A method for synthesizing 3-difluoromethyl-1-methylpyrazole-4-ethyl formate

Abstract

The application discloses a synthesis method of 3-difluoromethyl-1-methylpyrazole-4-methyl ethyl formate. The synthesis method is to synthesize 3-difluoromethyl-1-methylpyrazole-4-methyl ethyl formate by taking 5-difluoromethyl-1-methylpyrazole-4-methyl ethyl formate and dimethyl carbonate as raw materials and under the action of a porous organic polymer catalyst with solidified Lewis acid. The porous organic polymer catalyst with solidified Lewis acid comprises a porous organic polymer, and the porous organic polymer is solidified with Lewis acid. In the synthesis method, under the action of the porous organic polymer catalyst with solidified Lewis acid, not only a high reaction conversion rate can be obtained at normal temperature, but also a large number of side reactions caused by high temperature can be effectively avoided, thereby the impurity content can be obviously reduced, and the synthesis method has the advantages of simple operation, good catalyst activity, mild reaction condition, few side reactions, fast reaction rate, high yield and the like, is suitable for industrial application, and has a good market prospect.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of compound intermediate synthesis, and relates to a synthesis method of 3-difluoromethyl-1-methylpyrazole-4-ethyl formate. BACKGROUND

[0002] 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid is an important pesticide intermediate, and succinate dehydrogenase inhibitors (SDHI) fungicides synthesized from the intermediate include five kinds of flumetover, benzovindiflupyr, bixafen, fluometover and pyraclostrobin. In recent years, these pesticide varieties have a high market demand and great commercial value.

[0003] 3-difluoromethyl-1-methylpyrazole-4-ethyl formate is a key intermediate for preparing 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid, and is a research hotspot at present. There are two main industrial synthesis routes for 3-difluoromethyl-1-methylpyrazole-4-ethyl formate. One is a difluoroacetyl acetic acid ethyl ester route, that is, difluoroacetyl acetic acid ethyl ester is used as a raw material, reacts with triethyl orthoformate to produce an intermediate, and then the intermediate is cyclized with methyl hydrazine to obtain 3-difluoromethyl-1-methylpyrazole-4-ethyl formate. The other is an acyl fluoride route, that is, difluoroacetyl fluoride is used as a raw material, reacts with N,N-dimethyl acrylate to produce an intermediate, and then the intermediate is cyclized with methyl hydrazine to obtain 3-difluoromethyl-1-methylpyrazole-4-ethyl formate. However, the two synthesis routes have a common problem, that is, when the intermediate is cyclized with methyl hydrazine to obtain 3-difluoromethyl-1-methylpyrazole-4-ethyl formate, 5-difluoromethyl-1-methylpyrazole-4-ethyl formate (referred to as “isomer”) is inevitably produced, and the content of the isomer is relatively high, more than 10%, and the isomer can only be removed as an impurity in the post-processing process, thereby affecting the total yield of synthesis.

[0004] In addition, the prior art reports a method for rearranging 5-difluoromethyl-1-methylpyrazole-4-ethyl formate (isomer) with trimethyl phosphate under the catalysis of phosphoric acid or sulfonic acid to obtain 3-difluoromethyl-1-methylpyrazole-4-ethyl formate, but the method has problems of high reaction temperature, long reaction time, many side reactions, low conversion rate, and deep color of the reaction solution, and great difficulty in post-processing.

[0005] In addition, the prior art reports a method for rearranging 5-difluoromethyl-1-methylpyrazole-4-ethyl formate (isomer) with dimethyl sulfate and dimethylformamide to obtain 3-difluoromethyl-1-methylpyrazole-4-ethyl formate, but the method also has problems of high reaction temperature, slow reaction rate, low conversion rate, and great toxicity of dimethyl sulfate, difficulty in recovery of dimethylformamide, and high synthesis cost, and is not suitable for industrial production.

