Preparation method of picoxystrobin

Abstract

The invention provides a preparation method of picoxystrobin, and belongs to the technical field of bactericides. According to the preparation method of picoxystrobin, no intermediate needs to be separated in the preparation process, side reactions are few, production operation is simpler, the product yield and purity are high, and the preparation method is suitable for industrial production. And the etherification reaction raw material used in the invention is 2-chloro-6-trifluoromethylpyridine, has no large corrosivity or safety risk, is convenient for post-treatment, has low requirements on production equipment, and is lower in cost.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of fungicides, and particularly relates to a preparation method of picoxystrobin. BACKGROUND

[0002] Picoxystrobin (common name: picoxystrobin, trade name: Acanto) is a methoxy acrylate fungicide. Due to the systemic activity and evaporation activity of picoxystrobin, the effective component can be redistributed and fully transmitted after application, so picoxystrobin has better curative activity than commercial azoxystrobin and trifloxystrobin, is widely applied to the treatment of diseases of crops such as cereals and vegetables, has good control effect on diseases such as powdery mildew, leaf blight and brown spot, and has a good broad market prospect.

[0003] At present, the routes for synthesizing picoxystrobin reported in the literature mainly include the following: 1) 3-isochromone is reacted with thionyl chloride to obtain o-chloromethyl phenylacetic acid methyl ester, then etherification is performed with 2-hydroxy-6-trifluoromethyl pyridine, ester condensation and methylation are performed to obtain picoxystrobin; 2) 3-isochromone is subjected to ester condensation, methylation and ring opening, and then etherification is performed with 2-hydroxy-6-trifluoromethyl pyridine to obtain picoxystrobin; 3) o-methyl phenylacetic acid is used as a raw material, esterification, ester condensation and methylation are performed to synthesize (E)-3-methoxy-2-o-tolyl propenoic acid methyl ester, and then (E)-3-methoxy-2-(2-chloromethyl phenyl)-2-propenoic acid methyl ester is obtained by chlorination with N-chlorosuccinimide (NCS).

[0004] Among them, the synthesis route 1) and the synthesis route 2) both need to use thionyl chloride for ring opening and esterification, the amount of thionyl chloride used is large, the corrosion is strong, a large amount of waste water is generated by tail gas absorption, the environmental protection treatment cost is high, and the safety risk is large, which is not suitable for large-scale production process. Although the synthesis route 3) directly bypasses the intermediate step of synthesizing 3-isochromone, picoxystrobin is synthesized from the more initial o-methyl phenylacetic acid, from the perspective of atomic economy, there is a certain cost advantage, but in the ester condensation reaction process with methyl formate, the chain-like benzyl acetate itself has self-condensation phenomenon, which leads to extremely low reaction yield and difficult separation of reaction products, and cannot be applied to large-scale industrial production. SUMMARY

[0005] The purpose of the present application is to provide a preparation method of picoxystrobin, the present application uses 2-chloro 6-trifluoromethyl pyridine and 3-isochromone as raw materials, and picoxystrobin is obtained through condensation, methylation, alkaline hydrolysis and etherification reaction, the present application does not need to separate any intermediate in the preparation process, the production operation is simpler and the product yield is higher, and the present application is suitable for industrial production.

[0006] In order to achieve the purpose of the present application, the present application provides the following technical solutions: A preparation method of pyriclor, comprising the following steps: mixing 3-isochromone, methyl formate, a first alkaline substance and an organic solvent, performing a condensation reaction to obtain a condensate of formula I; formula I; mixing the condensate of formula I, a methylating agent and a second alkaline substance, performing a methylation reaction, performing liquid separation on the obtained methylation reaction liquid and removing the organic solvent to obtain a methylate of formula II; formula II; mixing the methylate of formula II and sodium methoxide, performing alkaline hydrolysis to obtain an esterate of formula III; formula III; mixing the esterate of formula III and 2-chloro-6-trifluoromethylpyridine, performing etherification to obtain the pyriclor.

[0007] Preferably, the first alkaline substance comprises one or more of alkali metal alcoholate, alkali metal hydride and lithium diisopropylamide; The molar ratio of the first alkaline substance to 3-isochromone is 1.0-3.0:1; The molar ratio of the methyl formate to 3-isochromone is 2-5:1.

[0008] Preferably, the organic solvent is a benzene solvent and / or a halogenated hydrocarbon solvent; and the mass ratio of the organic solvent to 3-isochromone is 2.0-40.0:1.

[0009] Preferably, the second alkaline substance comprises one or more of alkali metal carbonate, alkali metal bicarbonate, alkali metal hydroxide and organic base; The molar ratio of the second alkaline substance to 3-isochromone is 0.2-2.0:1.

