Novel pymetrozine intermediate and preparation method thereof

Abstract

The invention belongs to the field of organic synthesis, and discloses a novel pymetrozine intermediate and a preparation method thereof. The structure of the novel pymetrozine intermediate is as shown in a formula I. The preparation method comprises the following steps: (1) reacting propionyl hydrazine, butyrylhydrazine or isobutyrylhydrazine with phosgene or solid phosgene in a solvent to obtain corresponding ethyl oxadiazolone, n-propyl oxadiazolone or isopropyl oxadiazolone, and then removing hydrogen chloride gas to obtain a uniform reaction solution; (2) adding an inorganic base, a phase transfer catalyst and chloroacetone into the reaction liquid obtained in the step (1) to react, and then sequentially desalting, distilling and concentrating to obtain a corresponding acetonyl intermediate; and (3) adding alcohol and hydrazine hydrate into the acetone-based intermediate obtained in the step (2), and sequentially cooling, crystallizing and separating after reaction. Compared with traditional acetamido triazinone, the acetamido triazinone is easier to synthesize, lower in cost, good in thermal stability and capable of remarkably reducing the cost of pymetrozine, and in the formula I, R is ethyl, propyl or isopropyl. Formula I.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis, specifically relating to a novel intermediate of pymetrozine and its preparation method. Background Technology

[0002] Pymetrozine (common name: pymetrozine) is a novel heterocyclic, highly effective, and selective insecticide developed by Novartis in Switzerland in 1988. It is characterized by high efficiency, low toxicity, high selectivity, and environmental friendliness. Its unique mode of action primarily affects insect feeding behavior, causing them to refuse food and die. It is effective against both larvae and adults. This pesticide quickly penetrates plant leaves, with a residual effect lasting over one month. Due to the absence of cross-resistance and high safety for natural enemies, it is highly suitable for controlling resistant pests and integrated pest management. It exhibits high efficacy against aphids, planthoppers, leafhoppers, whiteflies, and stink bugs in crops such as rice, vegetables, cotton, wheat, and fruit trees. According to statistics from the China Pesticide Industry Association, by the end of 2023, the domestic production capacity of pymetrozine technical grade pesticide in China had reached over 8,000 tons.

[0003] The synthesis technology of pymetrozine is basically mature. Currently, both domestically and internationally, hydrazine hydrate and ethyl acetate or methyl acetate are used as starting materials. The hydrazinolysis yields acetylhydrazine, which is then cyclized to obtain 5-methyl-1,3,4-oxadiazole-2-( 3H )-ketone, abbreviated as methyloxadiazolone; methyloxadiazolone reacts with chloroacetone, followed by hydrazolysis and rearrangement to yield acetamidotriazinone, namely 4,5-dihydro-4-acetamido-6-methyl-1,2,4-triazin-3-( 2H )-ketone; acetamidotriazinone is hydrolyzed to give aminotriazinone, which is then condensed with nicotinaldehyde to give pymetrozine technical grade. The synthetic route is as follows:

[0004] Although the above-mentioned route is already in use in industrial production, methyloxadiazolone is a solid with very low solubility in solvents such as dichloroethane, chloroform, chlorobenzene, and toluene. Its synthesis and reaction with chloroacetone must be carried out in large solvents, and the preparation process must be conducted in two separate stages: low temperature and high temperature. Otherwise, the reaction yield will decrease significantly. These drawbacks result in low production efficiency, high investment in production facilities, high production costs, and difficulties in VOC control.

[0005] Furthermore, the acetamidotriazinone prepared via the above route contains water of crystallization and is unstable after losing this water. The hydrolysis of acetamidotriazinone is typically carried out in concentrated hydrochloric acid, and the presence of water of crystallization is detrimental to the hydrolysis reaction.

