阅读说明：本技术 一种丙硫菌唑缓释剂的制备方法 (Preparation method of prothioconazole sustained-release agent ) 是由 丁红霞 吴钊 茆卫兵 于 2021-06-22 设计创作，主要内容包括：本发明提供了一种丙硫菌唑缓释剂的制备方法,该缓释剂具有自组装,水溶性强,高效持续给药的特性,很好的解决了微胶囊悬浮剂的成本问题以及水溶性问题。本发明通过丙硫菌唑和聚乙二醇的有机结合,丙硫菌唑具备很好的水溶性,且通过聚乙二醇的自然降解,可持续的释放出丙硫菌唑原药,达到缓释的效果。(The invention provides a preparation method of a prothioconazole sustained-release agent, which has the characteristics of self-assembly, strong water solubility and high-efficiency continuous administration, and well solves the cost problem and the water solubility problem of a microcapsule suspending agent. According to the invention, the prothioconazole and the polyethylene glycol are organically combined, the prothioconazole has good water solubility, and the prothioconazole can be released continuously through natural degradation of the polyethylene glycol, so that the slow release effect is achieved.)

1. A preparation method of a prothioconazole sustained-release agent is characterized by comprising the following steps: dissolving prothioconazole in a solvent, adding polyethylene glycol methacrylate and a catalyst, heating for reaction, detecting the completion of the reaction, filtering to remove the catalyst, removing the solvent, adding an ether solvent into a crude product, stirring for dispersion, and filtering to obtain a product.

2. The method according to claim 1, wherein the molecular weight distribution of the polyethylene glycol methacrylate is between 200 and 20000.

3. The method according to claim 1, wherein the ratio of the molar amount of the polyethylene glycol methacrylate to the prothioconazole is 0.01-1: 1.

4. The production method according to claim 1, characterized in that the catalyst is neutral alumina.

5. The method according to claim 1, wherein the ratio of the molar amount of the catalyst to the prothioconazole is 0.01-5: 1.

6. The method according to claim 1, wherein the solvent is one or more selected from DMF, acetonitrile, DMSO, dichloroethane, dichloromethane, and diethyl ether.

7. The method according to claim 1, wherein the ether solvent is one or more selected from diethyl ether, petroleum ether, ethylene glycol dimethyl ether, and methyl tert-ether.

8. The method according to claim 1, wherein the reaction temperature is 70 to 160 ℃.

9. The process according to claim 1, wherein the reaction time is from 1 to 10 hours.

10. The method according to claim 1, wherein the detection method is HPLC detection; and determining the detection result by using the normalized percentage of the peak area.

Technical Field

The invention belongs to the technical field of pesticide preparations, and particularly relates to a preparation method of a prothioconazole sustained-release agent.

Background

Prothioconazole (Prothioconazole) is a broad-spectrum, highly effective, triazolethione fungicide developed by bayer corporation in germany, under the english generic name: prothioconazole, trade name: proline, the original drug is light brown needle crystal with CAS number of 178928-70-6, the chemical name is (RS) -2- [2- (1-chloro cyclopropyl) -3- (2-chlorophenyl) -2-hydroxypropyl ] -2, 4-dihydro-1, 2, 4-triazole-3-thione, and is mainly used for preventing and treating a plurality of diseases of cereals, wheat and bean crops and the like.

The prothioconazole is raceme, can show good systemic activity, excellent protective, therapeutic and eradicating activity on crops, and has long lasting period. Through a large number of field efficacy tests, the results show that the prothioconazole has good guarantee on the safety of crops, has outstanding effects on the aspects of disease prevention, disease treatment and the like, has obvious yield-increasing effect on the crops, and has broader bactericidal activity compared with other triazole bactericides on the market.

The advantages of broad sterilization spectrum, high pesticide effect, low toxicity and low residue are completely suitable for the development of modern pesticides, and the global sales increase year by year since the market of 2004, so that the third bactericide in the world is leaped.

Prothioconazole can be compounded with other medicines to form a plurality of bactericidal medicines, but most of compounded preparations have poor water solubility and do not have the functions of slow release, controllability and the like.

