A novel synthesis method of methyl (E)-2-(2-chloromethylphenyl)-2-methoxyiminoacetate

Abstract

The invention relates to a novel synthesis method of (E)-2-(2-chloromethylphenyl)-2-methoxyiminoacetic acid methyl ester. The method comprises the following steps: Step 1: 2-methyl-α-methoxyiminophenylacetonitrile is used as a raw material and dissolved in a methanol solvent; Step 2: the temperature is controlled at 40-50 DEG C, chlorine is slowly introduced, and the heat preservation reaction time is 5-6 hours; Step 3: methyl is chlorinated, and the hydrogen chloride generated at the same time causes the cyano group to be esterified, so that the key intermediate (E)-2-(2-chloromethylphenyl)-2-methoxyiminoacetic acid methyl ester of trifloxystrobin or kresoxim-methyl is obtained by a "one-pot method", and the temperature is lowered to 0-5 degrees after the heat preservation reaction is completed, and the product is filtered out. The invention uses 2-methyl-α-methoxyiminophenylacetonitrile as a raw material and adopts safe and reliable sodium nitrite as an oximation reagent, avoids the use of inflammable and explosive nitrites, avoids the use of expensive o-hydroxymethylphenylacetic acid lactone, has a safe and reliable reaction, low raw material cost, adopts a "one-pot method", has a simple and smooth process, a short route, and is suitable for industrialized scale-up production.

Description

Technical Field

[0001] The invention relates to the technical field of organic synthesis, and in particular to a new synthesis method of (E)-2-(2-chloromethylphenyl)-2-methoxyiminoacetic acid methyl ester. 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] (E)-2-(2-chloromethylphenyl)-2-methoxyiminoacetic 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, then cyano hydrolysis and re-esterification, and methyl is then brominated to obtain the target compound analog, or expensive o-hydroxymethylphenylacetic acid lactone is used as a raw material, reacted with tert-butyl nitrite under strong alkaline conditions, then methylated with dimethyl sulfate, and then chlorinated with thionyl chloride to obtain the target product. This type of synthesis method requires the use of nitrite that is flammable and explosive, there is a great safety hazard, and the reaction operation steps are complicated, and the intermediates need to be post-processed, separated, purified, and other operations. The synthesis method has a long reaction route, high raw material cost, and more three wastes, which is not suitable for industrial scale-up production.

[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 add dimethyl sulfate dropwise under alkaline conditions below 10°C, filter after reaction, perform rotary evaporation, dissolve in ethyl acetate and other post-processing operations, finally hydrolyze the cyano group to form amide, esterify with hydrochloric acid gas, and finally brominate with NBS or dibromohydantoin to obtain the analog bromide of the target product. This synthesis method uses tert-butyl nitrite, which is flammable and explosive, and the raw material price is high, the route is too long, and the operation steps are cumbersome.

[0006] The synthesis method reported in Chinese patent CN105294490 is to use o-hydroxymethylphenylacetic acid lactone as raw material, add nitrite under strong base sodium methoxide condition, then methylate with dimethyl sulfate under alkaline condition, and then chlorinate with thionyl chloride to obtain the target product. This synthesis method also uses flammable and explosive nitrite compounds, and the raw materials are expensive, the route is too long, and the operation steps are also cumbersome.

[0007] Therefore, seeking a simple and smooth process, low cost, and suitable for industrial scale-up production of trifloxystrobin and kresoxim-methyl intermediate (E)-2-(2-chloromethylphenyl)-2-methoxyiminoacetic acid methyl ester synthesis process is the focus of research in this field. Summary of the invention

[0008] The present invention provides a novel synthesis method of (E)-2-(2-chloromethylphenyl)-2-methoxyiminoacetic acid methyl ester, aiming to overcome the shortcomings of the synthesis method described in the above 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 a short synthesis route, a simple and smooth process, and is suitable for industrialized scale-up production.

[0009] The present invention solves the above-mentioned technical problem in the following way: a new synthesis method of (E)-2-(2-chloromethylphenyl)-2-methoxyiminoacetic acid methyl ester, and its preparation method comprises the following steps:

[0010] Step 1: Take 2-methyl-α-methoxyiminophenylacetonitrile as raw material and dissolve it in methanol solvent;

[0011] Step 2: Control the temperature at 40-50°C, slowly introduce chlorine gas, and keep the reaction for 5-6 hours;

[0012] Step 3: Chlorination of methyl group, the generated hydrogen chloride will also cause esterification of cyano group, thus obtaining the key intermediate (E)-2-(2-chloromethylphenyl)-2-methoxyiminoacetic acid methyl ester of trifloxystrobin or kresoxim-methyl in one pot. After the reaction is completed, the temperature is lowered to 0-5 degrees, and the product is filtered out. 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, in the Step 2, the molar ratio of 2-methyl-α-methoxyiminophenylacetonitrile to chlorine is 1:0.5 to 1:1.5.

