A carvacrol quaternary ammonium salt derivative and its synthesis method and application
By introducing linkers and antibacterial peptide derivatives on carvacrol, the synthesis of highly efficient amphiphilic carvacrol quaternary ammonium salt derivatives was solved, and the problem of insufficient antibacterial activity of carvacrol was achieved and the broad-spectrum antibacterial effect on a variety of bacteria was achieved.
Patent Information
- Application Number
- CN202311455851.0
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- Filing Date
- 2023-11-02
- Publication Date
- 2025-09-02
- Estimated Expiration
- 2043-11-02
AI Technical Summary
The antibacterial activity of existing carvacrol is not high enough and the antibacterial spectrum is narrow, making it difficult to effectively deal with the drug resistance challenges of multiple bacteria.
Based on carvacrol, linkers and antibacterial peptide derivatives of different lengths were introduced to synthesize a series of amphiphilic carvacrol quaternary ammonium derivatives, and compounds with high antibacterial activity were obtained through the synthesis route optimization.
The synthesized carvacrol quaternary ammonium derivatives show significant antibacterial activity against a variety of bacteria, which is better than carvacrol, and even comparable to commonly used antibiotics, with broad-spectrum antibacterial effects.
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Abstract
Description
Technical Field
[0001] The present invention belongs to the technical field of pharmaceutical chemistry, relates to corresponding active ingredient compounds, synthesis methods and applications thereof, and specifically relates to a carvacrol quaternary ammonium salt derivative, a synthesis method thereof and application thereof as an antibacterial agent. Background Art
[0002] Antibiotics, considered one of the greatest inventions of the 20th century, have saved tens of millions of lives. However, with the overuse of antibiotics and the slowdown in the development of new antibiotics, antibiotic resistance is becoming increasingly serious. The World Health Organization has repeatedly called attention to the crisis of antibiotic resistance, which has become a major global health challenge both now and in the future.
[0003] There are currently two main approaches to addressing bacterial resistance to antibiotics: the first is the appropriate use of existing antibiotics, and the second is the development of a new generation of antibiotics with novel structures and mechanisms of action. However, the rate at which bacteria develop resistance to antibiotics outpaces the development of new generations of antibiotics, posing a challenge to the research and development of new antibiotics. Therefore, the development of new antibiotics has become increasingly important.
[0004] Natural products have always been an important source for the discovery and development of antimicrobial drugs. However, the use of natural products themselves as antimicrobial drugs is limited by their water solubility, antimicrobial effects and antimicrobial spectrum. Therefore, it is necessary to rationally transform the structure of natural products.
[0005] In recent years, antimicrobial peptides have garnered widespread attention as a novel antimicrobial agent for combating bacterial resistance. While most conventional antibiotics primarily act by targeting bacterial organelles, antimicrobial peptides and their derivatives primarily act by disrupting bacterial membranes. Therefore, compared to traditional antibiotics, antimicrobial peptides are less likely to develop resistance to them. However, antimicrobial peptides currently suffer from limitations such as high in vivo toxicity and high manufacturing costs. Amphiphilic derivatives of antimicrobial peptides hold promise for improving their lipid-water partition coefficients, reducing their cost, and possessing similar antimicrobial mechanisms.
[0006] Oregano (Origanum vulgare L.), a perennial semishrub or herbaceous plant in the Lamiaceae family, is a traditional herbal medicine. It has been reported to exhibit antibacterial, antitumor, and anti-inflammatory properties. It contains over 30 antibacterial compounds, of which carvacrol exhibits the strongest antibacterial activity. However, carvacrol's antibacterial activity remains low and its antimicrobial spectrum is relatively narrow. Further research is needed to identify new antimicrobial compounds to enhance the antibacterial activity of existing carvacrol.
