Gemini quaternary ammonium salt antibacterial agent and preparation method thereof

Abstract

The invention relates to a gemini quaternary ammonium salt antibacterial agent and a preparation method thereof. Specifically, the antibacterial agent is synthesized by performing quaternization reaction with N, N-dimethyl benzylamine, 4-dimethylaminopyridine and a plurality of tertiary amines (12, 14, 16 and 18) with different chain lengths by taking biphenyl benzyl chloride and 1, 4-dibromobutane as linking groups. The preparation of the gemini quaternary ammonium salt antibacterial agent with diversified hydrophobic groups and carbon chain lengths is realized in the process. Compared with a traditional antibacterial agent, the gemini quaternary ammonium salt synthesized by the method has the remarkable advantages that the synthesis condition is mild, the antibacterial effect is good, and the stability is excellent. In order to verify the antibacterial efficacy, escherichia coli and staphylococcus aureus are selected as model strains for strict antibacterial experiments. Experimental results show that the antibacterial agent shows strong bactericidal activity, which indicates that the antibacterial agent has huge application prospects and potential in the field of antibacterial materials.

Description

Technical Field

[0001] This application relates to the field of chemistry and involves a gemini quaternary ammonium salt antibacterial agent and its preparation method. Background Art

[0002] As a highly efficient and widely used antibacterial agent, quaternary ammonium salts have shown great potential in inhibiting and killing harmful microorganisms due to their excellent antibacterial activity.

[0003] However, pathogenic bacteria and fungi often form hard and difficult-to-remove microbial biofilms on various surfaces, which not only exacerbates scaling and pollution problems but may also lead to resistance issues, making traditional antibacterial methods ineffective. To overcome this severe challenge, researchers have continuously conducted in-depth studies and successfully developed various quaternary ammonium salt derivatives. These derivatives cleverly combine the synergistic effects of quaternary ammonium salts and drug additives, effectively enhancing the antibacterial effect and providing new ideas for solving the biofilm problem.

[0004] The quaternization reaction is achieved through the alkylation reaction of tertiary amines with halogenated hydrocarbons, which provides an effective way for us to prepare quaternary ammonium salts with different alkyl chain lengths. Taking the reaction of alkyldimethylamine with benzyl chloride as an example, through this reaction, we can synthesize quaternary ammonium salt compounds such as benzalkonium chloride with powerful bactericidal efficacy.

[0005] Quaternary ammonium salts, as an important class of cationic surfactants, are characterized by having a hydrophobic tail and a positively charged head composed of an alkyl chain. This unique structure enables quaternary ammonium salts to form stable micelles in solution, thereby exhibiting excellent surface activity and antibacterial properties. Depending on the structure, quaternary ammonium salts can be monomers, dimers, trimers, or polymeric quaternary ammonium salts, showing diverse chemical properties and application prospects.

[0006] Currently, the research on monomeric quaternary ammonium salts in the market has been relatively mature, and a large number of successful products have been successfully developed, such as benzalkonium chloride, germicide (chlorine type), and benzalkonium bromide (bromine type). These single quaternary ammonium salt products have been widely used in the fields of medicine, hygiene, daily chemicals, etc., and have achieved remarkable results. However, compared with single-chain quaternary ammonium salts, the research on double-chain quaternary ammonium salts (especially gemini quaternary ammonium salts) is relatively less, but their potential application value cannot be ignored.

[0007] Gemini quaternary ammonium salts are considered to have a broader bactericidal activity and a lower minimum inhibitory concentration (MIC), which means that they can achieve the same antibacterial effect at a lower concentration, thereby reducing the use cost and environmental pollution. In addition, combined with the advantages of the quaternary ammonium salt itself, such as low toxicity, high stability, non-irritating to the skin, low corrosiveness, high penetration ability, and long residence time, Gemini quaternary ammonium salts can endow them with a wider range of application scenarios, such as medical device disinfection, food processing, water treatment and other fields. Therefore, the research and development and application prospects of Gemini quaternary ammonium salts are broad, and it is worthy of further in-depth research and exploration by scientific researchers. Summary of the Invention

[0008] The purpose of the present application is that the purpose of the present invention is to overcome the deficiencies of the existing technology and provide a preparation method of a Gemini quaternary ammonium salt antibacterial agent. The present invention uses biphenyl dichlorobenzyl and 1,4-dibromobutane as linking groups, and carries out quaternization reactions with N,N-dimethylbenzylamine, 4-dimethylaminopyridine and tertiary amines with various different chain lengths (12, 14, 16, 18) for synthesis. This process realizes the preparation of Gemini quaternary ammonium salt antibacterial agents with diverse hydrophobic groups and carbon chain lengths. Compared with traditional antibacterial agents, the Gemini quaternary ammonium salts synthesized by the present invention exhibit significant advantages: mild synthesis conditions, good sterilization effect and excellent stability. In order to verify its antibacterial efficacy, we selected Escherichia coli and Staphylococcus aureus as model strains for strict antibacterial experiments. The experimental results show that the antibacterial agent of the present invention exhibits strong bactericidal activity, indicating that it has great application prospects and potential in the field of antibacterial materials.

