Alkyl-linked benzisothiazolinone quaternary phosphonium salt derivative as well as preparation method and application thereof

Abstract

The invention discloses a preparation method of an alkyl-linked benzisothiazolinone quaternary phosphonium salt derivative, which comprises the following steps: (1) sequentially adding a compound S01 and a compound S02 into a reaction container, reacting in a first reaction solvent ethyl acetate or toluene at the temperature of 0-120 DEG C for 1-24 hours, and cooling, concentrating and recrystallizing after the reaction is completed to obtain a compound M; and (2) in the reaction container, carrying out substitution reaction on the compound M and the compound S03 in a second reaction solvent under the action of alkali at the reaction temperature of 0-150 DEG C for 1-36 hours, and after the reaction is completed, evaporating, concentrating and recrystallizing to obtain the compound alkyl-linked benzisothiazolinone quaternary phosphonium salt derivative. The antibacterial performance and the antibacterial spectrum are improved, the advantages of rapid sterilization and long-acting bactericide are achieved, and the efficient and broad-spectrum sterilization effect is achieved.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, and to an alkyl-linked benzisothiazolinone quaternary phosphonium salt derivative, its preparation method, and its application. Background Technology

[0002] 2-Butyl-1,2-benzisothiazolin-3-one, commonly known as BBIT, is an organic compound that is a brownish-yellow viscous liquid at room temperature.

[0003]

[0004] BBIT is a highly effective industrial bactericide, preservative, and fungicide. Its mechanism of action involves disrupting the cell membranes of microorganisms and inhibiting their respiration, leading to microbial death. Its antimicrobial spectrum includes bacteria (especially Gram-positive bacteria), fungi (molds), and yeasts. Due to its high efficiency and liquid properties, BBIT is widely used in both aqueous and non-aqueous systems requiring long-lasting microbial protection. For example, in the polymer and adhesive industry: it is formulated into aqueous polymer emulsions as an in-can preservative, protecting acrylic, VAE, and styrene-butadiene emulsions from microbial contamination and deterioration (odor, demulsification, clumping) during production, storage, and transportation. In adhesives and sealants: it is used in water-based and solvent-based adhesives and sealants to prevent failure due to mold growth. In plastics: it can be added as an additive to PVC and other plastics to provide durable anti-mold properties, commonly used in waterproof membranes and outdoor plastic products. In coatings and paints, it provides protection during storage and imparts long-lasting anti-mildew and anti-algae properties to the dry film, making it particularly suitable for interior and exterior wall coatings in humid environments. In metalworking fluids, it acts as a bactericide in water-based metalworking fluids (cutting fluids, grinding fluids), effectively extending their service life, preventing odor and deterioration due to microbial spoilage, and protecting machine tools and workpieces. In water treatment, it is used in industrial circulating cooling water systems, paper mill white water systems, etc., as a bactericide and algaecide to control sludge formation in the system.

[0005] Triphenyl quaternary phosphonium salts can be used as a key component in antibacterial masterbatches, added to plastic products to create materials with long-lasting antibacterial properties. Due to their excellent thermal stability, they can withstand the processing temperatures (typically exceeding 200°C) of most plastics (such as PP, PE, ABS, etc.) without decomposing or failing during processing. They exhibit good inhibitory and bactericidal effects against Gram-positive bacteria, Gram-negative bacteria, molds, yeasts, and even algae; they have good chemical stability: heat-resistant, acid and alkali-resistant, and light-stable, with a wide range of applications; they have low toxicity and relatively good environmental compatibility: at the correct concentration, they have low toxicity to mammals and better biodegradability than some traditional antibacterial agents; they are long-lasting: due to their good stability, they are not easily lost, providing long-lasting protection; and they have strong surface affinity: their positively charged properties allow them to firmly adsorb onto the surfaces of various materials, providing continuous contact antibacterial protection.

[0006] Triphenyl quaternary phosphonium salt antibacterial agents are generally more expensive to produce than traditional cationic antibacterial agents such as quaternary ammonium salts; their antibacterial efficacy may be affected by water hardness, organic matter, or anionic surfactants; and long-term use alone may still lead to a certain degree of drug resistance in microorganisms. Therefore, in practical applications, it is often recommended to use them in combination with or in rotation with bactericides of other mechanisms of action.