[0007] How to conduct research based on carvacrol to obtain a carvacrol derivative with good antibacterial activity to solve the problem that the antibacterial activity of carvacrol is not high enough has become a technical problem that needs to be solved urgently. Summary of the Invention
[0008] The present invention is to solve the above technical problems, thereby providing a carvacrol quaternary ammonium salt derivative and its synthesis method and use as an antibacterial agent. The technical purpose of the present invention is to provide a series of carvacrol quaternary ammonium salt derivatives in order to find new antibacterial substances with good antibacterial activity.
[0009] The present invention first provides a carvacrol quaternary ammonium salt derivative, the structural formula of the carvacrol quaternary ammonium salt derivative is shown in the following formula <Ⅰ>:
[0010]
[0011] In formula , n=3, 4, 5;
[0012] Wherein, R is selected from n-propylamine n-Butylamine n-Amylamine n-Hexylamine dipropylamine Dibutylamine diisopropylamine diisobutylamine Morpholine or thiomorpholinyl
[0013] The present invention synthesizes a series of amphiphilic carvacrol quaternary ammonium salt derivatives by introducing linkers of varying lengths and different antimicrobial peptide derivatives into carvacrol. These carvacrol quaternary ammonium salt derivatives were subjected to in vitro antimicrobial activity tests, ultimately screening and obtaining the derivatives of the present invention. The tests revealed that all of the carvacrol quaternary ammonium salt derivatives possessed high antimicrobial activity. The series of carvacrol quaternary ammonium salt derivatives provided by the present invention exhibit excellent antibacterial activity against six bacteria: Staphylococcus aureus (S. aureus ATCC 29213), methicillin-resistant Staphylococcus aureus (MRSA 21-5), Pseudomonas aeruginosa (P. aeruginosa 19-7), vancomycin-resistant Enterococci (VRE ATCC 51299), Enterobacter faecalis (E. faecalis ATCC 29212), and Escherichia coli (E. coli ATCC 25922). Their antibacterial activity is far superior to that of carvacrol, and some are even comparable to that of vancomycin and ampicillin. Compared with the compounds of the present invention, other carvacrol quaternary ammonium salt derivatives have significantly inferior antibacterial activity.
[0014] The second object of the present invention is to provide a method for synthesizing the above-mentioned carvacrol quaternary ammonium salt derivatives, and the synthesis route is as follows:
[0015]
[0016] The specific synthesis steps are as follows:
[0017] Step 1: Add the corresponding dibromoalkane and potassium carbonate to an acetone solution of carvacrol, and heat the resulting mixture to 65°C with stirring for 5 hours. After cooling the solution to room temperature, filter it, and remove the solvent by rotary evaporation under reduced pressure. The product is then subjected to flash silica gel column chromatography using petroleum ether as the eluent to obtain the corresponding intermediate Fn.
[0018] Step 2: Dissolve the corresponding amine and potassium carbonate in dichloromethane. Slowly add bromoacetyl bromide dropwise to the mixture at 0°C and stir for 3-5 hours. After the reaction is complete, extract with ethyl acetate, dry over anhydrous sodium sulfate, and remove the solvent under reduced pressure to obtain the corresponding intermediate 1A-J.
[0019] Step 3: Dissolve intermediate 1A-J in acetone, add potassium carbonate and a 40 wt.% aqueous dimethylamine solution, and stir at room temperature for 12-18 hours. After the reaction is complete, filter, remove the solvent by rotary evaporation under reduced pressure, and perform flash silica gel column chromatography using dichloromethane / methanol (20:1, v / v) as the eluent to obtain the corresponding intermediate 2A-J.
[0020] Step 4: Dissolve intermediate Fn and intermediate 2A-J in anhydrous acetonitrile, heat to 85°C, and stir for 24 hours. After the reaction is complete, remove the solvent by rotary evaporation under reduced pressure. Perform flash silica gel column chromatography using dichloromethane / methanol (20:1-40:1, v / v) as the eluent to obtain carvacrol quaternary ammonium salt derivatives F-nA-J.