[0009] To achieve the above object, the present invention adopts the following technical solutions:

[0010] A preparation method of a Gemini quaternary ammonium salt antibacterial agent, comprising the following steps:

[0011] This Gemini quaternary ammonium salt antibacterial agent uses biphenyl dichlorobenzyl and 1,4-dibromobutane as linking groups to synthesize Gemini biphenyl dichlorobenzyl quaternary ammonium salt antibacterial agent and 1,4-dibromobutane quaternary ammonium salt antibacterial agent. Without changing the linking group, the present invention synthesizes Gemini quaternary ammonium salt antibacterial agents with different hydrophobic groups and different carbon chain lengths by carrying out quaternization reactions with N,N-dimethylbenzylamine, 4-dimethylaminopyridine and tertiary amines with various different chain lengths (12, 14, 16, 18). The preparation method of the Gemini quaternary ammonium salt antibacterial agent includes the following steps:

[0012] (1) The preparation method of biphenyl dichlorobenzyl quaternary ammonium salt is: put biphenyl dichlorobenzyl, tertiary amine and solvent into a three-necked flask equipped with a magnetic stirrer and a condenser, and react at 40-60 °C for 12-24 h. After the reaction is completed, cool to room temperature, wash with solvent, stir, filter, and vacuum dry for 12-24 h to obtain the target product 1.

[0013] (2) The preparation method of 1,4-dibromobutane quaternary ammonium salt is as follows: 1,4-dibromobutane, tertiary amine and solvent are loaded into a three-necked flask equipped with a magnetic stirrer and a condenser, and the reaction is carried out at 40-60 °C for 12-24 h. After the reaction is completed, it is cooled to room temperature, washed with solvent, stirred, filtered, and dried under vacuum for 12-24 h to obtain the target product 2.

[0014] Preferably, in the step (1), the molar ratio of the diphenyl dichlorobenzyl to the tertiary amine is 1:(1.5-2.0).

[0015] Preferably, in the step (1), the reaction is carried out under a nitrogen protection atmosphere, and the reaction solvent should be one of dichloromethane, ethyl acetate and acetonitrile.

[0016] Preferably, in the step (1), the tertiary amine is one of dodecyl dimethyl tertiary amine, tetradecyl dimethyl tertiary amine, hexadecyl dimethyl tertiary amine, octadecyl dimethyl tertiary amine, N,N-dimethylbenzylamine, 4-dimethylaminopyridine.

[0017] Preferably, in the step (1), the washing solvent is one of acetone, ether, ethyl acetate and petroleum ether.

[0018] Preferably, in the step (2), the reaction is carried out under a nitrogen protection atmosphere, and the molar ratio of the 1,4-dibromobutane to the tertiary amine is 1:(1.5-2.0).

[0019] Preferably, in the step (2), the reaction solvent should be one of dichloromethane, ethyl acetate and acetonitrile.

[0020] Preferably, in the step (2), the tertiary amine is one of dodecyl dimethyl tertiary amine, tetradecyl dimethyl tertiary amine, hexadecyl dimethyl tertiary amine, octadecyl dimethyl tertiary amine, N,N-dimethylbenzylamine, 4-dimethylaminopyridine.

[0021] Preferably, when in the step (2), the washing solvent is one of acetone, ether, ethyl acetate and petroleum ether.

