CN111296457A - Pyridine quaternary ammonium salt type chloramine antibacterial agent with alkyl chain and synthetic method thereof - Google Patents

Pyridine quaternary ammonium salt type chloramine antibacterial agent with alkyl chain and synthetic method thereof Download PDF

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CN111296457A
CN111296457A CN202010156088.1A CN202010156088A CN111296457A CN 111296457 A CN111296457 A CN 111296457A CN 202010156088 A CN202010156088 A CN 202010156088A CN 111296457 A CN111296457 A CN 111296457A
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chloramine
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李令东
贾冬雪
王瀚德
马晗雪
张广庆
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Dalian University of Technology
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Abstract

The invention provides a pyridine quaternary ammonium salt type chloramine antibacterial agent with an alkyl chain and a synthesis method thereof, belonging to the field of chemical synthesis and technical application of chloramine antibacterial agents. The bromine alkyl 5, 5-dimethyl hydantoin is used as a raw material, two pyridine quaternary ammonium salt type chloramine precursors are prepared through different chemical synthesis routes, and the two pyridine quaternary ammonium salt type chloramine compounds are obtained after chlorination. According to the invention, the alkyl long-chain pyridinium quaternary ammonium salt unit and the chloramine unit are covalently combined into the same molecule to prepare two pyridinium quaternary ammonium salt type chloramines with different connection modes, and the antibacterial performance of the chloramines is tested. The introduction of the pyridinium quaternary ammonium salt group into the chloramine compound can effectively improve the water solubility of the whole chloramine compound and give consideration to the respective specific antibacterial capacities of chloramine and alkyl long-chain pyridinium quaternary ammonium salt; meanwhile, the long alkyl chain connected with the quaternary pyridinium salt group can realize the synergistic bactericidal effect of the two groups with chloramine group, thereby providing a material basis for preparing the chloramine compound antibacterial agent and exploring the detailed antibacterial mechanism of the compound antibacterial agent.

Description

Pyridine quaternary ammonium salt type chloramine antibacterial agent with alkyl chain and synthetic method thereof
Technical Field
The invention relates to a pyridine quaternary ammonium salt type chloramine antibacterial agent with an alkyl chain and a synthesis method thereof, belonging to the fields of chemical synthesis and technical application of chloramine antibacterial agents.
Background
Currently reported antibacterial agents are mainly classified into three types, i.e., natural antibacterial agents, inorganic antibacterial agents, and organic antibacterial agents. Compared with natural and inorganic antibacterial agents, organic antibacterial agents are favored because of their advantages of wide variety, fast sterilization speed, high efficiency, stability, broad spectrum of antibacterial property, etc., and quaternary ammonium salts and chloramines are the two most widely studied classes of organic antibacterial agents. However, the use of large amounts of quaternary ammonium based antibacterial agents for long periods of time is prone to bacterial resistance and secondary contamination, and the toxicity of the pyridine quaternary ammonium based compounds to mammalian cells is relatively low (j.med. microbiol.,2013,62, 241-. The chloramine antibacterial agent oxidizes an intracellular receptor through an N-Cl bond (mainly obtained by chlorinating an amide N-H bond) in the structure of the chloramine antibacterial agent to inactivate bacteria, and the unique antibacterial mechanism ensures that the chloramine antibacterial agent is not easy to generate drug resistance, thereby becoming a research hotspot in the field of antibacterial agents. However, the conversion of the N-H bond to the N-Cl bond in the chloramine precursor greatly reduces both hydrophilicity and antimicrobial efficiency. A series of ionic chloramine antimicrobials have recently been developed in this group, including quaternary ammonium chloramines (Adv Healthcare mater, 2012,1, 609-) 620) (RSC Adv, 2015,5, 93877-. Among them, chloramine of quaternary ammonium salt type was successfully integrated on polyurethane (can.j.chem.,2018,96,939-948), and chloramine of pyridinium type was also integrated on the surface of cotton fabric (j.appl.polym.sci.,2017,38,45323) (CN 106518904 a), and the corresponding chloramine-based high-efficiency antibacterial material was prepared.
Disclosure of Invention
The invention aims to provide two pyridine quaternary ammonium salt type chloramine antibacterial agents with alkyl chains and a synthesis route thereof. The invention has the advantages of easily obtained raw materials, simple synthesis method and easy operation.
The technical scheme of the invention is as follows:
the chloramine antibacterial agent of quaternary pyridinium type with alkyl chain has the structural formula as follows:
Figure BDA0002404092780000021
in the formula n1And n2Are all selected from integers of 5-11.