[0021] The third object of the present invention is to provide the use of the above-mentioned carvacrol quaternary ammonium salt derivatives in the preparation of antibacterial agents.
[0022] The beneficial effects of the present invention are as follows:
[0023] (1) The present invention introduces linkers of different lengths and different antimicrobial peptide derivatives into carvacrol to synthesize a series of amphiphilic carvacrol quaternary ammonium salt derivatives. The carvacrol quaternary ammonium salt derivatives obtained by the present invention have the characteristics of good antimicrobial activity;
[0024] (2) The present invention also provides a method for synthesizing the above-mentioned amphiphilic carvacrol quaternary ammonium salt derivatives. A series of carvacrol quaternary ammonium salt derivatives synthesized by the method of the present invention show good antibacterial activity against six bacteria, including Staphylococcus aureus (S.aureus ATCC29213), methicillin-resistant Staphylococcus aureus (MRSA 21-5), Pseudomonas aeruginosa (P.Aeruginosa 19-7), vancomycin-resistant Enterococcus (VRE ATCC 51299), Enterobacter faecalis (E.faecalis ATCC 29212), and Escherichia coli (E.coli ATCC 25922). The antibacterial activity is far superior to that of carvacrol, and some are even comparable to those of vancomycin and ampicillin, and can be used as new bacterial antibacterial agents. BRIEF DESCRIPTION OF THE DRAWINGS
[0025] Figure 1 This is a synthetic route for carvacrol quaternary ammonium salt derivatives.
[0026] Figure 2 This is the hydrogen spectrum of compound F-3I.
[0027] Figure 3 This is the carbon spectrum of compound F-3I.
[0028] Figure 4 This is the hydrogen spectrum of compound F-4I.
[0029] Figure 5 This is the carbon spectrum of compound F-4I.
[0030] Figure 6 This is the hydrogen spectrum of compound F-5I.
[0031] Figure 7 This is the carbon spectrum of compound F-5I. DETAILED DESCRIPTION
[0032] In order to make the purpose, technical solutions and advantages of the present invention more clearly understood, the present invention is described in detail below with reference to the following embodiments. It is necessary to point out that the following embodiments are only used to explain and illustrate the present invention and are not intended to limit the present invention. Some non-essential improvements and adjustments made by those skilled in the art based on the above invention content still fall within the scope of protection of the present invention.
[0033] Example 1
[0034] 1. The synthesis of compound F-3I comprises the following steps:
[0035] Step 1: To a solution of carvacrol (3.0 g, 20 mmol) in acetone (20 ml) were added 1,3-dibromopropane (12.1 g, 60 mmol) and potassium carbonate (8.2 g, 60 mmol). The resulting mixture was heated to 65°C and stirred for 5 h. After the solution was cooled to room temperature and filtered, the solvent was removed by rotary evaporation under reduced pressure. The mixture was then eluted with petroleum ether and subjected to flash silica gel column chromatography to afford the corresponding intermediate F-3 (3.2 g, 59.1% yield). The reaction equation is as follows:
[0036]
[0037] Step 2: Dissolve n-hexylamine (1.5 g, 15.2 mmol) and potassium carbonate (3.2 g, 22.8 mmol) in dichloromethane (20 ml). Slowly add bromoacetyl bromide (4.6 g, 22.8 mmol) dropwise to the mixture at 0°C and stir for 3-5 hours. After completion of the reaction, extract with ethyl acetate, dry over anhydrous sodium sulfate, and remove the solvent by rotary evaporation under reduced pressure to yield the corresponding intermediate 1I.