[0022] Compared with the prior art, the present invention has the following obvious and prominent substantive features and remarkable advantages: The gemini quaternary ammonium salt antibacterial agent of the present invention uses biphenyl dichlorobenzyl and 1,4-dibromobutane as innovative linking groups to cleverly connect N,N-dimethylbenzylamine, 4-dimethylaminopyridine and various tertiary amines with different chain lengths to form a unique gemini structure. On one end, due to the presence of the biphenyl structure, the interaction between the antibacterial agent molecule and the material surface is enhanced, improving its adhesion and wear resistance on the surface, and ensuring the stability and durability of the antibacterial layer; on the other end, a variety of tertiary amine groups are incorporated. After the quaternization reaction, these groups not only enhance the adsorption and penetration ability of the antibacterial agent to bacteria, significantly improving the bactericidal effect, but also the tertiary amines with different chain lengths endow the antibacterial agent with adjustable hydrophilic-hydrophobic balance, effectively preventing oil stain adsorption and maintaining the cleanliness of the material surface and the long-term stability of the antibacterial performance. Description of the Drawings

[0023] Figure 1 For the examples, the bacteriostatic rate of the antibacterial agent against Staphylococcus aureus at different concentrations was measured by the OD600 method.

[0024] Figure 2 For the examples, the bacteriostatic rate of the antibacterial agent against Escherichia coli at different concentrations was measured by the OD600 method. Examples

[0025] Unless otherwise specified, implied from the context or in accordance with the conventions of the prior art, all parts and percentages in this application are based on weight, and the test and characterization methods used are synchronized with the filing date of this application. Where applicable, any patents, patent applications or published content referred to in this application are incorporated herein by reference in their entirety, and their equivalent family patents are also incorporated by reference, particularly the definitions of synthetic techniques, products and processing designs, polymers, comonomers, initiators or catalysts, etc. in the art disclosed in these documents. If the definition of a specific term disclosed in the prior art is inconsistent with any definition provided in this application, the definition of the term provided in this application shall prevail.

[0026] The technical solutions of this application will be clearly and completely described below in conjunction with the examples of this application. Unless otherwise specified, the reagents and raw materials used can be purchased through commercial channels. The experimental methods without specific conditions noted in the following examples are carried out according to conventional methods and conditions, or are selected according to the product instructions.

[0027] Escherichia coli, Staphylococcus aureus, and ultrapure water were all provided by the School of Life Sciences, Shanghai University. Biphenyl dichlorobenzyl, N, N-dimethylbenzylamine, 4-dimethylaminopyridine, dichloromethane, acetone, and petroleum ether were all provided by Aladdin; petroleum ether, dichloromethane, and 1,4-dibromobutane were purchased from Shanghai Titan Technology Co., Ltd.; dodecyl dimethyl tertiary amine, tetradecyl dimethyl tertiary amine, hexadecyl dimethyl tertiary amine, octadecyl dimethyl tertiary amine, ether, yeast extract, agar powder, and sodium chloride were purchased from Sinopharm Chemical Reagent Co., Ltd.

[0028] The Gram-positive bacterium representative Staphylococcus aureus (S. aureus) and the Gram-negative bacterium representative Escherichia coli (E. coli) were selected as the test strains, and LB (Giuseppe Bertani) medium was selected as the medium for the antibacterial experiment. The OD600 method was used to determine the antibacterial rate.

[0029] Example 1

[0030] In this example, the preparation method of biphenyl dichlorobenzyl quaternary ammonium salt (N,N'-([1,1'-biphenyl]-4,4'-diylbis(methylene))bis(N,N-dimethyldodecyl / tetradecyl / hexadecyl / octadecyl-1-ammonium) dichloride (LB12 / 14 / 16 / 18)) includes the following steps:

[0031]

[0032] Biphenyl dichlorobenzyl benzyl quaternary ammonium salt synthesis route 1

[0033] Biphenyl dichlorobenzyl, dodecyl dimethyl tertiary amine (or tetradecyl dimethyl tertiary amine, hexadecyl dimethyl tertiary amine, octadecyl dimethyl tertiary amine) were loaded into a three-necked flask equipped with a magnetic stirrer and a condenser with a feeding ratio of 1:1.5 and the solvent dichloromethane, and reacted at 40 °C for 12 h. After the reaction was completed, the solvent was removed by a rotary evaporator to obtain a yellow solid. Petroleum ether was added for pulping, filtered by suction, and dried under vacuum to obtain Product 1.

[0034] Example 2

[0035] This example is basically the same as the previous example, with the special feature that:

[0036] The preparation method of biphenyl dichlorobenzyl quaternary ammonium salt (1,1'-([1,1'-biphenyl]-4,4'-diyl)bis(N-benzyl-N,N-dimethylmethanaminium) dichloride (LBBA)) includes the following steps:

[0037]

[0038] Biphenyl dichlorobenzyl benzyl quaternary ammonium salt synthesis route 2

[0039] Biphenyl dichlorobenzyl, dimethylbenzylamine with a feed ratio of 1:1.5 and the solvent dichloromethane were charged into a three-necked flask equipped with a magnetic stirrer and a condenser, and reacted at 40 °C for 12 h. After the reaction, a large amount of white solid precipitated. The white solid was added to petroleum ether for pulping, filtered by suction, and dried under vacuum to obtain Product 2.

