Production method for synthesizing methoxyfenozide
Through esterification, amine transesterification, N-tert-butylation and amidation reactions, the problems of low yield and unfriendly methazide in the prior art are solved, and efficient and low-cost methazide production are achieved.
Patent Information
- Application Number
- CN202510799668.5
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-06-16
- Publication Date
- 2025-08-15
AI Technical Summary
The existing methazole hydrazide synthesis process has low yields, high materials are expensive and environmentally unfriendly, making it difficult to meet market demand.
Using 3-methoxy-2-methylbenzoic acid as the raw material, the reaction conditions are optimized to improve yield and purity through four steps of esterification, amine transesterification, N-tert-butylation and amidation.
The production of methazide with high yield and high purity is achieved, which reduces production costs and environmental pollution, simplifies the process flow, and improves atomic economy.
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Abstract
Description
Technical Field
[0001] The invention belongs to the technical field of compound preparation, and particularly relates to a production method for synthesizing methoxyfenozide. Background Art
[0002] Methoxyfenozide is a specific, low-toxic phenylhydrazine insecticide with highly selective insecticidal activity against lepidopteran pests on crops such as vegetables, flowers, rice, and soybeans. It lacks penetrating or phloem-systemic activity, primarily acting as a stomach toxicant, but also exhibits some contact and ovicidal activity. Like other bisacylhydrazine insecticides such as chlorfenapyr, chlorfenapyr, and tebufenozide, methoxyfenozide is an ecdysone agonist, causing lepidopteran larvae to cease feeding and accelerate molting, resulting in premature molting and death before maturity. This drug, with its mechanism of action opposite to that of agents that inhibit molting, can be used throughout the larval stage.
[0003] The preparation methods of methoxyfenozide reported in the current literature are mainly the following:
[0004] In the prior art, it is roughly as follows:
[0005] Route 1: Oxadiazole ring-opening method
[0006]
[0007] This route involves the ring-opening of oxadiazole compounds under acidic conditions. Although this process is short in steps, the raw materials are expensive and difficult to obtain.
[0008] Route 2: Amino group protection method
[0009]
[0010] This route uses 2-methyl-3-methoxybenzoic acid as the starting material. Tert-butyl hydrazine is first protected with Boc anhydride, then reacted with 3,5-dimethylbenzoyl chloride. After the Boc group is removed, the product reacts with 2-methyl-3-methoxybenzoyl chloride to produce methoxyfenozide. This route involves a long reaction process, the raw material Boc anhydride is expensive, and the reaction produces a large amount of wastewater.
[0011] Route 3: Direct synthesis
[0012]
[0013] This route uses 2-methyl-3-methoxybenzoyl chloride as the raw material, which reacts directly with tert-butylhydrazine, followed by 3,5-dimethylbenzoyl chloride to obtain the finished product. The reaction steps are short, and the selectivity of the reaction between tert-butylhydrazine and the acyl chloride is poor, making it difficult to obtain a high-purity intermediate, resulting in low product yields.
[0014] In summary, the yield of existing methoxyfenozide synthesis processes is less than ideal, making it difficult to obtain high-content intermediates. The product yield and content are both low, which cannot meet the demand for use. Therefore, it is necessary to find a new green and environmentally friendly methoxyfenozide preparation method with high yield, low production cost, low production equipment requirements, low production energy consumption, and mild reaction conditions to meet the urgent market demand for this product.
[0015] In view of this, the present invention is proposed. Summary of the Invention
[0016] The present invention aims to solve the technical problems existing in the above-mentioned prior art and provides a production method for synthesizing methoxyfenozide.
[0017] To achieve the above object, the present invention adopts the following technical solutions:
[0018] A production method for synthesizing methoxyfenozide comprises the following steps:
[0019] (1) Using 3-methoxy-2-methylbenzoic acid as a raw material, an esterification reaction is carried out with a certain volume of solvent a under the catalysis of sulfuric acid;
[0020] (2) reacting the product after the esterification reaction in step (1) in solvent b and 1-10 equivalents (eq) of hydrazine hydrate for a period of time to perform amine transesterification;
[0021] (3) N-tert-butylating the product after the amine transesterification in step (2) with tert-butyl alcohol under the catalysis of hydrochloric acid;
[0022] (4) The N-tert-butylated product in step (3) is amidated with 3,5-dimethylbenzoyl chloride in solvent c and alkali solution to obtain methoxyfenozide.
