CN117730857A - A β-cyclodextrin-coated tebuconazole metal complex antifungal agent and its preparation method - Google Patents

Abstract

The invention discloses a β-cyclodextrin-coated tebuconazole metal complex antifungal agent and a preparation method thereof. It is made from the following components by weight: 0.1-5 parts of tebuconazole and 0.1-5 parts of metal salt compounds. 5 parts, emulsifier 0.1-3 parts, N,N-dimethylformamide 1-20 parts, β-cyclodextrin 5-25 parts, propylene glycol 0.1-10 parts, pure water 20-50 parts. The present invention selects silver, copper, zinc and other metal compounds with antibacterial activity to form a complex with tebuconazole. Compared with tebuconazole, the complex has better antibiological activity against some harmful microorganisms and at the same time improves the water solubility of the complex. and stability; its appearance changes from the dark blue of the tebuconazole copper sulfate complex to off-white after wrapping, which greatly reduces the color difference produced by the complex during application and reduces its impact on the appearance of white products such as water-based coatings and white latex. . Its toxicity has been improved, and the anti-mold durability of the complex in coating applications has also been improved.

Description

A β-cyclodextrin-coated tebuconazole metal complex antifungal agent and its preparation method

Technical field

The present invention relates to the technical field of microcapsules, and specifically to a β-cyclodextrin-coated tebuconazole metal complex antifungal agent and a preparation method thereof.

Background technique

Water-based coatings are currently indispensable and important materials in the field of building materials. Because the formula contains a large amount of emulsions, thickeners, defoaming agents and other raw materials that are easily exploited by microorganisms, they are prone to mildew, powdering, etc. during the application process. unpleasant sight. Adding antifungal agents is one of the important ways to effectively prevent this type of situation from happening. Currently, commonly used antifungal active substances include isothiazolinone compounds, carbendazim, etc. These substances have problems such as skin irritation, poor stability, poor water solubility, and regulatory restrictions.

Tebuconazole is a triazole fungicide mainly used to control a variety of fungal diseases on wheat, vegetables, apples and other crops. The EU BPR Regulation (Biocidal Products Regulation, Regulation (EU) 528/2012) has officially recognized tebuconazole for use in film preservatives and building material preservatives in 2015. After tebuconazole forms a complex with a metal compound, its bactericidal effect can be enhanced. However, some tebuconazole complexes have a darker appearance, some metal ions have a sensitizing effect on the photodecomposition of tebuconazole, and have low water solubility. properties, limiting its application in water-based coatings.

At present, the commonly used anti-mildew components have certain defects. Patent CN102702839B discloses a can and dry film antiseptic and anti-mildew agent composition for coatings. The 2-methylisothiazolinone and 1,2-benzisothiazolinone components used therein are irritating to human skin. The 1,3,5-tris(2-hydroxyethyl)-s-triazine component is a formaldehyde releaser and is strictly limited in use by regulations. At the same time, the application of isothiazolinone compounds is greatly affected by the acidity and alkalinity of the system, the redox value, etc., and is easy to decompose and become ineffective. Patent CN1947510A discloses a bactericidal combination of tebuconazole and carbendazim for the prevention and control of agricultural diseases. Its component carbendazim is restricted from being added to green products in the coating field.

Finding antifungal agents suitable for coatings is currently a technical problem in this field.

Contents of the invention

The purpose of the present invention is to overcome the shortcomings of the prior art and provide a β-cyclodextrin-coated tebuconazole metal complex antifungal agent with good antifungal effect and low color difference and a preparation method thereof. The present invention uses β-cyclodextrin to wrap the metal complex of tebuconazole, thereby reducing the color difference produced by the complex during application, improving the water solubility and stability of the complex, and reducing toxic and side effects.

In order to achieve the above objects, the present invention adopts the following technical solutions:

A β-cyclodextrin-coated tebuconazole metal complex antifungal agent is made of the following components by weight:

Tebuconazole 0.1-5 parts, metal salt compound 0.1-5 parts, emulsifier 0.1-3 parts, N,N-dimethylformamide 1-20 parts, β-cyclodextrin 5-25 parts, propylene glycol 0.1- 10 parts, pure water 20-50 parts.