[0007] Therefore, combining 2-butyl-1,2-benzisothiazolin-3-one compounds with quaternary phosphine salts can overcome the shortcomings of each other, overcome drug resistance, and exert maximum effect, which is a direction worthy of future research. Summary of the Invention

[0008] In view of the problems existing in the prior art, the present invention develops an alkyl-linked benzisothiazolinone quaternary phosphonium salt derivative. Its preparation method solves the problems of multiple steps, low yield and harsh reaction conditions in the production of benzisothiazolinone compounds in the current technology. The target compound obtained by this method has the characteristics of good antibacterial properties, broad antibacterial spectrum, low toxicity, low drug resistance, high temperature resistance and high stability.

[0009] This invention also discloses a method for preparing alkyl-linked benzisothiazolinone quaternary phosphonium salt derivatives, comprising the following steps: The chemical reaction equation is as follows: , (1) Compound SO1 and compound SO2 were added to the reaction vessel in sequence. The reaction was carried out in the first reaction solvent, ethyl acetate or toluene, at a temperature of 0℃-120℃ for 1-24 h. After the reaction was completed, the mixture was cooled, concentrated, and recrystallized to obtain compound M. (2) In a reaction vessel, compound M and compound SO3 undergo a substitution reaction in the second reaction solvent under the action of an alkali. The reaction temperature is 0-150℃ and the reaction time is 1-36h. After the reaction is complete, the mixture is evaporated, concentrated, and recrystallized to obtain an alkyl-linked benzisothiazolinone quaternary phosphorus salt derivative. The second reaction solvent is selected from one or more of acetonitrile, acetone, tetrahydrofuran, DMF, DMSO, and 1,4-dioxane. The alkali is selected from one or more of lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, lithium isopropoxide, sodium isopropoxide, potassium isopropoxide, sodium hydride, and potassium hydride. In the formula, R is selected from C1-C straight-chain or branched alkyl groups with substituents, five-membered rings or aryl groups with substituents, wherein the substituents in the C1-C straight-chain or branched alkyl groups with substituents, five-membered rings or aryl groups with substituents are at least one hydrogen, halogen, trifluoromethyl, C1-C6 alkyl; X is selected from chlorine or bromine; n=0-10.

[0010] In a preferred embodiment of the present invention, in step (2), the molar ratio of compound M to compound SO3 is 1:0.3-3.

[0011] In a preferred embodiment of the present invention, in step (1), compound SO1 is triphenylphosphine; in step (2), compound P-O2 is a triphenylalkyl-linked benzoisothiazolinone quaternary phosphonium salt compound. In the formula, X is selected from chlorine or bromine; n = 1-6.

[0012] This invention discloses an alkyl-linked benzisothiazolinone quaternary phosphonium salt derivative, the general structural formula of which is shown in Formula P. In the formula, R is selected from C1-C straight-chain or branched alkyl groups with substituents, five-membered rings or aryl groups with substituents, wherein the substituent in the C1-C straight-chain or branched alkyl groups with substituents, the five-membered rings or aryl groups with substituents is at least one hydrogen, halogen, trifluoromethyl, C1-C6 alkyl; X is selected from chlorine or bromine; n=0-10.

[0013] In a preferred embodiment of the present invention, its general structural formula is shown in formula P-02. In the formula, X is selected from chlorine or bromine; n = 1-6.

[0014] In a preferred embodiment of the present invention, the representative compound structure is as follows: .

[0015] The present invention also discloses the application of an alkyl-linked benzisothiazolinone quaternary phosphonium salt derivative as an antibacterial agent or antibacterial drug.

[0016] In a preferred embodiment of the present invention, the use as an antibacterial agent or antimicrobial drug includes its use against Escherichia coli, Candida albicans, Staphylococcus aureus, Salmonella, Pseudomonas aeruginosa, or Aspergillus niger.

[0017] This invention comprises two functional groups, benzisothiazolinone and quaternary phosphine salt, which synergistically kill bacteria, improving antibacterial properties and antibacterial spectrum. It has the advantages of rapid and long-lasting bactericidal action, and has broad application prospects and development space. In particular, it has a highly efficient and broad-spectrum bactericidal effect in the biomedical, healthcare and food packaging industries. At the same time, this invention improves the problem of easy precipitation in resins caused by the small molecular weight and weak interaction of 2-butyl-1,2-benzisothiazolin-3-one, thus improving the durability of antibacterial ability. Detailed Implementation

[0018] 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.