The synthesis method of the pyridine quaternary ammonium salt type chloramine antibacterial agent with the alkyl chain comprises the following steps:
the bromopropyl 5, 5-dimethyl hydantoin (II) is used as an initial raw material to prepare a product through etherification, quaternization and chlorination, and the synthetic route is as follows:
Figure BDA0002404092780000022
the specific process is as follows:
(1a) synthesizing an alkyl pyridine ether compound (III);
(1b) dissolving hydroxypyridine in acetonitrile, adding anhydrous potassium carbonate, heating, stirring and refluxing for 1h, adding bromopropyl 5, 5-dimethylhydantoin (II), continuously refluxing for 4h, removing inorganic salts, separating by using column chromatography, and taking methanol/dichloromethane with the volume ratio of 2/25-1/10 as an eluent; collecting the organic phase containing the product, and removing the solvent to obtain a hydantoin pyridine ether compound (VI); wherein the molar ratio of the hydroxypyridine to the bromopropyl 5, 5-dimethylhydantoin is 1: 1-1: 2;
(2a) dissolving an alkyl pyridine ether compound (III) in acetonitrile, adding bromopropyl 5, 5-dimethylhydantoin (II), heating and refluxing overnight, removing a solvent, separating by using column chromatography, collecting an elution component containing a product by using methanol/dichloromethane with a volume ratio of 1/20-3/20 as an eluent, and removing the solvent to obtain a brominated pyridine quaternary ammonium salt type chloramine precursor; dissolving the brominated pyridinium quaternary ammonium salt type chloramine precursor in a small amount of deionized water, and slowly passing the solution through chlorine type anion exchange resin to obtain a pyridinium chloride quaternary ammonium salt type chloramine precursor (IV); wherein the molar ratio of the hydroxypyridine to the anhydrous potassium carbonate to the bromopropyl 5, 5-dimethylhydantoin is 1: 2: 1; the molar ratio of the alkyl pyridine ether compound to the bromopropyl 5, 5-dimethylhydantoin is 1: 1.1-1: 1.3;
(2b) dissolving a hydantoin pyridine ether compound (VI) in acetonitrile, adding n-brominated alkane, heating and refluxing for overnight, removing a solvent, separating by using column chromatography, collecting an elution component containing a product by using methanol/dichloromethane with a volume ratio of 2/25-1/10 as an eluent, and removing the solvent to obtain a brominated pyridine quaternary ammonium salt type chloramine precursor; dissolving the brominated pyridinium quaternary ammonium salt type chloramine precursor in a small amount of deionized water, and slowly passing the solution through chlorine type anion exchange resin to obtain a pyridinium chloride quaternary ammonium salt type chloramine precursor (VII); wherein the molar ratio of the hydantoin pyridine ether compound to the n-bromoalkane is 1: 1.5;
(3) dissolving the pyridinium quaternary ammonium salt type chloramine precursor in a mixed solution of tertiary butanol and water with the volume ratio of 4/1, adding excessive tert-butyl hypochlorite, stirring for 24-36h at normal temperature in a dark place, and vacuum concentrating to obtain the pyridinium quaternary ammonium salt type chloramine compound (I) with different alkyl chains1) And (I)2) Namely, the pyridine quaternary ammonium salt type chloramine antibacterial agent with alkyl chain; wherein the molar ratio of the pyridinium quaternary ammonium salt chloramine to the tert-butyl hypochlorite is 1: 3-1: 5.
the hydroxypyridine is m-hydroxypyridine and p-hydroxypyridine.
The invention has the beneficial effects that: the introduction of the quaternary pyridinium salt group into the chloramine compound can effectively improve the water solubility of the whole chloramine compound and essentially give consideration to the respective specific antibacterial capacities of chloramine and alkyl long-chain quaternary pyridinium salt; meanwhile, the long alkyl chain connected with the quaternary pyridinium salt group can realize the synergistic sterilization effect of the two groups with chloramine group, thereby providing a material basis for preparing the chloramine compound antibacterial agent and exploring the detailed antibacterial mechanism of the compound antibacterial agent.
Detailed Description
The features of the present invention are further illustrated by the following examples, but the scope of protection of this patent is not limited by the following specific examples.
Figure BDA0002404092780000041
Example 1
Dissolving hydroxypyridine (1.33g, 14.0mmol) in a 20mL N-dimethylformamide solution, adding anhydrous potassium carbonate (3.87g, 28.0mmol), heating and refluxing at 75 ℃ for 1h, adding 1-bromo-N-hexane (2.30g, 1.95mL, 14.0mmol), continuing to reflux overnight, cooling, removing inorganic salts, adding 30mL water and 30mL ethyl acetate, extracting, concentrating the organic phase, separating and purifying by column chromatography, collecting and concentrating the organic phase containing the product by using methanol/dichloromethane (0-1/10, v/v) as an eluent, and obtaining pyridylalkyl ether compound 2(1.38g, 55%).1H NMR(500MHz,CHCl3)δ7.23(d,2H), 6.32(d,2H),3.70(t,J＝7.2Hz,2H),1.75–1.63(m,2H),1.24(m,6H),0.82(t, J＝6.2Hz,3H).