Preferably, in the above-mentioned β-cyclodextrin-coated tebuconazole metal complex antifungal agent, the metal salt compound is copper acetate, copper citrate, copper sulfate, copper chloride, copper nitrate, zinc acetate, sulfate Zinc, zinc chloride, silver sulfate or silver nitrate.

Preferably, in the above-mentioned β-cyclodextrin-coated tebuconazole metal complex antifungal agent, the emulsifier is hydrogenated castor oil, dodecylphenol polyoxyethylene ether, alkylphenol ether sulfosuccinic acid Ester sodium salt, fatty alcohol polyoxyethylene ether sodium sulfate, sodium dodecylbenzene sulfonate, sodium dodecyl sulfate, phenethylphenol polyoxyethylene ether, sodium xylene sulfonate or polyvinylpyrrolidone.

The preparation method of the above-mentioned β-cyclodextrin-coated tebuconazole metal complex antifungal agent includes the following steps:

(1) Add tebuconazole to N,N-dimethylformamide and stir until it is completely dissolved into a transparent and clear solution;

(2) Slowly add copper sulfate and stir until it is completely dissolved into a blue-green transparent solution to obtain component A for later use;

(3) Add β-cyclodextrin to pure water, heat it in a water bath at 50-70°C, and stir to completely dissolve it into a transparent and clear solution;

(4) Add emulsifier to step (3) and stir until it is completely dissolved into a transparent and clear solution;

(5) Add propylene glycol to the transparent solution in step (4) to obtain a colorless transparent solution, which is component B;

(6) Keep component B in a water bath at 50-70°C, slowly add component A, and react for 1-6 hours to obtain an almost colorless and transparent solution;

(7) Air-dry the reacted solution in step (6) at 80-180°C for 3-8 hours to obtain off-white crystals, which is the finished product.

Compared with the prior art, the present invention has the following beneficial effects:

(1) The present invention uses metal compounds with antibacterial activity such as silver, copper, and zinc to form a complex with tebuconazole. Compared with tebuconazole, the complex has better antimicrobial activity against some harmful microorganisms.

(2) In the present invention, the complex is dissolved and combined with β-cyclodextrin to improve the water solubility and stability of the complex; after the raw material of the present invention is wrapped, taking the metal salt compound as copper sulfate as an example, its appearance changes from tebuconazole to The dark blue color of the copper sulfate complex turns into an off-white color after being wrapped, which greatly reduces the color difference produced by the complex during application and reduces its impact on the appearance of white products such as water-based coatings and white latex.

(3) After the raw material β-cyclodextrin of the present invention wraps the tebuconazole metal complex, its toxicity is improved, and the anti-mold durability of the complex in coating applications is also improved.

Description of drawings

Figure 1 shows the relationship between the concentration of different fungicides and time;

Figure 2 is a comparison of the appearance of the tebuconazole metal complex before and after being wrapped with β-cyclodextrin;

Among them, the complex is not wrapped (left), but is wrapped with β-cyclodextrin (right);

Figure 3 is a comparison of the appearance of the tebuconazole metal complex before and after being coated with β-cyclodextrin;

Among them, the 0.5% concentration complex is uncoated and insoluble in water (left), the 0.5% concentration complex is uncoated and soluble in organic solvents (middle), and the 2% concentration complex is soluble in water after being coated with β-cyclodextrin (right) ).

Detailed ways

The method for measuring inclusion compound content in the present invention: weigh 0.1 g of the β-cyclodextrin-coated tebuconazole metal complex, place it in a Buchner funnel lined with filter paper, and wash it three times with 10 ml of ethyl acetate. . The sample was then dissolved in methanol solution and ultrasonic shaken for 30 min, left to stand for 2 h, and a liquid chromatograph was used to detect the amount of active substances.