There are patents reporting that prothioconazole can be prepared into microcapsule suspending agents, but the microcapsule suspending agents have the disadvantages of complex process, high preparation cost, poor slow release effect and poor water solubility.

Disclosure of Invention

The invention aims to overcome the defects of the prior art and provides a preparation method of a prothioconazole sustained-release agent, which has the characteristics of self-assembly, strong water solubility and efficient and continuous administration and well solves the problems of cost and water solubility of a microcapsule suspending agent.

According to the invention, the prothioconazole and the polyethylene glycol are organically combined, the prothioconazole has good water solubility, and the prothioconazole can be released continuously through natural degradation of the polyethylene glycol, so that the slow release effect is achieved.

The invention provides the following technical scheme: a preparation method of a prothioconazole sustained-release agent comprises the following steps: dissolving prothioconazole in a solvent, adding polyethylene glycol methacrylate and a catalyst, heating for reaction, filtering to remove the catalyst after detection reaction is finished, adding petroleum ether into a crude product after desolventizing, stirring for dispersion, and filtering to obtain a product; the reaction formula is as follows:

。

preferably, in the step, the molecular weight distribution of the polyethylene glycol methacrylate is between 200 and 20000.

Preferably, in the step, the ratio of the molar weight of the polyethylene glycol methacrylate to the prothioconazole is 0.01-1: 1.

Preferably, in the step, the catalyst is neutral alumina or the like.

Preferably, in the step, the ratio of the molar amount of the catalyst to the prothioconazole is 0.01-5: 1.

Preferably, in the step, the solvent is one or more of DMF, acetonitrile, DMSO, dichloroethane, dichloromethane, diethyl ether and other common solvents.

Preferably, in the step, the ether solvent is one or more of diethyl ether, petroleum ether, ethylene glycol dimethyl ether and methyl tertiary ether.

Preferably, in the step, the reaction temperature is 70-160 ℃.

Preferably, in the step, the reaction time is 1-10 h.

Preferably, in the step, the detection method is HPLC detection; and determining the detection result by using the normalized percentage of the peak area.

The invention has the following beneficial effects:

1. the invention provides a preparation method of a prothioconazole sustained-release agent, which has simple process and lower cost;

2. the prothioconazole sustained-release agent prepared by the invention has good water solubility, can be applied in various administration modes, and has low pesticide residue;

3. the prothioconazole sustained-release agent prepared by the invention has the advantages of controllable release, environmental protection and the like.

Detailed Description

The invention is further illustrated by the following specific examples.

Example 1

Adding 0.1 mol of prothioconazole, 150 mL of DMF, 0.5 mol of polyethylene glycol methacrylate (average molecular weight 360) and 0.1 mol of neutral aluminum oxide into a 250 mL four-mouth bottle, stirring and heating to 100 ℃, reacting for 5 hours, and stopping the reaction when the content of the prothioconazole is less than 0.5% by HPLC (high performance liquid chromatography) detection; filtering to remove the catalyst, and removing the solvent under reduced pressure; and adding 200 g of diethyl ether into the crude product, stirring for dispersion, and filtering to obtain the prothioconazole sustained-release agent product with the yield of 85%.

30 g of a polyethylene glycol methacrylate (average molecular weight 360) graft copolymer of prothioconazole is added into 100 g of water, and the mixture is stirred for 10 minutes at normal temperature, so that the prothioconazole graft is completely dissolved. The comparative prothioconazole bulk drug has a solubility of 0.3 g/L in water at pH = 8.

A300 mg/L solution was prepared for soil spray test (laboratory data, 20 ℃), soil DT50 for 5-8 days, and decomposition product desulfurization-prothioconazole soil DT50 for 7-34 days. The soil DT50 of the prothioconazole bulk drug is compared for 0.07-1.3 days. Meanwhile, a field spraying test shows that the cucumber powdery mildew control agent has a good control effect on cucumber powdery mildew.