[0019] All raw materials used in this invention are purchased from the market.

[0020] I. Synthesis of compounds P1-P12 Example 1

[0021]

[0022] (1) Synthesis of compound M-1: Under magnetic stirring, 1,4-dibromobutane (120 g, 556 mmol, 1.0 eq) and triphenylphosphine (146 g, 556 mmol, 1.0 eq) were dissolved in 1000 mL of ethyl acetate in a 1 L four-necked flask, and the mixture was refluxed for 8 hours under argon protection. 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 206 g of (4-bromobutyl)triphenylphosphine bromide as a white solid, with a yield of 78% and a purity of 99%.

[0023] 1H NMR (400 MHz, CDCl3) δ 7.97-7.56 (m, 15H), 4.06-3.92 (m, 2H), 3.61(t, J = 5.8 Hz, 2H), 2.43-2.27 (m, 2H), 1.94-1.76 (m, 2H) ppm. ESI-HRMS (m / z): 397.2 [M-Br] + ; (2) Synthesis of compound P1.

[0024] Under magnetic stirring, 1,2-benzisothiazol-3-one (20 g, 133.2 mmol, 1.0 eq) was dissolved in THF (300 mL) in a 1 L four-necked flask. Sodium tert-butoxide (14 g, 146 mmol, 1.1 eq) was slowly added in portions at room temperature. The reaction was allowed to proceed for 0.5 h at room temperature. Then, (4-bromobutyl)triphenylphosphine bromide (63.3 g, 133.2 mmol, 1.0 eq) was added, and the reaction was allowed to proceed for 14 h at room temperature. After the reaction was completed under the monitoring of TLC and HPLC, the solvent was directly evaporated by rotary evaporation and concentrated to obtain a light yellow viscous semi-solid. Isopropanol (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 isopropanol (50 mL). The filter cake was dried to obtain 48 g of white solid. Yield: 66%, Purity: 98%.

[0025] ESI-HRMS (m / z): 468.2 [M-Br] + Calculated molecular weight: 548.48. Example 2

[0026] Synthesis of compound P2

[0027] Following the synthetic method of compound M-1, 80 g of (3-bromopropyl)triphenylphosphine bromide was synthesized.

[0028] Under magnetic stirring, 1,2-benzisothiazol-3-one (21 g, 138.9 mmol, 1.0 eq) was dissolved in THF (300 mL) in a 1 L four-necked flask. Sodium tert-butoxide (14.7 g, 152.8 mmol, 1.1 eq) was slowly added in portions at room temperature. The reaction was allowed to proceed for 0.5 h at room temperature. Then, (3-bromopropyl)triphenylphosphine bromide (64.5 g, 138.9 mmol, 1.0 eq) was added. After reacting for 11 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 light yellow viscous semi-solid. Isopropanol (300 mL) was added, and the mixture was mechanically stirred and cooled in an ice bath for 1 h. The mixture was then filtered, and the filter cake was washed with isopropanol (50 mL). The filter cake was dried to obtain 40 g of white solid. Yield: 54%, Purity: 97%.

[0029] ESI-HRMS (m / z): 454.2 [M-Br] + Calculated molecular weight: 534.45. Example 3

[0030] Synthesis of compound P3

[0031] 100g of (5-bromopentyl)triphenylphosphine bromide was synthesized using the same method as compound M-1.

[0032] Under magnetic stirring, 1,2-benzisothiazol-3-one (20.5 g, 135.6 mmol, 1.0 eq) was dissolved in 300 mL of THF in a 1 L four-necked flask. Sodium tert-butoxide (14.3 g, 149.1 mmol, 1.1 eq) was slowly added in portions at room temperature. The reaction was allowed to proceed for 0.5 h at room temperature. Then, (5-bromopentyl)triphenylphosphine bromide (66.7 g, 135.5 mmol, 1.0 eq) was added. After reacting for 8 h at room temperature, the reaction was monitored by TLC and HPLC. The solvent was then directly evaporated by rotary evaporation and concentrated to obtain a light yellow viscous semi-solid. Isopropanol (300 mL) was added, and the mixture was mechanically stirred and cooled in an ice bath for 1 h. The mixture was then filtered, and the filter cake was washed with isopropanol (50 mL). The filter cake was dried to obtain 39 g of white solid. Yield: 51%, Purity: 96%.

