Preparation process of bactericide

Abstract

The invention relates to the technical field of bactericides, and discloses a preparation process of a bactericide, which comprises the following steps: carrying out substitution reaction on secondary amine in N1, N3-diacetyl diethylenetriamine and 1, 4-dibromobutane to obtain an intermediate product 1, hydrolyzing amido bonds of the intermediate product 1 under the action of a water system and sodium hydroxide to obtain an intermediate product 2, and carrying out reaction on the intermediate product 2 and the intermediate product 3 to obtain the bactericide. The preparation method comprises the following steps: carrying out a ring-opening reaction on cinnamyl aldehyde and aziridine to obtain an intermediate product 3, carrying out an aldehyde-amine condensation reaction to condense carbonyl of cinnamyl aldehyde and amino of the intermediate product 3 to obtain an intermediate product 4, and carrying out a quaternization reaction on tertiary amine in the intermediate product 4 and alkyl bromide to obtain the bactericide. The bactericide prepared by the invention has an excellent bactericidal effect on escherichia coli and staphylococcus aureus, and the highest bactericidal effect can reach 99.9%.

Description

Technical Field

[0001] The present invention relates to the technical field of fungicides, and specifically to a preparation process of a fungicide. Background Art

[0002] A large number of harmful microorganisms existing in nature not only endanger people's physical health, but also cause the deterioration and corruption of various materials, harm the environment and the production of industry and agriculture, and bring significant economic losses. Therefore, improving the bactericidal effect on harmful microorganisms has always been a research hotspot for researchers.

[0003] One of the effective ways to sterilize is to use fungicides. Among them, quaternary ammonium salt fungicides are widely used due to their strong bactericidal power and rapid onset. However, the long-term use of quaternary ammonium salt fungicides will cause serious problems of drug resistance and secondary pollution, and due to the slow degradation caused by the increase in the usage amount and the enhancement of bacterial drug resistance, the concentration in the environment continues to rise. Therefore, the traditional single quaternary ammonium salt fungicide can no longer solve the existing problems, and it is necessary to prepare a new type of environmentally friendly quaternary ammonium salt fungicide.

[0004] Cinnamaldehyde, also known as cinnamic aldehyde and acrolein, is a natural plant essential oil widely present in cinnamon oil, cassia bark oil, rose oil, etc. It has excellent physiological activities, such as antibacterial, antioxidant, anti-inflammatory effects, etc. However, its poor water solubility and easy volatility limit its application in the production processes of medicine, food, etc. Therefore, if it is applied in fungicides, the problem of easy volatility of cinnamaldehyde needs to be solved. Summary of the Invention

[0005] The purpose of the present invention is to overcome one or more deficiencies in the prior art and provide a fungicide. The fungicide prepared by this method has excellent bactericidal performance against Escherichia coli and Staphylococcus aureus.

[0006] To achieve the above purpose, a technical solution adopted by the present invention is: A preparation process of a fungicide, the preparation process includes the following steps: Add intermediate product 4, bromoalkane, and acetonitrile to a flask, stir and disperse, control the temperature at 40 - 50 °C, react for 20 - 30 h. After the reaction ends, cool to room temperature, add ether for washing, filter, and dry to obtain the fungicide. Use the tertiary amine in intermediate product 4 to carry out a quaternization reaction with bromoalkane to obtain the fungicide, and its synthesis route is: .

[0007] In one embodiment, preferably, the molar ratio of intermediate product 4 to bromoalkane is 1:6 - 8.

[0008] In one embodiment, preferably, the bromoalkane is one of dodecyl bromide, tetradecyl bromide, and hexadecyl bromide.

[0009] In one embodiment, preferably, the preparation process of the intermediate 4 is as follows: A1. Add N 1 ,N 3 -diacetyldiethylenetriamine, 1,4-dibromobutane, and ethanol solvent into a flask, stir and disperse, control the reaction temperature at 70 - 80 °C, stir and react for 10 - 15 h. After the reaction is completed, perform rotary evaporation under reduced pressure, extract with ether, recrystallize with acetone, wash with deionized water, and dry to obtain intermediate 1; wherein, the molar ratio of N 1 ,N 3 -diacetyldiethylenetriamine to 1,4-dibromobutane is 2 - 2.2:1. Using the secondary amine in N 1 ,N 3 -diacetyldiethylenetriamine and 1,4-dibromobutane undergo a substitution reaction to obtain intermediate 1, and its synthetic route is: .