[0006] Therefore, based on this, the technical solution of the present invention is proposed. Summary of the Invention

[0007] To address the problems existing in the prior art, the present invention provides a novel pymetrozine intermediate, which is a novel amide triazinone compound, and the structure of the novel pymetrozine intermediate is shown in Formula I:

[0008] Formula I Wherein: R group is ethyl, n-propyl or isopropyl.

[0009] Preferably, the R group is n-propyl or isopropyl.

[0010] Based on the same technical concept, another aspect of the present invention is to provide a method for preparing a novel intermediate of pymetrozine, the method comprising the following steps: (1) Reaction of propionylhydrazine, butyrylhydrazine or isobutyrylhydrazine with phosgene, diphosgene or solid phosgene in a solvent to obtain the corresponding ethyl oxadiazolone, n-propyl oxadiazolone or isopropyl oxadiazolone (as shown in Formula II), and then dehydrochlorination to obtain a homogeneous reaction solution. (2) Add inorganic base, phase transfer catalyst and chloroacetone to the reaction solution obtained in step (1) and react. Then, desalt and distill to concentrate the solution to obtain the corresponding acetone intermediate (as shown in Formula III). (3) Add alcohol and hydrazine hydrate to the acetone intermediate obtained in step (2), and after the reaction, cool down and crystallize and separate to obtain the new pymetrozine intermediate. The new pymetrozine intermediate is propionylaminotriazinone, butyrylaminotriazinone or isobutyrylaminotriazinone (as shown in Formula I).

[0011] The reaction process is as follows:

[0012] The solvent is a non-polar solvent such as dichloroethane, chloroform, chlorobenzene, or toluene, with dichloroethane and toluene being preferred.

[0013] Preferably, in step (2), the inorganic base is sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, calcium oxide, or calcium hydroxide.

[0014] To facilitate understanding of this invention, the research process of this invention will be briefly described: This invention, through careful research, discovered that propionic acid, butyric acid, isobutyric acid, or their esters can be used instead of acetate to prepare the corresponding acylhydrazides, which are then reacted with phosgene, diphosgene, or solid-light reactions to generate 5-ethyl-1,3,4-oxadiazole-2-( 3H )-ketone, 5-propyl-1,3,4-oxadiazole-2-( 3H )-ketone and 5-isopropyl-1,3,4-oxadiazole-2-( 3HThese three compounds, abbreviated as ethyl oxadiazolone, propyl oxadiazolone, and isopropyl oxadiazolone, are liquids at room temperature and readily soluble in nonpolar solvents such as dichloroethane, chloroform, chlorobenzene, and toluene. Therefore, their synthesis and application are very convenient, significantly reducing solvent usage and improving production efficiency, thereby lowering production costs and reducing the difficulty of VOC treatment. The synthesis of these three compounds and their reaction with chloroacetone can be carried out smoothly in small or appropriate amounts of nonpolar solvents such as dichloroethane, chloroform, chlorobenzene, and toluene. The reactions are conducted at room temperature to reflux, without requiring a low-temperature process, and can be prepared in stoichiometric or excellent yields. The reaction with chloroacetone can proceed smoothly in the same solvent. Since the reaction substrates are all liquid and the reaction products are also liquid, they are completely miscible with the solvent. This characteristic greatly reduces the amount of reaction solvent used, and the reaction rate is significantly faster, with higher yields and significantly improved production efficiency.

[0015] Furthermore, it was unexpectedly discovered that 4,5-dihydro-4-propionylamino-6-methyl-1,2,4-triazine-3-( 2H )-ketone, 4,5-dihydro-4-butyrylamino-6-methyl-1,2,4-triazine-3-( 2H )-ketone, 4,5-dihydro-4-isobutyrylamino-6-methyl-1,2,4-triazine-3-( 2H )-ketones, abbreviated as propionylaminotriazinone, butyrylaminotriazinone, and isobutyrylaminotriazinone respectively, are all white crystals, all anhydrous, have good stability, are easy to dry, and are beneficial to the next step of hydrolysis reaction.