[0038] Step 3: Dissolve intermediate 1I in acetone (15 ml), add potassium carbonate (3.2 g, 22.8 mmol) and a 40 wt.% aqueous dimethylamine solution (2.5 g, 22.8 mmol), and stir at room temperature for 12-18 hours. After the reaction is complete, filter and remove the solvent by rotary evaporation under reduced pressure. Perform flash silica gel column chromatography using dichloromethane / methanol (20:1, v / v) as the eluent to obtain the corresponding intermediate 2I (1.8 g, 63.6% yield). The reaction equation is as follows:
[0039]
[0040] Step 4: Dissolve intermediate F-3 (0.22 g, 0.81 mmol) and intermediate 2I (0.23 g, 1.2 mmol) in anhydrous acetonitrile (10 ml), heat to 85°C, and stir for 24 h. After the reaction is complete, remove the solvent by rotary evaporation under reduced pressure. The product is then subjected to flash silica gel column chromatography using dichloromethane / methanol (20:1-40:1, v / v) as the eluent to obtain the carvacrol quaternary ammonium salt derivative F-3I (0.19 g, 51.2% yield). The reaction equation is as follows:
[0041]
[0042] The compound F-3I obtained above was identified by nuclear magnetic resonance. 1HNMR(600MHz,Methanol-d4)δ6.99(d,J=7.6Hz,1H,-Ph),6.73(s,1H,-Ph),6.70(d,J=7.6Hz,1H,-Ph), 4.16(s,2H,-CH2-),4.08(t,J=5.7Hz,2H,-CH2-),3.83-3.81(m,2H,-CH2-),3.35(s,6H,N-CH3),3.20( t,J=7.1Hz,2H,-CH2-),2.84-2.80(m,1H,-CH-),2.33-2.29(m,2H,-CH2-),2.15(s,3H,-CH3),1.53-1. 48(m,2H,-CH2-),1.31-1.26(m,6H,-CH2-),1.20(d,J=6.9Hz,6H,-CH3),0.86(t,J=6.9Hz,3H,-CH3).. 13 C NMR(151MHz,Methanol-d4)δ163.15,156.45,147.94,130.17,123.61,118.31,109.29,64.25,63.2 1,62.44,51.55(2×C),39.21,34.04,31.26,28.73,26.38,23.21(2×C),23.17,22.28,14.78,13.04.
[0043] Example 2
[0044] 2. Synthesis of Compound F-4I
[0045] Step 1: To a solution of carvacrol (3.0 g, 20 mmol) in acetone (20 ml) was added 1,4-dibromobutane (13.0 g, 60 mmol) and potassium carbonate (8.2 g, 60 mmol). The resulting mixture was heated to 65°C and stirred for 5 h. After the solution was cooled to room temperature and filtered, the solvent was removed by rotary evaporation under reduced pressure. The mixture was then subjected to flash silica gel column chromatography using petroleum ether as the eluent to obtain the corresponding intermediate F-4 (3.5 g, 61.4% yield). The reaction equation is as follows:
[0046]
[0047] Step 2: Dissolve n-hexylamine (1.5 g, 15.2 mmol) and potassium carbonate (3.2 g, 22.8 mmol) in dichloromethane (20 ml). Slowly add bromoacetyl bromide (4.6 g, 22.8 mmol) dropwise to the mixture at 0°C and stir for 3-5 hours. After completion of the reaction, extract with ethyl acetate, dry over anhydrous sodium sulfate, and remove the solvent by rotary evaporation under reduced pressure to yield the corresponding intermediate 1I.