[0010] A2. Add intermediate 1 and ethanol into a flask, stir and disperse, then add sodium hydroxide and deionized water thereto, heat under reflux for 24 h. After hydrolysis is completed, dropwise add concentrated hydrochloric acid until the pH is 1, filter, perform rotary evaporation, adjust the pH to 7 with sodium hydroxide while it is hot, then add ethanol thereto, stir and mix evenly, filter, perform rotary evaporation, and distill under reduced pressure to obtain intermediate 2; wherein, the molar ratio of intermediate 1 to sodium hydroxide is 1:1.2 - 1.5. Under the action of an aqueous system and sodium hydroxide, the amide bond in intermediate 1 is hydrolyzed to obtain intermediate 2, and its synthetic route is: .

[0011] A3. Add intermediate 2, formic acid, and deionized water into a flask, stir and disperse, control the temperature at 40 - 55 °C, add aziridine thereto, raise the temperature to 65 - 80 °C, stir and react for 8 - 12 h. After the reaction is completed, cool to room temperature, separate the organic phase, dry, filter, and distill under reduced pressure to obtain intermediate 3; wherein, the molar ratio of intermediate 2, formic acid, to aziridine is 1:0.4 - 0.6:8 - 12; under the catalysis of, intermediate 2 and aziridine undergo a ring-opening reaction to obtain intermediate 3, and its synthetic route is: .

[0012] A4. Add the intermediate product 3, potassium hydroxide, and ethanol to the flask, stir and disperse them, then add cinnamaldehyde thereto, control the temperature at 50 - 60 °C, react for 3 - 6 h. After the reaction is completed, cool to room temperature, filter, wash with ether, and dry to obtain the intermediate product 4; wherein, the molar ratio of the intermediate product 3, potassium hydroxide, and cinnamaldehyde is 1:8 - 9:8 - 10. Using the aldehyde - amine condensation reaction, the carbonyl group of cinnamaldehyde is condensed with the amino group of the intermediate product 3 to obtain the intermediate product 4, and its synthesis route is as follows: 。

[0013] Due to the application of the above - mentioned technical solution, the present invention has the following advantages compared with the prior art: The bactericide prepared by the present invention through a series of reactions has a novel structure and a highly regular molecular structure. And the bactericide prepared by the present invention has a greater positive - charge density and alkane - chain density compared with ordinary quaternary - ammonium - salt - type bactericides. Due to the greater positive - charge density, the bactericide can use the higher - density positive charges to firmly adsorb the hydrophobic structures (such as alkane chains, cinnamaldehyde structures) to the negatively - charged bacterial cell surface through electrostatic force and hydrogen - bond force, aggregate on the cell wall, produce a steric - hindrance effect, resulting in the inhibition of bacterial growth and death. On the one hand, the relatively large number of alkane chains contained therein can enter the hydrophobic part of the cell phospholipid bilayer, change the membrane permeability, cause cytolysis, destroy the cell structure, and cause cell lysis and death to achieve the purpose of killing bacteria; on the other hand, the relatively large number of cinnamaldehyde structures contained therein can penetrate the cell wall and act on the cell membrane, causing the disruption of ion homeostasis, and the massive leakage of electrolytes disintegrates the cell - membrane barrier, affects the bacterial metabolism, and further improves the bactericidal effect. In addition, since cinnamaldehyde itself is volatile, the present invention fixes it on the quaternary - ammonium - salt skeleton to reduce the volatility and increase the long - term bactericidal property, and synergistically improves the bactericidal effect of the bactericide with the quaternary - ammonium - salt structure. Specific Embodiments

[0014] The following further describes in detail the preparation process of a bactericide in combination with specific embodiments. These embodiments are only for comparison and explanation purposes, and the present invention is not limited to these embodiments.