[0016] The beneficial effects of this invention are as follows: In this invention, the intermediates ethyl oxadiazolone, propyl oxadiazolone, and isopropyl oxadiazolone are liquid at room temperature and readily soluble in nonpolar solvents such as dichloroethane, which can significantly reduce the amount of reaction solvent used, lower VOC emissions, and reduce the difficulty of treatment, thus meeting environmental protection requirements. Furthermore, the target intermediates (propionylaminotriazinone, butyrylaminotriazinone, and isobutyrylaminotriazinone) are anhydrous, exhibit excellent chemical stability, and are easy to dry and store, effectively promoting the smooth progress of subsequent hydrolysis reactions and avoiding reaction obstacles caused by existing intermediates containing water of crystallization. In addition, measurements show that the three-step reaction separation yield is as high as 95.5%, a significant improvement compared to the 60% yield of the existing technology, with a product purity of up to 99.2%, significantly reducing production costs. More importantly, the process route is simple and continuous, the reaction conditions are mild and easily controlled, no special equipment is required, and it is suitable for large-scale industrial production, effectively solving the core pain points of existing technologies such as high solvent consumption, low yield, and unstable intermediates. Detailed Implementation

[0017] To make the objectives, technical solutions, and advantages of this invention clearer, the technical solutions of this invention will be described in detail below. Obviously, the described embodiments are merely some embodiments of this invention, and not all embodiments. Based on the embodiments of this invention, all other implementation methods obtained by those skilled in the art without creative effort are within the scope of protection of this invention.

[0018] Example 1 This embodiment provides a method for preparing a novel intermediate of pymetrozine, the method comprising the following steps: (1) At room temperature, 89.0 g (1.0 mol) propionyl hydrazine and 250 g dichloroethane were added to a 1 L reaction flask and stirred. At 75 °C, a dichloroethane solution (250 g) containing 101.9 g (0.34 mol) phosgene (i.e. triphosgene, the same below) was added dropwise over 2 hours. The mixture was kept warm at this temperature for 3 hours. After the reaction was completed, the mixture was degassed for 10 minutes to obtain an ethyl oxadiazolone solution.

[0019] (2) At 25°C, 128.6 g sodium carbonate (1.2 mol), 16.2 g tetrabutylammonium bromide (0.05 mol), and 93.4 g chloroacetone (1.0 mol) were added to the ethyl oxadiazolone solution. The temperature was then raised to 80°C and reacted for 3 hours. After the reaction was completed, the temperature was lowered to room temperature. The solid salt was filtered off to obtain the acetone-based intermediate solution. The solution was then distilled under negative pressure to recover dichloroethane and obtain the acetone-based intermediate.

[0020] (3) At 25°C, 200g of methanol and 65.8g of hydrazine hydrate (80%, 1.05mol) were added to the acetone intermediate. After the addition was complete, the temperature was raised to 75°C and the reaction was carried out for 3 hours. After the reaction was completed, the temperature was lowered to 0°C and filtered. After the solid was dried, 163.3g of propionylaminotriazine ketone with a purity of 99.0% was obtained. The separation yield of the three-step reaction was 87.8%.

[0021] Example 2 This embodiment provides a method for preparing a novel intermediate of pymetrozine, the method comprising the following steps: (1) At room temperature, 104.2 g (1.0 mol) butyrylhydrazine and 250 g dichloroethane were added to a 1 L reaction flask, and stirring was started. A solution of 250 g containing 101.9 g (0.34 mol) of dichloroethane was added dropwise over 2 hours at 75 °C, and the mixture was kept at this temperature for another 3 hours. After the reaction was completed, the mixture was degassed for 10 minutes to obtain a propyloxadiazolone solution.

