阅读说明：本技术 一种适合制备悬浮剂的喹啉铜的制备方法 (Preparation method of oxine-copper suitable for preparing suspending agent ) 是由 赵帅 祝帅 柴泽宇 孙小娟 邱森森 史天笑 于 2020-12-25 设计创作，主要内容包括：本发明公开了一种适合制备悬浮剂的喹啉铜的制备方法。所述制备方法包括如下步骤：1)8-羟基喹啉与铜盐在水中进行反应,反应结束后降温；所述铜盐为氯化铜、硫酸铜、硝酸铜、乙酸铜、碱式硫酸铜或碱式氯化铜；2)将碱溶液加入至反应体系中,调节体系pH至3.0～6.0,控制体系温度为40～70℃,滴加结束后降温；析出固体即为喹啉铜。本发明通过调整反应温度梯度、反应时间、铜盐类型及烘干温度等反应条件,反应过程更温和,反应过程较快,且利于含结晶水喹啉铜晶体生成长大,合成得到的产物为绿色的含2分子结晶水喹啉原药。采用该原药制备的含30～45％喹啉铜单剂悬浮剂及含喹啉铜30～45％混剂悬浮剂产品,制剂稳定性比常规不含结晶水喹啉铜原药制备的悬浮剂稳定性大大提高。(The invention discloses a preparation method of oxine-copper suitable for preparing a suspending agent. The preparation method comprises the following steps: 1) 8-hydroxyquinoline reacts with copper salt in water, and the temperature is reduced after the reaction is finished; the copper salt is copper chloride, copper sulfate, copper nitrate, copper acetate, basic copper sulfate or basic copper chloride; 2) adding an alkali solution into a reaction system, adjusting the pH value of the system to 3.0-6.0, controlling the temperature of the system to be 40-70 ℃, and cooling after dropwise adding; the precipitated solid is the oxine-copper. According to the invention, reaction conditions such as reaction temperature gradient, reaction time, copper salt type, drying temperature and the like are adjusted, so that the reaction process is milder and quicker, the crystal growth of the crystal water-containing oxine-copper crystal is facilitated, and the synthesized product is green 2-molecule crystal water-containing quinoline original drug. The single-agent suspending agent containing 30-45% of oxine-copper and the mixed-agent suspending agent containing 30-45% of oxine-copper prepared by the raw pesticide have greatly improved preparation stability compared with the suspending agent prepared by the conventional raw pesticide containing no crystal water oxine-copper.)

1. A process for preparing oxine-copper suitable for the preparation of suspension concentrates comprising the steps of:

1) 8-hydroxyquinoline reacts with copper salt in water, and the temperature is reduced after the reaction is finished;

the copper salt is copper chloride, copper sulfate, copper nitrate, copper acetate, basic copper sulfate or basic copper chloride;

2) adding an alkali solution into a reaction system, adjusting the pH value of the system to 3.0-6.0, controlling the temperature of the system to be 40-70 ℃, and cooling after dropwise adding; the precipitated solid is the oxine-copper.

2. The method of claim 1, wherein: the reaction temperature is 40-80 ℃, and the reaction time is 2-4 h.

3. The method of claim 2, wherein: the procedure for the reaction was as follows:

firstly reacting for 1-2 h at 50-65 ℃, then heating to 65-80 ℃, and continuing to react for 1-2 h.

4. The production method according to any one of claims 1 to 3, characterized in that: in the step 1), cooling to 20-30 ℃ after the reaction is finished;

in the step 2), cooling to 20-30 ℃ after the dropwise addition is finished.

5. The production method according to any one of claims 1 to 4, characterized in that: the alkali solution is sodium hydroxide aqueous solution, and the concentration of the sodium hydroxide aqueous solution is 10-50%.

6. The production method according to any one of claims 1 to 5, characterized in that: the mass ratio of the 8-hydroxyquinoline to the copper salt to the sodium hydroxide is 30-50: 12-48: 8-15.

7. The production method according to any one of claims 1 to 6, characterized in that: the method further comprises the step of washing the precipitated solid with water and drying the solid at the temperature of 50-80 ℃.

Technical Field

The invention relates to a preparation method of oxine-copper suitable for preparing a suspending agent, belonging to the technical field of organic synthesis.

