 mL of ethyl acetate in a 1 L four-necked flask, and the mixture was refluxed under nitrogen protection for 24 hours. After the mixture cooled to room temperature, it was concentrated under vacuum. The residue was crystallized from ethyl acetate, slurried, washed, and dried to give 36 g of the corresponding 3-(propylcarboxy)tris(4-fluoro-phenyl)phosphine bromide, a white solid, with a yield of 62% and a purity of 95%.

[0054] ESI-HRMS (m / z): 403.2 [M-Br] + Calculated value: 403.11 [M-Br] + .

[0055] (2) Synthesis of compound P7 Under magnetic stirring, 4-maleiminophenol (10 g, 52.9 mmol, 1.0 eq) and 3-(propylcarboxy)tris(4-fluoro-phenyl)phosphine bromide (26.8 g, 55.5 mmol, 1.05 eq) were dissolved in CH2Cl2 (200 mL) in a 1 L four-necked flask. N,N'-diisopropylcarbodiimide (DIC, 8 g, 63.4 mmol, 1.2 eq) was slowly added at room temperature. After reacting for 16 h at room temperature, the reaction was monitored by TLC and HPLC. The solvent was directly evaporated by rotary evaporation and concentrated to obtain a yellow viscous semi-solid. Ethanol (120 mL) was added, and the mixture was mechanically stirred, cooled in an ice bath, and slurried for 1 h. The mixture was then filtered, and the filter cake was washed with ethanol (50 mL). The filter cake was dried to obtain 18 g of white solid. Yield: 52%, Purity: 96%.

[0056] ESI-HRMS (m / z): 574.2 [M-Br] + The calculated value is 574.14 [M-Br]. + . Example 8

[0057] Synthesis of compound P8

[0058] (1) Synthesis of compound 3-(propanoyl)tris(4-methyl-phenyl)phosphine bromide: Under stirring, ω-bromocarboxylic acid (20 g, 120 mmol, 1.0 eq) and tris(4-methylphenyl)phosphine (38.3 g, 126 mmol, 1.0 eq) were dissolved in 500 mL of ethyl acetate in a 1 L four-necked flask, and the mixture was refluxed under nitrogen protection for 24 hours. After the mixture cooled to room temperature, it was concentrated under vacuum. The residue was crystallized from ethyl acetate, slurried, washed, and dried to give 44 g of the corresponding 3-(propylcarboxy)tris(4-methyl-phenyl)phosphine bromide, a white solid, with a yield of 78% and a purity of 96%.

[0059] ESI-HRMS (m / z): 391.2 [M-Br] + Calculated value: 391.18 [M-Br] + .

[0060] (2) Synthesis of compound P8 Under magnetic stirring, 4-maleiminophenol (10 g, 52.9 mmol, 1.0 eq) and 3-(propylcarboxy)tris(4-methyl-phenyl)phosphine bromide (26.2 g, 55.5 mmol, 1.05 eq) were dissolved in CH2Cl2 (150 mL) in a 1 L four-necked flask. N,N'-diisopropylcarbodiimide (DIC, 8 g, 63.4 mmol, 1.2 eq) was slowly added at room temperature. After reacting for 16 h at room temperature, the reaction was monitored by TLC and HPLC. The solvent was directly evaporated by rotary evaporation and concentrated to obtain a yellow viscous semi-solid. Ethanol (300 mL) was added, and the mixture was mechanically stirred, cooled in an ice bath, and slurried for 1 h. The mixture was then filtered, and the filter cake was washed with ethanol (100 mL). The filter cake was dried to obtain 22 g of white solid. Yield: 65%, Purity: 96%.

[0061] ESI-HRMS (m / z): 562.2 [M-Br] + The calculated value is 562.21 [M-Br]. + . Example 9

[0062] Synthesis of compound P9

[0063] (1) Synthesis of compound (9-carboxynonyl)-tris(4-trifluoromethyl-phenyl)phosphine bromide: Under stirring, 10-bromodecanoic acid (10 g, 39.8 mmol, 1.0 eq) and tris(4-trifluoromethylphenyl)phosphine (18.8 g, 40 mmol, 1.0 eq) were dissolved in 500 mL of ethyl acetate in a 1 L four-necked flask, and the mixture was refluxed under nitrogen protection for 20 hours. After the mixture cooled to room temperature, it was concentrated under vacuum. The residue was crystallized from ethyl acetate, slurried, washed, and dried to give 20 g of (9-carboxynonyl)-tris(4-methyl-phenyl)phosphine bromide, a white solid, with a yield of 70% and a purity of 95%.