[0022] (2) At 25°C, 128.6 g sodium carbonate (1.2 mol), 16.2 g tetrabutylammonium bromide (0.05 mol), and 93.4 g chloroacetone (1.0 mol) were added to the propyl oxadiazolone solution. The temperature was then raised to 80°C and reacted for 3 hours. After the reaction was completed, the temperature was lowered to room temperature. The solid salt was filtered off to obtain the acetone-based intermediate solution. The solution was then distilled under negative pressure to recover dichloroethane and obtain the acetone-based intermediate.

[0023] (3) At 25°C, 200 g of methanol and 65.8 g of hydrazine hydrate (80%, 1.05 mol) were added to the acetone intermediate. After the addition was complete, the temperature was raised to 75°C and the reaction was carried out for 3 hours. After the reaction was completed, the temperature was lowered to 0°C and filtered. After drying the solid, 190.9 g of butyrylaminotriazine was obtained with a purity of 99.2%. The separation yield of the three-step reaction was 95.5%.

[0024] Example 3 This embodiment provides a method for preparing a novel intermediate of pymetrozine, the method comprising the following steps: (1) At room temperature, 104.2 g (1.0 mol) isobutyrylhydrazine and 250 g dichloroethane were added to a 1 L reaction flask, and stirring was started. At 75 °C, a solution of 250 g of dichloroethane containing 101.9 g (0.34 mol) of solid light was added dropwise over 2 hours. The mixture was kept warm at this temperature for 3 hours. After the reaction was completed, the mixture was degassed for 10 minutes to obtain an isopropyl oxadiazolone solution.

[0025] (2) At 25°C, 128.6 g sodium carbonate (1.2 mol), 16.2 g tetrabutylammonium bromide (0.05 mol), and 93.4 g chloroacetone (1.0 mol) were added to the isopropyl oxadiazolone solution. The temperature was then raised to 80°C and reacted for 3 hours. After the reaction was completed, the temperature was lowered to room temperature, and the solid salt was filtered off to obtain an acetone-based intermediate solution. The acetone-based intermediate was obtained by negative pressure distillation to recover dichloroethane.

[0026] (3) At 25°C, 200 g of methanol and 65.8 g of hydrazine hydrate (80%, 1.05 mol) were added to the acetone intermediate. After the addition was complete, the temperature was raised to 75°C and the reaction was carried out for 3 hours. After the reaction was completed, the temperature was lowered to 0°C and filtered. After drying the solid, 189.9 g of isobutyrylaminotriazinone was obtained with a purity of 99.1%. The separation yield of the three-step reaction was 95.0%.

[0027] Comparative Example 1 (1) At room temperature, 74.8 g (1.0 mol) acetylhydrazine and 1000 g dichloroethane were added to a 2 L reaction flask and stirred. At 15 °C, 250 g of dichloroethane solution containing 101.9 g (0.34 mol) of solid light was added dropwise. After the gas was purged, the temperature was raised to 75 °C and kept at this temperature for 3 hours. After the reaction was completed, the gas was degassed for 10 minutes to obtain methyl oxadiazolone solution.

[0028] (2) At 25°C, 128.6 g sodium carbonate (1.2 mol), 16.2 g tetrabutylammonium bromide (0.05 mol), and 93.4 g chloroacetone (1.0 mol) were added to the methyl oxadiazolone solution. The temperature was then raised to 80°C and reacted for 3 hours. After the reaction was completed, the temperature was lowered to room temperature. The solid salt was filtered off to obtain an acetone-based intermediate solution. The solution was then distilled under negative pressure to recover dichloroethane and obtain the acetone-based intermediate.

[0029] (3) At 25°C, 200g of methanol and 65.8g of hydrazine hydrate (80%, 1.05mol) were added to the acetone intermediate. After the addition was complete, the temperature was raised to 75°C and reacted for 3 hours. After the reaction was completed, the temperature was lowered to 0°C and filtered. After the solid was dried, 116.3g of acetaminotriazine monohydrate was obtained. The content of acetaminotriazine monohydrate was 97.2%. The separation yield of the three-step reaction was 60.0%.