Inclusion compound content (%) = drug content in sample/sample amount × 100%

Embedding rate (%) = Drug content of inclusion compound sample/Amount of drug input × 100%

Example 1:

Add 2 parts of tebuconazole to 10 parts of N,N-dimethylformamide, and stir with electric stirring until it is completely dissolved into a colorless and transparent solution. Slowly add 2 parts of copper acetate, and stir with electric stirring until it is completely dissolved into a blue-green transparent solution. Solution, get component A for later use. In addition, take a beaker and add 15 parts of β-cyclodextrin to 40 parts of pure water. Heat it in a 60°C water bath and use electric stirring to completely dissolve it into a transparent and clear solution. Add 1 part of sodium dodecylbenzene sulfonate and stir with electric stirring to completely dissolve it into a transparent and clear solution. Add 5 parts of propylene glycol and stir evenly with electric power to obtain a transparent solution, which is component B. Keep component B at a constant temperature of 70°C, slowly add component A, and react for 3 hours to obtain a light blue-green transparent solution. The reacted solution was air-dried at 150°C for 5 hours to obtain an off-white crystalline finished product, which is a β-cyclodextrin-coated tebuconazole copper acetate complex antifungal agent.

Example 2:

Add 1 part of tebuconazole to 5 parts of N,N-dimethylformamide, stir with electric stirring until it is completely dissolved into a colorless and transparent solution, slowly add 1 part of copper sulfate, stir with electric stirring until it is completely dissolved into a blue-green transparent solution Solution, get component A for later use. In addition, take a beaker and add 15 parts of β-cyclodextrin to 40 parts of pure water. Heat it in a water bath at 60°C and use electric stirring to completely dissolve it into a transparent and clear solution to obtain a colorless and transparent solution, which is component B. Keep component B at a constant temperature of 70°C, slowly add component A, and react for 3 hours to obtain a light blue-green transparent solution. The reacted solution was air-dried at 150°C for 5 hours to obtain an off-white crystalline finished product, which is a β-cyclodextrin-coated tebuconazole copper sulfate complex antifungal agent.

Example 3:

Add 4 parts of tebuconazole to 20 parts of N,N-dimethylformamide, and stir with electric stirring until it is completely dissolved into a colorless and transparent solution. Slowly add 4 parts of copper acetate, and stir with electric stirring until it is completely dissolved into a blue-green transparent solution. Solution, get component A for later use. In addition, take a beaker and add 25 parts of β-cyclodextrin to 50 parts of pure water. Heat it in a 60°C water bath and use electric stirring to completely dissolve it into a transparent and clear solution. Add 2 parts of sodium dodecylbenzene sulfonate and stir with electric stirring to completely dissolve it into a transparent clear solution. Then add 10 parts of propylene glycol and stir evenly with electric power to obtain a transparent clear solution, which is component B. Keep component B at a constant temperature of 70°C, slowly add component A, and react for 3 hours to obtain a light blue-green transparent solution. The reacted solution was air-dried at 150°C for 5 hours to obtain an off-white crystalline finished product, which is a β-cyclodextrin-coated tebuconazole copper acetate complex antifungal agent.

Example 4:

Add 2 parts of tebuconazole to 10 parts of N,N-dimethylformamide, stir it with electric stirring until it is completely dissolved into a colorless and transparent solution, slowly add 2 parts of zinc chloride, and stir with electric stirring until it is completely dissolved until it is colorless. Clear solution, get component A for later use. In addition, take a beaker and add 15 parts of β-cyclodextrin to 40 parts of pure water. Heat it in a 60°C water bath and use electric stirring to completely dissolve it into a transparent and clear solution. Add 1 part of sodium dodecylbenzene sulfonate and stir with electric stirring to completely dissolve it into a transparent and clear solution. Add 5 parts of propylene glycol and stir evenly with electric power to obtain a transparent solution, which is component B. Keep component B at a constant temperature of 70°C, slowly add component A, and react for 3 hours to obtain a colorless and transparent solution. The reacted solution was air-dried at 150°C for 5 hours to obtain a white crystalline finished product, which is a β-cyclodextrin-coated tebuconazole zinc chloride complex antifungal agent.

