A method for synthesizing kresoxim-methyl

Abstract

This invention belongs to the field of fine chemical technology, specifically relating to the synthesis technology of pesticide chemicals, and particularly to a method for synthesizing azoxystrobin. The invention uses 2-(2-methylphenoxymethyl)benzoyl cyanide as the starting material, which reacts with methoxyamine hydrochloride. After the reaction is complete, hydrochloric acid gas is introduced into the system. This method has a short reaction cycle, high conversion rate, and excellent product quality. The synthesized azoxystrobin has a purity of over 99%, meeting market technical requirements for azoxystrobin.

Description

Technical Field

[0001] This invention belongs to the field of fine chemical technology, and relates to the synthesis technology of pesticide chemicals, and in particular to a method for synthesizing azoxystrobin. Background Technology

[0002] Azoxystrobin is one of the earliest discovered methoxyacrylate fungicides. In addition to its fungicidal effect, azoxystrobin can also promote the growth of many cereal crops, delay plant senescence, and enhance the absorption and utilization of nitrogen and carbon dioxide by plants. It has great application prospects in the market.

[0003] Currently, the main methods for preparing azoxystrobin are as follows:

[0004] Synthesis Route 1:

[0005]

[0006] Using phthalide as a raw material, phthalide reacts with o-cresol to produce 2-(2-methylphenoxymethyl)benzoic acid, which is then chlorinated to obtain acyl chloride, which is then cyanided with sodium cyanide to obtain 2-(2-methylphenoxymethyl)benzoyl cyanide. 2-(2-methylphenoxymethyl)benzoyl cyanide is added to methanol and passed through hydrochloric acid gas to obtain methyl 2-(2-methylphenoxymethyl)benzoylformate, which is then oximated with methoxyamine hydrochloride and subjected to configurational conversion through hydrochloric acid gas to produce azoxystrobin.

[0007] The above preparation methods have low overall reaction yields, with a total yield of only 55%. The reaction steps and cycle are long, and the synthesis method uses a large amount of hydrochloric acid gas, which cannot be recovered after use, causing great pollution to the environment.

[0008] Synthesis Route 2:

[0009]

[0010] Using o-methylbenzoic acid as a raw material, an acyl chloride is prepared via a chlorination reaction with thionyl chloride. This chloride is then reacted with sodium cyanide to prepare o-methylbenzoyl cyanide. Hydrochloric acid gas is then introduced to obtain methyl o-methylbenzoylformate, which is subsequently oxime-treated with methoxyamine hydrochloride. Configurational transposition is then performed with hydrochloric acid gas to obtain methyl (E)-2-methoxyimino-[(2-o-methylphenyl)]acetate, which is then reacted with bromine and finally with o-cresol to obtain azoxystrobin. This process route has an overall yield of only 35% and is costly, and it still uses a large amount of hydrochloric acid gas.

[0011] Therefore, choosing a synthesis process that is economical, inexpensive, simple to operate, safe, environmentally friendly, and has a short cycle will have great economic value. Summary of the Invention

[0012] To address the aforementioned problems, this invention provides a method for synthesizing azoxystrobin, which features high yield, short reaction cycle, environmental friendliness, energy saving, and low cost. This invention uses 2-(2-methylphenoxymethyl)benzoyl cyanide and methoxyamine hydrochloride as raw materials, first undergoing oxime dehydration to obtain 2-methoxyimino-2-[2-(2-methylphenoxymethyl)phenyl]acetonitrile, and then performing a Pinner reaction to obtain azoxystrobin.