[0030] Comparative Example 2 (1) At room temperature, 74.8 g (1.0 mol) acetylhydrazine and 1000 g dichloroethane were added to a 2 L reaction flask and stirred. At 70-80 °C, 250 g of dichloroethane solution containing 101.9 g (0.34 mol) of solid light was added dropwise. After the gas was purged, the temperature was maintained for 3 hours. After the reaction was completed, the gas was degassed for 10 minutes to obtain methyl oxadiazolone solution.

[0031] (2) At 25°C, 128.6 g sodium carbonate (1.2 mol), 16.2 g tetrabutylammonium bromide (0.05 mol), and 93.4 g chloroacetone (1.0 mol) were added to the methyl oxadiazolone solution. The temperature was then raised to 80°C and reacted for 3 hours. After the reaction was completed, the temperature was lowered to room temperature. The solid salt was filtered off to obtain an acetone-based intermediate solution. The solution was then distilled under negative pressure to recover dichloroethane and obtain the acetone-based intermediate.

[0032] (3) At 25°C, 200g of methanol and 65.8g of hydrazine hydrate (80%, 1.05mol) were added to the acetone intermediate. After the addition was complete, the temperature was raised to 75°C and reacted for 3 hours. After the reaction was completed, the temperature was lowered to 0°C and filtered. After the solid was dried, 107.2g of acetaminotriazine monohydrate was obtained. The content of acetaminotriazine monohydrate was 96.8%, and the separation yield of the three-step reaction was 55.2%.

[0033] Comparative Examples 1 and 2 were prepared using conventional techniques to produce pyridine intermediates. Due to poor reaction selectivity and instability of the intermediates, the separation yields were lower than those of the present invention.

[0034] The above description is merely a specific embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any variations or substitutions that can be easily conceived by those skilled in the art within the technical scope disclosed in the present invention should be included within the scope of protection of the present invention. Therefore, the scope of protection of the present invention should be determined by the scope of the claims.

Claims

1. A novel pymetrozine intermediate, characterized in that, The novel pymetrozine intermediate is a novel amide triazinone compound, and its structure is shown in Formula I: Formula I Wherein: R group is ethyl, n-propyl or isopropyl.

2. The novel pymetrozine intermediate according to claim 1, characterized in that, The R group is n-propyl or isopropyl.

3. The method for preparing the novel pymetrozine intermediate according to claim 1 or 2, characterized in that, The preparation method includes the following steps: (1) Reaction of propionylhydrazine, butyrylhydrazine or isobutyrylhydrazine with phosgene, diphosgene or solid phosgene in a solvent to obtain the corresponding ethyl oxadiazolone, n-propyl oxadiazolone or isopropyl oxadiazolone, and then dehydrochlorination to obtain a homogeneous reaction solution. (2) Add inorganic base, phase transfer catalyst and chloroacetone to the reaction solution obtained in step (1) and react. Then, desalt and distill to concentrate the solution to obtain the corresponding acetone intermediate. (3) Add alcohol and hydrazine hydrate to the acetone intermediate obtained in step (2), and after the reaction, cool down and crystallize and separate to obtain the new pymetrozine intermediate. The new pymetrozine intermediate is propionylaminotriazinone, butyrylaminotriazinone or isobutyrylaminotriazinone.

4. The method for preparing the new pymetrozine intermediate according to claim 3, characterized in that, The solvent is a non-polar solvent; the non-polar solvent is dichloroethane, chloroform, chlorobenzene or toluene.

5. The method for preparing the new pymetrozine intermediate according to claim 4, characterized in that, The nonpolar solvent is dichloroethane or toluene.

6. The method for preparing the new pymetrozine intermediate according to claim 3, characterized in that, In step (2), the inorganic base is sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, calcium oxide, or calcium hydroxide.

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