[0006] Therefore, the synthesis method of 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid ethyl ester has the advantages of simple process, convenient operation, low cost, low reaction temperature, fast reaction rate and high yield, and is of great significance for promoting the industrialized production and wide use of succinate dehydrogenase inhibitor (SDHI) fungicides. SUMMARY

[0007] The technical problem to be solved by the present application is to overcome the shortcomings of the prior art and provide a synthesis method of 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid ethyl ester, which has the advantages of simple process, convenient operation, low cost, low reaction temperature, fast reaction rate and high yield.

[0008] To solve the above technical problems, the present application adopts the following technical solutions:

[0009] The synthesis method of 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid ethyl ester uses 5-difluoromethyl-1-methylpyrazole-4-carboxylic acid ethyl ester and dimethyl carbonate as raw materials, and synthesizes 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid ethyl ester under the action of a porous organic polymer catalyst with immobilized Lewis acid.

[0010] The synthesis method is further improved, and the porous organic polymer catalyst with immobilized Lewis acid is prepared by the following method: mixing Lewis acid, porous organic polymer and organic solvent, stirring, heating and reacting, filtering, washing, and drying to obtain the porous organic polymer catalyst with immobilized Lewis acid.

[0011] The synthesis method is further improved, and the mass ratio of the Lewis acid to the porous organic polymer is 0.5-1.0:1.0.

[0012] The synthesis method is further improved, and the Lewis acid is one of aluminum chloride, iron trichloride and tin tetrachloride.

[0013] The synthesis method is further improved, and the porous organic polymer is a conjugated microporous phthalocyanine polymer.

[0014] The synthesis method is further improved, and the organic solvent is one of toluene, xylene and chlorobenzene.

[0015] The synthesis method is further improved, and the stirring time is 0.5h-2h; the reaction is carried out at a temperature of 80-110 DEG C; the reaction time is 1-4h; the drying is carried out under vacuum; and the drying time is 2-5h.

[0016] The synthesis method is further improved, and 3-difluoromethyl-1-methylpyrazole-4-ethyl formate is synthesized from 5-difluoromethyl-1-methylpyrazole-4-ethyl formate and dimethyl carbonate under the action of a porous organic polymer catalyst with immobilized Lewis acid, and the method comprises the following steps: mixing 5-difluoromethyl-1-methylpyrazole-4-ethyl formate, dimethyl carbonate and the porous organic polymer catalyst with immobilized Lewis acid to perform a synthesis reaction, filtering, removing dimethyl carbonate, and obtaining 3-difluoromethyl-1-methylpyrazole-4-ethyl formate.

[0017] The synthesis method is further improved, and the mass ratio of the porous organic polymer catalyst with immobilized Lewis acid to the 5-difluoromethyl-1-methylpyrazole-4-ethyl formate is 0.03-0.1:1.

[0018] The synthesis method is further improved, and the molar ratio of the 5-difluoromethyl-1-methylpyrazole-4-ethyl formate to the dimethyl carbonate is 1.0:3.0-5.0.

[0019] The synthesis method is further improved, and the synthesis reaction is performed at a temperature of 25-80 DEG C, and the synthesis reaction time is 1-4 hours.

[0020] The synthesis method is further improved, and after the filtering is completed, the porous organic polymer catalyst with immobilized Lewis acid obtained after the filtering is continuously used to synthesize 3-difluoromethyl-1-methylpyrazole-4-ethyl formate.

[0021] Compared with the prior art, the synthesis method has the following advantages:

[0022] (1) In view of the problems existing in the prior synthesis method, the application creatively provides a synthesis method of 3-difluoromethyl-1-methylpyrazole-4-ethyl formate, which synthesizes 3-difluoromethyl-1-methylpyrazole-4-ethyl formate from 5-difluoromethyl-1-methylpyrazole-4-ethyl formate and dimethyl carbonate under the action of a porous organic polymer catalyst with immobilized Lewis acid, wherein the porous organic polymer catalyst with immobilized Lewis acid is a porous organic polymer and a Lewis acid immobilized on the porous organic polymer. In the porous organic polymer catalyst with immobilized Lewis acid adopted in the application, the porous organic polymer is used as a carrier, and the π electrons on the aromatic ring can form a stable coordination structure with the Lewis acid. Meanwhile, the porous organic polymer has excellent specific surface area, so that the catalyst has good catalytic efficiency and chemical stability. Therefore, when the porous organic polymer catalyst with immobilized Lewis acid is used for catalytic synthesis of 3-difluoromethyl-1-methylpyrazole-4-ethyl formate, dimethyl carbonate is more likely to alkylate 5-difluoromethyl-1-methylpyrazole-4-ethyl formate to form unstable pyrazolium cation, and then rearrangement is performed to obtain stable 3-difluoromethyl-1-methylpyrazole-4-ethyl formate, so that the reaction temperature is reduced and the reaction time is shortened. Not only a high reaction conversion rate can be obtained at normal temperature, but also a large number of side reactions caused by high temperature can be effectively avoided, thereby the impurity content can be significantly reduced, and the reaction formula is as follows:

[0023]

[0024] (2) In the application, dimethyl carbonate is used as a reaction raw material and a solvent. After the reaction is completed, the reaction liquid is filtered to remove the catalyst, and then dimethyl carbonate is removed to obtain the target product, so that the operation process is simplified, the catalyst is recycled and reused, and the production cost of solvent separation and recovery caused by additional use of the reaction solvent is avoided.

[0025] (3) In the application, the effective component in the porous organic polymer catalyst with immobilized Lewis acid has good stability, and the filtered catalyst can be recycled for multiple times, so that the utilization efficiency of the catalyst is improved, the use cost is reduced, and the industrial application is promoted.

[0026] (4) In the application, the mass ratio of the Lewis acid to the porous organic polymer is optimized to 0.5-1.0:1.0, so that the catalyst has excellent stability and catalytic performance. In particular, when the mass ratio is too high, the coordination structure of the catalyst is unstable, and the catalyst is deactivated; and when the mass ratio is too low, the activity of the catalyst is reduced, and the catalytic effect is affected. DETAILED DESCRIPTION

[0027] The present invention will be further described below in conjunction with specific preferred embodiments, but the scope of protection of the present invention is not limited thereby.

[0028] In the following examples of the present invention, unless otherwise specified, the materials and instruments used are commercially available, the equipment used is conventional equipment, and the data obtained are the average values ​​of more than three repeated experiments.

[0029] Example 1

[0030] A method for synthesizing ethyl 3-difluoromethyl-1-methylpyrazole-4-carboxylate comprises the following steps:

[0031] In a three-necked flask (250 mL) equipped with a mechanical stirrer, a condenser, and a thermometer, 52.0 g of 5-difluoromethyl-1-methylpyrazole-4-carboxylic acid ethyl ester (98%, 0.25 mol), 68.2 g of dimethyl carbonate (99%, 0.75 mol), and 1.6 g of a Lewis acid-supported porous organic polymer catalyst (aluminum trichloride-supported porous organic polymer) were added. The mixture was stirred and reacted at 80° C. for 1 h. The mixture was cooled to room temperature and filtered to separate the catalyst. The dimethyl carbonate was removed by distillation under reduced pressure to obtain 50.6 g of 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid ethyl ester as a light yellow solid with a content of 99.2%, of which 5-difluoromethyl-1-methylpyrazole-4-carboxylic acid ethyl ester (isomer) accounted for 0.3% and the yield was 98.4% (based on 5-difluoromethyl-1-methylpyrazole-4-carboxylic acid ethyl ester).

[0032] In this embodiment, the Lewis acid-supported porous organic polymer catalyst (aluminum chloride-supported porous organic polymer) was prepared by the following method:

[0033] In a three-necked flask (100 mL) equipped with a mechanical stirrer, a condenser, and a thermometer, 37.2 g of toluene (99%, 0.4 mol), 2.7 g of anhydrous aluminum chloride (99%, 0.02 mol), and 5.4 g of a conjugated microporous phthalocyanine polymer (CoPP-FePc-CMP, commercially available) were added, stirred for 0.5 h, mixed evenly, heated to 80° C., and kept warm for 1 h. After the insulation was completed, the mixture was cooled to room temperature and filtered. The resulting precipitate was washed with toluene and water, respectively, and dried under vacuum conditions for 2 h to obtain 7.2 g of a porous organic polymer catalyst supported on Lewis acid (aluminum chloride supported porous organic polymer).