[0023] The concentration of sulfuric acid in step (1) is 5%-50%.
[0024] In step (1), the solvent a is selected from one or more of methanol, ethanol or isopropanol, and the volume of the solvent a is 1-20 times the volume of the raw material 3-methoxy-2-methylbenzoic acid; and the reaction temperature is 30-100°C.
[0025] The solvent b in step (2) is an alcohol solvent, and the alcohol solvent includes a substance containing an alcoholic hydroxyl group, and the substance containing an alcoholic hydroxyl group includes one or more of methanol, ethanol, tert-butanol, isopropanol or benzyl alcohol.
[0026] The reaction time in step (2) is 3-20 hours, and the reaction temperature is 20-100°C.
[0027] The material molar ratio of tert-butyl alcohol to amine ester exchange product in step (3) is 1-10:1
[0028] The reaction temperature in step (3) is 80-100°C.
[0029] In the step (4), the solvent c is an aprotic solvent, including one or more of toluene, tetrahydrofuran or dichloromethane; the molar ratio of the N-tert-butylated product to 3,5-dimethylbenzoyl chloride is 1:1.0-1.1; and the alkali solution is an inorganic base, including one or more of sodium hydroxide, potassium hydroxide, sodium carbonate or sodium bicarbonate.
[0030] The reaction temperature in step (4) is 0-30°C.
[0031] The synthetic route of the methoxyfenozide is as follows:
[0032] Wherein R is methyl, ethyl or isopropyl.
[0033] The beneficial effects of the present invention are as follows:
[0034] (1) This application uses 3-methoxy-2-methylbenzoic acid as a raw material, and obtains the product methoxyfenozide through esterification, amine transesterification, N-tert-butylation, and amidation. Compared with the traditional process, this process has the advantages of a short route, cheap raw material price, less wastewater, high yield, and high purity;
[0035] (2) The technical solution disclosed in this application has simple and easy-to-obtain raw materials, simple reaction operation, and is green and environmentally friendly. This route reduces safety hazards, is environmentally friendly, reduces production energy consumption and the cost of three wastes, has good reaction atom economy, low raw material cost, high yield, high product quality, and low industrialization cost. It is a practical and feasible industrial production method. DETAILED DESCRIPTION
[0036] To make the purpose, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention are described clearly and completely below. Where specific conditions are not specified in the embodiments, conventional conditions or conditions recommended by the manufacturer are used. Where the manufacturer of the reagents or instruments is not specified, all are conventional products that can be purchased commercially.
[0037] In the description of the embodiments of this application, technical terms such as "first" and "second" are only used to distinguish different objects and cannot be understood as indicating or implying relative importance or implicitly indicating the number, specific order or primary and secondary relationship of the indicated technical features.
[0038] Reference herein to an "embodiment" means that a particular feature, structure, or characteristic described in connection with the embodiment may be included in at least one embodiment of the present application. The appearance of the phrase in various places in the specification does not necessarily refer to the same embodiment, nor does it constitute an independent or alternative embodiment that is mutually exclusive with other embodiments.
[0039] In the embodiment of the present application, the term "or / and" is only a description of the association relationship of associated objects, indicating that three relationships may exist. For example, A or / and B can represent three situations: A exists alone, A and B exist at the same time, and B exists alone.
[0040] In addition, the character “ / ” in this article generally indicates that the previous and next related objects are in an “or” relationship.
[0041] In the embodiments of the present application, "multiple" means more than two (including two). Similarly, "multiple groups" means more than two groups (including two groups), and "multi-layer" means more than two layers (including two layers), unless otherwise clearly specified and limited.
[0042] In the embodiments of the present application, “at least one” means one or more than one.
[0043] A production method for synthesizing methoxyfenozide comprises the following steps:
[0044] (1) 3-methoxy-2-methylbenzoic acid is used as a raw material, and an esterification reaction is carried out with a certain volume of solvent a under the catalysis of sulfuric acid with a concentration of 5% to 50%; wherein the solvent a is selected from one or more of methanol, ethanol or isopropanol, and the volume of the solvent a is 1 to 20 times the volume of the raw material 3-methoxy-2-methylbenzoic acid; the reaction temperature is 30 to 100°C.
