Preparation method of aryl sulfonylamino quaternary ammonium salt antibacterial agent

Abstract

The invention discloses a preparation method of an aryl sulfonyl amino quaternary ammonium salt antibacterial agent. The aryl sulfonyl amino quaternary ammonium salt antibacterial agent is prepared by taking aryl sulfonyl chloride, terminal tertiary amino straight-chain fatty amine and halogenated hydrocarbon as raw materials. The preparation method comprises the following steps: under the condition of taking alkali as an acid-binding agent, preparing an aryl sulfonamide compound by using aryl sulfonyl chloride and terminal tertiary amino straight-chain fatty amine as raw materials, and performing heating reflux reaction on tertiary amino functional groups in the sulfonamide compound and halogenated hydrocarbon to prepare the aryl sulfonyl amino quaternary ammonium salt. The obtained target product quaternary ammonium salt is high in purity, excellent in yield, simple and convenient to operate and green and environment-friendly in process, and the obtained product has good antibacterial ability.

Description

Technical Field

[0001] The invention relates to the technical field of chemical product preparation, in particular to a method for preparing an arylsulfonylamino quaternary ammonium salt antibacterial agent. Background Art

[0002] Pathogenic microorganisms such as bacteria, fungi and viruses have always been able to cause pathological changes in body tissues, threatening human health and even life safety. With the improvement of living standards, people's awareness of living environment and quality of life are constantly increasing, especially their awareness of health is constantly increasing. Diseases caused by the spread of infection by pathogenic microorganisms such as harmful bacteria, fungi and viruses have gradually become a major social problem, attracting widespread attention from humans.

[0003] The adhesion of pathogenic microorganisms such as bacteria, fungi and viruses to the surface of materials is the first step to cause infection. They adhere to the surface of materials, and then communicate with each other through signal molecules, attracting the same kind of aggregation, thus forming a complete biofilm structure and causing persistent infection. Therefore, it is of great significance to carry out research on the antibacterial properties of materials.

[0004] In order to make the surface of materials have antibacterial properties, it is necessary to construct antibacterial surfaces in a targeted manner based on the mechanism of bacterial infection. The main methods include antibacterial adhesion, sterilization, antibacterial adhesion-sterilization (anti-killing) combination and antibacterial adhesion-sterilization conversion. Introducing antibacterial agents on the surface of materials for sterilization is a common and effective method for constructing antibacterial surfaces.

[0005] The existing antimicrobial agents mainly include inorganic antimicrobial agents and organic antimicrobial agents. Among them, organic antimicrobial agents have the characteristics of fast sterilization speed, high antimicrobial efficacy, convenient processing, stable color, etc. They have a long history of use and play an irreplaceable role in many fields. Quaternary ammonium salt antimicrobial agents among organic antimicrobial agents have been widely studied and used because of their low price and fast sterilization speed. Summary of the invention

[0006] The invention provides a method for preparing an arylsulfonylamino quaternary ammonium salt antibacterial agent to prepare a novel quaternary ammonium salt antibacterial agent so as to effectively construct an antibacterial surface.

[0007] In order to solve the above technical problems, the present invention provides a method for preparing an arylsulfonylamino quaternary ammonium salt antibacterial agent, comprising the following steps:

[0008] (1) adding a linear fatty amine having a tertiary amino group at the end, an arylsulfonyl chloride and an inorganic base into a reaction container, reacting in an aqueous phase, and after the reaction, separating the reaction solution into layers, washing and drying to obtain an arylsulfonamide compound;

[0009] The structural formula of the straight-chain fatty amine with a tertiary amino group at the end is:

[0010]

[0011] Wherein, n is an integer from 0 to 12;

[0012] R 2 C 1 ~C 4 A straight chain alkyl group;

[0013] (2) adding the obtained arylsulfonamide compound and halogenated hydrocarbon into a reaction container, heating and refluxing in an organic solvent for reaction, cooling and crystallizing after the reaction, filtering, washing and drying to obtain the arylsulfonylamino quaternary ammonium salt antibacterial agent.

[0014] In a preferred embodiment of the present invention, in step (1), the molar ratio of the linear fatty amine having a tertiary amino group at the end, the aryl sulfonyl chloride and the inorganic base is 1:1-1.4:1-1.5.