Example 2

Adding 0.5 mol of prothioconazole, 200 mL of DMF, 0.5 mol of polyethylene glycol methacrylate (average molecular weight 360) and 0.1 mol of neutral aluminum oxide into a 250 mL four-mouth bottle, stirring and heating to 100 ℃, reacting for 6 h, and stopping the reaction when the content of the prothioconazole is less than 0.5% by HPLC (high performance liquid chromatography) detection; filtering to remove the catalyst, and removing the solvent under reduced pressure; and adding 250 g of diethyl ether into the crude product, stirring for dispersion, and filtering to obtain the prothioconazole sustained-release agent product with the yield of 91%.

30 g of a polyethylene glycol methacrylate (average molecular weight 360) graft copolymer of prothioconazole is added into 100 g of water, and the mixture is stirred for 10 minutes at normal temperature, so that the prothioconazole graft is completely dissolved. The comparative prothioconazole bulk drug has a solubility of 0.3 g/L in water at pH = 8.

A300 mg/L solution was prepared for soil spray test (laboratory data, 20 ℃), soil DT50 for 5-8 days, and decomposition product desulfurization-prothioconazole soil DT50 for 7-34 days. The soil DT50 of the prothioconazole bulk drug is compared for 0.07-1.3 days. Meanwhile, a field spraying test shows that the cucumber powdery mildew control agent has a good control effect on cucumber powdery mildew.

Example 3

Adding 0.5 mol of prothioconazole, 200 mL of DMF, 0.5 mol of polyethylene glycol methacrylate (average molecular weight 360) and 0.5 mol of neutral aluminum oxide into a 250 mL four-mouth bottle, stirring and heating to 100 ℃, reacting for 6 h, and stopping the reaction when the content of the prothioconazole is less than 0.5% by HPLC (high performance liquid chromatography) detection; filtering to remove the catalyst, and removing the solvent under reduced pressure; and adding 250 g of diethyl ether into the crude product, stirring and dispersing, and filtering to obtain the prothioconazole sustained-release agent product with the yield of 95%.

30 g of a polyethylene glycol methacrylate (average molecular weight 360) graft copolymer of prothioconazole is added into 100 g of water, and the mixture is stirred for 10 minutes at normal temperature, so that the prothioconazole graft is completely dissolved. The comparative prothioconazole bulk drug has a solubility of 0.3 g/L in water at pH = 8.

A300 mg/L solution was prepared for soil spray test (laboratory data, 20 ℃), soil DT50 for 5-8 days, and decomposition product desulfurization-prothioconazole soil DT50 for 7-34 days. The soil DT50 of the prothioconazole bulk drug is compared for 0.07-1.3 days. Meanwhile, a field spraying test shows that the cucumber powdery mildew control agent has a good control effect on cucumber powdery mildew.

Example 4

Adding 0.1 mol of prothioconazole, 200 mL of DMF, 0.5 mol of polyethylene glycol methacrylate (average molecular weight 1000) and 0.1 mol of neutral aluminum oxide into a 250 mL four-mouth bottle, stirring and heating to 120 ℃, reacting for 8 hours, and stopping the reaction when the content of the prothioconazole is less than 0.5% by HPLC (high performance liquid chromatography) detection; filtering to remove the catalyst, and removing the solvent under reduced pressure; adding 250 g of diethyl ether into the crude product, stirring and dispersing, and filtering to obtain the prothioconazole sustained-release agent product with the yield of 81%.

10 g of a polyethylene glycol methacrylate (average molecular weight 360) graft copolymer of prothioconazole is taken, added into 100 g of water, stirred for 10 minutes at normal temperature, and the prothioconazole graft is completely dissolved. The comparative prothioconazole bulk drug has a solubility of 0.3 g/L in water at pH = 8.

A300 mg/L solution was prepared for soil spray test (laboratory data, 20 ℃), soil DT50 for 9-10 days, and decomposition product desulfurization-prothioconazole soil DT50 for 10-40 days. The soil DT50 of the prothioconazole bulk drug is compared for 0.07-1.3 days. Meanwhile, a field spraying test shows that the cucumber powdery mildew control agent has a good control effect on cucumber powdery mildew.