Background

Oxine-copper is a chemical substance, is yellow to green powder, is non-volatile, does not deliquesce, turns black at high temperature, and is insoluble in water and most solvents. The oxine-copper can be used as a medical synthetic metal corrosion inhibitor; is used as bactericide in agriculture. Also used as mildew preventive for ropes, wires, leather and vinyl plastics. Is used as a bactericide in agriculture for preventing and treating cucumber bacterial angular leaf spot, mango bacterial angular leaf spot, citrus canker, apple ring rot and the like.

The common production method of the raw medicinal copper quinolate is to chelate 8-hydroxyquinoline and copper sulfate which are used as raw materials in water at high temperature to obtain a product, and the method has violent reaction conditions and stronger system acidity in the reaction process, so that the obtained dark yellow raw medicinal copper quinolate without crystal water is obtained. Practice proves that the technical grade of the crystal water-free oxine-copper is only suitable for being processed into solid pesticide preparations such as wettable powder, water dispersible granules, granules and the like, and the unstable phenomena such as large particle size, layered precipitation and the like are easily generated when the technical grade is processed into an aqueous suspension. The solid pesticide preparation has a plurality of defects, such as large dust in the processing process, large influence on the environment and high requirement on environment-friendly treatment; when in use, the pesticide has the defects of poor dispersibility in water, large pesticide particle size, poor pesticide effect and the like. Therefore, it is required to provide a preparation method of oxine-copper raw drug suitable for preparing suspending agent.

Disclosure of Invention

The invention aims to provide a preparation method of crystal water-containing oxine-copper suitable for preparing a suspending agent, which has the advantages of simple preparation process steps, stable product quality, stable color and environmental friendliness.

The preparation method of oxine-copper suitable for preparing the suspending agent, provided by the invention, comprises the following steps:

1) 8-hydroxyquinoline reacts with copper salt in water, and the temperature is reduced after the reaction is finished;

the copper salt is copper chloride, copper sulfate, copper nitrate, copper acetate, basic copper sulfate or basic copper chloride;

2) adding an alkali solution into a reaction system, adjusting the pH value of the system to 3.0-6.0, controlling the temperature of the system to be 40-70 ℃, and cooling after dropwise adding; the precipitated solid is the oxine-copper.

In the preparation method, the reaction temperature is 40-80 ℃, and the reaction time is 2-4 h; the following reaction sequence is preferably employed:

firstly reacting for 1-2 h at 50-65 ℃, then heating to 65-80 ℃, and continuing to react for 1-2 h.

In the preparation method, in the step 1), the temperature is reduced to 20-30 ℃ after the reaction is finished;

in the step 2), cooling to 20-30 ℃ after the dropwise addition is finished.

In the above preparation method, the alkali solution is a sodium hydroxide aqueous solution, and the concentration of the sodium hydroxide aqueous solution is 10% to 50%.

In the preparation method, the mass ratio of the 8-hydroxyquinoline to the copper salt to the sodium hydroxide is 30-50: 12-48: 8-15, such as 30-50: 12-48: 11. 40: 28-37: 11. 40: 28: 11 or 40: 37: 11;

in the preparation method, the method also comprises the step of washing the precipitated solid with water and drying the solid at 50-80 ℃;

washing with water for 2-3 times until there is no sulfate ion, chloride ion, acetate ion, and nitrate ion.

The oxine-copper raw pesticide prepared by the method contains 2 molecules of crystal water per molecule of product.

The oxine-copper raw medicine prepared by the method has the content of oxine-copper of more than or equal to 90 percent, and the rest components are mainly crystal water and a very small amount of free water.

Compared with the suspending agent prepared from the conventional raw oxine-copper without crystal water, the single-dose suspending agent or mixed-dose suspending agent containing the raw oxine-copper prepared by the method disclosed by the invention is greatly improved in stability, wherein the mass content of the raw oxine-copper can be 30-45%.

According to the invention, reaction conditions such as reaction temperature gradient, reaction time, copper salt type, drying temperature and the like are adjusted, so that the reaction process is milder and quicker, the crystal growth of the crystal water-containing oxine-copper crystal is facilitated, and the synthesized product is green 2-molecule crystal water-containing quinoline original drug. The single-agent suspending agent containing 30-45% of oxine-copper and the mixed-agent suspending agent containing 30-45% of oxine-copper prepared by the raw pesticide have greatly improved preparation stability compared with the suspending agent prepared by the conventional raw pesticide containing no crystal water oxine-copper.

