A method for one-pot synthesis of an oxime ether fungicide intermediate

Abstract

The application relates to a one-pot method for synthesizing an intermediate oxime ether of a bactericide, and belongs to the technical field of organic synthesis. The method flow comprises the following steps: Step 1: adding o-halotoluene, methyl glyoxylate, methoxyamine hydrochloride and a solvent into a reaction bottle, wherein X in the o-halotoluene is chlorine, adding a base and a catalyst, the catalyst is Cu-TMEDA, and the reaction is carried out after heat preservation; Step 2: after the reaction is completed, water is added for washing, and the organic phase is concentrated under reduced pressure to recover the solvent to obtain the oxime ether. In the application, compared with a traditional oxime ether synthesis method, the oxime ether is synthesized by using o-halotoluene, methyl glyoxylate and methoxyamine hydrochloride as raw materials in a one-pot catalytic synthesis mode, the reaction process is safe and reliable, the raw material cost is low, and the three-waste output is less. The oxime ether synthesis method is simple and efficient, the reaction condition is mild, a toxic sodium cyanide reagent or flammable and explosive tert-butyl nitrite is not needed, the reaction process is safer, and the method is suitable for industrialized scale production.

Description

Technical Field

[0001] The invention relates to the technical field of organic synthesis, in particular to a one-pot method for synthesizing a fungicide intermediate oxime ether. Background Art

[0002] Trifloxystrobin and kresoxim-methyl are highly effective and safe strobilurin fungicides with high efficacy, low toxicity, and a broad spectrum of activity. They are effective against powdery mildew, leaf spot, rust, downy mildew, and apple scab. The chemical structures of trifloxystrobin, kresoxim-methyl, and their key intermediates are as follows:

[0003]

[0004] Oxime ethers are key intermediates for the synthesis of trifloxystrobin and kresoxim-methyl. In existing synthesis methods, most involve condensing o-methylbenzene acetonitrile with nitrite under alkaline conditions, separating and purifying the reaction, and then reacting with a methylating agent. The cyano group is then hydrolyzed and esterified to obtain the target compound. This type of synthesis method requires the use of flammable and explosive nitrites, which poses a significant safety hazard. Furthermore, the reaction steps are complex, and the intermediates require post-processing, separation, and purification. These methods are not suitable for industrial scale-up production, or use o-methylbenzoyl cyanide as a raw material. However, these methods require the use of a highly toxic reagent, sodium cyanide, for preparation. Furthermore, the synthesis method has a long reaction route, high raw material costs, and a high level of waste.

[0005] The synthesis method reported in Chinese patent CN108863845 involves reacting o-methylphenylacetonitrile with tert-butyl nitrite at 60°C under alkaline conditions, followed by demethanol removal under reduced pressure, acidification with hydrochloric acid, extraction with ethyl acetate, drying, and desolventization. Dimethyl sulfate is then added dropwise under alkaline conditions below 10°C. After the reaction, the reaction is filtered, rotary evaporation is performed, and dissolution with ethyl acetate is performed. Finally, the cyano group is hydrolyzed to form an amide, which is then esterified with hydrochloric acid gas to obtain the target product. This synthesis method uses tert-butyl nitrite, which is flammable and explosive, and the operation steps are cumbersome.

[0006] Zhu Xiaomeng [Master's thesis, Shandong Normal University, 2013] condensed o-methylbenzene acetonitrile and ethyl nitrite under alkaline conditions. After post-treatment, the solvent DMF was replaced and reacted with dimethyl sulfate under alkaline conditions. The target product was then obtained by cyanide hydroesterification in a sulfuric acid-methanol system. This synthesis method also uses flammable and explosive nitrite compounds, and the operation steps are cumbersome.

[0007] Therefore, seeking a simple and smooth process, low cost, and suitable for industrial scale-up production of trifloxystrobin and kresoxim-methyl intermediate oxime ether synthesis process is the focus of research in this field. Summary of the Invention

[0008] The application provides a one-pot method for synthesizing an intermediate oxime ether of a bactericide, solves the problems in the background art, and has the advantages that the raw materials of the synthesis method are cheap and easy to obtain, the method is safe and reliable, the process is simple, the reaction conditions are mild, and the method is suitable for industrial scale-up production.

[0009] The application solves the above technical problems in the following manner: a one-pot method for synthesizing an intermediate oxime ether of a bactericide, which comprises the following steps:

[0010] Step 1: adding o-halotoluene, methyl glyoxylate, methoxyamine hydrochloride and a solvent into a reaction bottle, the molar ratio of the methyl glyoxylate, the methoxyamine hydrochloride and the o-halotoluene being 1:1.0-1.3:1.0-1.3, the solvent being toluene, X in the o-halotoluene being chlorine, adding a base and a catalyst, the base being sodium carbonate or potassium carbonate, the catalyst being Cu-TMEDA, and then performing heat preservation reaction after the addition is completed, the heat preservation temperature being 50-60 DEG C, and the heat preservation time being 5-6 hours;

[0011] Step 2: after the reaction is completed, water is added for washing, and the organic phase is concentrated under reduced pressure to recover the solvent to obtain the oxime ether, and the synthesis process route is as follows:

[0012]

[0013] On the basis of the above technical solution, the application can also be improved in the following manner.