[0015] N 1 ,N 3 -Diacetyldiethylenetriamine preparation process: Add 10.3 g of diethylenetriamine and 35.2 g of ethyl acetate to the flask, heat under reflux for 48 h. After completion, perform rotary evaporation, leave it overnight at room temperature, and recrystallize to obtain N 1 ,N 3 -diacetyldiethylenetriamine, and the reaction route is as follows: 。 Example 1

[0016] Step A1: Add 0.2 mol of N 1 ,N 3 -diacetyldiethylenetriamine, 0.1 mol of 1,4-dibromobutane, and 150 mL of ethanol solvent. Stir to disperse, control the reaction temperature at 75 °C, and stir the reaction for 12 h. After the reaction is completed, perform rotary evaporation under reduced pressure, extract with ether, recrystallize with acetone, wash with deionized water, and dry to obtain intermediate 1 with a yield of 85.48%.

[0017] Step A2: Add 40 mmol of intermediate 1 and 100 mL of ethanol to the flask, stir to disperse, then add 50 mmol of sodium hydroxide and 5 mL of deionized water thereto, heat under reflux for 24 h. After hydrolysis is completed, add concentrated hydrochloric acid dropwise until the pH is 1, filter, perform rotary evaporation, adjust the pH to 7 with sodium hydroxide while it is hot, then add ethanol thereto, stir and mix evenly, filter, perform rotary evaporation, and distill under reduced pressure to obtain intermediate 2 with a yield of 70.50%.

[0018] Step A3: Add 50 mmol of intermediate 2, 30 mmol of formic acid, and 200 mL of deionized water to the flask, stir to disperse, control the temperature at 40 °C, add 500 mmol of aziridine thereto, raise the temperature to 65 °C, and stir the reaction for 12 h. After the reaction ends, cool to room temperature, separate the organic phase, dry, filter, and distill under reduced pressure to obtain intermediate 3 with a yield of 78.09%.

[0019] Step A4: Add 40 mmol of intermediate 3, 340 mmol of potassium hydroxide, and 200 mL of ethanol to the flask, stir to disperse, then add 360 mmol of cinnamaldehyde thereto, control the temperature at 60 °C, and react for 3 h. After the reaction ends, cool to room temperature, filter, wash with ether, and dry to obtain intermediate 4 with a yield of 77.04%.

[0020] Step A5: Add 10 mmol of intermediate 4, 60 mmol of bromotetradecane, and 100 mL of acetonitrile to the flask, stir to disperse, control the temperature at 40 °C, and react for 30 h. After the reaction ends, cool to room temperature, add ether for washing, filter, and dry to obtain the fungicide with a yield of 90.31%. Example 2

[0021] Step A1: Add 0.22 mol of N 1 ,N 3 -diacetyldiethylenetriamine, 0.1 mol of 1,4-dibromobutane, and 150 mL of ethanol solvent. Stir to disperse, control the reaction temperature at 70 °C, and stir the reaction for 15 h. After the reaction is completed, perform rotary evaporation under reduced pressure, extract with ether, recrystallize with acetone, wash with deionized water, and dry to obtain intermediate 1 with a yield of 90.46%.

[0022] Step A2: Add 40 mmol of intermediate 1 and 100 mL of ethanol to a flask, stir to disperse, then add 55 mmol of sodium hydroxide and 5 mL of deionized water thereto, heat under reflux for 24 h. After hydrolysis is completed, add concentrated hydrochloric acid dropwise until the pH is 1, filter, rotary evaporate, adjust the pH to 7 with sodium hydroxide while it is hot, then add ethanol thereto, stir to mix evenly, filter, rotary evaporate, and distill under reduced pressure to obtain intermediate 2, with a yield of 70.02%.

[0023] Step A3: Add 50 mmol of intermediate 2, 30 mmol of formic acid, and 200 mL of deionized water to a flask, stir to disperse, control the temperature at 50 °C, add 600 mmol of aziridine thereto, raise the temperature to 70 °C, stir and react for 10 h. After the reaction is completed, cool to room temperature, separate the organic phase, dry, filter, and distill under reduced pressure to obtain intermediate 3, with a yield of 79.41%.