Drawings

Fig. 1 is a TGA diagram of a technical copper quinolate prepared in example 1 of the present invention.

Figure 2 is a TGA plot of a technical copper quinolate prepared in example 2 of the present invention.

Detailed Description

The experimental procedures used in the following examples are all conventional procedures unless otherwise specified.

Materials, reagents and the like used in the following examples are commercially available unless otherwise specified.

EXAMPLE 1 preparation of crystalline oxine-copper suitable for the preparation of suspension concentrates

Adding 400g of 8-hydroxyquinoline, 280g of copper acetate monohydrate and 1000g of water into a reactor with a stirring device at normal temperature (25 ℃), heating to 55 ℃, keeping for 2 hours, continuously heating to 75 ℃, and keeping for 1 hour; after the reaction is finished, cooling to room temperature, slowly dropwise adding 380g of 30% sodium hydroxide aqueous solution, adjusting the pH of the system to about 5.0, controlling the temperature of the system to be below 50 ℃, continuously cooling to 20-30 ℃ after the dropwise adding is finished, and precipitating green oxine-copper original drug crystals containing crystal water. And (3) carrying out vacuum filtration on the precipitated crystals, washing the crystals for 2-3 times by using water, drying the crystals at 60 ℃ for 12 hours until the weight of the crystals is unchanged to obtain 537.7g of the original crystal water-containing oxine-copper, wherein the content of the original crystal water-containing oxine-copper is 90.2% by liquid chromatography detection, the calculated reaction yield is 99.8%, the original crystal water-containing oxine-copper contains 9.2% by TGA thermogravimetric analysis, and the original crystal water-containing oxine-copper contains 2 molecules by molecular weight calculation, and the TGA diagram is shown in figure 1.

Comparative examples 1,

At normal temperature (25 ℃), adding 400g of 8-hydroxyquinoline, 280g of copper acetate monohydrate and 1000g of water into a reactor with a stirring, condensing and refluxing device, directly heating to 75 ℃ for reaction, wherein a reaction system becomes very viscous within a few minutes, the stirring resistance is large, and the reaction state is uneven; if the reaction is continuously kept at 75 ℃, after 30 minutes, the reaction system is changed from emerald green to yellow brown, the reaction is kept for 3 hours, the reaction system is naturally cooled to room temperature, 380g of 30% sodium hydroxide aqueous solution is slowly dripped, the pH value of the system is adjusted to about 5.0, the temperature of the system is controlled below 50 ℃, and the temperature is continuously reduced to 20-30 ℃ after the dripping is finished. And (3) carrying out suction filtration on the reaction system after cooling and crystallization, washing the obtained solid product with water for 3 times, drying at 60 ℃ for 12 hours to obtain a tan powdery product, weighing 468.4g, detecting the content by liquid chromatography to be 98.1%, calculating the reaction yield to be 94.7%, and showing that the product does not contain crystal water according to the content of oxine-copper and the color appearance of the product.

As can be seen from the comparison of example 1 and comparative example 1, the reaction is carried out under the reaction temperature gradient, which is more favorable for stirring, prevents the occurrence of uneven heat transfer due to overlarge viscosity, and the gradient temperature reaction procedure is more favorable for the formation of crystal nucleus containing crystal water, thereby obtaining the oxine-copper containing crystal water.

EXAMPLE 2 preparation of crystalline oxine-copper suitable for the preparation of suspension concentrates

Adding 400g of 8-hydroxyquinoline, 370g of copper sulfate pentahydrate and 950g of water into a reactor with a stirring device at normal temperature (25 ℃), heating to 50 ℃, keeping for 2 hours, continuously heating to 75 ℃, and keeping for 1 hour; after the reaction is finished, cooling to room temperature, slowly dropwise adding 380g of 30% sodium hydroxide aqueous solution, adjusting the pH of the system to about 4.0, controlling the temperature of the system to be below 50 ℃, continuously cooling to 20-30 ℃ after the dropwise adding is finished, and precipitating green oxine-copper original drug crystals containing crystal water. And (3) carrying out vacuum filtration on the precipitated crystals, washing the crystals for 2-3 times by using water, drying the crystals at 60 ℃ for 12 hours until the weight of the crystals is unchanged to obtain 536.8g of the original crystal water-containing oxine-copper, wherein the content is 90.4% by liquid chromatography, the reaction yield is 99.9% by calculation, the crystals contain 9.01% by TGA thermogravimetric analysis, and each molecule of the original crystal water-containing oxine-copper contains 2 molecules of crystal water, and the TGA diagram is shown in figure 2.