[0045] (2) reacting the product after the esterification reaction in step (1) in solvent b and 1-10 equivalents (eq) of hydrazine hydrate for a period of time to perform amine ester exchange; solvent b is an alcohol solvent, and the alcohol solvent includes a substance containing an alcoholic hydroxyl group, and the substance containing an alcoholic hydroxyl group includes one or more of methanol, ethanol, tert-butanol, isopropanol or benzyl alcohol; the reaction time is 3-20 hours, and the reaction temperature is 20-100°C.
[0046] (3) The product after the amine ester exchange in step (2) is subjected to N-tert-butylation with tert-butyl alcohol under the catalysis of hydrochloric acid; the material molar ratio of tert-butyl alcohol to the amine ester exchange product is 1-10:1.
[0047] (4) the N-tert-butylated product in step (3) is amidated with 3,5-dimethylbenzoyl chloride in solvent c and alkali solution to obtain methoxyfenozide; the solvent c is an aprotic solvent, including one or more of toluene, tetrahydrofuran or dichloromethane, etc.; the molar ratio of the N-tert-butylated product to 3,5-dimethylbenzoyl chloride is 1:1.0-1.1; the alkali solution is an inorganic base, including one or more of sodium hydroxide, potassium hydroxide, sodium carbonate or sodium bicarbonate, etc.; the reaction temperature is 0-30°C.
[0048] The synthetic route of methoxyfenozide disclosed in this application is as follows:
[0049] Wherein R is methyl, ethyl or isopropyl.
[0050] Example
[0051] The specific experimental process of the synthetic methoxyfenozide route is divided into the following steps:
[0052] (1) Take a clean 500 ml three-necked flask, add 300 ml of anhydrous methanol, 20 g of 50% sulfuric acid, and 80 g of 3-methoxy-2-methylbenzoic acid, and reflux for 5 h. After HPLC detection shows that the reaction raw material is less than 1%, the excess methanol is evaporated under normal pressure, and the resulting oil is washed with 100 ml of water. The oil (esterification product) is separated and used for separation. The yield is 97% and the content is greater than 98%.
[0053] (2) In a clean 500 ml three-necked flask, add the above oil (esterification product) and 300 g of 50% hydrazine hydrate, raise the temperature to reflux, and keep the reaction for 5 h. During the control, most of the hydrazine hydrate and water are evaporated under reduced pressure, and the temperature is cooled to room temperature and filtered to obtain a white solid (amine transesterification product). The product is dried to obtain a yield of 98% and an HPLC content of 99%;
[0054] (3) In a clean 500 ml three-necked flask, 72 g of the above-mentioned amine transesterification product, 150 g of water, and 10 g of concentrated hydrochloric acid were added at room temperature. The temperature was raised to 100° C., and 40 g of tert-butyl alcohol was added dropwise while maintaining the temperature at 98-100° C. The addition was completed within 2 h. The reaction was refluxed at 100° C. for 5 h until the raw material concentration was less than 1%. A small amount of liquid caustic soda was added to adjust the pH to 8-9. The mixture was filtered, rinsed with water, and dried to obtain 89 g of an off-white solid (N-tert-butylated product) with a yield of 95% and a content of 99%.
[0055] (4) In a clean 500 ml three-necked flask, 50 g of the N-tert-butylated product obtained in the previous step and 150 ml of toluene were added dropwise at room temperature. A toluene solution containing 39.2 g of 3,5-dimethylbenzoyl chloride and 30 g of 30% liquid caustic soda were added dropwise. The pH of the addition process was controlled between 6 and 7. After the addition was completed, the mixture was kept warm for 1 h, filtered, and dried to obtain 75 g of a white solid (methoxyfenozide) with a yield of 95% and a content of more than 98%.