[0015] In a preferred embodiment of the present invention, the aryl sulfonyl chloride includes at least one of benzenesulfonyl chloride, p-toluenesulfonyl chloride, 2-toluenesulfonyl chloride, 3-toluenesulfonyl chloride, 4-ethylbenzenesulfonyl chloride, 4-butylbenzenesulfonyl chloride, 4-methoxybenzenesulfonyl chloride, 4-ethoxybenzenesulfonyl chloride, 2,4,6-trimethylbenzenesulfonyl chloride, 2,5-xylenesulfonyl chloride, 2,4-xylenesulfonyl chloride, 4-fluorobenzenesulfonyl chloride, 4-chlorobenzenesulfonyl chloride, 4-bromobenzenesulfonyl chloride, 4-iodobenzenesulfonyl chloride, 2,4,6-triisopropylbenzenesulfonyl chloride, 2-naphthalenesulfonyl chloride, 2-nitrobenzenesulfonyl chloride, 3-nitrobenzenesulfonyl chloride or 4-nitrobenzenesulfonyl chloride.

[0016] In a preferred embodiment of the present invention, the inorganic base includes at least one of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, strontium carbonate or lithium carbonate.

[0017] In a preferred embodiment of the present invention, the reaction temperature in step (1) is 10-40°C.

[0018] In a preferred embodiment of the present invention, in step (2), the molar ratio of the arylsulfonamide compound to the halogenated hydrocarbon is 1:1 to 1.2.

[0019] In a preferred embodiment of the present invention, the halogenated hydrocarbon is C 1 -C 18 Aliphatic chain alkyl chlorides or bromides.

[0020] In a preferred embodiment of the present invention, the reaction temperature in step (2) is 80-100°C.

[0021] The invention has the beneficial effects of: providing a method for preparing an arylsulfonylamino quaternary ammonium salt antibacterial agent, using arylsulfonyl chloride, a straight-chain fatty amine with a tertiary amino group at the end and a halogenated hydrocarbon as raw materials, and preparing the arylsulfonylamino quaternary ammonium salt through a two-step reaction; the target product quaternary ammonium salt obtained by the invention has high purity, excellent yield, simple and convenient operation, green and environmentally friendly process, and the obtained product has good antibacterial ability. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1 This is the NMR spectrum of N-(2-(benzenesulfonylamino)ethyl)-N,N-dimethyldodecane-1-ammonium bromide prepared in Example 1 of the present invention. DETAILED DESCRIPTION

[0023] The preferred embodiments of the present invention are described in detail below in conjunction with the accompanying drawings so that the advantages and features of the present invention can be more easily understood by those skilled in the art, thereby making a clearer and more definite definition of the protection scope of the present invention.

[0024] The invention discloses a method for preparing an arylsulfonylamino quaternary ammonium salt antibacterial agent, which is prepared by using arylsulfonyl chloride, a straight-chain fatty amine with a tertiary amino group at the end and a halogenated hydrocarbon as raw materials, and specifically comprises the following steps:

[0025] (1) adding a straight-chain fatty amine having a tertiary amino group at the end, an aryl sulfonyl chloride and an inorganic base in a molar ratio of 1:1 to 1.4:1 to 1.5 to a reaction container, reacting at 0 to 60° C., preferably 10 to 40° C. in an aqueous phase, and after the reaction, separating the solution into layers, washing and drying to obtain an aryl sulfonamide compound;

[0026] (2) Adding the arylsulfonamide compound and halogenated hydrocarbon prepared in step (1) to a reaction vessel in a molar ratio of 1:1 to 1.2, heating and refluxing in an organic solvent such as acetonitrile, ethyl acetate, propyl acetate, butyl acetate or acetone at 50 to 120° C., preferably 80 to 100° C., cooling and crystallizing after the reaction, filtering, washing and drying to obtain the arylsulfonylamino quaternary ammonium salt antibacterial agent.