[0040] Example 3

[0041] This example is basically the same as the foregoing examples, with the special feature being that:

[0042] In this example, the preparation method of biphenyl dichlorobenzyl quaternary ammonium salt (N,N'-([1,1'-biphenyl]-4,4'-diylbis(methylene))bis(N,N-dimethylpyridin-4-amine) dichloride (LBBD)) comprises the following steps:

[0043]

[0044] Synthesis route 3 of biphenyl dichlorobenzyl benzyl quaternary ammonium salt

[0045] Biphenyl dichlorobenzyl and dimethylaminopyridine with a feed ratio of 1:1.5 and the solvent dichloromethane were charged into a three-necked flask equipped with a magnetic stirrer and a condenser, and reacted at 40 °C for 12 h. After the reaction, a large amount of white solid precipitated. The white solid was added to petroleum ether for pulping, filtered by suction, and dried under vacuum to obtain Product 3.

[0046] Example 4

[0047] In this example, the preparation method of 1,4-dibromobutane quaternary ammonium salt (N 1 ,N 4 -bis(dodecyl / tetradecyl / hexadecyl / octadecyl)-N 1 ,N 1 ,N 4 ,N 4 -tetramethylbutane-1,4-diammonium (BQ12 / 14 / 16 / 18)) comprises the following steps:

[0048]

[0049] Synthesis route 1 of 1,4-dibromobutane alkyl quaternary ammonium salt

[0050] 1,4-Dibromobutane, N,N-dimethyl-1-dodecylamine (or N,N-dimethyl-1-tetradecylamine, N,N-dimethyl-1-hexadecylamine, N,N-dimethyl-1-octadecylamine) with a feed ratio of 1:1.5 and the solvent methanol were charged into a three-necked flask equipped with a magnetic stirrer and a condenser, and reacted at 60 °C for 24 h. After the reaction, the solvent was removed by a rotary evaporator to obtain a pale yellow oil, ethyl acetate was added, and a white solid precipitated. It was filtered by suction and dried under vacuum to obtain Product 4.

[0051] Example 5

[0052] In this example, a preparation method of 1,4-dibromobutane quaternary ammonium salt (N,N-dibenzyl-N,N,N,N-tetramethylbutane-1,4-diammonium dibromide (BQBA)) includes the following steps: 1 , N 4 -dibenzyl-N 1 , N 1 , N 4 , N 4 -tetramethylbutane-1,4-diammonium (BQBA)) is as follows:

[0053]

[0054] 1-4 dibromobutane alkyl quaternary ammonium salt synthesis route 2

[0055] Charge 1,4-dibromobutane, dimethylbenzylamine and solvent methanol with a feed ratio of 1:1.5 into a three-necked flask equipped with a magnetic stirrer and a condenser, and react at 60 °C for 12 h. After the reaction, remove the solvent with a rotary evaporator to obtain a pale yellow oily liquid. Add ethyl acetate to precipitate a white solid, filter by suction, and dry in vacuum to obtain product 5.

[0056] Example 6

[0057] In this example, a preparation method of 1,4-dibromobutane quaternary ammonium salt (N,N,N,N-tetramethyl-N,N-bis(pyridin-4-yl)butane-1,4-diammonium dibromide (BQBD)) includes the following steps: 1 , N 1 , N 4 , N 4 -tetramethyl-N 1 , N 4 -bis(pyridin-4-yl)butane-1,4-diammonium (BQBD)) is as follows:

[0058]

[0059] 1-4 dibromobutane alkyl quaternary ammonium salt synthesis route 2

[0060] Charge 1,4-dibromobutane, dimethylaminopyridine and solvent methanol with a feed ratio of 1:1.5 into a three-necked flask equipped with a magnetic stirrer and a condenser, and react at 60 °C for 12 h. After the reaction is completed, cool to room temperature to precipitate a white solid, then add ethyl acetate to precipitate more white solids, filter by suction, and dry in vacuum to obtain product 6.

[0061] Comparative example

[0062] Sterile ultrapure water.

[0063] Experimental test analysis:

[0064] The NMR results analysis of the synthesized gemini quaternary ammonium salt is as follows:

[0065] Example 1: The 1H NMR analysis of biphenyl dichlorobenzyl alkyl quaternary ammonium salts (LB12 / 14 / 16 / 18) is as follows: The peak positions of the 1H NMR images of LB12, LB14, LB16, and LB18 are basically similar.