[0034] Example 2

[0035] A method for synthesizing ethyl 3-difluoromethyl-1-methylpyrazole-4-carboxylate comprises the following steps:

[0036] In a three-necked flask (250 mL) equipped with a mechanical stirrer, a condenser and a thermometer, 52.0 g of ethyl 5-difluoromethyl-1-methylpyrazole-4-carboxylate (98%, 0.25 mol), 113.7 g of dimethyl carbonate (99%, 1.25 mol) and 5.2 g of the porous organic polymer catalyst supported with Lewis acid (porous organic polymer supported with ferric trichloride) were added. The stirring was started and the reaction was carried out at 25°C for 4 h, then the temperature was decreased to room temperature. The catalyst was filtered off and the dimethyl carbonate was removed by distillation under reduced pressure. 50.8 g of ethyl 3-difluoromethyl-1-methylpyrazole-4-carboxylate were obtained as a light yellow solid with a content of 99.5% and a content of ethyl 5-difluoromethyl-1-methylpyrazole-4-carboxylate (isomer) of 0.2%, with a yield of 99.1% (calculated as ethyl 5-difluoromethyl-1-methylpyrazole-4-carboxylate).

[0037] In this example, the porous organic polymer catalyst supported with Lewis acid (porous organic polymer supported with ferric trichloride) was prepared by the following method:

[0038] In a three-necked flask (100 mL) equipped with a mechanical stirrer, a condenser and a thermometer, 42.9 g of dimethylbenzene (99%, 0.4 mol), 3.3 g of anhydrous ferric trichloride (98%, 0.02 mol) and 3.3 g of the conjugated microporous phthalocyanine polymer (CoPP-FePc-CMP) were added. The stirring was started and the mixture was homogenized for 2 h. The temperature was increased to 110°C and the reaction was carried out for 2 h. After the reaction, the temperature was decreased to room temperature. The catalyst was filtered off and the precipitate was washed with dimethylbenzene and water and dried under vacuum for 5 h. 36.0 g of the porous organic polymer catalyst supported with Lewis acid (porous organic polymer supported with ferric trichloride) were obtained.

[0039] Example 3

[0040] A process for the synthesis of ethyl 3-difluoromethyl-1-methylpyrazole-4-carboxylate, comprising the following steps: in a three-necked flask (250 mL) equipped with a mechanical stirrer, a condenser and a thermometer, 52.0 g of ethyl 5-difluoromethyl-1-methylpyrazole-4-carboxylate (98%, 0.25 mol), 90.9 g of dimethyl carbonate (99%, 1.0 mol) and 2.6 g of the porous organic polymer catalyst supported with Lewis acid (porous organic polymer supported with tin tetrachloride) were added. The stirring was started and the reaction was carried out at 60°C for 2 h, then the temperature was decreased to room temperature. The catalyst was filtered off and the dimethyl carbonate was removed by distillation under reduced pressure. 50.4 g of ethyl 3-difluoromethyl-1-methylpyrazole-4-carboxylate were obtained as a light yellow solid with a content of 99.3% and a content of ethyl 5-difluoromethyl-1-methylpyrazole-4-carboxylate (isomer) of 0.5%, with a yield of 98.1% (calculated as ethyl 5-difluoromethyl-1-methylpyrazole-4-carboxylate).