[0013] The specific synthesis route is as follows:

[0014]

[0015] The steps are as follows:

[0016] (1) Preparation of 2-methoxyimino-2-[2-(2-methylphenoxymethyl)phenyl]acetonitrile

[0017] 2-(2-methylphenoxymethyl)benzoyl cyanide and methoxyamine hydrochloride were added to methanol, a catalyst was added, the temperature was raised to 55℃-65℃, and the temperature was maintained until 0.5% of 2-(2-methylphenoxymethyl)benzoyl cyanide remained, to obtain a methanol solution of 2-methoxyimino-2-[2-(2-methylphenoxymethyl)phenyl]acetonitrile;

[0018] (2) Preparation of azoxystrobin via Pinner reaction

[0019] After cooling a methanol solution of 2-methoxyimino-2-[2-(2-methylphenoxymethyl)phenyl]acetonitrile to 5-10℃, hydrochloric acid gas is introduced into the system. After the hydrochloric acid gas is completely introduced, the temperature is slowly raised to 15-30℃ and maintained at this temperature until 10%-15% of 2-methoxyimino-2-[2-(2-methylphenoxymethyl)phenyl]acetonitrile remains. Then, the temperature is slowly raised to reflux and refluxed until 0.5% of 2-methoxyimino-2-[2-(2-methylphenoxymethyl)phenyl]acetonitrile remains. The reaction is then complete. The solution is cooled and filtered to obtain crude azoxystrobin. The crude azoxystrobin is then added to aqueous methanol, and after slurrying, the solution is cooled to 0-20℃ and filtered to obtain refined azoxystrobin.

[0020] Furthermore, based on the molar ratio of pure substances, the ratio of 2-(2-methylphenoxymethyl)benzoyl cyanide: methoxyamine hydrochloride: catalyst: hydrochloric acid gas in steps (1) and (2) is 1:(1.02-1.1):(0.005-1.05):1.1; preferably, the ratio of 2-(2-methylphenoxymethyl)benzoyl cyanide: methoxyamine hydrochloride: catalyst: hydrochloric acid gas is 1:1.05:0.01:1.1.

[0021] Further, the catalyst in step (1) is at least one of an organic base or a phase transfer catalyst; preferably, the organic base is selected from any one of triethylamine, triethylenediamine, 1,8-diazabicycloundec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]-5-nonene (DBN), 4-dimethylaminopyridine, N-methylmorpholine, tetramethylethylenediamine or tributylamine;

[0022] The phase transfer catalyst is selected from any one of 18-crown 6, 15-crown 5, cyclodextrin, benzyltriethylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium hydrogen sulfate, trioctylmethylammonium chloride, dodecyltrimethylammonium chloride, or tetradecyltrimethylammonium chloride; preferably tetrabutylammonium chloride.

[0023] Furthermore, in step (2), the water content of the aqueous methanol ranges from 10% to 50%; preferably 20%.

[0024] Further, in step (2), after cooling the methanol solution of 2-methoxyimino-2-[2-(2-methylphenoxymethyl)phenyl]acetonitrile to 5-10°C, hydrochloric acid gas is introduced into the system. After the hydrochloric acid gas is introduced, the temperature is slowly raised to 28°C and the reaction is maintained until 10%-15% of 2-methoxyimino-2-[2-(2-methylphenoxymethyl)phenyl]acetonitrile remains. Then, the temperature is slowly raised to reflux and refluxed until 0.5% of 2-methoxyimino-2-[2-(2-methylphenoxymethyl)phenyl]acetonitrile remains. After the reaction is completed, the temperature is lowered and the product is filtered to obtain crude azoxystrobin. Then, the crude azoxystrobin is added to aqueous methanol, and after slurrying, the temperature is lowered to 15°C and the product is filtered to obtain refined azoxystrobin.

[0025] Compared with the prior art, the present invention has the following advantages:

[0026] This invention provides a method for synthesizing azoxystrobin. This method involves the simultaneous oximation, configuration inversion, and Pinner reaction of 2-(2-methylphenoxymethyl)benzoyl cyanide and methoxyamine hydrochloride, directly synthesizing and simply purifying azoxystrobin with high content. Compared to the traditional process of esterification followed by oximation and configuration inversion of 2-(2-methylphenoxymethyl)benzoyl cyanide, the yield is increased by more than 15%, the cycle time is reduced by more than 60 hours per batch, and the amount of hydrochloric acid gas used is reduced by more than 60%, as is the amount of by-product hydrochloric acid treated. This invention is a low-cost, simple, safe, environmentally friendly, and short-cycle synthesis method. Detailed Implementation

[0027] The present invention will be further described below with reference to specific embodiments, and the advantages and features of the present invention will become clearer with the description. However, the embodiments are merely exemplary and do not constitute any limitation on the scope of the present invention. Those skilled in the art should understand that modifications or substitutions can be made to the details and form of the technical solutions of the present invention without departing from the spirit and scope of the present invention, but all such modifications and substitutions fall within the protection scope of the present invention.