Example 5:

Add 2 parts of tebuconazole to 10 parts of dimethyl sulfoxide, stir with electric stirring until it is completely dissolved into a colorless and transparent solution, slowly add 2 parts of zinc chloride, stir with electric stirring until it is completely dissolved into a colorless and transparent solution, and obtain Component A is reserved. In addition, take a beaker and add 15 parts of β-cyclodextrin to 40 parts of pure water. Heat it in a 60°C water bath and use electric stirring to completely dissolve it into a transparent and clear solution. Add 1 part of sodium dodecylbenzene sulfonate and stir with electric stirring to completely dissolve it into a transparent and clear solution. Add 5 parts of propylene glycol and stir evenly with electric power to obtain a transparent solution, which is component B. Keep component B at a constant temperature of 70°C, slowly add component A, and react for 3 hours to obtain a colorless and transparent solution. The reacted solution was air-dried at 150°C for 5 hours to obtain a white crystalline finished product, which is a β-cyclodextrin-coated tebuconazole zinc chloride complex antifungal agent.

Comparative example 1:

Add 2 parts of tebuconazole to 10 parts of purified water prepared in the laboratory, stir it with electric stirring to disperse it in the water, slowly add 2 parts of copper acetate, stir it with electric stirring to completely dissolve it into a blue-green transparent solution, and obtain component A for later use. In addition, take a beaker and add 15 parts of β-cyclodextrin to 40 parts of pure water. Heat it in a 60°C water bath and use electric stirring to completely dissolve it into a transparent and clear solution. Add 1 part of sodium dodecylbenzene sulfonate and stir with electric stirring to completely dissolve it into a transparent and clear solution. Add 5 parts of propylene glycol and stir evenly with electric power to obtain a transparent solution, which is component B. Keep component B at a constant temperature of 70°C, slowly add component A, and react for 3 hours to obtain a light blue-green transparent solution. The reacted solution was air-dried at 150°C for 5 hours to obtain a light blue-green crystalline product.

Comparative example 2:

Add 2 parts of tebuconazole to 10 parts of N,N-dimethylformamide, and stir with electric stirring until it is completely dissolved into a colorless and transparent solution. Slowly add 2 parts of copper acetate, and stir with electric stirring until it is completely dissolved into a blue-green transparent solution. Solution, get component A for later use. In addition, take a beaker and add 15 parts of polyvinyl alcohol to 40 parts of pure water. Heat it in a 60°C water bath and use electric stirring to completely dissolve it into a transparent and clear solution. Add 1 part of sodium dodecylbenzene sulfonate and stir with electric stirring to completely dissolve it into a transparent and clear solution. Add 5 parts of propylene glycol and stir evenly with electric power to obtain a transparent solution, which is component B. Keep component B at a constant temperature of 70°C, slowly add component A, and react for 3 hours to obtain a light blue-green transparent solution. The reacted solution was air-dried at 150°C for 5 hours to obtain a light blue-green crystalline product.

Comparative example 3:

Add 2 parts of tebuconazole to 10 parts of N,N-dimethylformamide, and stir with electric stirring until it is completely dissolved into a colorless and transparent solution. Slowly add 2 parts of copper acetate, and stir with electric stirring until it is completely dissolved into a blue-green transparent solution. Solution, get component A for later use. In addition, take a beaker and add 15 parts of maltodextrin to 40 parts of pure water. Heat it in a 60°C water bath and use electric stirring to completely dissolve it into a transparent and clear solution. Add 1 part of sodium dodecylbenzene sulfonate and stir with electric stirring to completely dissolve it into a transparent and clear solution. Add 5 parts of propylene glycol and stir evenly with electric power to obtain a transparent solution, which is component B. Keep component B at a constant temperature of 70°C, slowly add component A, and react for 3 hours to obtain a light blue-green transparent solution. The reacted solution was air-dried at 150°C for 5 hours to obtain a light blue-green crystalline product.

