A method for synthesizing a key intermediate of myclobutanil

Abstract

The application relates to the technical field of chemical synthesis, in particular to a synthesis method of a key intermediate of pentconazole, which comprises the following steps: S1, Witting-Horner reaction of 2,4-dichlorobenzophenone and (diethoxy) phosphoethyl acetate under the action of a strong base to generate 3-(2,4-dichlorophenyl)-2-en-hexanoic acid ethyl ester; S2, Prilezhaev epoxidation reaction of 3-(2,4-dichlorophenyl)-2-en-hexanoic acid ethyl ester and meta-chloro peroxybenzoic acid to generate 3-(2,4-dichlorophenyl)-2,3-epoxy-hexanoic acid ethyl ester; and S3, base hydrolysis and acidification of 3-(2,4-dichlorophenyl)-2,3-epoxy-hexanoic acid ethyl ester to obtain a key intermediate 2-(2,4-dichlorophenyl) pentanal of pentconazole. The application has the effects of higher reaction yield, lower toxicity of reaction raw materials and more gentle reaction conditions.

Description

TECHNICAL FIELD

[0001] The application relates to the technical field of chemical synthesis, in particular to a synthesis method of a triconazole key intermediate. BACKGROUND

[0002] Triconazole is a kind of endosporal triazole fungicide with protection, treatment and eradication effects, is a sterol demethylation inhibitor, can be absorbed by crop roots, stems and leaves and transmitted upwards, and indoor activity determination and field efficacy test results show that triconazole has good prevention and treatment effects on grape white rot.

[0003] At present, there are the following technical routes for synthesizing triconazole:

[0004] 1. Liu Li and Li Xiang published a paper entitled Synthesis of Fungicide Triconazole in February 2006, which describes three process routes:

[0005] Process route (1): 2,4-dichlorobenzyl cyanide is used as a raw material, and triconazole is obtained through alkylation, esterification, reduction, methanesulfonylation and finally condensation with triazole, and the reaction route is as follows:

[0006]

[0007] Process route (2): 2,4-dichlorobenzyl cyanide is used as a raw material, and triconazole is obtained through alkylation, normal-pressure hydrogenation, high-pressure hydrogenation and cyclization, and the reaction route is as follows:

[0008]

[0009] The route needs to use 1-bromopropane in the list of class 2B carcinogens, and the occupational health and safety risk is large, the first step is an alkylation reaction, and the second step and the third step are hydrogenation reactions, which belong to high-risk processes;

[0010] Process route (3): m-dichlorobenzene is reacted with butyryl chloride to obtain 2,4-dichlorobenzyl ketone, then the 2,4-dichlorobenzyl ketone is reacted with triazole methyl phosphate, and finally hydrogenation is carried out to obtain triconazole, and the reaction route is as follows:

[0011]

[0012] The raw material used in the second step of the route is triazole methyl phosphate, which is expensive, and the third step is a hydrogenation reaction, which belongs to a high-risk process;

[0013] 2. Wang Jin, Chen Hua and Liao Wenbin published a paper entitled Synthesis of Triconazole in 2006, which describes a route for preparing triconazole from 2,4-dichlorobenzyl acid (process route (4) as follows).

[0014] Process route (4): 2,4-dichlorobenzyl acid is esterified, alkylated, reduced, sulfonated and synthesized to obtain triconazole, and the reaction route is as follows:

[0015]

[0016] This route uses dimethyl sulfate, which is highly toxic, similar to mustard gas, with acute toxicity similar to phosgene, 15 times greater than chlorine. It has strong irritating effect on the eyes and upper respiratory tract, and strong corrosive effect on the skin. It also uses 1-bromopropane, a 2B carcinogen, which has high occupational health and safety risk.

[0017] 3. Ge Zhongqun, Chen Hua, and Pan Guangfei, 2013, "Study on a New Process for the Synthesis of the Fungicide Trifconazole", describe a route for preparing trifconazole from 2,4-dichlorobutanone (Process Route (5) below):

[0018] Process Route (5): Trifconazole is prepared from 2,4-dichlorobutanone through cyclization, rearrangement, reduction, methanesulfonylation, and condensation. The reaction route is as follows:

[0019]

[0020] This route uses dimethyl sulfate, which is highly toxic, similar to mustard gas, with acute toxicity similar to phosgene, 15 times greater than chlorine. It has strong irritating effect on the eyes and upper respiratory tract, and strong corrosive effect on the skin. It also uses 1-bromopropane, a 2B carcinogen, which has high occupational health and safety risk, uses low-boiling, volatile, and foul-smelling dimethyl sulfide, pollutes the atmosphere, and is not environmentally friendly.