[0028] Example 1

[0029] A method for synthesizing azoxystrobin, the specific steps of which are as follows:

[0030] (1) Preparation of 2-methoxyimino-2-[2-(2-methylphenoxymethyl)phenyl]acetonitrile

[0031] 1 mol of 2-(2-methylphenoxymethyl)benzoyl cyanide and 1.1 mol of methoxyamine hydrochloride were added to 5 times the volume of methanol, and 0.01 mol of benzyltriethylammonium chloride was added. The mixture was heated to 60 °C and kept at that temperature until 0.5% of 2-(2-methylphenoxymethyl)benzoyl cyanide remained, to obtain a methanol solution of 2-methoxyimino-2-[2-(2-methylphenoxymethyl)phenyl]acetonitrile.

[0032] (2) Preparation of azoxystrobin via Pinner reaction

[0033] The methanol solution of 2-methoxyimino-2-[2-(2-methylphenoxymethyl)phenyl]acetonitrile obtained above was cooled to 5°C, and hydrochloric acid gas was introduced into the system at a rate of 1.1 mol. After the hydrochloric acid gas was introduced, the temperature was slowly raised to 15°C and maintained at this temperature until 11% of 2-methoxyimino-2-[2-(2-methylphenoxymethyl)phenyl]acetonitrile remained. Then, the temperature was slowly raised to reflux until 0.5% of 2-methoxyimino-2-[2-(2-methylphenoxymethyl)phenyl]acetonitrile remained, at which point the reaction was considered complete. The solution was then cooled and filtered to obtain crude azoxystrobin. The crude azoxystrobin was then added to methanol containing 15% water, and after slurrying, the solution was cooled to 9°C and filtered to obtain refined azoxystrobin. The total yield was 90%, and the purity was 99.3%.

[0034] Example 2

[0035] A method for synthesizing azoxystrobin, the specific steps of which are as follows:

[0036] (1) Preparation of 2-methoxyimino-2-[2-(2-methylphenoxymethyl)phenyl]acetonitrile: 2 mol of 2-(2-methylphenoxymethyl)benzoyl cyanide and 2.1 mol of methoxyamine hydrochloride were added to 6 times the volume of methanol, and 0.02 mol of tetrabutylammonium bromide was added. The temperature was raised to 58 °C and kept at that temperature until 0.5% of 2-(2-methylphenoxymethyl)benzoyl cyanide remained, to obtain a methanol solution of 2-methoxyimino-2-[2-(2-methylphenoxymethyl)phenyl]acetonitrile;

[0037] (2) Preparation of azoxystrobin via Pinner reaction

[0038] The methanol solution of 2-methoxyimino-2-[2-(2-methylphenoxymethyl)phenyl]acetonitrile obtained above was cooled to 8°C, and hydrochloric acid gas was introduced into the system at a rate of 2.3 mol. After the hydrochloric acid gas was introduced, the temperature was slowly raised to 20°C and maintained at this temperature until 13% of 2-methoxyimino-2-[2-(2-methylphenoxymethyl)phenyl]acetonitrile remained. Then, the temperature was slowly raised to reflux until 0.5% of 2-methoxyimino-2-[2-(2-methylphenoxymethyl)phenyl]acetonitrile remained, at which point the reaction was considered complete. The solution was then cooled and filtered to obtain crude azoxystrobin. The crude azoxystrobin was then added to methanol containing 20% ​​water, and after slurrying, the solution was cooled to 15°C and filtered to obtain refined azoxystrobin. The total yield was 92.5%, and the purity was 99.1%.