Example 2
Dissolving the compound 1(1.03g, 4.15mmol) in 20mL acetonitrile solution, adding the alkyl pyridine ether compound 2(0.68g, 3.77mmol), heating at 100 ℃ for reflux overnight, cooling, concentrating in vacuum, separating and purifying by column chromatography, and collecting and concentrating the organic phase containing the product by using methanol/dichloromethane (0-3/20, v/v) as eluent to obtain a light yellow solid (1.19g, 73.7%). Dissolving the compound in a small amount of deionized water, slowly passing through chlorine type anion exchange resin, collecting leacheate, and concentrating in vacuum to obtain the chlorinated pyridine quaternary ammonium salt type chloramine precursor compound 6.1H NMR(500MHz,D2O)δ8.51(d,2H),7.36 (d,2H),4.34(t,J＝7.2Hz,2H),4.29(t,J＝5.4Hz,2H),3.64(t,J＝6.2Hz,2H),2.12(m, 2H),1.91–1.83(m,2H),1.32(s,6H),1.21(m,6H),0.77(t,J＝6.1Hz,3H)；13C NMR (126MHz,D2O)δ180.8,170.2,157.4,145.4,113.6,68.6,60.0,59.1,48.9,35.7,30.3, 26.5,24.8,23.4,21.7,13.2.
Example 3
Dissolving the compound 6(0.40g, 1.04mmol) in 3.60mL of a mixed solution of tert-butyl alcohol and water (4/1, v/v), adding tert-butyl hypochlorite (0.34g, 0.36mL, 3.13mmol), stirring for 24h under the condition of keeping out of the light, and concentrating in vacuum to obtain the pyridinium chloride quaternary ammonium salt type chloramine compound 10.1H NMR(500MHz,D2O) δ8.52(d,2H),7.41–7.28(d,2H),4.35(t,J＝7.1Hz,2H),4.30(t,J＝5.4Hz,2H),3.73 (t,J＝6.2Hz,2H),2.14(m,2H),1.88(m,2H),1.39(s,6H),1.22–1.16(m,6H),0.77(t, J＝6.2Hz,3H)；13C NMR(126MHz,D2O)δ176.9,170.1,155.8,145.5,113.6,69.7, 68.7,66.2,60.0,37.0,30.3,29.6,26.4,24.8,21.7,13.2.
Example 4
Hydroxypyridine (0.92g, 9.65mmol) is dissolved in 20mL of N-dimethylformamide, anhydrous potassium carbonate (2.62g, 19.3mmol) is added thereto, the mixture is heated and refluxed at 75 ℃ for 1h, 1-bromo-N-octane (1.86g, 1.68, 9.65mmol) is further added thereto, the reflux is continued overnight, the inorganic salt is removed after cooling, 30mL of water and 30mL of ethyl acetate are added thereto for extraction and liquid separation, the organic phase is concentrated and purified by column chromatography, and the organic phase containing the product is collected and concentrated using methanol/dichloromethane (0 to 1/10, v/v) as an eluent, to obtain an alkylpyridinyl ether compound 3(0.95g, 47.5%).1H NMR(500MHz,CHCl3)δ7.23 (d,2H),6.32(d,2H),3.70(t,J＝7.2Hz,2H),1.70(m,J＝6.6Hz,2H),1.29–1.14(m, 10H),0.81(t,J＝6.7Hz,3H)；13C NMR(126MHz,CHCl3)δ178.8,139.7,118.6,77.4, 57.1,31.6,30.9,29.0,26.2,22.5,14.0.
Example 5
Dissolving compound 1(1.25g, 5.01mmol) in 20mL acetonitrile solution, adding alkyl pyridine ether compound 3(0.95g, 4.59mmol), heating at 100 deg.C under reflux overnight, cooling, vacuum concentrating, separating and purifying with column chromatography, eluting with methanol/dichloromethane (0-3/20, v/v), collecting and concentrating product containing organic compoundsThe organic phase yielded a pale yellow solid (1.35g, 64.5%). Dissolving the compound in a small amount of deionized water, slowly passing through chlorine type anion exchange resin, collecting leacheate, and concentrating in vacuum to obtain the chlorinated pyridine quaternary ammonium salt type chloramine precursor compound 7.1H NMR(500MHz,D2O)δ8.52(d,2H),7.37 (d,2H),4.35(t,J＝7.1Hz,2H),4.29(t,J＝5.4Hz,2H),3.64(t,J＝6.2Hz,2H),2.12(m, 2H),1.87(m,2H),1.32(s,6H),1.25–1.09(m,10H),0.76(t,J＝6.7Hz,3H)；13C NMR (126MHz,D2O)δ180.7,170.2,157.4,145.4,113.6,68.6,60.0,59.1,48.9,35.7,30.9, 30.1,28.2,26.5,25.1,23.5,22.0,13.4.