Example 5

Adding 0.1 mol of prothioconazole, 150 mL of DMF, 0.5 mol of polyethylene glycol methacrylate (average molecular weight 200) and 0.1 mol of neutral aluminum oxide into a 250 mL four-mouth bottle, stirring and heating to 100 ℃, reacting for 5 hours, and stopping the reaction when the content of the prothioconazole is less than 0.5% by HPLC (high performance liquid chromatography) detection; filtering to remove the catalyst, and removing the solvent under reduced pressure; and adding 200 g of diethyl ether into the crude product, stirring for dispersion, and filtering to obtain the prothioconazole sustained-release agent product with the yield of 89%.

40 g of a polyethylene glycol methacrylate (average molecular weight 200) graft copolymer of prothioconazole is taken, added into 100 g of water, stirred for 10 minutes at normal temperature, and the prothioconazole graft is completely dissolved. The comparative prothioconazole bulk drug has a solubility of 0.3 g/L in water at pH = 8.

A300 mg/L solution was prepared for soil spray test (laboratory data, 20 ℃), soil DT50 for 4-6 days, and decomposition product desulfurization-prothioconazole soil DT50 for 5-20 days. The soil DT50 of the prothioconazole bulk drug is compared for 0.07-1.3 days. Meanwhile, a field spraying test shows that the cucumber powdery mildew control agent has a good control effect on cucumber powdery mildew.

Example 6

Adding 0.1 mol of prothioconazole, 150 mL of DMF, 0.5 mol of polyethylene glycol methacrylate (average molecular weight 360) and 0.1 mol of neutral aluminum oxide into a 250 mL four-mouth bottle, stirring and heating to 70 ℃, reacting for 10h, and stopping the reaction when the content of the prothioconazole is less than 0.5% by HPLC (high performance liquid chromatography) detection; filtering to remove the catalyst, and removing the solvent under reduced pressure; and adding 200 g of diethyl ether into the crude product, stirring for dispersion, and filtering to obtain the prothioconazole sustained-release agent product with the yield of 90%.

30 g of a polyethylene glycol methacrylate (average molecular weight 360) graft copolymer of prothioconazole is added into 100 g of water, and the mixture is stirred for 10 minutes at normal temperature, so that the prothioconazole graft is completely dissolved. The comparative prothioconazole bulk drug has a solubility of 0.3 g/L in water at pH = 8.

A300 mg/L solution was prepared for soil spray test (laboratory data, 20 ℃), soil DT50 for 5-8 days, and decomposition product desulfurization-prothioconazole soil DT50 for 7-34 days. The soil DT50 of the prothioconazole bulk drug is compared for 0.07-1.3 days. Meanwhile, a field spraying test shows that the cucumber powdery mildew control agent has a good control effect on cucumber powdery mildew.

Example 7

Adding 0.1 mol of prothioconazole, 150 mL of DMF, 0.5 mol of polyethylene glycol methacrylate (average molecular weight 360) and 0.1 mol of neutral aluminum oxide into a 250 mL four-mouth bottle, stirring and heating to 160 ℃, reacting for 1h, and stopping the reaction when the content of the prothioconazole is less than 0.5% by HPLC (high performance liquid chromatography) detection; filtering to remove the catalyst, and removing the solvent under reduced pressure; and adding 200 g of diethyl ether into the crude product, stirring for dispersion, and filtering to obtain the prothioconazole sustained-release agent product with the yield of 73%.

30 g of a polyethylene glycol methacrylate (average molecular weight 360) graft copolymer of prothioconazole is added into 100 g of water, and the mixture is stirred for 10 minutes at normal temperature, so that the prothioconazole graft is completely dissolved. The comparative prothioconazole bulk drug has a solubility of 0.3 g/L in water at pH = 8.

A300 mg/L solution was prepared for soil spray test (laboratory data, 20 ℃), soil DT50 for 5-8 days, and decomposition product desulfurization-prothioconazole soil DT50 for 7-34 days. The soil DT50 of the prothioconazole bulk drug is compared for 0.07-1.3 days. Meanwhile, a field spraying test shows that the cucumber powdery mildew control agent has a good control effect on cucumber powdery mildew.