[0039] Example 3

[0040] A method for synthesizing azoxystrobin, the specific steps of which are as follows:

[0041] (1) Preparation of 2-methoxyimino-2-[2-(2-methylphenoxymethyl)phenyl]acetonitrile: 2.5 mol of 2-(2-methylphenoxymethyl)benzoyl cyanide and 2.7 mol of methoxyamine hydrochloride were added to 3 times the volume of methanol, and 2.7 mol of 4-dimethylaminopyridine was added. The temperature was raised to 55 °C and kept at that temperature until 0.5% of 2-(2-methylphenoxymethyl)benzoyl cyanide remained, thus obtaining a methanol solution of 2-methoxyimino-2-[2-(2-methylphenoxymethyl)phenyl]acetonitrile.

[0042] (2) Preparation of azoxystrobin via Pinner reaction

[0043] The methanol solution of 2-methoxyimino-2-[2-(2-methylphenoxymethyl)phenyl]acetonitrile obtained above was cooled to 10°C, and hydrochloric acid gas was introduced into the system at a rate of 3.1 mol. After the hydrochloric acid gas was introduced, the temperature was slowly raised to 18°C ​​and maintained at this temperature until 10% of the 2-methoxyimino-2-[2-(2-methylphenoxymethyl)phenyl]acetonitrile remained. Then, the temperature was slowly raised to reflux until 0.5% of the 2-methoxyimino-2-[2-(2-methylphenoxymethyl)phenyl]acetonitrile remained, at which point the reaction was considered complete. The solution was then cooled and filtered to obtain crude azoxystrobin. The crude azoxystrobin was then added to methanol containing 17% water, and after slurrying, the solution was cooled to 17°C and filtered to obtain refined azoxystrobin. The total yield was 92%, and the purity was 98.9%.

[0044] Example 4

[0045] A method for synthesizing azoxystrobin, the specific steps of which are as follows:

[0046] (1) Preparation of 2-methoxyimino-2-[2-(2-methylphenoxymethyl)phenyl]acetonitrile: 1.3 mol of 2-(2-methylphenoxymethyl)benzoyl cyanide and 1.5 mol of methoxyamine hydrochloride were added to 4 times the volume of methanol, and 1.4 mol of N-methylmorpholine was added. The temperature was raised to 55 °C and kept at that temperature until 0.5% of 2-(2-methylphenoxymethyl)benzoyl cyanide remained, thus obtaining a methanol solution of 2-methoxyimino-2-[2-(2-methylphenoxymethyl)phenyl]acetonitrile.

[0047] (2) Preparation of azoxystrobin via Pinner reaction

[0048] The methanol solution of 2-methoxyimino-2-[2-(2-methylphenoxymethyl)phenyl]acetonitrile obtained above was cooled to 5°C, and hydrochloric acid gas was introduced into the system at a rate of 2.5 mol. After the hydrochloric acid gas was introduced, the temperature was slowly raised to 28°C and maintained at this temperature until 12% of 2-methoxyimino-2-[2-(2-methylphenoxymethyl)phenyl]acetonitrile remained. Then, the temperature was slowly raised to reflux until 0.5% of 2-methoxyimino-2-[2-(2-methylphenoxymethyl)phenyl]acetonitrile remained, at which point the reaction was considered complete. The solution was then cooled and filtered to obtain crude azoxystrobin. The crude azoxystrobin was then added to methanol containing 20% ​​water, and after slurrying, the solution was cooled to 15°C and filtered to obtain refined azoxystrobin. The total yield was 94%, and the purity was 99.3%.