[0041] In this embodiment, the porous organic polymer catalyst supported Lewis acid (porous organic polymer supported aluminum chloride) is prepared by the following method:

[0042] In a three-necked flask (100 mL) equipped with mechanical stirring, condenser and thermometer, 37.2 g of toluene (99%, 0.4 mol), 5.3 g of anhydrous tin tetrachloride (99%, 0.02 mol) and 5.3 g of conjugated microporous phthalocyanine polymer (CoPP-FePc-CMP) were added, stirred for 1 h, mixed uniformly, heated to 90°C, and incubated for 4 h. After incubation, it was cooled to room temperature, filtered, precipitated, washed with toluene and water respectively, and dried in vacuum for 3 h. 10.1 g of porous organic polymer catalyst supported Lewis acid (porous organic polymer supported tin tetrachloride) was obtained.

[0043] Example 4

[0044] A method for synthesizing 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid ethyl ester, comprising the following steps:

[0045] In a three-necked flask (250 mL) equipped with mechanical stirring, condenser and thermometer, 52.01 g of 5-difluoromethyl-1-methylpyrazole-4-carboxylic acid ethyl ester (98%, 0.25 mol), 68.2 g of dimethyl carbonate (99%, 0.75 mol) and 1.6 g of porous organic polymer catalyst supported Lewis acid (porous organic polymer supported aluminum chloride) were added, stirred at 80°C for 1 h, cooled to room temperature, filtered, separated the catalyst, and removed dimethyl carbonate by distillation under reduced pressure. 50.7 g of 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid ethyl ester was obtained as a light yellow solid, with a content of 99.2%, a content of 5-difluoromethyl-1-methylpyrazole-4-carboxylic acid ethyl ester (isomer) of 0.3%, and a yield of 98.6% (based on 5-difluoromethyl-1-methylpyrazole-4-carboxylic acid ethyl ester).

[0046] In this embodiment, the porous organic polymer catalyst supported Lewis acid (porous organic polymer supported aluminum chloride) is prepared by the following method:

[0047] In a three-necked flask (100 mL) equipped with mechanical stirring, condenser and thermometer, 45.5 g of chlorobenzene (99%, 0.4 mol), 2.7 g of anhydrous aluminum chloride (99%, 0.02 mol) and 5.4 g of conjugated microporous phthalocyanine polymer (CoPP-FePc-CMP) were added, stirred for 0.5 h, mixed uniformly, heated to 100°C, and incubated for 1 h. After incubation, it was cooled to room temperature, filtered, precipitated, washed with chlorobenzene and water respectively, and dried in vacuum for 5 h. 7.5 g of porous organic polymer catalyst supported Lewis acid (porous organic polymer supported aluminum chloride) was obtained.

[0048] Comparative Example 1

[0049] A synthesis method of 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid ethyl ester, comprising the following steps:

[0050] In a three-necked flask (250 mL) equipped with mechanical stirring, condenser, thermometer, 52.0 g of 5-difluoromethyl-1-methylpyrazole-4-carboxylic acid ethyl ester (98%, 0.25 mol), 68.2 g of dimethyl carbonate (99%, 0.75 mol) were added, stirring was started, and the reaction was carried out at 80°C for 4 h, then it was cooled to room temperature, filtered, and dimethyl carbonate was removed by distillation under reduced pressure to obtain 51.3 g of a light yellow liquid with a content of 3.2% of 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid ethyl ester and 95.9% of 5-difluoromethyl-1-methylpyrazole-4-carboxylic acid ethyl ester (isomer), with a yield of 3.2% (based on 5-difluoromethyl-1-methylpyrazole-4-carboxylic acid ethyl ester). In Comparative Example 1, the basic reason for the low yield is that without the addition of the porous organic polymer catalyst supporting Lewis acid catalyst, it is difficult to promote the effective progress of the reaction.

[0051] Comparative Example 2

[0052] A synthesis method of 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid ethyl ester, which is basically the same as that in Example 4, with the only difference being that in Comparative Example 2, aluminum chloride is used instead of the porous organic polymer catalyst supporting Lewis acid catalyst.