[0033] ESI-HRMS (m / z): 482.2 [M-Br], calculated molecular weight: 562.51. Example 4

[0034] Synthesis of compound P4

[0035] Following the synthetic method of compound M-1, 100g of (6-bromohexyl)triphenylphosphine bromide was synthesized.

[0036] Under magnetic stirring, 1,2-benzisothiazol-3-one (21.5 g, 142.2 mmol, 1.0 eq) was dissolved in THF (300 mL) in a 1 L four-necked flask. Sodium tert-butoxide (15 g, 156.4 mmol, 1.1 eq) was slowly added in portions at room temperature. The reaction was allowed to proceed for 0.5 h at room temperature. Then, (6-bromohexyl)triphenylphosphine bromide (72 g, 142.2 mmol, 1.0 eq) was added. After reacting for 8 h at room temperature, the reaction was monitored by TLC and HPLC. The solvent was then directly evaporated by rotary evaporation and concentrated to obtain a light yellow viscous semi-solid. Isopropanol (300 mL) was added, and the mixture was mechanically stirred and cooled in an ice bath for 1 h. The mixture was then filtered, and the filter cake was washed with isopropanol (50 mL). The filter cake was dried to obtain 40 g of white solid. Yield: 49%, Purity: 95%.

[0037] ESI-HRMS (m / z): 496.2 [M-Br], calculated molecular weight: 576.53. Example 5

[0038] Synthesis of compound P5

[0039] Following the synthetic method of compound M-1, 95 g of (7-bromoheptyl)triphenylphosphine bromide was synthesized.

[0040] Under magnetic stirring, 1,2-benzisothiazol-3-one (22 g, 145.5 mmol, 1.0 eq) was dissolved in THF (300 mL) in a 1 L four-necked flask. Sodium tert-butoxide (15.4 g, 160.1 mmol, 1.1 eq) was slowly added in portions at room temperature. The reaction was allowed to proceed for 0.5 h at room temperature. Then, (7-bromoheptyl)triphenylphosphine bromide (75.7 g, 145.5 mmol, 1.0 eq) was added. After reacting for 8 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 light yellow viscous semi-solid. Isopropanol (300 mL) was added, and the mixture was mechanically stirred and cooled in an ice bath for 1 h. The mixture was then filtered, and the filter cake was washed with isopropanol (50 mL). The filter cake was dried to obtain 45 g of white waxy solid. Yield: 52%, Purity: 95%.

[0041] ESI-HRMS (m / z): 510.2 [M-Br], calculated molecular weight: 590.56. Example 6

[0042] Synthesis of compound P6

[0043] Following the synthetic method of compound M-1, 57 g of (8-bromooctyl)triphenylphosphine bromide was synthesized.

[0044] Under magnetic stirring, 1,2-benzisothiazol-3-one (10 g, 66.2 mmol, 1.0 eq) was dissolved in THF (250 mL) in a 1 L four-necked flask. Sodium tert-butoxide (7 g, 72.8 mmol, 1.1 eq) was slowly added in portions at room temperature. The reaction was allowed to proceed for 0.5 h at room temperature. Then, (8-bromooctyl)triphenylphosphine bromide (35.3 g, 66.2 mmol, 1.0 eq) was added and the reaction was allowed to proceed for 12 h at room temperature. After the reaction was completed under TLC and HPLC monitoring, the solvent was directly evaporated by rotary evaporation and concentrated to obtain a light yellow viscous semi-solid. Isopropanol (200 mL) was added, and the mixture was mechanically stirred and cooled in an ice bath for 1 h. The mixture was then filtered, and the filter cake was washed with isopropanol (50 mL). The filter cake was dried to obtain 22 g of a white oily liquid. Yield: 55%, Purity: 93%.

[0045] ESI-HRMS (m / z): 524.2 [M-Br], calculated molecular weight: 604.59. Example 7

[0046] Synthesis of compound P7

[0047] Following the synthetic method of compound M-1, 85g of (4-chlorobutyl)triphenylphosphine chloride was synthesized.