[0027] Wherein, the arylsulfonyl chloride The invention comprises at least one of benzenesulfonyl chloride, p-toluenesulfonyl chloride, 2-toluenesulfonyl chloride, 3-toluenesulfonyl chloride, 4-ethylbenzenesulfonyl chloride, 4-butylbenzenesulfonyl chloride, 4-methoxybenzenesulfonyl chloride, 4-ethoxybenzenesulfonyl chloride, 2,4,6-trimethylbenzenesulfonyl chloride, 2,5-xylenesulfonyl chloride, 2,4-xylenesulfonyl chloride, 4-fluorobenzenesulfonyl chloride, 4-chlorobenzenesulfonyl chloride, 4-bromobenzenesulfonyl chloride, 4-iodobenzenesulfonyl chloride, 2,4,6-triisopropylbenzenesulfonyl chloride, 2-naphthalenesulfonyl chloride, 2-nitrobenzenesulfonyl chloride, 3-nitrobenzenesulfonyl chloride or 4-nitrobenzenesulfonyl chloride.

[0028] The inorganic base includes at least one of sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide, calcium hydroxide, magnesium hydroxide, zinc hydroxide, iron hydroxide, aluminum hydroxide, barium hydroxide, sodium carbonate, potassium carbonate, strontium carbonate or lithium carbonate. The inorganic base is used as an acid binding agent. In the aqueous phase, under the action of the inorganic base, aryl sulfonyl chloride and a straight-chain fatty amine with a tertiary amino group at the end synthesize an aryl sulfonamide compound.

[0029] The halogenated hydrocarbon C 1 -C 18 Aliphatic chain alkyl chlorides or bromides.

[0030] The structural formula of the straight-chain fatty amine with a tertiary amino group at the end is:

[0031]

[0032] wherein n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; R 2 C 1 ~C 4 of a straight chain alkyl group.

[0033] The reaction formula of the above reaction process is as follows:

[0034]

[0035] The process of the present invention is described in detail below through specific embodiments.

[0036] Example 1

[0037] Synthesis of N-(2-(Benzenesulfonylamino)ethyl)-N,N-dimethyldodecane-1-ammonium bromide

[0038]

[0039]

[0040] Add 88 g of N,N-dimethylethylenediamine and 500 ml of water to the reaction flask, cool with ice water, control the temperature at about 15°C, and simultaneously dropwise add 195 g of benzenesulfonyl chloride and 600 ml of 2N sodium hydroxide aqueous solution; after the dropwise addition is completed, stir and react at room temperature for 2 hours, let stand and separate, remove the upper aqueous phase, wash with cold water 3 times, and vacuum dry to obtain 218 g of oily product N-(2-(dimethylamino)ethyl)benzenesulfonamide, with a yield of 96%; 1H (NMR, CDCl3): δ7.66 (m, 2H), 7.39 (m, 1H), 7.35 (m, 2H), 2.85 (t, 2H), 2.16 (t, 2H), 1.96 (s, 6H).

[0041] Take 2.3 g of N-(2-(dimethylamino)ethyl)benzenesulfonamide and 2.8 g of 1-bromodecane and dissolve them in 15 ml of ethyl acetate, heat and reflux for 4 hours; slowly cool and crystallize, filter, wash with ethyl acetate, and vacuum dry to obtain 4.5 g of solid product N-(2-(benzenesulfonylamino)ethyl)-N,N-dimethyldodecane-1-ammonium bromide, with a yield of 94%; 1H (NMR, d6-DMSO): δ8.12 (t, 1H), 7.86 (m, 2H), 7.2 (m, 1H), 7.65 (m, 2H), 3.40 (m, 2H), 3.28 (m, 2H), 3.19 (m, 2H), 3.05 (s, 6H), 1.64 (m, 2H), 1.26 (m, 18H), 0.86 (t, 3H).

[0042] Example 2

[0043] Synthesis of N-(3-(2,4,6-trimethylbenzenesulfonylamino)propyl)-N,N-dimethyldodecane-1-ammonium bromide

[0044]

[0045] Add 51 g of 3-N,N-dimethylaminopropylamine, 82 g of potassium carbonate and 600 ml of water to the reaction flask, stir thoroughly to dissolve, cool with ice water, control the temperature at about 10°C, and add 121 g of 2,4,6-trimethylbenzenesulfonyl chloride in batches within 1 hour under vigorous stirring; after the addition is completed, continue to react with vigorous stirring at room temperature for 2 hours, filter, wash with ice water, and vacuum dry to obtain 135 g of solid product N-(3-(dimethylamino)propyl)-2,4,6-trimethylbenzenesulfonamide, with a yield of 95%; 1H (NMR, d6-DMSO): δ7.06 (s, 1H), 6.95 (s, 2H), 2.92 (t, 2H), 2.62 (s, 6H), 2.31 (t, 2H), 2.28 (s, 3H), 2.16 (s, 6H), 1.66 (m, 2H).

