A kind of synthesis method of 2-methyl-α-methoxyiminophenylacetic acid methyl ester

Abstract

The present invention relates to a synthetic method of 2-methyl-α-methoxyiminophenylacetic acid methyl ester, and the method flow comprises the following: Step 1: using o-methylphenylacetic acid or o-methylphenylacetamide or o-methylphenylacetic acid methyl ester as raw material, first directly oximating and esterifying with sodium nitrite in sulfuric acid in a solvent; Step 2: "one-pot method" hydrogenation of sodium hydroxide or potassium hydroxide to control pH value, and reacting with dimethyl sulfate to obtain 2-methyl-α-methoxyiminophenylacetic acid methyl ester. The present invention uses o-methylphenylacetic acid or o-methylphenylacetamide or o-methylphenylacetic acid methyl ester as raw material, and adopts safe and reliable sodium nitrite as oximation reagent, avoids using nitrite esters that are flammable and explosive, avoids using expensive methoxyamine hydrochloride, has safe and reliable reaction, low raw material cost, and adopts "one-pot method" in the operation process, has simple and smooth process, mild reaction conditions, and is suitable for industrialized amplification production.

Description

Technical Field

[0001] The invention relates to the technical field of organic synthesis, and in particular to a method for synthesizing methyl 2-methyl-α-methoxyiminophenylacetate. Background Art

[0002] Trifloxystrobin and kresoxim-methyl are highly effective and safe methoxyacrylate fungicides with the characteristics of high efficiency, low toxicity and broad fungicide spectrum. They are effective against powdery mildew, leaf spot, rust, downy mildew, apple scab, etc. The chemical structural formulas of trifloxystrobin, kresoxim-methyl and their key intermediates are as follows:

[0003]

[0004] 2-Methyl-α-methoxyiminophenylacetic acid methyl ester is a key intermediate for the synthesis of trifloxystrobin and kresoxim-methyl. In the existing synthesis methods, most of them are condensation reaction of o-methylbenzene acetonitrile and nitrite under alkaline conditions, separation and purification, and then reaction with a methylating agent, and then cyanohydrolysis and esterification to obtain the target compound. This type of synthesis method requires the use of nitrite, which is flammable and explosive, and there is a great safety hazard, and the reaction operation steps are complicated, and the intermediate needs post-processing separation and purification. It is not suitable for industrial amplification, or it is obtained by using o-methylbenzoyl cyanide as a raw material, first hydrolyzing and esterifying the cyano group in excess sulfuric acid, and then condensing with expensive methoxyamine hydrochloride. The synthesis method reaction route is long, the raw material cost is high, and there are more three wastes.

[0005] The synthesis method reported in Chinese patent CN108863845 is to react o-methylbenzene acetonitrile and tert-butyl nitrite at 60°C under alkaline conditions, demethylate under reduced pressure, acidify with hydrochloric acid, extract with ethyl acetate, dry, desolventize and other post-processing, then dropwise add dimethyl sulfate under alkaline conditions below 10°C, filter after reaction, rotary evaporation, dissolve in ethyl acetate and other post-processing operations, and finally hydrolyze the cyano group into amide, and esterify 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 complicated.

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

[0007] The synthesis method reported in Chinese patent CN110396054 is to use o-methylbenzene acetonitrile as a raw material, add nitrite under organic solvent and alkaline conditions, filter to obtain oxime salt after the reaction is completed, and dry; or add hydrochloric acid to the system and then filter to obtain an intermediate, and then react with dimethyl sulfate under alkaline conditions to obtain the target product. This synthesis method also uses flammable and explosive nitrite compounds, and the operation steps are also cumbersome.

[0008] Therefore, seeking a simple and smooth process, low cost, and suitable for industrial scale-up production of trifloxystrobin and kresoxim-methyl intermediate 2-methyl-α-methoxyiminophenylacetic acid methyl ester synthesis process is the focus of research in this field. Summary of the invention

[0009] The present invention provides a method for synthesizing methyl 2-methyl-α-methoxyiminophenylacetate, which solves the problems raised by the above-mentioned background technology. The method has cheap and readily available process raw materials, avoids the use of flammable and explosive nitrite, is safe and reliable, has mild reaction conditions, is simple and smooth in process, and is suitable for industrialized scale-up production.