[0056] The present application uses 3-methoxy-2-methylbenzoic acid as a raw material, and obtains the product methoxyfenozide through esterification, amine transesterification, N-tert-butylation, and amidation. Compared with traditional processes, the process has the advantages of a short route, low raw material prices, less wastewater, high yield, and high purity. The disclosed technical solution has simple and readily available raw materials, simple reaction operations, and is green and environmentally friendly. The route reduces safety hazards, is environmentally friendly, reduces production energy consumption and three waste costs, has good reaction atom economy, low raw material costs, high yield, high product quality, and low industrialization costs. It is a practical and feasible industrial production method.
[0057] The raw materials used in the existing technical route 1 are expensive and difficult to obtain, while the raw materials used in the technical solution of the present invention are cheap and readily available. The existing technical route 2 requires the use of Boc to protect the amino group, which has high raw material prices, a long route, and low atom utilization. The technical solution of the present invention has a simple route and the raw materials are readily available and cheap. The condensation reaction of tri-tert-butylhydrazine with acyl chloride in the existing technical route has poor selectivity and isomeric impurities cannot be avoided. The technical solution of the present invention replaces the original amide condensation reaction with an amine transesterification reaction, which has good selectivity, can prepare a high-purity intermediate, and improves the yield.
[0058] The above are merely preferred embodiments of the present invention and are not intended to limit the present invention. Those skilled in the art will readily appreciate that various modifications and variations of the present invention are possible. Any modifications, equivalent substitutions, or improvements made within the spirit and principles of the present invention shall be included within the scope of protection of the present invention.
Claims
1. A method for producing methoxyfenozide, characterized in that: The steps include: (1) Using 3-methoxy-2-methylbenzoic acid as a raw material, an esterification reaction is carried out with a certain volume of solvent a under the catalysis of sulfuric acid; (2) reacting the product after the esterification reaction in step (1) in solvent b and 1-10 equivalents (eq) of hydrazine hydrate for a period of time to perform amine transesterification; (3) N-tert-butylating the product after the amine transesterification in step (2) with tert-butyl alcohol under the catalysis of hydrochloric acid; (4) The N-tert-butylated product in step (3) is amidated with 3,5-dimethylbenzoyl chloride in solvent c and alkali solution to obtain methoxyfenozide.
2. The method for producing a synthetic methoxyfenozide according to claim 1, wherein: The concentration of sulfuric acid in step (1) is 5%-50%.
3. The method for producing a synthetic methoxyfenozide according to claim 1, wherein: In step (1), the solvent a is selected from one or more of methanol, ethanol or isopropanol, and the volume of the solvent a is 1-20 times the volume of the raw material 3-methoxy-2-methylbenzoic acid; and the reaction temperature is 30-100°C.
4. The method for producing a synthetic methoxyfenozide according to claim 1, wherein: The solvent b in step (2) is an alcohol solvent, and the alcohol solvent includes a substance containing an alcoholic hydroxyl group, and the substance containing an alcoholic hydroxyl group includes one or more of methanol, ethanol, tert-butanol, isopropanol or benzyl alcohol.
5. The method for producing a synthetic methoxyfenozide according to claim 1, wherein: The reaction time in step (2) is 3-20 hours, and the reaction temperature is 20-100°C.
6. The method for producing a synthetic methoxyfenozide according to claim 1, wherein: The material molar ratio of tert-butyl alcohol to the amine ester exchange product in step (3) is 1-10:
1.
7. The method for producing a synthetic methoxyfenozide according to claim 1, wherein: The reaction temperature in step (3) is 80-100°C.
8. The method for producing a synthetic methoxyfenozide according to claim 1, wherein: In the step (4), the solvent c is an aprotic solvent, including one or more of toluene, tetrahydrofuran or dichloromethane; the molar ratio of the N-tert-butylated product to the 3,5-dimethylbenzoyl chloride material is 1:1.0-1.1; and the alkali solution is an inorganic base, including one or more of sodium hydroxide, potassium hydroxide, sodium carbonate or sodium bicarbonate.
9. The method for producing a synthetic methoxyfenozide according to claim 1, wherein: The reaction temperature in step (4) is 0-30°C.
10. The method for producing a synthetic methoxyfenozide according to claim 1, wherein: The synthetic route of the methoxyfenozide is as follows: Wherein R is methyl, ethyl or isopropyl.