[0010] Preferably, the methylating agent is one or more of dimethyl carbonate, dimethyl sulfate and methyl iodide; The molar ratio of the methylating agent to 3-isochromone is 1.0-3.0:1.

[0011] Preferably, the molar ratio of the sodium methoxide to 3-isochromone is 0.8-1.2:1.

[0012] Preferably, the molar ratio of the 3-isochromone to 2-chloro-6-trifluoromethylpyridine is 1-3:1.

[0013] Preferably, the condensation reaction is performed at a temperature of 10-50 DEG C for 1-4 h; The methylation is performed at a temperature of 10-50 DEG C for 3-5 h.

[0014] Preferably, the temperature of the alkaline hydrolysis is 50-150℃, and the time is 6-12h.

[0015] Preferably, the temperature of the etherification reaction is 80-200℃, and the time is 8-12h.

[0016] The application provides a preparation method of pyriclor, which comprises the following steps: mixing 3-isochromone, methyl formate, a first alkaline substance and an organic solvent, performing condensation reaction to obtain a condensate of formula I; mixing the condensate of formula I, a methylation reagent and a second alkaline substance, performing methylation reaction, performing liquid-phase separation on the obtained methylation reaction liquid and removing the organic solvent to obtain a methylated product of formula II; mixing the methylated product of formula II and sodium methoxide, performing alkaline hydrolysis to obtain an esterified product of formula III; and mixing the esterified product of formula III and 2-chloro-6-trifluoromethylpyridine, performing etherification reaction to obtain the pyriclor. In the preparation process, the intermediate product generated in the condensation reaction liquid and participating in the generation of the structure of the final product is not separated and purified, the methylation reaction is continuously performed in the reaction liquid, the methylation reaction liquid after the methylation reaction is only simply subjected to liquid-phase separation and removal of the organic solvent, and then the alkaline hydrolysis and the etherification are continuously performed, so that the pyriclor can be obtained. In the preparation process, no intermediate is separated, the side reaction is less, the production operation is simpler, the product yield and purity are higher, and the industrial production is suitable. Moreover, the raw material used in the application is 2-chloro-6-trifluoromethylpyridine, which has no great corrosion or safety risk, the post-treatment is convenient, the requirement on the production equipment is not high, and the cost is lower. DETAILED DESCRIPTION

[0017] The application provides a preparation method of pyriclor, which comprises the following steps: The application provides a preparation method of pyriclor, which comprises the following steps: Mixing 3-isochromone, methyl formate, a first alkaline substance and an organic solvent, performing condensation reaction to obtain a condensate of formula I; Formula I; Mixing the condensate of formula I, a methylation reagent and a second alkaline substance, performing methylation reaction, performing liquid-phase separation on the obtained methylation reaction liquid and removing the organic solvent to obtain a methylated product of formula II; Formula II; Mixing the methylated product of formula II and sodium methoxide, performing alkaline hydrolysis to obtain an esterified product of formula III; Formula III; Mixing the esterified product of formula III and 2-chloro-6-trifluoromethylpyridine, performing etherification reaction to obtain the pyriclor.

[0018] In the present application, all the raw materials for preparation are commercially available products well known to those skilled in the art, unless otherwise specified.

[0019] In the present application, the first basic substance includes one or more of alkali metal alcoholate, alkali metal hydride and lithium diisopropylamide; the alkali metal alcoholate can be sodium methoxide, sodium ethoxide or potassium tert-butoxide; the alkali metal hydride can be potassium hydride or sodium hydride; the molar ratio of the first basic substance to 3-isochromone is 1.0-3.0:1, which can be 1.3:1, 1.5:1, 2.0:1 or 2.4:1 in specific embodiments; the molar ratio of methyl formate to 3-isochromone is 3-5:1, which can be 3:1 in specific embodiments.

[0020] In the present application, the solvent used in the condensation reaction is a benzene solvent and / or a halogenated hydrocarbon solvent; the benzene solvent can be toluene, xylene or mesitylene; the halogenated hydrocarbon solvent can be dichloromethane, dichloroethane or chloroform; the mass ratio of the solvent to 3-isochromone is 2.0-40.0:1, which can be 4:1, 10:1, 15:1 or 25:1 in specific embodiments.

[0021] In the present application, the temperature of the condensation reaction is 10-50℃, which can be 20 or 40℃ in specific embodiments, and the time is 1-4h, which can be 2 or 3h in specific embodiments. After obtaining the condensate of formula I, the present application mixes the condensate of formula I, a methylating agent and a second basic substance to perform a methylation reaction, thereby obtaining a methylate of formula II. In the present application, the second basic substance includes one or more of alkali metal carbonate, alkali metal bicarbonate, alkali metal hydroxide and organic base; the alkali metal carbonate can be sodium carbonate or potassium carbonate; the alkali metal bicarbonate can be sodium bicarbonate; the alkali metal hydroxide is sodium hydroxide or potassium hydroxide; the organic base can be triethylamine or pyridine; the molar ratio of the second basic substance to 3-isochromone is 0.2-2.0:1, which can be 0.4:1, 1.0:1 or 1.5:1 in specific embodiments.