[0064] ESI-HRMS (m / z): 637.2 [M-Br] + Calculated value: 637.19 [M-Br] + .

[0065] (2) Synthesis of compound P9 Under magnetic stirring, 4-maleiminophenol (10 g, 52.9 mmol, 1.0 eq) and (9-carboxynonyl)tris-(4-trifluoromethyl-phenyl)phosphine bromide (35.4 g, 55.5 mmol, 1.0 eq) were dissolved in CH2Cl2 (500 mL) in a 1 L four-necked flask. N,N'-diisopropylcarbodiimide (DIC, 8 g, 63.4 mmol, 1.2 eq) was slowly added at room temperature. After reacting for 36 h at room temperature, the reaction was monitored by TLC and HPLC. The solvent was then directly rotary evaporated and concentrated to obtain a yellow viscous liquid. Rapid silica gel column chromatography was performed with MeOH:CH2Cl2 as eluent at a ratio of 1:50 ~ 1:20 to obtain 28 g of a white solid. Yield: 60%, purity: 95%.

[0066] ESI-HRMS (m / z): 808.3 [M-Br] + The calculated value is 808.2 [M-Br]. + .

[0067] II. Microbial sterilization rate test: Preparation of antibacterial plastic test samples and testing of their antibacterial properties: Take 100 parts of polystyrene, polyethylene, or polypropylene powder, and in each example, 1.5, 2, or 3 parts of the product powder, and mix thoroughly. Add the mixture to a micro twin-screw extruder at a processing temperature of 170℃-230℃ for melt blending and granulation; then, prepare 50mm*50mm test samples at an injection molding temperature of 190℃-210℃. The test method follows the People's Republic of China National Standard GB / T 31402-2015 / ISO 22916:2007, using the film-coating method to test the samples. The test bacteria are Escherichia coli and Staphylococcus aureus.

[0068] The results of the antibacterial activity tests of the compounds are as follows (Table 1):

[0069] illustrate: 1. No colony growth was observed in the negative control group.

[0070] In conclusion, the quaternary phosphonium salt derivatives of phenol-based maleimide exhibit excellent bactericidal effects against *Escherichia coli*, *Candida albicans*, *Staphylococcus aureus*, *Salmonella*, *Pseudomonas aeruginosa*, and *Aspergillus niger*. They also demonstrate strong bactericidal activity against *Candida albicans* and *Aspergillus niger*, which are less inhibited by phenol-based maleimide, thus expanding the antibacterial spectrum and application range of phenol-based maleimide. Specifically, P1 shows excellent bactericidal activity against *Escherichia coli*, *Candida albicans*, *Staphylococcus aureus*, *Salmonella*, *Pseudomonas aeruginosa*, and *Aspergillus niger*, while P1-P9 all show excellent bactericidal activity against *Escherichia coli*.

[0071] The above examples are only for illustrating the technical concept and features of the present invention, and are intended to enable those skilled in the art to understand the content of the present invention and implement it accordingly. They should not be used to limit the scope of protection of the present invention. All equivalent transformations or modifications made in accordance with the spirit and essence of the present invention should be covered within the scope of protection of the present invention.

Claims

1. A phenol-based maleimide quaternary phosphine salt derivative, characterized in that, Its general structural formula is shown in equation P. In the formula, R is selected from C1-C8 straight-chain or branched alkyl groups with substituents, and aryl groups with substituents, wherein the substituents in the C1-C8 straight-chain or branched alkyl groups with substituents are at least one hydrogen, halogen, trifluoromethyl, or C1-C6 alkyl; X is selected from chlorine or bromine; n=0-10.

2. The phenol-based maleimide quaternary phosphine salt derivative according to claim 1, characterized in that, Its general structural formula is shown in formula P-02. In the formula, X is selected from chlorine or bromine; n = 1-6.

3. The phenol-based maleimide quaternary phosphine salt derivative according to claim 1 or 2, characterized in that, The structures of its representative compounds are as follows: .