[0048] Under magnetic stirring, 1,2-benzisothiazol-3-one (20.5 g, 135.6 mmol, 1.0 eq) was dissolved in THF (300 mL) in a 1 L four-necked flask. Sodium tert-butoxide (14.3 g, 149 mmol, 1.1 eq) was slowly added in portions at room temperature. The reaction was allowed to proceed for 0.5 h at room temperature. Then, (4-chlorobutyl)triphenylphosphine chloride (58.8 g, 135.6 mmol, 1.0 eq) was added. After reacting for 10 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 light yellow viscous semi-solid. Isopropanol (300 mL) was added, and the mixture was mechanically stirred and cooled in an ice bath for 1 h. The mixture was then filtered, and the filter cake was washed with isopropanol (50 mL). The filter cake was dried to obtain 44 g of white solid. Yield: 64%, Purity: 97%.

[0049] ESI-HRMS (m / z): 468.1 [M-Br], calculated molecular weight: 590.56. Example 8

[0050] Synthesis of compound P8

[0051] Following the synthetic method of compound M-1, 54 g of (4-bromobutyl)tributylphosphine bromide was synthesized.

[0052] Under magnetic stirring, 1,2-benzisothiazol-3-one (10 g, 66.2 mmol, 1.0 eq) was dissolved in THF (100 mL) in a 1 L four-necked flask. Sodium tert-butoxide (7 g, 72.8 mmol, 1.1 eq) was slowly added in portions at room temperature. The reaction was allowed to proceed for 0.5 h at room temperature. Then, (4-bromobutyl)tributylphosphine bromide (22.4 g, 66.2 mmol, 1.0 eq) was added. After reacting for 10 h at room temperature, the reaction was monitored by TLC and HPLC. The solvent was then directly rotary evaporated and concentrated to obtain a light yellow viscous semi-solid. Rapid silica gel column chromatography was performed with MeOH:CH2Cl2 as eluent at a ratio of 1:50 to 1:20 to obtain 15 g of white solid. Yield: 55%, purity: 94%.

[0053] ESI-HRMS (m / z): 408.2 [M-Br], calculated molecular weight: 488.51. Example 9

[0054] Synthesis of compound P9

[0055] Following the synthetic method of compound M-1, 47 g of (4-bromobutyl)-tert-butyldiphenylphosphine bromide was synthesized. Under magnetic stirring, 1,2-benzisothiazol-3-one (10 g, 66.2 mmol, 1.0 eq) was dissolved in THF (100 mL). Sodium tert-butoxide (7 g, 72.8 mmol, 1.1 eq) was slowly added in portions at room temperature. The reaction was allowed to proceed for 0.5 h at room temperature. Then, (4-bromobutyl)-tert-butyldiphenylphosphine bromide (25 g, 66.2 mmol, 1.0 eq) was added, and the reaction was allowed to proceed for 8 h at room temperature. After the reaction was completed under TLC and HPLC monitoring, the solvent was directly rotary evaporated and concentrated to obtain a light yellow viscous semi-solid. Rapid silica gel column chromatography was performed with MeOH:CH2Cl2 as eluent at a ratio of 1:50 ~ 1:20 to obtain 18 g of a white solid. Yield: 67%, purity: 94%.

[0056] ESI-HRMS (m / z): 448.2 [M-Br], calculated molecular weight: 528.49. Example 10

[0057] Synthesis of compound P10

[0058] Following the synthetic method of compound M-1, 53 g of (4-bromobutyl)tris-(4-fluoro-phenyl)phosphine bromide was synthesized.

[0059] Under magnetic stirring, 1,2-benzisothiazol-3-one (10 g, 66.2 mmol, 1.0 eq) was dissolved in THF (100 mL) in a 1 L four-necked flask. Sodium tert-butoxide (7 g, 72.8 mmol, 1.1 eq) was slowly added in portions at room temperature. The reaction was allowed to proceed for 0.5 h at room temperature. Then (4-bromobutyl)tris-(4-fluoro-phenyl)phosphine bromide (35.2 g, 66.2 mmol, 1.0 eq) was added. After reacting for 8 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 light yellow viscous semi-solid. Isopropanol (150 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 isopropanol (50 mL). The filter cake was dried to obtain 20 g of white solid. Yield: 50%, Purity: 96%.

[0060] ESI-HRMS (m / z): 522.1 [M-Br], calculated molecular weight: 602.45. Example 11

[0061] Synthesis of compound P11

[0062] Following the synthetic method of compound M-1, 82g of (4-bromobutyl)tris-(4-trifluoromethyl-phenyl)phosphine bromide was synthesized.