Comparative example 4:

Add 2 parts of tebuconazole to 10 parts of N,N-dimethylformamide, and stir with electric stirring until it is completely dissolved into a colorless and transparent solution. Slowly add 2 parts of copper acetate, and stir with electric stirring until it is completely dissolved into a blue-green transparent solution. Solution, get component A for later use. In addition, take a beaker and add 15 parts of gum arabic to 40 parts of pure water. Heat it in a water bath at 60°C and use electric stirring to completely dissolve it into a transparent and clear solution. Add 1 part of sodium dodecylbenzene sulfonate and stir with electric stirring to completely dissolve it into a transparent and clear solution. Add 5 parts of propylene glycol and stir evenly with electric power to obtain a transparent solution, which is component B. Keep component B at a constant temperature of 70°C, slowly add component A, and react for 3 hours to obtain a light blue-green transparent solution. The reacted solution was air-dried at 150°C for 5 hours to obtain a light blue-green crystalline product.

Example 6: Embedding rate test

The existing embedding rate test method was used to conduct the embedding rate test on Examples 1-5 and Comparative Examples 1-4. The results are shown in Table 1. It can be seen from Table 1 that the embedding rate of the present invention is significantly improved compared to the comparative examples.

Example 7: Mildew-proof grade test

Examples 1-5 and Comparative Examples 1-4 were subjected to a mildew resistance grade test.

Experimental addition plan: Add 2% addition amount to the water-based paint base (no antifungal agent added), mix evenly, and test the antifungal performance after tableting according to GB/T 1741.

Experimental basis: GB/T 1741-2020 "Method for determination of mold resistance of paint films"

*Grading standards: Level 0 - no growth; Level 1 - trace growth, covering less than 10% of the sample surface; Level 2 - small amount of growth, covering 10% to 30% of the sample surface; Level 3 - medium Degree of growth, the coverage area on the sample surface is 30% to 60%; Level 4 - severe growth, the coverage area on the sample surface is greater than 60%.

*Test strains: Aspergillus niger CGMCC 3.5487, Aspergillus flavus CGMCC 3.4324, Cladosporium herbarum CGMCC 3.9389, Paecilomyces varioti CGMCC 3.5452, Penicillium citrinum) CGMCC 3.6675, Trichoderma viride CGMCC 3.2941, Aureobasidium pullulans CGMCC 3.837, Alternaria alternata CGMCC 3.4255.

The results are shown in Table 2. It can be seen from Table 2 that the anti-mildew effect of the present invention is significantly improved compared to the comparative examples.

Example 8: Antifungal agent content test

The β-cyclodextrin-coated tebuconazole copper sulfate and tebuconazole zinc chloride complex antifungal agents prepared in Examples 2 and 4 were added to the laboratory preparation at an effective concentration of 1% tebuconazole metal complex. Dissolve in purified water with electric stirring for 30 minutes at room temperature. Observe its appearance and use high performance liquid chromatography to detect the content of water-soluble antifungal agents, as shown in Table 3:

Example 9: Appearance test

Different effective concentrations of tebuconazole copper sulfate complex were added to the water-based coating base material (no antifungal agent was added) to observe the effect on the appearance of the applied product. The specific data are shown in Table 4:

Example 10: Photolysis test of antifungal agent

The β-cyclodextrin prepared in Examples 2 and 4 is used to coat the tebuconazole copper sulfate and tebuconazole zinc chloride complex fungicides, and the tebuconazole, tebuconazole copper sulfate complex and β-cyclodextrin are Finely wrapped copper tebuconazole sulfate is diluted or dispersed in distilled water according to 1% effective active component content, and placed outdoors under natural light for 30 days. The effective concentration of the antifungal agent is detected to evaluate the photolysis of each antifungal agent. The specific data are shown in Table 5:

Example 11: Test on the relationship between antifungal agent concentration and time

The β-cyclodextrin-coated tebuconazole copper sulfate complex antifungal agent prepared in Examples 2 and 4, the β-cyclodextrin-coated tebuconazole zinc chloride complex antifungal agent, and the tebuconazole copper sulfate Complex, tebuconazole zinc chloride complex; the effective concentration of tebuconazole metal complex is 1% when added to water-based industrial products such as water-based coatings and white latex to record the level of antifungal agents in industrial products over time. The concentration of different antifungal agents and the relationship between time are shown in Figure 1. As can be seen from Figure 1, the antifungal agents of Examples 2 and 4 can maintain a stable concentration all the time, while for comparison, the tebuconazole copper sulfate complex and tebuconazole zinc chloride complex began to decline on about the 18th day. It shows a downward trend, with a rapid decline starting from the 40th day.