Example 6
Dissolving the compound 7(0.50g, 1.22mmol) in 4.50mL of a mixed solution of tert-butyl alcohol and water (4/1, v/v), adding tert-butyl hypochlorite (0.40g, 0.42mL, 3.65mmol), stirring for 24h under the condition of keeping out of the light, and concentrating in vacuum to obtain the pyridinium chloride quaternary ammonium salt type chloramine compound 11.1H NMR(500MHz,D2O) δ8.53(d,2H),7.36(d,2H),4.36(t,J＝6.9Hz,2H),4.30(t,J＝5.3Hz,2H),3.73(t, J＝6.1Hz,2H),2.19–2.09(m,2H),1.87(m,2H),1.39(s,6H),1.22–1.13(m,10H), 0.75(t,J＝6.5Hz,3H)；13C NMR(126MHz,D2O)δ176.8,170.1,155.7,145.5,113.6, 68.7,66.2,60.0,37.0,31.0,30.1,29.6,28.2,26.4,25.1,22.0,21.0,13.4.
Example 7
Hydroxypyridine (1.01g, 10.6mmol) is dissolved in a 20mL N-dimethylformamide solution, anhydrous potassium carbonate (2.90g, 21.3mmol) is added thereto, the mixture is heated and refluxed at 75 ℃ for 1h, 1-bromo-N-decane (2.34g, 2.25mL, 10.6mmol) is further added thereto, the reflux is continued overnight, the inorganic salt is removed after cooling, 30mL water and 30mL ethyl acetate are added thereto to extract a liquid separation, the organic phase is concentrated and purified by column chromatography, and the organic phase containing the product is collected and concentrated using methanol/dichloromethane (0 to 1/10, v/v) as an eluent, to obtain an alkylpyridinium ether compound 4(1.35g, 53.8%).1H NMR(500MHz,CHCl3)δ7.28 (d,2H),6.36(d,2H),3.75(t,J＝7.2Hz,2H),1.81–1.69(m,2H),1.26(m,14H),0.85 (t,J＝7.0Hz,3H).
Example 8
The compound 1(1.56g, 6.29mmol) is dissolved in 20mL acetonitrile solution, the alkyl pyridine ether compound 4(1.35g, 5.72mmol) is added to the acetonitrile solution, the mixture is heated and refluxed at 100 ℃ overnight, the mixture is cooled and concentrated in vacuum, and the product-containing organic phase is collected and concentrated by column chromatography separation and purification, methanol/dichloromethane (0-3/20, v/v) is used as an eluent, so that light yellow solid (1.68g, 60.7%) is obtained. Dissolving the compound in a small amount of deionized water, slowly passing through chlorine type anion exchange resin, collecting leacheate, and concentrating in vacuum to obtain the chlorinated pyridine quaternary ammonium salt type chloramine precursor compound 8.1H NMR(500MHz,D2O)δ8.69(d,2H),7.45 (d,2H),4.53–4.40(t,J＝7.1Hz,2H),4.39–4.30(t,J＝5.4Hz,2H),3.62(t,J＝6.3Hz, 2H),2.16–2.05(m,2H),1.89(m,2H),1.32(s,6H),1.22–1.00(m,14H),0.64(t, J＝6.1Hz,3H)；13C NMR(126MHz,D2O)δ180.1,170.3,157.2,145.7,117.4,113.8,69.0,59.0,35.6,31.6,30.7,29.0,28.8,26.7,25.6,23.7,22.4,13.7.
Example 9
Compound 8(0.50g, 1.14mmol) was dissolved in 4.50mL of a mixture of t-butanol and water (4/1, v/v), tert-butyl hypochlorite (0.37g, 0.40mL, 3.42mmol) was added, and the mixture was stirred for 24 hours under dark conditions and concentrated in vacuo to give pyridinium chloride quaternary ammonium salt-type chloramine compound 12.1H NMR(500MHz,D2O) δ8.62(d,2H),7.42(d,2H),4.52–4.39(t,J＝6.9Hz,2H),4.35(t,J＝5.7Hz,2H),3.73 (t,J＝6.1Hz,2H),2.22–2.07(m,2H),1.95–1.83(m,2H),1.37(s,6H),1.06(m,14H), 0.67(d,J＝6.7Hz,3H)；13C NMR(126MHz,D2O)δ176.1,170.3,155.4,145.7,113.8, 68.9,66.1,60.0,37.0,31.6,30.5,29.6,29.1,28.8,26.6,25.5,23.6,22.4,21.3,13.7.
Example 10
Dissolving hydroxypyridine (0.90g, 9.50mmol) in 20mL of N-dimethylformamide, adding anhydrous potassium carbonate (2.63g, 19.0mmol), heating and refluxing at 75 deg.C for 1h, adding 1-bromododecane (2.36g, 2.30mL, 9.50mmol), refluxing overnight, cooling, removing inorganic salt, adding 30mL of water and 30mL of ethyl acetate, extracting, separating, concentrating, and separating pure organic phase by column chromatographyAnd (3) carrying out alkylation, and collecting and concentrating an organic phase containing the product by using methanol/dichloromethane (0-1/10, v/v) as an eluent to obtain the alkyl pyridine ether compound 5(1.60g, 64.0%).1H NMR(500MHz,CHCl3)δ7.28 (d,2H),6.38(d,2H),3.76(t,J＝7.2Hz,2H),1.81–1.66(m,2H),1.27(m,18H),0.87 (t,J＝6.7Hz,3H).