[0022] In the present application, the methylating agent is one or more of dimethyl carbonate, dimethyl sulfate and iodomethane, which can be dimethyl sulfate in specific embodiments; the molar ratio of the methylating agent to 3-isochromone is 1.0-3.0:1, which can be 1.2:1, 1.8:1 or 2.5:1 in specific embodiments.

[0023] In the present application, the temperature of the methylation reaction is 10-50℃, and in specific embodiments, it can be 20 or 40℃, and the time is 1-4h, and in specific embodiments, it can be 2 or 3h.

[0024] The methylation reaction liquid obtained in the present application is subjected to liquid phase separation and removal of solvent; the liquid phase separation is not particularly limited in the present application, and a manner well known to those skilled in the art can be used; the removal of solvent can be rotary evaporation.

[0025] After obtaining the methylation product of formula II, the methylation product of formula II and sodium methoxide are mixed to perform alkaline hydrolysis to obtain the ester product of formula III. In the present application, the molar ratio of sodium methoxide to 3-isochromone is 0.8-1.2:1, and in specific embodiments, it can be 1.0:1; the temperature of the alkaline hydrolysis is 50-150℃, and in specific embodiments, it can be 60, 90 or 120℃, and the time is 6-12h, and in specific embodiments, it can be 8 or 10h.

[0026] After obtaining the ester product of formula III, the ester product of formula III and 2-chloro-6-trifluoromethylpyridine are mixed to perform etherification reaction to obtain the silthiofuranate. In the present application, the molar ratio of 3-isochromone to 2-chloro-6-trifluoromethylpyridine is 1-3:1, and in specific embodiments, it can be 1.1:1; the temperature of the etherification reaction is 80-200℃, and in specific embodiments, it can be 90, 130 or 150℃, and the time is 8-12h, and in specific embodiments, it can be 10h.

[0027] In the present application, 2-chloro-6-trifluoromethylpyridine is used as the etherification and chlorination reagent, compared with the process of using thionyl chloride for ring opening, the reaction sites are more in the chlorination reaction stage, and the content of the main product is generally not more than 90%, and the present application has a higher product content; and in the preparation method provided in the present application, by controlling the water content in the alkaline hydrolysis process, hydrolysis impurities are prevented from being generated by contacting water in the alkaline hydrolysis stage, and the ester group is not damaged.

[0028] After the etherification reaction, the present application further includes sequentially performing cooling, crystallization, solid-liquid separation and drying; the cooling can be water cooling, and in specific embodiments of the present application, cooling to 0-10℃ is performed to stand and crystallize; the solid-liquid separation and drying are not particularly limited in the present application, and a manner well known to those skilled in the art can be used.

[0029] In order to further illustrate the present application, the preparation method of silthiofuranate provided in the present application is described in detail below in combination with examples, but they should not be understood as limiting the scope of protection of the present application.

[0030] Example 1 Silthiofuranate is prepared according to the following reaction formula: The specific steps are as follows: In a 500 mL four-necked flask, 60 g of sodium tert-butoxide and 200 g of chloroform were mixed, 45 g of 3-isoflavone was added, 54 g of methyl formate was added dropwise at 40°C, and after the addition was completed, it was kept at 40°C for 3 h to obtain a chloroform solution of the condensate of formula I; 12 g of sodium carbonate and 200 g of water were added, and 38 g of dimethyl sulfate was added dropwise below 40°C, and after the addition was completed, it was kept at 40°C for 3 h, the oil layer was separated, and 100 g of chloroform was distilled off to obtain the methylate of formula II; 16 g of sodium methoxide was added, and the temperature was raised to 60°C to reflux for 10 h to obtain the esterate of formula III; 54 g of 2-chloro-6-trifluoromethylpyridine was continuously added dropwise, the temperature was raised to 90°C to reflux for 10 h, and after the reaction was completed, 200 g of water was added to cool to 0°C for 2 h, and then filtered and dried to obtain 102.5 g of white pydiflumetofen, with an external standard quantitative amount of 98.2% and a yield of 92%.