[0021] 4. The invention patent with publication number CN102584726A discloses a preparation method for the fungicide trifconazole. Its feature is that it uses 2,4-dichlorobutanone, sodium methoxide, methyl chloroacetate, methyl sulfonyl chloride, and triazole as the main raw materials, and adopts a four-step reaction synthesis technology route of Darzen condensation, potassium borohydride reduction, esterification, and synthesis to prepare trifconazole. The purpose is to provide a preparation method for the fungicide trifconazole with high yield and purity and short process flow (Process Route (6) below):

[0022]

[0023]

[0024] This route has lower occupational health risk and is more environmentally friendly than Process Routes (1)-(5), but it uses Darzen condensation to prepare 2-(2,4-dichlorophenyl)pentanal, which has more impurities, lower content (90.2%), and lower yield (85.3%). SUMMARY

[0025] The technical problem solved by the present application is to provide a method for preparing a key intermediate of pentanoazole, which has milder reaction conditions, higher yield and safer raw materials.

[0026] To solve the above technical problems, the present application adopts the following technical solutions:

[0027] A synthesis method of a key intermediate of pentanoazole, comprising the following steps:

[0028] S1, dissolve (diethoxy) phosphorus ethyl acetate in DMF, add strong base in batches, after the addition is completed, continue to stir and drop 2,4-dichlorobenzophenone DMF solution, continue to stir to make 2,4-dichlorobenzophenone and (diethoxy) phosphorus ethyl acetate react under the action of strong base to generate 3-(2,4-dichlorophenyl)-2-alkene-hexanoic acid ethyl ester, after the reaction is completed, the product is dried in vacuum, the temperature is 135-140 DEG C, the air pressure is-0.090MPa~ -0.099MPa, the dried product is put into a mixture of toluene and water for extraction, and 3-(2,4-dichlorophenyl)-2-alkene-hexanoic acid ethyl ester toluene solution is obtained.

[0029] S2, add deionized water and sodium bicarbonate to the 3-(2,4-dichlorophenyl)-2-alkene-hexanoic acid ethyl ester toluene solution obtained in step S1, slowly drop m-chloroperbenzoic acid ethanol solution in a low temperature environment, maintain low temperature to make 3-(2,4-dichlorophenyl)-2-alkene-hexanoic acid ethyl ester and m-chloroperbenzoic acid react to generate Prilezhaev epoxidation reaction, after the reaction is completed, 10% sodium hydroxide solution is added to the mixture to adjust pH, the water solution layer is separated, and 3-(2,4-dichlorophenyl)-2,3-epoxy-hexanoic acid ethyl ester toluene solution is obtained.

[0030] S3, add sodium hydroxide solution to the 3-(2,4-dichlorophenyl)-2,3-epoxy-hexanoic acid ethyl ester toluene solution obtained in step S2, hydrolyze at high temperature for 2-5 hours, then cool and drop hydrochloric acid solution to adjust pH, separate the water solution layer, obtain 2-(2,4-dichlorophenyl) pentanal toluene solution, and vacuum dry the solution to remove toluene to obtain the target product 2-(2,4-dichlorophenyl) pentanal.

[0031] Compared with the process route (1), the process route (1) no longer uses 2,4-dichlorobenzene acetonitrile and 1-bromopropane as raw materials, and has higher safety; compared with the process route (2), the process route (2) synthesizes the final product pentacinazole by first synthesizing the intermediate 2-(2,4-dichlorophenyl) pentanitrile and then performing multiple hydrogenation reactions to form a ring, and the hydrogenation reaction needs to be completed under high temperature and high pressure, and the experiment is relatively dangerous, in the technical scheme, the target product pentacinazole is produced by sequentially performing reduction, sulfonation and ring closure after the intermediate 2-(2,4-dichlorophenyl) pentanal is synthesized, the reaction conditions for synthesizing the intermediate 2-(2,4-dichlorophenyl) pentanal are more moderate, and the safety is higher; compared with the process route (3), the raw material triazole methyl phosphate used in the process route (3) is much more expensive than the technical scheme, and the technical scheme has stronger economic applicability; compared with the process route (4) and the technical scheme (5), the volatility and toxicity of the raw material 2,4-dichlorobenzene butanone used in the technical scheme are much lower than those of triazole methyl phosphate, and the safety is better; compared with the technical scheme (6), the target product and the by-product in the technical scheme have higher separation degree, and the reaction yield is higher.