[0066] LB12: 1H NMR (600 MHz, DMSO-d6) δ 7.79 (dd, J = 119.2, 7.9 Hz, 8H), 4.64 (s, 4H), 3.35 - 3.25 (m, 4H), 3.01 (s, 12H), 1.80 (dt, J = 15.2, 6.0 Hz, 4H), 1.51 - 1.12 (m, 36H), 0.86 (t, J = 6.8 Hz, 6H).

[0067] LB14: 1H NMR (600 MHz, DMSO-d6) δ 7.79 (dd, J = 118.0, 7.9 Hz, 8H), 4.65 (s, 4H), 3.34 - 3.26 (m, 4H), 3.01 (s, 12H), 1.93 - 1.75 (m, 4H), 1.49 - 1.12 (m, 44H), 0.85 (t, J = 6.8 Hz, 6H).

[0068] LB16: 1H NMR (600 MHz, DMSO-d6) δ 7.79 (dd, J = 122.5, 7.9 Hz, 8H), 4.63 (s, 4H), 3.34 - 3.26 (m, 4H), 3.01 (s, 12H), 1.87 - 1.73 (m, 4H), 1.44 - 1.14 (m, 52H), 0.85 (t, J = 6.9 Hz, 7H).

[0069] LB18: 1H NMR (600 MHz, DMSO-d6) δ 7.79 (dd, J = 126.4, 7.9 Hz, 8H), 4.61 (s, 4H), 3.33 - 3.24 (m, 4H), 3.00 (s, 12H), 1.89 - 1.75 (m, 4H), 1.43 - 1.11 (m, 60H), 0.85 (t, J = 6.9 Hz, 6H).

[0070] Taking the NMR spectrum of LB12 as an example, the peak positions of each hydrogen in the proton nuclear magnetic resonance spectrum are described as follows. The peak positions of the remaining hydrogens are roughly the same: the peak near δ = 7.79 ppm belongs to the eight hydrogens on the biphenyl group; the peak at δ = 4.64 ppm belongs to the four hydrogens of the methylene group on the side close to the benzene ring connected to the quaternary ammonium group; the peak at δ = 3.35 - 3.25 ppm belongs to the four hydrogens of the methylene group on the side far from the benzene ring connected to the quaternary ammonium group; the peak at δ = 3.01 ppm belongs to the twelve hydrogens on the four methyl groups directly connected to the quaternary ammonium group; δ = 1.80 ppm belongs to the four hydrogens of the second methylene group in the direction far from the benzene ring directly connected to the quaternary ammonium group; δ = 1.51 - 1.12 ppm belongs to the thirty-six hydrogens of the methylene group in the middle of the long-chain alkane; δ = 0.86 ppm belongs to the six hydrogens of the methyl group at the tail of the alkane chain. The nuclear magnetic resonance results are consistent with the expected structure, and the above results can prove that the quaternary ammonium salt antibacterial agents of biphenyl dichlorobenzyl with different alkane chain lengths have been successfully synthesized.

[0071] Example 2: The proton nuclear magnetic resonance spectrum analysis results of biphenyl dichlorobenzyl benzyl quaternary ammonium salt (LBBA) are as follows: LBBA: 1H NMR (600 MHz, Deuterium Oxide) δ 7.78 - 7.72 (m, 4H), 7.58 - 7.53 (m, 4H), 7.52 - 7.46 (m, 4H), 7.46 - 7.42 (m, 6H), 4.49 (dd, J = 11.6, 2.0 Hz, 8H), 3.11 - 2.53 (m, 12H).

[0072] δ = 7.78 - 7.72 ppm is the four hydrogens on the side where the biphenyl groups are close to each other; δ = 7.58 - 7.53 ppm is the four hydrogens on the benzyl benzene ring close to the quaternary ammonium group; δ = 7.52 - 7.46 ppm is the four hydrogens of the biphenyl group close to the quaternary ammonium group; δ = 7.46 - 7.42 ppm is the remaining six hydrogens on the benzyl benzene ring; δ = 4.49 ppm is the eight hydrogens on the methylene group directly connected to the quaternary ammonium group; δ = 3.11 - 2.53 ppm is the twelve hydrogens on the four methyl groups directly connected to the quaternary ammonium group. The nuclear magnetic resonance results are consistent with the expected structure, and the above results can prove that the biphenyl dichlorobenzyl benzyl quaternary ammonium salt antibacterial agent has been successfully synthesized.