[0014] Further, the amount of the Cu-TMEDA catalyst is 1-5% of the weight of the methyl glyoxylate and the methoxyamine hydrochloride.

[0015] The application has the following advantages: the application provides a one-pot method for synthesizing an intermediate oxime ether of a bactericide, which has the following advantages:

[0016] 1. Compared with the traditional oxime ether synthesis method, the oxime ether synthesis method uses o-halotoluene, methyl glyoxylate and methoxyamine hydrochloride as raw materials, and the oxime ether is obtained through one-pot catalytic synthesis, the reaction process is safe and reliable, the raw material cost is low, and the three-waste output is less.

[0017] 2. The oxime ether synthesis method has a simple and efficient process, mild reaction conditions, does not need to use toxic sodium cyanide reagent or flammable and explosive tert-butyl nitrite, the reaction process is safer, and is suitable for industrial scale-up production.

[0018] The above description is only a summary of the technical solutions of the application, in order to more clearly understand the technical means of the application and to implement the content of the description, the following will be described in detail with reference to the preferred embodiments of the application. The specific embodiments of the application are described in detail in the following examples. DETAILED DESCRIPTION

[0019] The principles and features of the present invention are described below. The examples provided are intended to illustrate the present invention only and are not intended to limit the scope of the present invention. The following paragraphs describe the present invention in more detail by way of example. The advantages and features of the present invention will become more apparent from the following description and claims.

[0020] It should be noted that when a component is referred to as being "fixed to" another component, it may be directly on the other component or there may also be a central component. When a component is considered to be "connected to" another component, it may be directly connected to the other component or there may also be a central component. When a component is considered to be "set on" another component, it may be directly set on the other component or there may also be a central component. The terms "vertical", "horizontal", "left", "right" and similar expressions used herein are for illustrative purposes only.

[0021] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this invention pertains. The terms used in this specification of the present invention are for the purpose of describing specific embodiments only and are not intended to limit the present invention. The term "and / or" as used herein includes any and all combinations of one or more of the associated listed items.

[0022] Example 1:

[0023] Step 1: In a reaction flask, add 15.2g of o-chlorotoluene, 8.8g (0.1mol) of methyl glyoxylate, 9.2g of methoxyamine hydrochloride, and 50g of toluene solvent, then add 12.7g of sodium carbonate and 0.1g of catalyst Cu-TMEDA. After the addition, heat at 50-60°C and react for 5 hours.

[0024] Step 2: After the reaction is completed, water is added for washing, and the organic phase is concentrated under reduced pressure to recover the solvent to obtain 19.2 g of oxime ether intermediate with a yield of 92.7%.

[0025] GCMS: m / z 207.

[0026] Example 2:

[0027] Step 1: In a reaction flask, add 15.2g of o-chlorotoluene, 8.8g (0.1mol) of methyl glyoxylate, 9.2g of methoxyamine hydrochloride, and 50g of toluene solvent, then add 16.6g of potassium carbonate and 0.1g of catalyst Cu-TMEDA. After the addition, heat at 50-60°C and react for 5 hours.

[0028] Step 2: After the reaction is complete, the product is washed with water and the organic phase is concentrated under reduced pressure to recover the solvent, yielding 19.3 g of the oxime ether intermediate (93.2% yield). GCMS: m / z 207.

[0029] The above merely describes preferred embodiments of the present application, and is not intended to limit the present application in any form. Those skilled in the art can easily implement the present application according to the above description. However, those skilled in the art can make some changes, modifications and equivalent changes to the above disclosed technical contents without departing from the technical solution of the present application, and such changes, modifications and equivalent changes are equivalent embodiments of the present application. Meanwhile, any equivalent changes, modifications and evolution of the above embodiments according to the essential technology of the present application are still within the protection scope of the technical solution of the present application.

Claims

1. A one-pot method for synthesizing a fungicide intermediate oxime ether, the synthesis method comprising the following steps: Step 1: Add o-halotoluene, methyl glyoxylate, methoxyamine hydrochloride and solvent to a reaction flask, wherein the molar ratio of the methyl glyoxylate, methoxyamine hydrochloride and o-halotoluene is 1:1.0-1.3:1.0-1.3, the solvent is toluene, and X in the o-halotoluene is chlorine. Add a base and a catalyst, wherein the base is sodium carbonate or potassium carbonate, and the catalyst is Cu-TMEDA. After the addition is completed, the reaction is kept warm at 50-60°C for 5-6 hours; Step 2: After the reaction is completed, water is added for washing, and the organic phase is concentrated under reduced pressure to recover the solvent to obtain oxime ether. The synthesis process is as follows:

2. The method for synthesizing a fungicide intermediate oxime ether in one pot according to claim 1, characterized in that: The amount of the Cu-TMEDA catalyst used is 1-5% of the weight of methyl glyoxylate and methoxyamine hydrochloride.

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