[0031] Example 2 In a 500 mL four-necked flask, 60 g of sodium tert-butoxide and 200 g of chloroform were mixed, 45 g of 3-isoflavone was added, 54 g of methyl formate was added dropwise at 40°C, and after the addition was completed, it was kept at 40°C for 3 h to obtain a chloroform solution of the condensate of formula I; 12 g of sodium carbonate and 200 g of water were added, and 38 g of dimethyl sulfate was added dropwise below 40°C, and after the addition was completed, it was kept at 40°C for 3 h, the oil layer was separated, and 100 g of chloroform was distilled off to obtain the methylate of formula II; 16 g of sodium methoxide was added, and the temperature was raised to 60°C to reflux for 10 h to obtain the esterate of formula III; 54 g of 2-chloro-6-trifluoromethylpyridine was continuously added dropwise, the temperature was raised to 90°C to reflux for 10 h, and after the reaction was completed, 200 g of water was added to cool to 0°C for 2 h, and then filtered and dried to obtain 102.5 g of white pydiflumetofen, with an external standard quantitative amount of 98.2% and a yield of 92%.

[0032] Example 3 In a 500 mL four-necked flask, 60 g of sodium tert-butoxide and 200 g of chloroform were mixed, 45 g of 3-isoflavone was added, 54 g of methyl formate was added dropwise at 40°C, and after the addition was completed, it was kept at 40°C for 3 h to obtain a chloroform solution of the condensate of formula I; 12 g of sodium carbonate and 200 g of water were added, and 38 g of dimethyl sulfate was added dropwise below 40°C, and after the addition was completed, it was kept at 40°C for 3 h, the oil layer was separated, and 100 g of chloroform was distilled off to obtain the methylate of formula II; 16 g of sodium methoxide was added, and the temperature was raised to 60°C to reflux for 10 h to obtain the esterate of formula III; 54 g of 2-chloro-6-trifluoromethylpyridine was continuously added dropwise, the temperature was raised to 90°C to reflux for 10 h, and after the reaction was completed, 200 g of water was added to cool to 0°C for 2 h, and then filtered and dried to obtain 102.5 g of white pydiflumetofen, with an external standard quantitative amount of 98.2% and a yield of 92%.

[0033] Although the above embodiments have been described in detail, it should be understood that these are only some embodiments of the present application, but not all embodiments, and other embodiments can be obtained without creativity on the basis of the above embodiments, and these embodiments all belong to the protection scope of the present application.

Claims

1. A method for preparing azoxystrobin, characterized in that, Includes the following steps: 3-Isochromone, methyl formate, the first basic substance and an organic solvent are mixed and subjected to a condensation reaction to obtain the condensate of formula I. Formula I; The condensate of Formula I, the methylating agent, and the second basic substance are mixed to carry out a methylation reaction. The resulting methylation reaction solution is then subjected to liquid-phase separation and removal of organic solvent to obtain the methylated product of Formula II. Formula II; The methyl compound of formula II was mixed with sodium methoxide and subjected to alkaline hydrolysis to obtain the ester compound of formula III; Formula III; The esterified compound of formula III was mixed with 2-chloro-6-trifluoromethylpyridine and subjected to an etherification reaction to obtain the pyridoxine.

2. The preparation method according to claim 1, characterized in that, The first alkaline substance includes one or more of alkali metal alkoxides, alkali metal hydrides, and lithium diisopropylamino. The molar ratio of the first alkaline substance to 3-isochromone is 1.0~3.0:1; The molar ratio of methyl formate to 3-isochromone is 2~5:

1.

3. The preparation method according to claim 1, characterized in that, The organic solvent is a benzene-based solvent and / or a halogenated hydrocarbon solvent; the mass ratio of the organic solvent to 3-isochromone is 2.0~40.0:

1.

4. The preparation method according to claim 1, characterized in that, The second alkaline substance includes one or more of alkali metal carbonates, alkali metal bicarbonates, alkali metal hydroxides, and organic bases; The molar ratio of the second alkaline substance to 3-isochromone is 0.2~2.0:

1.

5. The preparation method according to claim 1, characterized in that, The methylating agent is one or more selected from dimethyl carbonate, dimethyl sulfate, and iodomethane; The molar ratio of the methylating agent to 3-isochromone is 1.0~3.0:

1.

6. The preparation method according to claim 1, characterized in that, The molar ratio of sodium methoxide to 3-isochromone is 0.8~1.2:

1.

7. The preparation method according to claim 1, characterized in that, The molar ratio of 3-isochromone to 2-chloro-6-trifluoromethylpyridine is 1~3:

1.

8. The preparation method according to claim 1, characterized in that, The condensation reaction is carried out at a temperature of 10~50℃ for 1~4 hours. The methylation temperature is 10~50℃ and the time is 3~5h.

9. The preparation method according to claim 1, characterized in that, The alkaline hydrolysis is performed at a temperature of 50-150℃ for 6-12 hours.

10. The preparation method according to claim 1, characterized in that, The etherification reaction is carried out at a temperature of 80~200℃ for 8~12 hours.

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