[0073] Example 3: The proton nuclear magnetic resonance spectrum analysis results of biphenyl dichlorobenzyl pyridinium quaternary ammonium salt (LBBD) are as follows: LBBD: 1H NMR (600 MHz, Deuterium Oxide) δ 7.99 - 7.75 (m, 4H), 7.34 (d, J = 11.0 Hz, 4H), 7.28 - 7.18 (m, 4H), 6.69 - 6.55 (m, 4H), 5.11 - 5.04 (m, 4H), 3.02 - 2.91 (m, 12H).

[0074] δ = 7.99 - 7.75 ppm corresponds to the four hydrogens on the pyridine ring close to the N atom; δ = 7.34 ppm corresponds to the four hydrogens on the pyridine ring close to the quaternary ammonium group; δ = 7.28 - 7.18 ppm corresponds to the four adjacent hydrogens on the biphenyl group; δ = 6.69 - 6.55 ppm corresponds to the four hydrogens on the biphenyl group close to the quaternary ammonium group; δ = 5.11 - 5.04 ppm corresponds to the four hydrogens on the methylene group directly connected to the quaternary ammonium group; δ = 3.02 - 2.91 ppm corresponds to the twelve hydrogens on the four methyl groups directly connected to the quaternary ammonium group. The nuclear magnetic resonance results are consistent with the expected structure, and the above results can prove the successful synthesis of the biphenyl dichlorobenzyl pyridinium quaternary ammonium salt antibacterial agent.

[0075] Example 4: The 1H NMR analysis of dibromobutane alkyl quaternary ammonium salts (BQ12 / 14 / 16 / 18) is as follows: The 1 peak positions in the 1H NMR spectra of BQ12, BQ14, BQ16, and BQ18 are basically similar.

[0076] BQ12: 1H NMR (600 MHz, DMSO-d6) δ 3.30 (t, J = 7.6 Hz, 4H), 3.28 - 3.22 (m, 4H), 3.02 (s, 12H), 1.73 - 1.60 (m, 8H), 1.37 - 1.16 (m, 36H), 0.86 (t, J = 6.9 Hz, 6H).

[0077] BQ14: 1H NMR (600 MHz, DMSO-d6) δ 3.31 (t, J = 7.9 Hz, 4H), 3.29 - 3.23 (m, 4H), 3.02 (s, 12H), 1.67 (dp, J = 20.3, 7.2, 5.6 Hz, 8H), 1.34 - 1.20 (m, 44H), 0.86 (t, J = 6.8 Hz, 6H).

[0078] BQ16: 1H NMR (600 MHz, DMSO-d6) δ 3.31 (d, J = 7.5 Hz, 4H), 3.29 - 3.22 (m, 4H), 3.03 (s, 12H), 1.67 (p, J = 7.8, 6.1 Hz, 8H), 1.25 (d, J = 9.0 Hz, 52H), 0.86 (t, J = 6.8 Hz, 6H).

[0079] BQ18: 1H NMR (600 MHz, DMSO-d6) δ 3.32 (t, J = 7.1 Hz, 4H), 3.29 - 3.23 (m, 4H), 3.03 (s, 12H), 1.67 (hept, J = 6.7, 5.1 Hz, 8H), 1.25 (d, J = 8.9 Hz, 60H), 0.86 (t, J = 6.9 Hz, 6H).

[0080] Taking the NMR spectrum of BQ12 as an example to illustrate the peak positions of each hydrogen in the 1H NMR spectrum, the remaining peak positions are roughly the same: δ = 3.30 ppm corresponds to the four hydrogens on the two methylene groups where the butyl group is directly connected to the quaternary ammonium group; δ = 3.28 - 3.22 ppm corresponds to the four hydrogens on the methylene group where the long-chain alkane is directly connected to the quaternary ammonium group; δ = 3.02 ppm corresponds to the twelve hydrogens on the four methyl groups directly connected to the quaternary ammonium group; δ = 1.73 - 1.60 ppm corresponds to the four hydrogens on the two internal methylene groups in the butyl group and the four hydrogens on the second methylene group where the long-chain alkane is connected to the quaternary ammonium group; δ = 1.37 - 1.16 ppm corresponds to the thirty-six hydrogens on the methylene groups in the middle of the long-chain alkane; δ = 0.86 ppm corresponds to the six hydrogens on the two methyl groups at the tail of the long-chain alkane. The NMR results are consistent with the expected structure, and the above results can prove that the quaternary ammonium salt antibacterial agents of dibromobutane with different alkane chain lengths have been successfully synthesized.