Example 3 preparation of a 40% kasugamycin quinoline copper suspension

Test agents: preparation of technical copper quinolate containing water of crystallization prepared in example 1

Comparison reagent: prepared from outsourced oxine-copper raw material (without crystal water, Zhejiang Haizang Co., Ltd.)

The preparation method comprises the following steps: weighing corresponding materials according to mass percent, adding 2 percent of kasugamycin original drug, 38 percent of quinoline copper original drug containing crystal water (purchased quinoline copper original drug), 5 percent of phosphate, 0.5 percent of magnesium aluminum silicate, 3 percent of ethylene glycol and 0.5 percent of organic silicon oil, and the balance being water, adding the mixture into a dispersion kettle, pre-dispersing for 30 minutes under mechanical stirring, then transferring the dispersed liquid into a sand mill, circularly sanding for 1.5 hours, measuring D90 to be less than or equal to 5 mu m by a particle size analyzer, weighing the liquid mass after passing inspection, adding 0.15 percent of xanthan gum according to the proportion, and uniformly stirring and dispersing to obtain the suspension containing 40 percent of kasugamycin and quinoline copper.

TABLE 140% stability test results for kasugamycin-oxine-copper suspension

As can be seen from the heat storage comparison experiment in Table 1, the 40% kasugamycin-oxine-copper suspending agent (test medicament) prepared from the oxine-copper containing crystal water prepared by the invention has emerald green appearance after heat storage, normal viscosity, good fluidity, high and stable suspension rate, 2% heat storage decomposition rate and good stability; the 40% kasugamycin-oxine-copper suspending agent (contrast agent) prepared from purchased oxine-copper raw drug (without crystal water) is dark yellow after thermal storage, viscous, free of fluidity, pasty, poor in dispersion and suspension property in water, and poor in overall stability and unqualified, and the decomposition rate in thermal storage reaches 8.8% (higher than 5%).

Example 4 preparation of 33.5% Quinolinecopper suspension

Test agents: preparation of technical copper quinolate containing water of crystallization prepared in example 1

Comparison reagent: prepared from outsourced oxine-copper raw material (without crystal water, Zhejiang Haizang Co., Ltd.)

The preparation method comprises the following steps: weighing corresponding materials according to mass percent, adding 33.5 percent of crystalline water-containing oxine-copper raw material (purchased oxine-copper raw material), 4 percent of phosphate, 0.5 percent of magnesium aluminum silicate, 3 percent of glycol and 0.5 percent of organic silicon oil, and the balance being water, adding the raw material into a dispersion kettle, performing pre-dispersion for 30 minutes under mechanical stirring, transferring the dispersed liquid into a sand mill for circulating sand grinding for 1.5 hours, measuring D90 to be less than or equal to 5 mu m by a particle size analyzer, weighing the liquid mass after passing inspection, adding 0.2 percent of xanthan gum according to the proportion, and uniformly stirring and dispersing to obtain the 33.5 percent oxine-copper containing suspending agent.

TABLE 233.5 stability test results for copper quinolinate suspension

As can be seen from the comparative heat storage experiment shown in Table 2, the 33.5% oxine-copper suspending agent (test agent) prepared from the oxine-copper containing crystal water prepared by the invention has emerald green appearance after heat storage, normal viscosity, good fluidity, no layering and water separation phenomenon, high and stable suspension rate and 0.18% compound decomposition rate, and is very stable; the 33.5% oxine-copper suspending agent (contrast agent) prepared by using purchased oxine-copper raw material (without crystal water) is dark yellow after heat storage, the water evolution is obviously 1/3, the layering is serious, the suspension property is poor after dispersion in water, the heat storage decomposition rate is 6.5% (higher than 5%), and the overall stability is unqualified.