[0024] Step A4: Add 40 mmol of intermediate 3, 360 mmol of potassium hydroxide, and 200 mL of ethanol to a flask, stir to disperse, then add 380 mmol of cinnamaldehyde thereto, control the temperature at 60 °C, react for 6 h. After the reaction is completed, cool to room temperature, filter, wash with ether, dry to obtain intermediate 4, with a yield of 79.59%.

[0025] Step A5: Add 10 mmol of intermediate 4, 70 mmol of 1-bromododecane, and 100 mL of acetonitrile to a flask, stir to disperse, control the temperature at 45 °C, react for 24 h. After the reaction is completed, cool to room temperature, add ether to wash, filter, dry to obtain the fungicide, with a yield of 87.82%. Example 3

[0026] Step A1: Add 0.21 mol of N 1 ,N 3 -diacetyldiethylenetriamine, 0.1 mol of 1,4-dibromobutane, and 150 mL of ethanol solvent to a flask, stir to disperse, control the reaction temperature at 80 °C, stir and react for 10 h. After the reaction is completed, rotary evaporate under reduced pressure, extract with ether, recrystallize with acetone, wash with deionized water, dry to obtain intermediate 1, with a yield of 87.31%.

[0027] Step A2: Add 40 mmol of intermediate 1 and 100 mL of ethanol to a flask, stir to disperse, then add 50 mmol of sodium hydroxide and 5 mL of deionized water thereto, heat under reflux for 24 h. After hydrolysis is completed, add concentrated hydrochloric acid dropwise until the pH is 1, filter, rotary evaporate, adjust the pH to 7 with sodium hydroxide while it is hot, then add ethanol thereto, stir to mix evenly, filter, rotary evaporate, and distill under reduced pressure to obtain intermediate 2, with a yield of 70.58%.

[0028] Step A3: Add 50 mmol of intermediate 2, 20 mmol of formic acid, and 200 mL of deionized water into a flask, stir to disperse, control the temperature at 55 °C, add 400 mmol of aziridine thereto, raise the temperature to 80 °C, stir and react for 8 h. After the reaction is completed, cool to room temperature, separate the organic phase, dry, filter, and distill under reduced pressure to obtain intermediate 3 with a yield of 75.52%.

[0029] Step A4: Add 40 mmol of intermediate 3, 350 mmol of potassium hydroxide, and 200 mL of ethanol into a flask, stir to disperse, then add 320 mmol of cinnamaldehyde thereto, control the temperature at 50 °C, react for 4 h. After the reaction is completed, cool to room temperature, filter, wash with ether, dry to obtain intermediate 4 with a yield of 77.85%.

[0030] Step A5: Add 10 mmol of intermediate 4, 80 mmol of hexadecyl bromide, and 100 mL of acetonitrile into a flask, stir to disperse, control the temperature at 50 °C, react for 20 h. After the reaction is completed, cool to room temperature, add ether to wash, filter, dry to obtain the fungicide with a yield of 88.71%. Example 4

[0031] Step A1: Add 0.2 mol of N 1 ,N 3 -diacetyldiethylenetriamine, 0.1 mol of 1,4-dibromobutane, and 150 mL of ethanol solvent into a flask, stir to disperse, control the reaction temperature at 75 °C, stir and react for 12 h. After the reaction is completed, rotary evaporate under reduced pressure, extract with ether, recrystallize with acetone, wash with deionized water, dry to obtain intermediate 1 with a yield of 89.50%.

[0032] Step A2: Add 40 mmol of intermediate 1 and 100 mL of ethanol into a flask, stir to disperse, then add 48 mmol of sodium hydroxide and 5 mL of deionized water thereto, heat to reflux for 24 h. After hydrolysis is completed, add concentrated hydrochloric acid dropwise until the pH is 1, filter, rotary evaporate, adjust the pH to 7 with sodium hydroxide while it is hot, then add ethanol thereto, stir and mix evenly, filter, rotary evaporate, distill under reduced pressure to obtain intermediate 2 with a yield of 69.89%.