[0063] Under magnetic stirring, 1,2-benzisothiazol-3-one (10 g, 66.2 mmol, 1.0 eq) was dissolved in THF (100 mL) in a 1 L four-necked flask. Sodium tert-butoxide (7 g, 72.8 mmol, 1.1 eq) was slowly added in portions at room temperature. The reaction was allowed to proceed for 0.5 h at room temperature. Then, (4-bromobutyl)tris-(4-trifluoromethyl-phenyl)phosphine bromide (45 g, 66 mmol, 1.0 eq) was added. After reacting for 8 h at room temperature, the reaction was monitored by TLC and HPLC. The solvent was then directly evaporated by rotary evaporation and concentrated to obtain a light yellow viscous semi-solid. Isopropanol (200 mL) was added, and the mixture was mechanically stirred and cooled in an ice bath for 1 h. The mixture was then filtered, and the filter cake was washed with isopropanol (50 mL). The filter cake was dried to obtain 30 g of white solid. Yield: 60%, Purity: 96%.

[0064] ESI-HRMS (m / z): 672.1 [M-Br] + Calculated molecular weight: 752.47. Example 12

[0065] Synthesis of compound P12

[0066] Following the synthetic method of compound M-1, 62g of (4-bromobutyl)tris-(4-methyl-phenyl)phosphine bromide was synthesized.

[0067] Under magnetic stirring, 1,2-benzisothiazol-3-one (10 g, 66.2 mmol, 1.0 eq) was dissolved in THF (100 mL) in a 1 L four-necked flask. Sodium tert-butoxide (7 g, 72.8 mmol, 1.1 eq) was slowly added in portions at room temperature. The reaction was allowed to proceed for 0.5 h at room temperature. Then (4-bromobutyl)tris-(4-methyl-phenyl)phosphine bromide (34.4 g, 66 mmol, 1.0 eq) was added. After reacting for 8 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 light yellow viscous semi-solid. Isopropanol (250 mL) was added, and the mixture was mechanically stirred and cooled in an ice bath for 1 h. The mixture was then filtered, and the filter cake was washed with isopropanol (50 mL). The filter cake was dried to obtain 20 g of white solid. Yield: 51%, Purity: 98%.

[0068] ESI-HRMS (m / z): 510.2 [M-Br] + Calculated molecular weight: 590.56.

[0069] II. Microbial sterilization rate test: Referencing GB15979-2024 E.5.1, the bactericidal performance test of antibacterial agents; Preparation of bacterial suspension; Pick typical colonies from the target strain (purchased second or third generation strain slant) using an inoculation loop and inoculate them onto a nutrient agar slant. Incubate at 37°C for 18-24 hours to obtain the next generation culture (usually the third generation). Use a 5ml pipette to add 3-5ml of diluent to the slant tube, repeatedly pipetting and aspirating to wash away the bacterial growth. Then, use a 5ml pipette to transfer all the washings to another sterile test tube (empty tube), shake for 20 seconds, first roughly determine the bacterial concentration using a bacterial concentration turbidimetric method, and then dilute to the desired concentration with 9ml of diluent at a ratio of 1:10.

[0070] Microbial killing effect test: (1) Prepare the bacterial suspension for the experiment and roughly measure the concentration of the bacterial suspension using a bacterial turbidimeter; dilution solution: 0.03 mol / L PBS, pH 7.2 or 0.85-0.9% physiological saline; (2) Use a pipette to draw 4.5 ml of the disinfectant sample solution to be tested and inject it into a sterile test tube for later use. Perform 3 replicates for each sample. (3) Take 0.5 ml of the test bacterial suspension into a test tube containing 4.5 ml of the disinfectant sample solution to be tested, and shake to mix well; (4) After the disinfectant and bacterial suspension have reacted for 2 minutes, take 1.0 ml of sample solution and determine the number of viable bacteria according to the viable bacteria culture counting method. Each sample solution can be inoculated into 2 petri dishes. If there are many colonies growing on the plates, serial 10-fold dilutions can be performed before viable bacteria culture counting. (5) At the same time, a diluent was used instead of a disinfectant to conduct parallel tests as a positive control; (6) All test samples were cultured in an incubator at 37℃. The bacterial vegetative cells were cultured for 48 hours and the final results were observed. The Candida albicans samples were cultured for 72 hours and the final results were observed. (7) Candida albicans was cultured on Sabouraud agar, while other strains were cultured on nutrient agar; (8) Calculation of sterilization rate; In the formula: K – Sterilization rate; Nc – Average colony count of positive control samples, expressed in colony forming units per milliliter (CFU / mL). Ns – Average colony count of the test sample, expressed as colony forming units per milliliter (CFU / mL).