[0016] The beneficial effects of the present invention are as follows: the present invention provides a new synthesis method of (E)-2-(2-chloromethylphenyl)-2-methoxyiminoacetic acid methyl ester, which has the following advantages:

[0017] 1. Using 2-methyl-α-methoxyiminophenylacetonitrile as raw material and safe and reliable sodium nitrite as oximation reagent, avoiding the use of flammable and explosive nitrites and expensive o-hydroxymethylphenylacetic acid lactone, the reaction is safe and reliable, and the raw material cost is low.

[0018] 2. The operation process of the present invention adopts a "one-pot method", which has a simple and smooth process and a short route, and is suitable for industrialized scale-up production.

[0019] 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

[0020] 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.

[0021] 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 component centered. 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 component centered. 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 component centered. The terms "vertical", "horizontal", "left", "right" and similar expressions used herein are for illustrative purposes only.

[0022] 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.

[0023] The present invention provides a novel synthesis method of (E)-2-(2-chloromethylphenyl)-2-methoxyiminoacetic acid methyl ester, and the method flow comprises the following steps:

[0024] Step 1: Take 2-methyl-α-methoxyiminophenylacetonitrile as raw material and dissolve it in methanol solvent;

[0025] Step 2: Control the temperature at 40-50°C, slowly introduce chlorine gas, keep the temperature for 5-6 hours, and the molar ratio of 2-methyl-α-methoxyiminophenylacetonitrile to chlorine gas is 1:0.5 to 1:1.5;

[0026] Step 3: Chlorination of methyl group and the generated hydrogen chloride will also cause esterification of cyano group, thus obtaining the key intermediate (E)-2-(2-chloromethylphenyl)-2-methoxyiminoacetic acid methyl ester of trifloxystrobin or kresoxim-methyl in one pot. After the reaction is completed, the temperature is lowered to 0-5 degrees and the product is filtered out.

[0027] Embodiment 1:

[0028] Step 1: In a three-necked flask, add 100.0 g of methanol solvent and 50.0 g of 2-methyl-α-methoxyiminophenylacetonitrile;

[0029] Step 2: Control the temperature at 40-50℃, slowly introduce 20.4g of chlorine gas, and keep warm for 5h after completion;

[0030] Step 3: After the reaction is completed, the temperature is lowered to 0-5°C and filtered to obtain 61.5 g of the product with a yield of 88.6%.

[0031] Embodiment 2:

[0032] Step 1: In a three-necked flask, add 100.0 g of methanol solvent and 50.0 g of 2-methyl-α-methoxyiminophenylacetonitrile;

[0033] Step 2: Control the temperature at 40-50℃, slowly introduce 20.4g of chlorine gas, and keep warm for 5h after completion;

[0034] Step 3: After the reaction is finished, the temperature is lowered to 0-5°C, and the product 61.9g is obtained by filtration, with a yield of 89.2%. The above are only preferred embodiments of the present invention, and are not intended to limit the present invention in any form; any ordinary technician in the industry can smoothly implement the present invention as described above; however, any technician familiar with the profession, without departing from the scope of the technical solution of the present invention, makes some changes, modifications and equivalent changes made by using the technical content disclosed above, which are equivalent embodiments of the present invention; at the same time, any changes, modifications and evolutions of any equivalent changes 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 (E)-2-(2-chloromethylphenyl)-2-methoxyiminoacetic acid methyl ester, wherein the preparation method comprises the following steps: Step 1: Take 2-methyl-α-methoxyiminophenylacetonitrile as raw material and dissolve it in methanol solvent; Step 2: Control the temperature at 40-50°C, slowly introduce chlorine gas, and keep the reaction for 5-6 hours; Step 3: Chlorination of methyl group, and the generated hydrogen chloride will also cause esterification of cyano group, so as to obtain the key intermediate (E)-2-(2-chloromethylphenyl)-2-methoxyiminoacetic acid methyl ester of trifloxystrobin or kresoxim-methyl in one pot. After the reaction is completed, the temperature is lowered to 0-5 degrees, and the product is filtered out. In the step 2, the molar ratio of 2-methyl-α-methoxyiminophenylacetonitrile and chlorine is 1:0.5 to 1:1.

5. The synthetic process route is as follows: 。

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