[0081] Example 5: The 1H NMR analysis results of dibromobutane benzyl quaternary ammonium salt (BQBA) are as follows: BQBA: 1H NMR (600 MHz, DMSO-d6) δ 7.64 - 7.58 (m, 4H), 7.54 (qd, J = 8.7, 7.7, 3.6 Hz, 6H), 4.61 (s, 4H), 3.38 (d, J = 7.8 Hz, 4H), 3.01 (s, 12H), 1.82 (p, J = 3.5 Hz, 4H).

[0082] δ = 7.64 - 7.58 ppm corresponds to the four hydrogens on the side of the benzyl benzene ring close to the quaternary ammonium group; δ = 7.54 ppm corresponds to the remaining six hydrogens on the benzyl benzene ring; δ = 4.61 ppm corresponds to the four hydrogens on the methylene group of the benzyl; δ = 3.38 ppm corresponds to the four hydrogens on the two methylene groups of the butyl close to the quaternary ammonium group, which overlap with the water peak of the NMR reagent; δ = 3.01 ppm corresponds to the twelve hydrogens on the four methyl groups directly connected to the quaternary ammonium group; δ = 1.82 ppm corresponds to the four hydrogens on the two methylene groups in the middle of the butyl. The NMR results are consistent with the expected structure, and the above results can prove that the dibromobutane benzyl quaternary ammonium salt antibacterial agent has been successfully synthesized.

[0083] Example 6: The 1H NMR analysis results of dibromobutane pyridine quaternary ammonium salt (BQBD) are as follows: BQBD: 1H NMR (600 MHz, DMSO-d6) δ 8.55 - 8.04 (m, 4H), 7.31 - 6.71 (m, 4H), 4.23 (t, J = 4.9 Hz, 4H), 3.19 (s, 12H), 1.74 (q, J = 3.4 Hz, 4H).

[0084] δ = 8.55 - 8.04 ppm corresponds to the four hydrogens on the pyridine ring close to the N atom; δ = 7.31 - 6.71 ppm corresponds to the four hydrogens on the pyridine ring close to the quaternary ammonium group; δ = 4.23 ppm corresponds to the four hydrogens on the two methylene groups of the butyl group close to the quaternary ammonium group; δ = 3.19 ppm corresponds to the twelve hydrogens on the four methyl groups directly connected to the quaternary ammonium group; δ = 1.74 ppm corresponds to the four hydrogens on the two methylene groups in the middle of the butyl group. The nuclear magnetic resonance results are consistent with the expected structure, and the above results can prove that the dibromobutane pyridine quaternary ammonium salt antibacterial agent has been successfully synthesized.

[0085] The experimental results show that all antibacterial agents exhibit antibacterial effects against Staphylococcus aureus and Escherichia coli. The data measured by the inhibition zone method mainly reflect the diffusion performance of the antibacterial agent on the solid surface, while the OD600 method mainly focuses on its inhibitory ability on microbial growth. Antibacterial agents with different carbon chain lengths are affected by various factors such as their concentration, hydrophilic-hydrophobic properties, intermolecular forces, and chain entanglement, showing different antibacterial properties. See Figure 1 and Figure 2 , pyridine and benzyl quaternary ammonium salts exhibit excellent antibacterial properties at various concentration conditions, and their antibacterial rates reach 100%.

[0086] In summary, the present invention uses biphenyl dichlorobenzyl and 1,4-dibromobutane as linking groups to carry out quaternization reactions with N,N-dimethylbenzylamine, 4-dimethylaminopyridine, and various tertiary amines with different chain lengths (12, 14, 16, 18). This process realizes the preparation of gemini quaternary ammonium salt antibacterial agents with diverse hydrophobic groups and carbon chain lengths. Compared with traditional antibacterial agents, the gemini quaternary ammonium salts synthesized in the present invention show significant advantages: their synthesis conditions are mild, the antibacterial effect is good, and the stability is excellent.

[0087] The embodiments of the present invention have been described above in conjunction with the accompanying drawings, but the present invention is not limited to the above embodiments. Various changes can also be made according to the purpose of the invention of the present invention. Any changes, modifications, substitutions, combinations, or simplifications made based on the spirit and principle of the technical solution of the present invention shall be equivalent replacement methods. As long as they meet the invention purpose of the present invention and do not deviate from the technical principle and inventive concept of the present invention, they all fall within the protection scope of the present invention.