[0046] Take 2.9 g of N-(3-(dimethylamino)propyl)-2,4,6-trimethylbenzenesulfonamide and 2.8 g of 1-bromododecane and dissolve them in 15 ml of acetonitrile, heat and reflux for 4 hours; slowly cool and crystallize, filter, wash with acetonitrile, and vacuum dry to obtain 5.1 g of solid product N-(3-(2,4,6-trimethylbenzenesulfonylamino)propyl)-N,N-dimethyldodecane-1-ammonium bromide, with a yield of 96%; 1H(N MR, d6-DMSO): δ8.13 (t, 1H), 6.92 (s, 2H), 3.90 (m, 2H), 3.40 (m, 2H), 3.12 (m, 2H), 3.06 ( s, 6H), 2.65 (s, 6H), 2.23 (m, 2H), 2.21 (s, 3H), 1.64 (m, 2H), 1.28 (m, 18H), 0.88 (t, 3H).

[0047] Example 3

[0048] Synthesis of N-(3-(4-ethylbenzenesulfonylamino)propyl)-N,N-dimethylhexane-1-ammonium chloride

[0049]

[0050] Add 51 g of 3-N,N-dimethylaminopropylamine and 250 ml of water to the reaction flask, cool with ice salt, control the temperature at about 5°C, and simultaneously add dropwise 112 g of 4-ethylbenzenesulfonyl chloride and 300 ml of 2N potassium hydroxide aqueous solution; complete the addition within 2 hours, continue stirring at room temperature for 1 hour, let stand and separate, decant the upper aqueous phase, wash with cold water 3 times, and dry in vacuo to obtain 132 g of an oily product with a yield of 98%; 1H (NMR, d6-DMSO): δ7.75 (d, 2H), 7.40 (d, 2H), 7.26 (s, 1H), 2.91 (t, 2H), 2.68 (q, 2H), 2.31 (t, 2H), 2.16 (s, 6H), 1.64 (m, 2H), 1.20 (t, 3H).

[0051] Take 2.7 g of N-(3-(dimethylamino)propyl)-4-ethylbenzenesulfonamide and 1.5 g of 1-chlorohexane and dissolve them in 15 ml of butyl acetate, heat and reflux for 4 hours; cool to room temperature, then crystallize at 0°C for 1 hour, quickly filter, wash with frozen petroleum ether, and vacuum dry to obtain 3.7 g of solid product N-(3-(4-ethylbenzenesulfonylamino)propyl)-N,N-dimethylhexane-1-ammonium chloride, with a yield of 95%; 1H (NMR, d6-DMSO): δ8.12(t, 1H), 7.76(d, 2H), 7.41(d, 2H), 3.90(m, 2H), 3.40(m, 2H), 3.12(m, 2H), 3.06(s, 6H), 2.68(q, 2H), 2.23(m, 2H), 1.64(m, 2H), 1.28(m, 6H), 1.20(t, 3H), 0.88(t, 3H).

[0052] Antibacterial testing: Antibacterial application experiments using Staphylococcus aureus

[0053] 1. Bacterial culture:

[0054] Pick a single Staphylococcus aureus colony on the agar medium and place it in 5 mL of liquid culture medium, and culture it in a constant temperature shaking incubator at 37°C for 24 hours. Take 50 μL of bacterial solution and dilute it 100 times with liquid culture medium, and continue to culture the bacteria until the logarithmic phase (OD 600 is 0.5-0.6).