4. A method for preparing a phenol-based maleimide quaternary phosphine salt derivative, characterized in that, Includes the following steps, The chemical reaction equation is as follows: , (1) Compound SO1 and compound SO2 were added to the reaction vessel in sequence in ethyl acetate or toluene as the first reaction solvent. The reaction temperature was 0℃-120℃ and the reaction time was 8h-24h. After the reaction was complete, the mixture was cooled, concentrated, and recrystallized to obtain compound M1. (2) In the reaction vessel, compound M1 and compound SO3 undergo a condensation reaction in the second reaction solvent under the action of a condensing agent. The reaction temperature is 0-50℃ and the reaction time is 8h-24h. After the reaction is complete, the mixture is cooled, concentrated, and recrystallized to obtain a phenolic maleimide ester derivative. The second reaction solvent is selected from one or more of dichloromethane, tetrahydrofuran, DMF, DMSO, 1,4-dioxane, ethyl acetate, and 1,2-dichloroethane. The condensing agent is selected from one or more of DCC, DIC, EDC, EDCI, HATU, HBTU, TBTU, CDI, and EEDQ. In the formula, R is selected from C1-C8 straight-chain or branched alkyl groups with substituents, and aryl groups with substituents, wherein the substituents in the C1-C8 straight-chain or branched alkyl groups with substituents are at least one hydrogen, halogen, trifluoromethyl, or C1-C6 alkyl; X is selected from chlorine or bromine; n=0-10.

5. The method for preparing the phenol-based maleimide quaternary phosphine salt derivative according to claim 4, characterized in that, In step (2), the molar ratio of compound M1 to compound SO3 is 1:0.3-3.

6. The method for preparing the phenol-based maleimide quaternary phosphine salt derivative according to claim 5, characterized in that, In step (1), the compound SO1 is triphenylphosphine, and in step (2), the compound obtained is a triphenylphenol maleimide quaternary phosphine salt derivative, wherein X is selected from chlorine or bromine; n=1-6.

7. A method for preparing a phenol-based maleimide quaternary phosphine salt derivative, characterized in that, Includes the following steps, The chemical reaction equation is as follows: ， (1) Compound SO2 and compound SO3 are added sequentially to the second reaction solvent in a reaction vessel. Under the action of a condensing agent, a condensation reaction occurs. The reaction temperature is 0-80℃ and the reaction time is 1h-24h. After the reaction is complete, the mixture is cooled, concentrated, and recrystallized to obtain a phenolic maleimide ester derivative. The second reaction solvent is selected from one or more of dichloromethane, tetrahydrofuran, DMF, DMSO, 1,4-dioxane, ethyl acetate, and 1,2-dichloroethane. The condensing agent is selected from one or more of DCC, DIC, EDC, EDCI, HATU, HBTU, TBTU, CDI, and EEDQ. (2) In a reaction vessel, compound M2 and compound SO1 are reacted in the first reaction solvent, ethyl acetate or toluene, at a temperature of 0℃-150℃ for 8h-36h. After the reaction is complete, the mixture is cooled, concentrated, and recrystallized to obtain compound P. In the formula, R is selected from C1-C8 straight-chain or branched alkyl groups with substituents, and aryl groups with substituents, wherein the substituents in the C1-C8 straight-chain or branched alkyl groups with substituents are at least one hydrogen, halogen, trifluoromethyl, or C1-C6 alkyl; X is selected from chlorine or bromine; n=0-10.

8. A resin, characterized in that, Add the phenol-based maleimide quaternary phosphine salt derivative as claimed in any one of claims 1-3 or obtain the phenol-based maleimide quaternary phosphine salt derivative by the method for preparing the phenol-based maleimide quaternary phosphine salt derivative as claimed in any one of claims 4-7.

9. The phenol-based maleimide quaternary phosphine salt derivative prepared by the method according to any one of claims 1-3 or any one of claims 4-7, or the resin according to claim 8, as an antibacterial agent or antimicrobial drug.

10. The application of the phenol-based maleimide quaternary phosphine salt derivative according to claim 9 as an antibacterial agent, characterized in that, The applications as antibacterial agents or antimicrobial drugs include those against Escherichia coli, Candida albicans, yeast, Staphylococcus aureus, Salmonella, Bacillus subtilis, Listeria, sulfate-reducing bacteria, Pseudomonas aeruginosa, or Aspergillus niger.

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