[0048] Step 3: Dissolve intermediate 1I in acetone (15 ml), add potassium carbonate (3.2 g, 22.8 mmol) and a 40 wt.% aqueous dimethylamine solution (2.5 g, 22.8 mmol), and stir at room temperature for 12-18 hours. After the reaction is complete, filter and remove the solvent by rotary evaporation under reduced pressure. Perform flash silica gel column chromatography using dichloromethane / methanol (20:1, v / v) as the eluent to obtain the corresponding intermediate 2I (1.8 g, 63.6% yield). The reaction equation is as follows:
[0049]
[0050] Step 4: Dissolve intermediate F-4 (0.23 g, 0.8 mmol) and intermediate 2I (0.22 g, 1.2 mmol) in anhydrous acetonitrile (10 ml), heat to 85°C, and stir for 24 h. After the reaction is complete, remove the solvent by rotary evaporation under reduced pressure. The product is then subjected to flash silica gel column chromatography using dichloromethane / methanol (20:1-40:1, v / v) as the eluent to obtain the carvacrol quaternary ammonium salt derivative F-4I (0.28 g, 73.7% yield). The reaction equation is as follows:
[0051]
[0052] The compound F-4I obtained above was identified by nuclear magnetic resonance. 1 HNMR(400MHz,Methanol-d4)δ7.00(d,J=7.6Hz,1H,-Ph),6.74(d,J=1.4Hz,1H,-Ph),6.69(dd,J=7.6,1.4Hz,1H, -Ph),4.12(s,2H,-CH2-),4.04(t,J=5.9Hz,2H,-CH2-),3.71-3.66(m,2H,-CH2-),3.31(s,6H,N-CH3),3.18(t,J= 7.1Hz,2H,-CH2-),2.87-2.80(m,1H,-CH-),2.16(s,3H,-CH3),2.07-2.00(m,2H,-CH2-),1.92-1.86(m,2H,-CH2 -),1.53-1.47(m,2H,-CH2-),1.36-1.30(m,6H,-CH2-),1.21(d,J=6.9Hz,6H,-CH3),0.89(t,J=6.6Hz,3H,-CH3). 13C NMR(151MHz,Methanol-d4)δ163.20,156.81,147.86,130.1,123.48,117.92,109.25,66.6,65.23,62 .04,51.43(2×C),39.19,34.07,31.25,28.72,26.37,26.06,23.24(2×C),22.30,19.79,14.86,13.05.
[0053] Example 3
[0054] 3. Synthesis of Compound F-5I
[0055] Step 1: To a solution of carvacrol (3.0 g, 20 mmol) in acetone (20 ml) were added 1,5-dibromopentane (13.8 g, 60 mmol) and potassium carbonate (8.2 g, 60 mmol). The resulting mixture was heated to 65°C and stirred for 5 h. After the solution was cooled to room temperature and filtered, the solvent was removed by rotary evaporation under reduced pressure. The mixture was then subjected to flash silica gel column chromatography using petroleum ether as the eluent to obtain the corresponding intermediate F-5 (3.7 g, 61.9% yield). The reaction equation is as follows:
[0056]
[0057] Step 2: Dissolve n-hexylamine (1.5 g, 15.2 mmol) and potassium carbonate (3.2 g, 22.8 mmol) in dichloromethane (20 ml). Slowly add bromoacetyl bromide (4.6 g, 22.8 mmol) dropwise to the mixture at 0°C and stir for 3-5 hours. After completion of the reaction, extract with ethyl acetate, dry over anhydrous sodium sulfate, and remove the solvent by rotary evaporation under reduced pressure to yield the corresponding intermediate 1I.