Claims

1. A method for preparing a gemini quaternary ammonium salt antibacterial agent, characterized in that: The method comprises the following steps: using biphenyl dichlorobenzyl and 1,4-dibromobutane as connecting groups to synthesize a gemini biphenyl dichlorobenzyl quaternary ammonium salt antibacterial agent and a 1,4-dibromobutane quaternary ammonium salt antibacterial agent; and without changing the connecting group, synthesizing a gemini quaternary ammonium salt antibacterial agent with different hydrophobic groups and different carbon chain lengths by carrying out a quaternization reaction with N,N-dimethylbenzylamine, 4-dimethylaminopyridine and tertiary amines with different chain lengths.

2. The method according to claim 1, characterized in that The preparation method of the biphenyl dichlorobenzyl quaternary ammonium salt antibacterial agent is as follows: biphenyl dichlorobenzyl, tertiary amine and solvent are placed in a three-necked flask with a stirrer and a condenser, and reacted at 40-60° C. for 12-24 hours. After the reaction is completed, the mixture is cooled to room temperature, washed with solvent, stirred, filtered, and vacuum dried for 12-24 hours to obtain the target product 1.

3. The method according to claim 1, characterized in that The preparation method of the 1,4-dibromobutane quaternary ammonium salt antibacterial agent is as follows: 1,4-dibromobutane, tertiary amine and solvent are placed in a three-necked flask with a stirrer and a condenser, and reacted at 40-60° C. for 12-24 hours. After the reaction is completed, the mixture is cooled to room temperature, washed with solvent, stirred, filtered, and vacuum dried for 12-24 hours to obtain the target product 2.

4. The method according to claim 2, characterized in that: In the step, the ratio of the amount of biphenyl dichlorobenzyl to the amount of the tertiary amine is 1:(1.5-2.0).

5. The method according to claim 2, characterized in that: In the step, the reaction is carried out under a nitrogen atmosphere, and the reaction solvent is at least one of dichloromethane, ethyl acetate and acetonitrile; Preferably, the tertiary amine is one of dodecyldimethyl tertiary amine, tetradecyldimethyl tertiary amine, hexadecyldimethyl tertiary amine, octadecyldimethyl tertiary amine, N,N-dimethylbenzylamine and 4-dimethylaminopyridine; Preferably, the washing solvent is at least one of acetone, ether, ethyl acetate and petroleum ether.

6. The method according to claim 3, characterized in that In the step, the ratio of the amount of biphenyl dichlorobenzyl to the amount of the tertiary amine is 1:(1.5-2.0).

7. The method according to claim 3, characterized in that In the step, the reaction is carried out under a nitrogen protective atmosphere, and the reaction solvent should be at least one of dichloromethane, ethyl acetate and acetonitrile.

8. The method according to claim 3, characterized in that In the steps, the tertiary amine is one of dodecyldimethyl tertiary amine, tetradecyldimethyl tertiary amine, hexadecyldimethyl tertiary amine, octadecyldimethyl tertiary amine, N,N-dimethylbenzylamine and 4-dimethylaminopyridine.

9. The method according to claim 3, characterized in that: In the step, the washing solvent is at least one of acetone, ether, ethyl acetate and petroleum ether.

10. A Gemini quaternary ammonium salt antibacterial agent, characterized in that: The invention comprises a gemini-type biphenyl benzyl dichloride quaternary ammonium salt antibacterial agent, wherein the gemini-type biphenyl benzyl dichloride quaternary ammonium salt antibacterial agent comprises N,N'-([1,1'-biphenyl]-4,4'-diylbis(methylene))bis(N,N-dimethyldodecaproyl / tetradecyl / hexadecyl / octadecyl-1-ammonium dichloride; 1,1'-([1,1'-biphenyl]-4,4'-diyl)bis(N-benzyl-N,N-dimethylmethylammonium dichloride; N,N'-([1,1'-biphenyl]-4,4'-diylbis(methylene))bis(N,N-dimethylpyridin-4-amine dichloride; N1,N4-ditodecaproyl / tetradecyl / hexadecyl / octadecyl-N1,N1,N4,N4-tetramethylbutane-1,4-diammonium dibromide; N 1 , N 4 -Dibenzyl-N 1 , N 1 , N 4 , N 4 -tetramethylbutane-1,4-diammonium; and N-dibromide 1 , N 1 , N 4 , N 4 -Tetramethyl-N 1 , N 4 - one or more of di(pyridin-4-yl)butane-1,4-diammonium.

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