Example 11
The compound 1(1.66g, 6.67mmol) is dissolved in 20mL acetonitrile solution, the alkyl pyridine ether compound 5(1.59g, 6.07mmol) is added to the acetonitrile solution, the mixture is heated and refluxed at 100 ℃ overnight, the mixture is cooled and concentrated in vacuum, the product is separated and purified by column chromatography, and an organic phase containing the product is collected and concentrated by using methanol/dichloromethane (0-3/20, v/v) as an eluent, so that light yellow solid (2.26g, 72.9%) is obtained. Dissolving the compound in a small amount of deionized water, slowly passing through a chlorine type anion exchange resin, collecting eluent, and carrying out vacuum concentration to obtain the pyridinium chloride quaternary ammonium salt type chloramine precursor compound 9.1H NMR(500MHz,D2O)δ8.81–8.69(d, 2H),7.53–7.40(d,2H),4.52(t,J＝7.0Hz,2H),4.34(t,J＝5.3Hz,2H),3.61(t,J＝6.2Hz, 2H),2.16–2.05(m,2H),1.91(m,2H),1.32(s,6H),1.14(m,18H),0.66(t,J＝5.8Hz, 3H)；13C NMR(126MHz,D2O)δ179.9,170.3,157.1,146.2,145.8,113.8,69.1,59.8,58.9,35.5,31.8,30.9,29.6,29.5,29.3,29.2,27.8,26.8,25.8,23.7,22.5,13.8.
Example 12
Dissolving the compound 9(0.50g, 1.07mmol) in 4.50mL of a mixed solution of tert-butyl alcohol and water (4/1, v/v), adding tert-butyl hypochlorite (0.35g, 0.40mL, 3.21mmol), stirring for 24h under the condition of keeping out of the light, and concentrating in vacuum to obtain the pyridinium chloride quaternary ammonium salt type chloramine compound 13.1H NMR(500MHz,D2O) δ8.70(d,2H),7.46(d,2H),4.50(t,J＝6.1Hz,2H),4.36(t,J＝5.3Hz,2H),3.73(t, J＝6.1Hz,2H),2.25–2.03(m,2H),1.89(m,2H),1.37(s,6H),1.10(m,18H),0.63(t, J＝6.4Hz,3H)；13C NMR(126MHz,D2O)δ175.7,170.3,155.1,145.7,113.8,69.0, 66.0,59.9,37.0,31.7,30.7,29.6,29.6,29.4,29.1,26.6,25.7,23.7,22.5,21.4,21.2, 13.8.
Figure BDA0002404092780000091
Example 13
Dissolving hydroxypyridine (2.57g, 27mmol) in 70mL of acetonitrile solution, adding anhydrous potassium carbonate (7.46g, 54mmol), stirring and refluxing at 100 ℃ for 1h, adding bromopropylhydantoin (6.70g, 27mmol), continuing to reflux for 4h, cooling to room temperature, removing inorganic salts, vacuum-concentrating, separating and purifying by column chromatography, collecting and concentrating the organic phase containing the product by using methanol/dichloromethane (0-3/20, v/v) as an eluent, and obtaining the compound 14(4.74g, 61.5%).1H NMR(500MHz,CHCl3)δ7.84–7.78(d,2H), 6.53–6.46(d,2H),4.02(t,J＝6.9Hz,2H),3.47(t,J＝6.6Hz,2H),2.12(m,2H),1.28(s, 6H).
Example 14
Dissolving compound 14(1.23g, 4.68mmol) in acetonitrile solution, refluxing at 100 ℃ for 0.5h, adding 1-bromo-n-hexane (1.18g, 0.98mL, 7.02mmol), continuing to reflux overnight, cooling, concentrating in vacuum, separating and purifying by column chromatography, eluting with methanol/dichloromethane (0-3/20, v/v), collecting and concentrating the organic phase containing the product to obtain a white solid (1.16g, 58.1%). Dissolving the chloramine precursor compound in a small amount of deionized water, slowly passing through chlorine type anion exchange resin, collecting leacheate, and carrying out vacuum concentration to obtain the pyridinium chloride quaternary ammonium salt type chloramine precursor compound 15.1H NMR(500MHz,D2O)δ8.53(d,2H),7.38(d,2H), 4.38(t,J＝7.0Hz,2H),4.30(t,J＝6.5Hz,2H),3.49(t,J＝6.5Hz,2H),2.28–2.18(m, 2H),1.81(m,2H),1.41–1.21(m,12H),0.80(t,J＝6.8Hz,3H)；13C NMR(126MHz, D2O)δ180.6,170.9,157.1,145.4,113.8,71.4,59.1,57.0,35.2,30.6,28.6,27.7,24.6, 23.4,21.9,13.3.