Example 8

Adding 0.1 mol of prothioconazole, 150 mL of DMF, 0.5 mol of polyethylene glycol methacrylate (average molecular weight 360) and 0.1 mol of neutral aluminum oxide into a 250 mL four-mouth bottle, stirring and heating to 160 ℃, reacting for 10 hours, and stopping the reaction when the content of the prothioconazole is less than 0.5% by HPLC (high performance liquid chromatography) detection; filtering to remove the catalyst, and removing the solvent under reduced pressure; and adding 200 g of diethyl ether into the crude product, stirring for dispersion, and filtering to obtain the prothioconazole sustained-release agent product with the yield of 95%.

30 g of a polyethylene glycol methacrylate (average molecular weight 360) graft copolymer of prothioconazole is added into 100 g of water, and the mixture is stirred for 10 minutes at normal temperature, so that the prothioconazole graft is completely dissolved. The comparative prothioconazole bulk drug has a solubility of 0.3 g/L in water at pH = 8.

A300 mg/L solution was prepared for soil spray test (laboratory data, 20 ℃), soil DT50 for 5-8 days, and decomposition product desulfurization-prothioconazole soil DT50 for 7-34 days. The soil DT50 of the prothioconazole bulk drug is compared for 0.07-1.3 days. Meanwhile, a field spraying test shows that the cucumber powdery mildew control agent has a good control effect on cucumber powdery mildew.

Example 9

Adding 0.1 mol of prothioconazole, 150 mL of DMF, 0.5 mol of polyethylene glycol methacrylate (average molecular weight 360) and 0.1 mol of neutral aluminum oxide into a 250 mL four-mouth bottle, stirring and heating to 70 ℃, reacting for 10h, and stopping the reaction when the content of the prothioconazole is less than 0.5% by HPLC (high performance liquid chromatography) detection; filtering to remove the catalyst, and removing the solvent under reduced pressure; and adding 200 g of petroleum ether into the crude product, stirring and dispersing, and filtering to obtain the prothioconazole sustained-release agent product with the yield of 88%.

30 g of a polyethylene glycol methacrylate (average molecular weight 360) graft copolymer of prothioconazole is added into 100 g of water, and the mixture is stirred for 10 minutes at normal temperature, so that the prothioconazole graft is completely dissolved. The comparative prothioconazole bulk drug has a solubility of 0.3 g/L in water at pH = 8.

A300 mg/L solution was prepared for soil spray test (laboratory data, 20 ℃), soil DT50 for 5-8 days, and decomposition product desulfurization-prothioconazole soil DT50 for 7-34 days. The soil DT50 of the prothioconazole bulk drug is compared for 0.07-1.3 days. Meanwhile, a field spraying test shows that the cucumber powdery mildew control agent has a good control effect on cucumber powdery mildew.

Example 10

Adding 0.1 mol of prothioconazole, 150 mL of DMF, 0.5 mol of polyethylene glycol methacrylate (average molecular weight 360) and 0.1 mol of neutral aluminum oxide into a 250 mL four-mouth bottle, stirring and heating to 70 ℃, reacting for 10h, and stopping the reaction when the content of the prothioconazole is less than 0.5% by HPLC (high performance liquid chromatography) detection; filtering to remove the catalyst, and removing the solvent under reduced pressure; and adding 200 g of ethylene glycol dimethyl ether into the crude product, stirring and dispersing, and filtering to obtain the prothioconazole sustained-release agent product with the yield of 85%.

30 g of a polyethylene glycol methacrylate (average molecular weight 360) graft copolymer of prothioconazole is added into 100 g of water, and the mixture is stirred for 10 minutes at normal temperature, so that the prothioconazole graft is completely dissolved. The comparative prothioconazole bulk drug has a solubility of 0.3 g/L in water at pH = 8.

A300 mg/L solution was prepared for soil spray test (laboratory data, 20 ℃), soil DT50 for 5-8 days, and decomposition product desulfurization-prothioconazole soil DT50 for 7-34 days. The soil DT50 of the prothioconazole bulk drug is compared for 0.07-1.3 days. Meanwhile, a field spraying test shows that the cucumber powdery mildew control agent has a good control effect on cucumber powdery mildew.