[0058] Step 3: Dissolve intermediate 1I in acetone (15 ml), add potassium carbonate (3.2 g, 22.8 mmol) and a 40 wt.% aqueous dimethylamine solution (2.5 g, 22.8 mmol), and stir at room temperature for 12-18 hours. After the reaction is complete, filter and remove the solvent by rotary evaporation under reduced pressure. Perform flash silica gel column chromatography using dichloromethane / methanol (20:1, v / v) as the eluent to obtain the corresponding intermediate 2I (1.8 g, 63.6% yield). The reaction equation is as follows:
[0059]
[0060] Step 4: Dissolve intermediate F-5 (0.24 g, 0.8 mmol) and intermediate 2I (0.22 g, 1.2 mmol) in anhydrous acetonitrile (10 ml), heat to 85°C, and stir for 24 h. After the reaction is complete, remove the solvent by rotary evaporation under reduced pressure. The product is then subjected to flash silica gel column chromatography using dichloromethane / methanol (20:1-40:1, v / v) as the eluent to obtain the carvacrol quaternary ammonium salt derivative F-5I (0.21 g, 54.0% yield). The reaction equation is as follows:
[0061]
[0062] The compound F-5I obtained above was identified by nuclear magnetic resonance. 1 HNMR(400MHz,Methanol-d4)δ6.98(d,J=7.6Hz,1H,-Ph),6.73(d,J=1.5Hz,1H,-Ph),6.67(dd,J=7.6,1.5Hz,1H, -Ph),4.11(s,2H,-CH2-),4.00(t,J=6.1Hz,2H,-CH2-),3.62-3.58(m,2H,-CH2-),3.30(s,6H,N-CH3),3.20(t,J= 7.1Hz,2H,-CH2-),2.86-2.79(m,1H,-CH-),2.13(s,3H,-CH3),1.93-1.85(m,4H,-CH2-),1.63-1.55(m,2H,-CH2 -),1.55-1.48(m,2H,-CH2-),1.35-1.31(m,6H,-CH2-),1.21(d,J=6.9Hz,6H,-CH3),0.88(d,J=7.0Hz,3H,-CH3). 13 C NMR(151MHz,Methanol-d4)δ163.24,156.99,147.80,130.00,123.48,117.72,109.24,66.95,65.47,62.1 3,51.43(2×C),39.18,34.07,31.26,28.75,28.67,26.37,23.26(2×C),22.78,22.31,22.24,14.76,13.06.
[0063] Experimental Example 1
[0064] A series of carvacrol quaternary ammonium salt derivatives were prepared according to the synthesis methods of Examples 1-3 of the present invention. The synthesis paths are as follows: Figure 1As shown, the synthesized carvacrol quaternary ammonium salt derivatives are shown in Table 1, including compounds F-3A to F3J, F-4A to F4J, and F-5A to F5J, wherein the structural formulas of A to J are shown in Figure 1 The in vitro antibacterial activity of the series of compounds prepared above was tested.
[0065] Experimental strains: Staphylococcus aureus (S. aureus ATCC 29213), methicillin-resistant Staphylococcus aureus (MRSA 21-5), Pseudomonas aeruginosa (P. Aeruginosa 19-7), vancomycin-resistant Enterococci (VRE ATCC 51299), Enterobacter faecalis (E. faecalis ATCC 29212), Escherichia coli (E. coli ATCC 25922)
[0066] Positive control drugs: ampicillin, vancomycin
[0067] Culture medium: MH medium
[0068] Determination of MIC value: The minimum inhibitory concentration (MIC) of in vitro antimicrobial agents was determined using the agar two-fold dilution method recommended by the Clinical and Laboratory Standards Institute (CLSI) antimicrobial susceptibility testing operating procedures [(Performance Standards for Antimicrobial Susceptibility Testing; Twenty-Third Informational Supplement) M02-A11, M07-A9, and M11-A8, 2013] to determine the MIC value of the test sample against the test strain in MH medium. Specific method: add 1 ml of drug solution to a sterile plate, then add 14 ml of melted 50℃ MH medium and mix well to make the final drug concentration in each plate 128, 64, 32, 16, 8, 4, 2, 1, 0.5, 0.25, 0.125, 0.06, 0.03, 0.015, 0.008 mg / L in sequence; after cooling, use a multi-point inoculator (MIT-P, SUKUMA) to inoculate bacteria, and the inoculation amount is about 10 4 CFU / ml, cover the plate. Incubate in a 35-37°C incubator for 18-20 hours, and record the results. The lowest concentration of drug at which no bacterial growth is observed in the plate is determined as the minimum inhibitory concentration (MIC). The experimental results are shown in Table 1:
[0069] Table 1 Antibacterial activity of carvacrol quaternary ammonium salt derivatives
[0070]
[0071]
[0072] As can be seen from Table 1, compounds F-3I, F-4I, and F-5I have the best antibacterial effects and exhibit strong antibacterial activity against these six bacteria, with MIC values ranging from 2 to 32 μg / mL.