[0033] Step A3: Add 50 mmol of intermediate 2, 25 mmol of formic acid, and 200 mL of deionized water into a flask, stir to disperse, control the temperature at 45 °C, add 450 mmol of aziridine thereto, raise the temperature to 75 °C, stir and react for 10 h. After the reaction is completed, cool to room temperature, separate the organic phase, dry, filter, and distill under reduced pressure to obtain intermediate 3 with a yield of 76.85%.

[0034] Step A4: Add 40 mmol of intermediate 3, 320 mmol of potassium hydroxide, and 200 mL of ethanol to a flask, stir to disperse, then add 400 mmol of cinnamaldehyde thereto, control the temperature at 55 °C, react for 6 h. After the reaction is completed, cool to room temperature, filter, wash with ether, and dry to obtain intermediate 4 with a yield of 76.48%.

[0035] Step A5: Add 10 mmol of intermediate 4, 65 mmol of hexadecyl bromide, and 100 mL of acetonitrile to a flask, stir to disperse, control the temperature at 40 °C, react for 30 h. After the reaction is completed, cool to room temperature, add ether for washing, filter, and dry to obtain the fungicide with a yield of 87.08%.

[0036] Comparative Example 1 Step A1: Add 0.2 mol of N 1 ,N 3 -diacetyldiethylenetriamine, 0.1 mol of 1,4-dibromobutane, and 150 mL of ethanol solvent to a flask, stir to disperse, control the reaction temperature at 75 °C, stir and react for 12 h. After the reaction is completed, perform rotary evaporation under reduced pressure, extract with ether, recrystallize with acetone, wash with deionized water, and dry to obtain intermediate 1 with a yield of 85.48%.

[0037] Step A2: Add 40 mmol of intermediate 1 and 100 mL of ethanol to a flask, stir to disperse, then add 50 mmol of sodium hydroxide and 5 mL of deionized water thereto, heat to reflux for 24 h. After hydrolysis is completed, add concentrated hydrochloric acid dropwise until the pH is 1, filter, perform rotary evaporation, adjust the pH to 7 with sodium hydroxide while it is hot, then add ethanol thereto, stir and mix evenly, filter, perform rotary evaporation, and distill under reduced pressure to obtain intermediate 2 with a yield of 70.50%.

[0038] Step A3: Add 50 mmol of intermediate 2, 30 mmol of formic acid, and 200 mL of deionized water to a flask, stir to disperse, control the temperature at 40 °C, add 500 mmol of aziridine thereto, raise the temperature to 65 °C, stir and react for 12 h. After the reaction is completed, cool to room temperature, separate the organic phase, dry, filter, and distill under reduced pressure to obtain intermediate 3 with a yield of 78.09%.

[0039] Step A4: Add 40 mmol of intermediate 3, 340 mmol of potassium hydroxide, and 200 mL of ethanol to a flask, stir to disperse, then add 360 mmol of cinnamaldehyde thereto, control the temperature at 60 °C, react for 3 h. After the reaction is completed, cool to room temperature, filter, wash with ether, and dry to obtain the fungicide with a yield of 77.04%.

[0040] Escherichia coli and Staphylococcus aureus on the slant medium were inoculated into the broth medium in an Erlenmeyer flask and activated and cultured in a shaking incubator at 37°C for 24 h. Then it was diluted with the broth medium to make the concentration of the bacterial solution 1×10 7 CFU / mL for standby. A bactericide dilution with a mass fraction of 1% was prepared. Take 1.8 mL of the bactericide dilution with a mass fraction of 1% in a petri dish, add 0.2 mL of the test bacterial suspension thereto, and then add 18 mL of nutrient agar medium cooled to 45°C into the petri dish. Shake well, invert the petri dish after solidification, and culture at 37°C for 48 h. The control group was deionized water. Calculate the average number of colonies and calculate the bactericidal rate. Bactericidal rate (%) = (1 - number of bacteria in the experimental group / number of bacteria in the control group) × 100%.

[0041] Table 1:

[0042] Comparative Example 2 was a commercially available bactericide containing quaternary ammonium salts.