[0055] (II) Antimicrobial activity detection:

[0056] Bacteria with a concentration of 104 CFU / mL were mixed with quaternary ammonium salts with a concentration gradient (0, 31.25, 62.5, 125, 250, 500 μg / mL) and placed in a 96-well plate. The mixture was cultured at 37°C with constant temperature shaking for 8 hours in a microplate reader, and the turbidity change of the mixture was monitored at multiple points at OD 600. The bacterial growth curve was drawn and the minimum inhibitory concentration (MIC) value of the quaternary ammonium salt was detected. The results are shown in Table 1 below.

[0057] Table 1

[0058]

[0059] It can be seen from the test results in Table 1 that the quaternary ammonium salt prepared by the present invention has a significant inhibitory effect on the growth of Staphylococcus aureus, and is positively correlated with its concentration.

[0060] The above descriptions are merely embodiments of the present invention and are not intended to limit the patent scope of the present invention. Any equivalent structure or equivalent process transformation made using the contents of the present invention specification and drawings, or directly or indirectly applied in other related technical fields, are also included in the patent protection scope of the present invention.

Claims

1. A method for preparing an arylsulfonylamino quaternary ammonium salt antibacterial agent, characterized in that: The steps include: (1) adding a linear fatty amine having a tertiary amino group at the end, an arylsulfonyl chloride and an inorganic base into a reaction container, reacting in an aqueous phase, and after the reaction, separating the reaction solution into layers, washing and drying to obtain an arylsulfonamide compound; The structural formula of the straight-chain fatty amine with a tertiary amino group at the end is: Wherein, n is an integer from 0 to 12; R2 is a C1-C4 straight chain alkyl group; (2) adding the obtained arylsulfonamide compound and halogenated hydrocarbon into a reaction container, heating and refluxing in an organic solvent for reaction, cooling and crystallizing after the reaction, filtering, washing and drying to obtain the arylsulfonylamino quaternary ammonium salt antibacterial agent.

2. The method for preparing an arylsulfonylamino quaternary ammonium salt antibacterial agent according to claim 1, characterized in that: In step (1), the molar ratio of the linear fatty amine with a tertiary amino group at the end, the aryl sulfonyl chloride and the inorganic base is 1:1 to 1.4:1 to 1.

5.

3. The method for preparing an arylsulfonylamino quaternary ammonium salt antibacterial agent according to claim 2, characterized in that: The arylsulfonyl chloride includes at least one of benzenesulfonyl chloride, p-toluenesulfonyl chloride, 2-toluenesulfonyl chloride, 3-toluenesulfonyl chloride, 4-ethylbenzenesulfonyl chloride, 4-butylbenzenesulfonyl chloride, 4-methoxybenzenesulfonyl chloride, 4-ethoxybenzenesulfonyl chloride, 2,4,6-trimethylbenzenesulfonyl chloride, 2,5-xylenesulfonyl chloride, 2,4-xylenesulfonyl chloride, 4-fluorobenzenesulfonyl chloride, 4-chlorobenzenesulfonyl chloride, 4-bromobenzenesulfonyl chloride, 4-iodobenzenesulfonyl chloride, 2,4,6-triisopropylbenzenesulfonyl chloride, 2-naphthalenesulfonyl chloride, 2-nitrobenzenesulfonyl chloride, 3-nitrobenzenesulfonyl chloride or 4-nitrobenzenesulfonyl chloride.

4. The method for preparing an arylsulfonylamino quaternary ammonium salt antibacterial agent according to claim 2, characterized in that: The inorganic base includes at least one of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, strontium carbonate or lithium carbonate.

5. The method for preparing an arylsulfonylamino quaternary ammonium salt antibacterial agent according to claim 1, characterized in that: The reaction temperature in step (1) is 10-40°C.

6. The method for preparing an arylsulfonylamino quaternary ammonium salt antibacterial agent according to claim 1, characterized in that: In step (2), the molar ratio of the arylsulfonamide compound to the halogenated hydrocarbon is 1:1 to 1.

2.

7. The method for preparing an arylsulfonylamino quaternary ammonium salt antibacterial agent according to claim 6, characterized in that: The halogenated hydrocarbon is C1-C 18 Aliphatic chain alkyl chlorides or bromides.

8. The method for preparing an arylsulfonylamino quaternary ammonium salt antibacterial agent according to claim 1, characterized in that: The reaction temperature in step (2) is 80-100°C.

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