[0053] After testing, the content of 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid ethyl ester in the obtained product was 5.8%, the content of 5-difluoromethyl-1-methylpyrazole-4-carboxylic acid ethyl ester (isomer) was 92.5%, and the yield of the product was 5.7% (based on 5-difluoromethyl-1-methylpyrazole-4-carboxylic acid ethyl ester). Thus, it is concluded that when only aluminum chloride is used as the catalyst, the reaction speed is slow, the conversion rate of 5-difluoromethyl-1-methylpyrazole-4-carboxylic acid ethyl ester is low, and the yield is low.

[0054] The above results show that, compared with the conventional method, the synthesis method of 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid ethyl ester according to the present application, under the action of the porous organic polymer catalyst supporting Lewis acid catalyst, not only can obtain a higher reaction conversion rate at room temperature, but also can effectively avoid a large number of side reactions caused by high temperature, thereby significantly reducing the impurity content, and has the advantages of simple operation, good catalyst activity, mild reaction conditions, few side reactions, fast reaction rate, high yield, etc., and is suitable for industrial application and has a good market prospect.

[0055] The above examples are only preferred embodiments of the present application, and the protection scope of the present application is not limited to the above examples. Any technical scheme falling within the concept of the present application belongs to the protection scope of the present application. It should be pointed out that improvements and refinements made by those of ordinary skill in the art without departing from the principles of the present application should also be considered as falling within the protection scope of the present application.

Claims

1. A method for synthesizing ethyl 3-difluoromethyl-1-methylpyrazole-4-carboxylate, characterized in that: 5-difluoromethyl-1-methylpyrazole-4-carboxylic acid ethyl ester and dimethyl carbonate are used as raw materials to synthesize 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid ethyl ester under the action of a porous organic polymer catalyst supporting a Lewis acid. The porous organic polymer catalyst supporting a Lewis acid is prepared by the following method: mixing a Lewis acid, a porous organic polymer and an organic solvent, stirring, heating to react, filtering, washing and drying to obtain the porous organic polymer catalyst supporting a Lewis acid. The Lewis acid is one of aluminum trichloride, ferric trichloride and tin tetrachloride; the porous organic polymer is a conjugated microporous phthalocyanine polymer CoPP-FePc-CMP; and the organic solvent is one of toluene, xylene and chlorobenzene.

2. The synthesis method according to claim 1, wherein The mass ratio of the Lewis acid to the porous organic polymer is 0.5-1.0:1.

0.

3. The synthesis method according to claim 1, wherein The stirring time is 0.5h to 2h; the reaction is carried out at a temperature of 80°C to 110°C; the reaction time is 1h to 4h; the drying is carried out under vacuum conditions; and the drying time is 2h to 5h.

4. The synthesis method according to any one of claims 1 to 3, characterized in that The method uses 5-difluoromethyl-1-methylpyrazole-4-carboxylic acid ethyl ester and dimethyl carbonate as raw materials and synthesizes 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid ethyl ester under the action of a porous organic polymer catalyst supporting a Lewis acid. The method comprises the following steps: mixing 5-difluoromethyl-1-methylpyrazole-4-carboxylic acid ethyl ester, dimethyl carbonate and the porous organic polymer catalyst supporting a Lewis acid, carrying out a synthesis reaction, filtering, and removing dimethyl carbonate to obtain 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid ethyl ester.

5. The synthesis method according to claim 4, characterized in that The mass ratio of the Lewis acid-supported porous organic polymer catalyst to the 5-difluoromethyl-1-methylpyrazole-4-ethylcarboxylate is 0.03 to 0.1:

1.

6. The synthesis method according to claim 5, characterized in that The molar ratio of the 5-difluoromethyl-1-methylpyrazole-4-carboxylic acid ethyl ester to the dimethyl carbonate is 1.0:3.0-5.

0.

7. The synthesis method according to claim 6, characterized in that The synthesis reaction is carried out at a temperature of 25° C. to 80° C.; and the synthesis reaction time is 1 hour to 4 hours.

8. The synthesis method according to claim 4, characterized in that After the filtration is completed, the method further comprises: using the Lewis acid-supported porous organic polymer catalyst obtained after the filtration to synthesize ethyl 3-difluoromethyl-1-methylpyrazole-4-carboxylate.

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