Example 15
Dissolving the compound 15(0.44g, 1.08mmol) in 4.00mL of a mixed solution of tert-butyl alcohol and water (4/1, v/v), adding tert-butyl hypochlorite (0.35g, 0.40mL, 3.23mmol), stirring for 24h under the condition of keeping out of the light, and concentrating in vacuum to obtain the pyridinium chloride quaternary ammonium salt type chloramine compound 19.1H NMR(500MHz,D2O) δ8.53(d,2H),7.45–7.33(d,2H),4.39(t,J＝6.4Hz,2H),4.30(t,J＝5.8Hz,2H),3.58 (t,J＝5.8Hz,2H),2.32–2.20(m,2H),1.86–1.74(m,2H),1.33(m,J＝7.6Hz,12H), 0.80(t,J＝5.8Hz,3H)；13C NMR(126MHz,D2O)δ176.8,171.0,155.5,145.4,113.8, 71.4,66.3,56.9,36.4,30.6,28.5,27.7,24.6,21.9,20.9,13.3.
Example 16
Dissolving compound 14(1.16g, 4.39mmol) in acetonitrile solution, refluxing at 100 ℃ for 0.5h, adding 1-bromo-n-octane (1.27g, 1.13mL, 6.59mmol), continuing to reflux overnight, cooling, concentrating in vacuum, separating and purifying by column chromatography, eluting with methanol/dichloromethane (0-3/20, v/v), collecting and concentrating the organic phase containing the product to obtain a white solid (1.03g, 51.4%). Dissolving the chloramine precursor compound in a small amount of deionized water, slowly passing through chlorine type anion exchange resin, collecting eluent, and carrying out vacuum concentration to obtain the pyridinium chloride quaternary ammonium salt type chloramine precursor compound 16.1H NMR(500MHz,D2O)δ8.60(d,2H),7.40(d,2H), 4.40(t,J＝6.9Hz,2H),4.29(t,J＝6.3Hz,2H),3.46(t,J＝6.5Hz,2H),2.22(m,2H), 1.75(m,2H),1.38–1.14(m,16H),0.75(t,J＝6.3Hz,3H)；13C NMR(126MHz,D2O)δ 180.5,170.9,157.1,145.5,113.8,71.4,59.1,57.0,35.1,31.2,28.7,28.5,28.4,27.8, 25.0,23.4,22.1,13.5.
Example 17
Dissolving compound 16(0.44g, 1.08mmol) in 4.00mL of a mixture of tert-butyl alcohol and water (4/1, v/v), adding tert-butyl hypochlorite (0.35g, 0.40mL, 3.23mmol), stirring for 24h in the dark, and concentrating in vacuum to obtain pyridinium chloride quaternary ammonium salt type chloramine compound 20.1H NMR(500MHz,D2O) δ8.62(d,2H),7.41(d,2H),4.44(t,J＝6.7Hz,2H),4.31(t,J＝6.1Hz,2H),3.55(t, J＝6.5Hz,2H),2.29–2.19(m,2H),1.82–1.72(m,2H),1.44–1.07(m,18H),0.74(t, J＝6.2Hz,3H)；13C NMR(126MHz,D2O)δ176.4,170.8,155.2,145.7,113.8,71.4, 66.2,57.0,36.3,31.4,29.7,28.7,28.6,28.0,25.3,22.3,21.0,13.6.
Example 18
Dissolving compound 14(1.09g, 4.14mmol) in acetonitrile solution, refluxing at 100 deg.C for 0.5h, adding 1-bromo-n-butylDecane (1.37g, 1.30mL, 6.21mmol), reflux continued overnight, cooled and concentrated in vacuo, purified by column chromatography, eluting with methanol/dichloromethane (0-3/20, v/v), the product-containing organic phase was collected and concentrated to give a white solid (1.21g, 61.0%). Dissolving the chloramine precursor compound in a small amount of deionized water, slowly passing through chlorine type anion exchange resin, collecting eluent, and concentrating in vacuum to obtain the pyridinium chloride quaternary ammonium salt type chloramine precursor compound 17.1H NMR(500MHz,D2O)δ8.74–8.61(d,2H),7.41(d, 2H),4.48–4.37(t,J＝5.8Hz,2H),4.29(t,J＝5.8Hz,2H),3.40(t,J＝6.4Hz,2H),2.20 (m,2H),1.81–1.67(m,2H),1.35(d,J＝7.0Hz,2H),1.31(s,6H),1.18(m,12H),0.72 (d,J＝6.8Hz,3H)；13C NMR(126MHz,D2O)δ180.1,170.6,156.8,146.0,113.7,71.3, 66.1,59.0,57.0,36.4,31.8,29.5,29.4,29.2,29.0,28.3,25.6,23.6,22.5,13.8.