Example 12: Specific anti-mildew effect test

The β-cyclodextrin prepared by the invention is coated with tebuconazole copper sulfate and tebuconazole zinc chloride complex antifungal agent, and the minimum inhibitory concentration (Minimum Inhibitory Concentration, MIC) is used to evaluate the relationship between the wrapped complex and tebuconazole, tebuconazole and zinc chloride. The inhibitory effect of metal salts on mold, the specific MIC data (unit: mg/kg) is shown in Table 6:

Example 13: Antibacterial effect test

The β-cyclodextrin-coated tebuconazole copper sulfate and tebuconazole zinc chloride complex antifungal agent prepared in the present invention is added to water-based paints, white latex and other water-based paints with an effective concentration of tebuconazole metal complex of 0.2%. Among industrial products, it has a strong antibacterial effect on common harmful fungi such as Aspergillus niger, Penicillium citrinum, Trichoderma viride and Alternaria. The specific antifungal experimental data are shown in Table 7:

Example 14: Irritation test

The β-cyclodextrin-coated tebuconazole metal complex antifungal agent prepared in the present invention is diluted or dispersed to the target concentration with purified water prepared in the laboratory, and each antifungal agent is tested according to the "Technical Specifications for Safety of Cosmetics" (2015 Edition) For rabbit eye irritation, the experimental results are shown in Table 8:

.

Claims (4)

1. the beta-cyclodextrin coated tebuconazole metal complex mildew inhibitor is characterized by being prepared from the following components in parts by weight:

0.1-5 parts of tebuconazole, 0.1-5 parts of metal salt compound, 0.1-3 parts of emulsifier, 1-20 parts of N, N-dimethylformamide, 5-25 parts of beta-cyclodextrin, 0.1-10 parts of propylene glycol and 20-50 parts of pure water.

2. The beta-cyclodextrin coated tebuconazole metal complex antimycotic of claim 1, wherein the metal salt compound is copper acetate, copper citrate, copper sulfate, copper chloride, copper nitrate, zinc acetate, zinc sulfate, zinc chloride, silver sulfate, or silver nitrate.

3. The beta-cyclodextrin coated tebuconazole metal complex antimycotic of claim 1, wherein the emulsifier is hydrogenated castor oil, dodecylphenol polyoxyethylene ether, alkylphenol ether sulfosuccinate sodium salt, fatty alcohol polyoxyethylene ether sodium sulfate, sodium dodecylbenzene sulfonate, sodium dodecyl sulfate, phenethyl phenol polyoxyethylene ether, sodium xylene sulfonate or polyvinylpyrrolidone.

4. The method for preparing the beta-cyclodextrin coated tebuconazole metal complex mildew inhibitor as claimed in claim 1, which is characterized by comprising the following steps:

(1) Adding tebuconazole into N, N-dimethylformamide, and stirring to completely dissolve the tebuconazole into a transparent clear solution;

(2) Slowly adding copper sulfate into the transparent clear solution in the step (1), and stirring to completely dissolve the copper sulfate into a blue-green transparent solution to obtain a component A for later use;

(3) Adding beta-cyclodextrin into pure water, heating in 50-70deg.C water bath, and stirring to dissolve completely into transparent clear solution;

(4) Adding an emulsifying agent into the transparent clear solution in the step (3), and stirring to completely dissolve the emulsifying agent into the transparent clear solution;

(5) Adding propylene glycol into the transparent clear solution obtained in the step (4) to prepare a colorless transparent solution which is the component B;

(6) The component B is kept warm in a water bath at 50-70 ℃, the component A is slowly added, and the reaction is carried out for 1-6 hours, thus obtaining a nearly colorless transparent solution;

(7) And (3) drying the reacted solution in the step (6) by blowing at 80-180 ℃ for 3-8 hours to obtain white crystals, namely a finished product.