[0043] As can be seen from the table, the bactericide prepared by the present invention has excellent bactericidal effects on Escherichia coli and Staphylococcus aureus, and the bactericidal rate can reach 99.9%. From the data of Comparative Example 1 and the examples, it can be seen that the bactericide containing only the cinnamaldehyde structure has a bactericidal effect inferior to that of the bactericide containing both the cinnamaldehyde structure and the quaternary ammonium salt structure, indicating that the two have excellent synergistic effects. From Comparative Example 2 and the examples, it can be seen that the bactericide containing both the cinnamaldehyde structure and the quaternary ammonium salt structure has a better bactericidal effect.

[0044] The present invention illustrates a preparation process of a bactericide through the above examples, but the present invention is not limited to the above examples, that is, it does not mean that the present invention must rely on the above examples to be implemented. Those skilled in the art should understand that any improvement of the present invention, the equivalent substitution of each raw material of the product of the present invention, the addition of auxiliary components, the selection of specific methods, etc. all fall within the protection scope and the disclosure scope of the present invention.

Claims

1. A preparation process of a bactericide, characterized in that, The preparation process includes the following steps: Add the intermediate 4, bromoalkane, and acetonitrile into a flask, stir and disperse, control the temperature at 40 - 50 °C, react for 20 - 30 h. After the reaction, cool to room temperature, add ether for washing, filter, and dry to obtain the fungicide.

2. The preparation process of the fungicide according to claim 1, characterized in that, The molar ratio of the intermediate 4 to the bromoalkane is 1:6 - 8.

3. The preparation process of the fungicide according to claim 1, characterized in that, The bromoalkane is one of dodecyl bromide, tetradecyl bromide, and hexadecyl bromide.

4. The preparation process of the fungicide according to claim 1, characterized in that, The preparation process of the intermediate 4 is as follows: A1. Add N to the flask 1 , N 3 -diacetyldiethylenetriamine, 1,4-dibromobutane and ethanol solvent, stir and disperse, control the reaction temperature at 70-80 °C, stir and react for 10-15 h. After the reaction is completed, rotary evaporate under reduced pressure, extract with ether, recrystallize with acetone, wash with deionized water, and dry to obtain intermediate 1; A2: Add the intermediate 1 and ethanol into a flask, stir and disperse, then add sodium hydroxide and deionized water, heat under reflux for 24 h. After hydrolysis is completed, dropwise add concentrated hydrochloric acid until the pH is 1, filter, rotary evaporate, adjust the pH to 7 with sodium hydroxide while it is hot, then add ethanol, stir and mix evenly, filter, rotary evaporate, and perform vacuum distillation to obtain the intermediate 2; A3: Add the intermediate 2, formic acid, and deionized water into a flask, stir and disperse, control the temperature at 40 - 55 °C, add aziridine, raise the temperature to 65 - 80 °C, stir and react for 8 - 12 h. After the reaction, cool to room temperature, separate the organic phase, dry, filter, and perform vacuum distillation to obtain the intermediate 3; A4: Add the intermediate 3, potassium hydroxide, and ethanol into a flask, stir and disperse, then add cinnamaldehyde, control the temperature at 50 - 60 °C, react for 3 - 6 h. After the reaction, cool to room temperature, filter, wash with ether, and dry to obtain the intermediate 4.

5. The preparation process of the fungicide according to claim 4, characterized in that, In the above A1, N 1 , N 3 - The molar ratio of diacetyl diethylenetriamine to 1,4-dibromobutane is 2 - 2.2:

1.

6. The preparation process of the fungicide according to claim 4, characterized in that, In A2, the molar ratio of the intermediate 1 to sodium hydroxide is 1:1.2 - 1.

5.

7. The preparation process of the fungicide according to claim 4, characterized in that, In A3, the molar ratio of the intermediate 2, formic acid, and aziridine is 1:0.4 - 0.6:8 - 12.

8. The preparation process of the fungicide according to claim 4, characterized in that, In A4, the molar ratio of the intermediate 3, potassium hydroxide, and cinnamaldehyde is 1:8 - 9:8 - 10.

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