[0010] The present invention solves the above-mentioned technical problem in the following way: a method for synthesizing methyl 2-methyl-α-methoxyiminophenylacetate, the method flow of which comprises the following steps:

[0011] Step 1: Using o-methylphenylacetic acid, o-methylphenylacetamide or o-methylphenylacetic acid methyl ester as raw material, directly oximation and esterification with sodium nitrite in sulfuric acid in a solvent;

[0012] Step 2: "One-pot method" adding sodium hydroxide or potassium hydroxide to control the pH value, and reacting with dimethyl sulfate to obtain 2-methyl-α-methoxyiminophenylacetic acid methyl ester. The synthetic process route is as follows:

[0013]

[0014] Based on the above technical solution, the present invention can also be improved as follows.

[0015] Furthermore, the molar ratio of o-toluacetic acid or o-toluacetamide or methyl o-toluacetate to sodium nitrite in Step 1 is 1:1.0-1.5, the molar ratio of sodium nitrite to acid in Step 1 is 1:1.0-1.5, and the reaction temperature is 50-60°C.

[0016] Furthermore, the solvent in Step 1 is a mixed solvent of one or more solvents such as methanol, ethanol, n-propanol, isopropanol, butanol, toluene, xylene, dichloromethane, dichloroethane, dimethylformamide, N-methylpyrrolidone, water, etc.

[0017] Furthermore, the molar ratio of o-toluacetic acid or o-toluacetamide or methyl o-toluacetate to dimethyl sulfate in Step 2 is 1:1.0-1.5.

[0018] Furthermore, the alkali added in Step 2 controls the pH value to be between 7 and 8.

[0019] The beneficial effect of the present invention is that the present invention provides a method for synthesizing methyl 2-methyl-α-methoxyiminophenylacetate, which has the following advantages:

[0020] 1. Using o-methylphenylacetic acid or o-methylphenylacetamide or o-methylphenylacetic acid methyl ester as raw materials, and using safe and reliable sodium nitrite as oximation reagent, avoiding the use of flammable and explosive nitrites and expensive methoxyamine hydrochloride, the reaction is safe and reliable, and the raw material cost is low.

[0021] 2. The operation process adopts the "one-pot method", the process is simple and smooth, the reaction conditions are mild, and it is suitable for industrial scale-up production.

[0022] The above description is only an overview of the technical solution of the present invention. In order to more clearly understand the technical means of the present invention and implement it according to the contents of the specification, the preferred embodiments of the present invention are described in detail below. The specific implementation of the present invention is given in detail by the following embodiments. DETAILED DESCRIPTION

[0023] The principles and features of the present invention are described below, and the examples are only used to explain the present invention and are not used to limit the scope of the present invention. The present invention is described more specifically by way of example in the following paragraphs. According to the following description and claims, the advantages and features of the present invention will become clearer.

[0024] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art of the present invention. The terms used herein in the specification of the present invention are only for the purpose of describing specific embodiments and are not intended to limit the present invention. The term "and / or" used herein includes any and all combinations of one or more related listed items.

[0025] Example 1

[0026] A method for synthesizing methyl 2-methyl-α-methoxyiminophenylacetate comprises the following steps:

[0027] In a three-necked flask, add 100.0g of methanol solvent, 10.0g of water, 50.0g of o-methylphenylacetic acid, and 27.6g of sodium nitrite. Stir and heat to 50-60°C and keep warm for 1h. Control the temperature at 30-50°C, add 16.3g of sulfuric acid (98%) dropwise, and keep warm for 1h. Then add 50.4g of dimethyl sulfate dropwise, and at the same time add 10% sodium hydroxide solution to control the pH value between 7-8. After adding, keep warm for 2h, cool to room temperature, and filter to obtain 62.5g of product with a yield of 90.6%.