[0071] The results of the antibacterial activity tests of the compounds are as follows: (see Table 1):

[0072] illustrate: 1. Sample concentration: Prepare a 0.4% concentration using a 20% solution of P1-P12; 2. No colonies grew in the negative control group.

[0073] In conclusion, the quaternary phosphonium salt derivatives P1-P12 of benzisothiazolinone exhibit excellent bactericidal effects against Escherichia coli, Candida albicans, Staphylococcus aureus, Salmonella, Pseudomonas aeruginosa, and Aspergillus niger. In particular, they also show good bactericidal activity against Candida albicans and Aspergillus niger, which have relatively weak inhibitory effects on benzisothiazolinone, thus expanding the antibacterial spectrum and application range of benzisothiazolinone.

[0074] 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 method for preparing an alkyl-linked benzisothiazolinone quaternary phosphonium 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. The reaction was carried out in the first reaction solvent, ethyl acetate or toluene, at a temperature of 0℃-120℃ for 1-24 h. After the reaction was completed, the mixture was cooled, concentrated, and recrystallized to obtain compound M. (2) In a reaction vessel, compound M and compound SO3 undergo a substitution reaction in the second reaction solvent under the action of an alkali. The reaction temperature is 0-150℃ and the reaction time is 1-36h. After the reaction is complete, the mixture is evaporated, concentrated, and recrystallized to obtain an alkyl-linked benzisothiazolinone quaternary phosphorus salt derivative. The second reaction solvent is selected from one or more of acetonitrile, acetone, tetrahydrofuran, DMF, DMSO, and 1,4-dioxane. The alkali is selected from one or more of lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, lithium isopropoxide, sodium isopropoxide, potassium isopropoxide, sodium hydride, and potassium hydride. In the formula, R is selected from C1-C straight-chain or branched alkyl groups with substituents, five-membered rings or aryl groups with substituents, wherein the substituents in the C1-C straight-chain or branched alkyl groups with substituents, five-membered rings or aryl groups with substituents are at least one hydrogen, halogen, trifluoromethyl, C1-C6 alkyl; X is selected from chlorine or bromine; n=0-10.

2. The method for preparing the alkyl-linked benzisothiazolinone quaternary phosphonium salt derivative according to claim 1, characterized in that, In step (2), the molar ratio of compound M to compound SO3 is 1:0.3-3.

3. The method for preparing the alkyl-linked benzisothiazolinone quaternary phosphonium salt derivative according to claim 2, characterized in that, In step (1), compound SO1 is triphenylphosphine; in step (2), compound P-O2 is a triphenylalkyl-linked benzoisothiazolinone quaternary phosphonium salt compound. In the formula, X is selected from chlorine or bromine; n = 1-6.

4. An alkyl-linked benzisothiazolinone quaternary phosphorus salt derivative, characterized in that, Its general structural formula is shown in equation P. In the formula, R is selected from C1-C straight-chain or branched alkyl groups with substituents, five-membered rings or aryl groups with substituents, wherein the substituent in the C1-C straight-chain or branched alkyl groups with substituents, the five-membered rings or aryl groups with substituents is at least one hydrogen, halogen, trifluoromethyl, C1-C6 alkyl; X is selected from chlorine or bromine; n=0-10.

5. The alkyl-linked benzisothiazolinone quaternary phosphorus salt derivative according to claim 4, 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.

6. The alkyl-linked benzisothiazolinone quaternary phosphorus salt derivative according to claim 4 or 5, characterized in that, The structures of its representative compounds are as follows: 。 7. The use of the alkyl-linked benzisothiazolinone quaternary phosphonium salt derivative according to claim 4 or 5 as an antibacterial agent or antimicrobial drug.

8. The application of the alkyl-linked benzisothiazolinone quaternary phosphonium salt derivative according to claim 7 as an antibacterial agent, characterized in that, The applications include those against Escherichia coli, Candida albicans, Staphylococcus aureus, Salmonella, Pseudomonas aeruginosa, or Aspergillus niger.

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