Example 19
Compound 17(0.46g, 1.05mmol) was dissolved in 4.20mL of a mixture of t-butanol and water (4/1, v/v), t-butyl hypochlorite (0.34g, 0.36mL, 3.16mmol) was added, and the mixture was stirred for 24 hours in the dark, and concentrated in vacuo to give pyridinium chloride quaternary ammonium salt-type chloramine compound 21.1H NMR(500MHz,D2O) δ8.81–8.62(d,2H),7.44(d,2H),4.49(t,J＝6.7Hz,2H),4.36(t,J＝6.1Hz,2H),3.53 (t,J＝6.5Hz,2H),2.30(m,2H),1.84–1.65(m,2H),1.25(m,20H),0.73(t,J＝6.2Hz, 3H)；13C NMR(126MHz,D2O)δ176.0,170.6,155.0,146.0,113.80,71.3,66.1,59.0, 57.1,36.3,31.8,29.7,29.6,29.3,28.3,25.7,23.6,22.5,21.2,13.8.
Example 20
Compound 14(1.03g, 3.91mmol) was dissolved in acetonitrile solution, refluxed for 0.5h at 100 ℃, added with 1-bromododecane (1.46g, 1.40mL, 5.87mmol), refluxed overnight, cooled and concentrated in vacuo, purified by column chromatography, and the product-containing organic phase was collected and concentrated using methanol/dichloromethane (0-3/20, v/v) as eluent to give a white solid (0.90g, 45.1%). Dissolving in a small amount of deionized water, slowly passing through chlorine type anion exchange resin, collecting eluate, and vacuum concentrating to obtain quaternary ammonium salt of pyridine chlorideForm chloramine precursor compound 18.1H NMR(500MHz,D2O)δ8.74(d,2H),7.45(d,2H), 4.44(t,J＝6.0Hz,2H),4.31(t,J＝5.6Hz,2H),3.40(t,J＝6.3Hz,2H),2.19(m,2H), 1.79–1.68(m,2H),1.24(m,J＝7.13Hz,24H),0.77(t,J＝6.1Hz,3H)；13CNMR (126MHz,D2O)δ179.9,170.4,156.8,146.2,113.9,71.5,66.2,59.0,57.1,34.9,32.0,31.8,29.9,29.8,29.6,29.5,29.1,28.6,25.8,23.7,22.6,13.9.
Example 21
Dissolving compound 18(0.48g, 1.03mmol) in 4.31mL of a mixture of tert-butyl alcohol and water (4/1, v/v), adding tert-butyl hypochlorite (0.34g, 0.31mL, 3.48mmol), stirring for 24h in the dark, and vacuum concentrating to obtain pyridinium chloride quaternary ammonium salt type chloramine compound 22.1H NMR(500MHz,D2O) δ8.74(d,2H),7.45(d,2H),4.50(t,J＝6.1Hz,2H),4.33(t,J＝5.6Hz,2H),3.52(t, J＝6.5Hz,2H),2.31–2.21(m,2H),1.80–1.70(m,2H),1.37–1.08(m,24H),0.74(t, J＝6.4Hz,3H)；13C NMR(126MHz,D2O)δ175.9,170.5,155.0,146.1,113.8,71.3, 66.1,59.0,57.1,36.3,31.9,29.8,29.7,29.5,29.4,28.7,28.4,25.8,23.7,22.6,21.2, 13.9.
Example 22
Staphylococcus aureus (s.aureus ATCC 25923) was used as a model strain to examine the antibacterial performance of the two pyridine quaternary ammonium salt type chloramine precursors and the chloramine antibacterial agent, respectively. The specific method comprises the steps of respectively uniformly mixing 2 mu L of 0.28mol/L compounds 9, 13 and 18, 22 with 10mL of bacterial solution with a certain concentration, respectively acting for 5min, respectively taking out 1mL of mixed solution, uniformly mixing with 0.05% of 1mL of sodium thiosulfate, then gradually diluting and coating the mixed solution on a nutrient agar plate for culturing for 20-24h, finally determining the number of stored viable bacteria by using a plate counting method, and comparing the antibacterial performance of two antibacterial agents.