[0028] Example 2

[0029] A method for synthesizing methyl 2-methyl-α-methoxyiminophenylacetate comprises the following steps:

[0030] In a three-necked flask, add 100.0g of methanol solvent, 10.0g of water, 50.0g of o-methylphenylacetamide, and 27.8g of sodium nitrite. Stir and heat to 50-60°C and keep warm for 1h. Control the temperature at 30-50°C, add 16.4g of sulfuric acid (98%) dropwise, and keep warm for 1h. Then add 50.7g of dimethyl sulfate dropwise, and at the same time add 10% sodium hydroxide solution to control the pH value between 7-8. After adding, keep warm for 2h, cool to room temperature, and filter to obtain 64.1g of product with a yield of 92.3%.

[0031] Example 3

[0032] A method for synthesizing methyl 2-methyl-α-methoxyiminophenylacetate comprises the following steps:

[0033] In a three-necked flask, add 100.0g of methanol solvent, 10.0g of water, 50.0g of methyl o-toluacetate, and 25.2g of sodium nitrite. Stir and heat to 50-60°C and keep warm for 1h. Control the temperature at 30-50°C, add 14.9g of sulfuric acid (98%) dropwise, and keep warm for 1h. Then add 46.1g of dimethyl sulfate dropwise, and at the same time add 10% sodium hydroxide solution to control the pH value between 7-8. After adding, keep warm for 2h, cool to room temperature, and filter to obtain 59.2g of product with a yield of 93.8%.

[0034] The above description is only a preferred embodiment of the present invention and does not limit the present invention in any form. Any ordinary technician in the industry can smoothly implement the present invention as described above. However, any equivalent changes, modifications and evolutions made by technicians familiar with the profession without departing from the scope of the technical solution of the present invention using the technical content disclosed above are all equivalent embodiments of the present invention. At the same time, any equivalent changes, modifications and evolutions made to the above embodiments based on the essential technology of the present invention are still within the protection scope of the technical solution of the present invention.

Claims

1. A method for synthesizing methyl 2-methyl-α-methoxyiminophenylacetate, characterized in that: The method flow includes the following: Step 1: Using o-methylphenylacetic acid, o-methylphenylacetamide or o-methylphenylacetic acid methyl ester as raw materials, directly oximation and esterification with sodium nitrite in sulfuric acid in a solvent; Step 2: "One-pot method" adding sodium hydroxide or potassium hydroxide to control the pH value, and reacting with dimethyl sulfate to obtain 2-methyl-α-methoxyiminophenylacetic acid methyl ester. The synthetic process route is as follows:

2. The method for synthesizing methyl 2-methyl-α-methoxyiminophenylacetate according to claim 1, characterized in that: The molar ratio of o-toluacetic acid or o-toluacetamide or methyl o-toluacetate to sodium nitrite in Step 1 is 1:1.0-1.5, the molar ratio of sodium nitrite to acid in Step 1 is 1:1.0-1.5, and the reaction temperature is 50-60°C.

3. The method for synthesizing methyl 2-methyl-α-methoxyiminophenylacetate according to claim 1, characterized in that: The solvent in Step 1 is a mixed solvent of one or more solvents such as methanol, ethanol, n-propanol, isopropanol, butanol, toluene, xylene, dichloromethane, dichloroethane, dimethylformamide, N-methylpyrrolidone, water, etc.

4. The method for synthesizing methyl 2-methyl-α-methoxyiminophenylacetate according to claim 1, characterized in that: The molar ratio of o-toluacetic acid or o-toluacetamide or methyl o-toluacetate to dimethyl sulfate in Step 2 is 1:1.0-1.

5.

5. The method for synthesizing methyl 2-methyl-α-methoxyiminophenylacetate according to claim 1, characterized in that: The alkali added in Step 2 controls the pH value to be between 7 and 8.

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