Claims
1. A quaternary ammonium salt derivative of carvacrol, characterized in that: The structural formula of the carvacrol quaternary ammonium salt derivative is shown in the following formula <Ⅰ>: ； In formula , n = 3, 4, 5; Wherein, R is selected from n-propylamine, n-butylamine, n-pentylamine, n-hexylamine, dipropylamine, dibutylamine, diisopropylamine, diisobutylamine, morpholine or thiomorpholinyl.
2. A method for synthesizing the carvacrol quaternary ammonium salt derivatives according to claim 1, characterized in that: The following steps are involved: (1) Dibromoalkanes of different carbon chain lengths and potassium carbonate were added to an acetone solution of carvacrol, and the resulting mixed solution was heated to 65°C and stirred for 5 h. After the solution was cooled to room temperature, it was filtered and the solvent was removed by rotary evaporation under reduced pressure. Silica gel column chromatography was performed to obtain the corresponding intermediate Fn; (2) The corresponding amine and potassium carbonate were dissolved in dichloromethane, and bromoacetyl bromide was added dropwise to the mixed solution at 0°C. The mixture was stirred for 3-5 h. After the reaction was completed, the mixture was extracted and dried, and the solvent was removed to obtain the corresponding intermediates 1A-J. (3) Dissolve intermediate 1A-J in acetone solution, add potassium carbonate and dimethylamine aqueous solution, and stir at room temperature for 12-18 h. After the reaction is complete, filter, remove the solvent by vacuum rotary evaporation, and perform silica gel column chromatography to obtain the corresponding intermediate 2A-J; (4) The intermediate Fn and intermediate 2A-J were dissolved in anhydrous acetonitrile, heated to 85°C and stirred for 24 h. After the reaction was completed, the solvent was removed by rotary evaporation under reduced pressure, and silica gel column chromatography was performed to obtain the carvacrol quaternary ammonium salt derivative.
3. The preparation method according to claim 2, characterized in that The dibromoalkanes with different carbon chain lengths in step (1) include 1,3-dibromopropane, 1,4-dibromobutane or 1,5-dibromopentane.
4. The preparation method according to claim 2, characterized in that In step (1), rapid silica gel column chromatography is performed using petroleum ether as the eluent.
5. The preparation method according to claim 2, characterized in that The corresponding amine in step (2) includes n-propylamine, n-butylamine, n-pentylamine, n-hexylamine, dipropylamine, dibutylamine, diisopropylamine or diisobutylamine.
6. The preparation method according to claim 2, characterized in that In step (2), ethyl acetate is used for extraction, dried over anhydrous sodium sulfate, and the solvent is removed by rotary evaporation under reduced pressure.
7. The preparation method according to claim 2, characterized in that The mass concentration of the dimethylamine aqueous solution in step (3) is 40%.
8. The preparation method according to claim 2, characterized in that In step (3), silica gel column chromatography was performed using dichloromethane and methanol in a volume ratio of 20:1 as eluent.
9. The preparation method according to claim 2, characterized in that In step (4), silica gel column chromatography is performed using dichloromethane and methanol in a volume ratio of 20:1-40:1 as eluent.
10. Use of the carvacrol quaternary ammonium salt derivative according to claim 1 in the preparation of an antibacterial agent, characterized in that: The carvacrol quaternary ammonium salt derivatives are prepared into antibacterial agents for use in antibacterial activities against Staphylococcus aureus, methicillin-resistant Staphylococcus aureus, Pseudomonas aeruginosa, vancomycin-resistant enterococci, Enterobacter faecalis and Escherichia coli.