Figure BDA0002404092780000131
TABLE 1 antibacterial test results for long-chain pyridinium quaternary ammonium salts type chloramines 9, 13, 18 and 22
Figure BDA0002404092780000141
a) The concentration of Staphylococcus aureus is 5.50 × 107CFU/mL。(Colony-Forming Unites)
Figure BDA0002404092780000142
TABLE 2 antibacterial test results of pyridinium Quaternary ammonium chloramines 23 and 24 and Long chain pyridinium Quaternary ammonium chloramines 9 and 13
Figure BDA0002404092780000143
a) The concentration of Staphylococcus aureus is 4.32 × 106CFU/mL。(Colony-Forming Unites)
Table 1 shows the results of the antibacterial tests on two quaternary pyridinium chloramines, from which it can be seen that both chloramine precursor compounds have excellent antibacterial activity, and that chloramine precursor compound 18(0.42Log reduction) has an antibacterial efficiency superior to 9(0.04Log reduction), which should be mainly caused by the cell membrane puncture by the long chain alkyl group attached to the quaternary pyridinium chloramine precursor, compared to quaternary pyridinium chloramine precursor 23 (no antibacterial activity); the two pyridinium quaternary form chloramines exhibited excellent antimicrobial performance in comparison of antimicrobial activity, 92.8% bactericidal at 5min (1.14Log reduction) for chloramine compound 13 and 99.8% bactericidal at 5min (2.74Log reduction) for chloramine compound 22, which was significantly better than the antimicrobial activity of pyridinium quaternary form chloramine antimicrobial 24 (as shown in table 2), mainly due to the synergistic antimicrobial action of the pyridinium quaternary form chloramine units with the long alkyl chains attached to the pyridinium quaternary, and the chloramine compound 22 was better than the chloramine compound 13.

Claims (3)

1. The chloramine antibacterial agent of quaternary pyridinium salt type with alkyl chain is characterized in that the structural formula of the chloramine antibacterial agent of quaternary pyridinium salt type is as follows:
Figure FDA0002404092770000011
in the formula n1And n2Are all selected from integers of 5-11.
2. The synthesis method of the pyridine quaternary ammonium salt type chloramine antibacterial agent with the alkyl chain is characterized by comprising the following steps:
the bromopropyl 5, 5-dimethyl hydantoin (II) is used as an initial raw material, and the product is prepared by etherification, quaternization and chlorination, and the synthetic route is as follows:
Figure FDA0002404092770000012
the specific process is as follows:
(1a) synthesizing an alkyl pyridine ether compound (III);
(1b) dissolving hydroxypyridine in acetonitrile, adding anhydrous potassium carbonate, heating, stirring and refluxing for 1h, adding bromopropyl 5, 5-dimethylhydantoin (II), continuously refluxing for 4h, removing inorganic salts, separating by using column chromatography, and taking methanol/dichloromethane with the volume ratio of 2/25-1/10 as an eluent; collecting the organic phase containing the product, and removing the solvent to obtain a hydantoin pyridine ether compound (VI); wherein the molar ratio of the hydroxypyridine to the bromopropyl 5, 5-dimethylhydantoin is 1: 1-1: 2;
(2a) dissolving an alkyl pyridine ether compound (III) in acetonitrile, adding bromopropyl 5, 5-dimethylhydantoin (II), heating and refluxing overnight, removing a solvent, separating by using column chromatography, collecting an elution component containing a product by using methanol/dichloromethane with a volume ratio of 1/20-3/20 as an eluent, and removing the solvent to obtain a brominated pyridine quaternary ammonium salt type chloramine precursor; dissolving the brominated pyridinium quaternary ammonium salt type chloramine precursor in a small amount of deionized water, and slowly passing the solution through chlorine type anion exchange resin to obtain a pyridinium chloride quaternary ammonium salt type chloramine precursor (IV); wherein the molar ratio of the hydroxypyridine to the anhydrous potassium carbonate to the bromopropyl 5, 5-dimethylhydantoin is 1: 2: 1; the molar ratio of the alkyl pyridine ether compound to the bromopropyl 5, 5-dimethylhydantoin is 1: 1.1-1: 1.3;
(2b) dissolving a hydantoin pyridine ether compound in acetonitrile, adding n-bromoalkane, heating and refluxing overnight, removing a solvent, separating by using column chromatography, collecting an elution component containing a product by using methanol/dichloromethane with a volume ratio of 2/25-1/10 as an eluent, and removing the solvent to obtain a brominated pyridine quaternary ammonium salt type chloramine precursor; dissolving the brominated pyridinium quaternary ammonium salt type chloramine precursor in a small amount of deionized water, and slowly passing the solution through chlorine type anion exchange resin to obtain a pyridinium chloride quaternary ammonium salt type chloramine precursor (VII); wherein the molar ratio of the hydantoin pyridine ether compound to the n-bromoalkane is 1: 1.5;
(3) dissolving the pyridinium quaternary ammonium salt type chloramine precursor in a mixed solution of tertiary butanol and water with the volume ratio of 4/1, adding excessive tert-butyl hypochlorite, stirring for 24-36h at normal temperature in a dark place, and vacuum concentrating to obtain the pyridinium quaternary ammonium salt type chloramine compound (I) with different alkyl chains1) And (I)2) Namely, the pyridine quaternary ammonium salt type chloramine antibacterial agent with alkyl chain is obtained; wherein the molar ratio of the pyridinium quaternary ammonium salt chloramine to the tert-butyl hypochlorite is 1: 3-1: 5.
3. the method of claim 2, wherein the hydroxypyridine is m-hydroxypyridine or p-hydroxypyridine.
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