[0049] Control experiment on the synthesis process of ether ester

[0050] 54 g (0.2 mol) of 94% pure 2-(2-methylphenoxymethyl)benzoyl nitrile and 200 g of toluene were added to a flask. After cooling to -5°C, 90 g (2.4 mol) of dry hydrogen chloride gas was introduced for about 2 hours. The temperature was slowly raised to 20-25°C and the reaction was carried out for 10 hours. 50 g of methanol was added and the reaction was refluxed for another 6 hours. Then 100 g of water was added to the system, and the temperature was raised to 60°C and held for 4 hours. The lower water layer was removed at 60°C, and 100 g of secondary water was added for a second water wash. The organic phase was then subjected to negative pressure distillation to recover toluene, yielding methyl 2-(2-methylphenoxymethyl)benzoylformate.

[0051] The methyl 2-(2-methylphenoxymethyl)benzoylformate obtained in the previous step, 150g of methanol, and 20g of methoxyamine hydrochloride were refluxed for 6 hours, then cooled to 20°C. 50g of dry hydrogen chloride gas was uniformly introduced into the reactor over 2 hours. After the hydrogen chloride was completely introduced, the reaction was continued at 20-25°C for 16 hours. After the reaction was complete, the mixture was filtered, and the filter cake was washed with fresh methanol to obtain azoxystrobin. The azoxystrobin content was 95%, and the overall yield of the two-step reaction was 75%.

Claims

1. A method for synthesizing azoxystrobin, characterized in that: Using 2-(2-methylphenoxymethyl)benzoyl cyanide and methoxyamine hydrochloride as raw materials, 2-methoxyimino-2-[2-(2-methylphenoxymethyl)phenyl]acetonitrile was first obtained by oxime reaction, and then ether ester was obtained by passing hydrochloric acid gas through the Pinner reaction. The specific steps are as follows: (1) Preparation of 2-methoxyimino-2-[2-(2-methylphenoxymethyl)phenyl]acetonitrile: 2-(2-methylphenoxymethyl)benzoyl cyanide and methoxyamine hydrochloride were added to methanol, a catalyst was added, the temperature was raised to 55℃-65℃, and the temperature was maintained until the reaction was complete to obtain a methanol solution of 2-methoxyimino-2-[2-(2-methylphenoxymethyl)phenyl]acetonitrile; (2) Preparation of azoxystrobin via Pinner reaction: After cooling the methanol solution of 2-methoxyimino-2-[2-(2-methylphenoxymethyl)phenyl]acetonitrile to 5-10℃, hydrochloric acid gas is introduced into the system. After the hydrochloric acid gas is introduced, a certain temperature range is controlled until the reaction is completed. After the reaction is completed, the temperature is lowered and the crude azoxystrobin is obtained by vacuum filtration. Then, the crude azoxystrobin is added to aqueous methanol, and after slurrying, the temperature is lowered to 0-20℃ and the purified azoxystrobin is obtained by vacuum filtration. The catalyst in step (1) is a phase transfer catalyst; The phase transfer catalyst is benzyltriethylammonium chloride or tetrabutylammonium bromide, and the molar ratio of the catalyst to 2-(2-methylphenoxymethyl)benzoyl cyanide is 1:0.

01.

2. The method for synthesizing azoxystrobin according to claim 1, characterized in that: Based on the molar ratio of pure substances, the ratio of 2-(2-methylphenoxymethyl)benzoyl cyanide: methoxyamine hydrochloride: catalyst: hydrochloric acid gas in steps (1) and (2) is 1:(1.02-1.1):(0.005-1.05):1.

1.

3. The method for synthesizing azoxystrobin according to claim 2, characterized in that: Based on the molar ratio of pure substances, the ratio of 2-(2-methylphenoxymethyl)benzoyl cyanide: methoxyamine hydrochloride: hydrochloric acid gas in steps (1) and (2) is 1:1.05:1.

1.

4. The method for synthesizing azoxystrobin according to claim 1, characterized in that: The phase transfer catalyst is tetrabutylammonium bromide.

5. The method for synthesizing azoxystrobin according to claim 1, characterized in that: In step (2), the water content of the methanol is in the range of 10%-50%.

6. The method for synthesizing azoxystrobin according to claim 5, characterized in that: The water content of the methanol in step (2) is 20%.

Images