[0032] In the present application, the molar ratio of 2,4-dichlorobenzene butanone to (diethoxy) phosphoethyl acetate in step S1 is 1:1.1-1:1.3.

[0033] Through the above technical scheme, when 2,4-dichlorobenzene butanone and (diethoxy) phosphoethyl acetate react under the action of a strong base, the molar ratio is 1:1, but the reaction is not complete, and the addition of more (diethoxy) phosphoethyl acetate than 2,4-dichlorobenzene butanone can increase the reaction degree of 2,4-dichlorobenzene butanone and improve the reaction yield.

[0034] In the present application, the temperature for the witting-horner reaction of 2,4-dichlorobenzene butanone and (diethoxy) phosphoethyl acetate in step S1 is 0-30℃, and the reaction time is 1-2 hours.

[0035] Through the above technical scheme, when 2,4-dichlorobenzene butanone and (diethoxy) phosphoethyl acetate react, not only the reaction rate is fast, but also more by-products are easily produced at high temperature, maintaining a lower temperature can control the reaction rate, make the reaction more moderate, and reduce the production of by-products.

[0036] In the present application, the strong base in step S1 is one or a combination of sodium methoxide, potassium tert-butoxide and sodium tert-butoxide.

[0037] By adopting the above technical solution, sodium methoxide, potassium tert-butoxide and sodium tert-butoxide can not only provide strong basicity, but also are difficult to react with raw materials and intermediate products in the present application, thereby improving the purity of the product.

[0038] In the present application, the molar ratio of 2,4-dichlorobenzophenone to m-chloroperbenzoic acid in step S2 is 1:1.05-1:1.15.

[0039] By adopting the above technical solution, 3-(2,4-dichlorophenyl)-2-alkene-hexanoic acid ethyl ester reacts with m-chloroperbenzoic acid according to a molar ratio of 1:1, but the reaction is not complete, and adding more m-chloroperbenzoic acid can increase the reaction degree and improve the final yield.

[0040] In the present application, the temperature for Prilezhaev epoxidation reaction of 3-(2,4-dichlorophenyl)-2-alkene-hexanoic acid ethyl ester with m-chloroperbenzoic acid in step S2 is -5-10℃, and the reaction time is 6-8 hours.

[0041] By adopting the above technical solution, the by-product m-chlorobenzoic acid has strong irritability, which can reduce the volatility of raw materials and products in a low-temperature environment and protect the operators.

[0042] In the present application, the terminal pH of sodium hydroxide used for adjusting the alkali in step S2 is pH≥9.

[0043] By adopting the above technical solution, controlling the terminal pH of the alkali adjustment to be pH≥9 can quench the excess m-chloroperbenzoic acid to convert it into m-chlorobenzoic acid, and generate m-chlorobenzoic acid salt in an alkaline condition to dissolve in water, so that 3-(2,4-dichlorophenyl)-2,3-epoxy-hexanoic acid ethyl ester is more easily extracted by toluene solution, thereby improving the reaction yield.

[0044] In the present application, the molar ratio of 2,4-dichlorobenzophenone to added sodium hydroxide in step S3 is 1:1.3-1:1.6, the hydrolysis time is 2-5 hours, and the hydrolysis temperature is 75-80℃.

[0045] By adopting the above technical solution, the ester bond is easily hydrolyzed in an alkaline and heated environment, and a higher reaction temperature can increase the reaction process, and the amount of added sodium hydroxide is more than the raw material, so that the reaction degree is higher.

[0046] In the present application, the molar ratio of 2,4-dichlorobenzophenone to hydrochloric acid added in step S3 is 1:1.6-1:1.8, the end point pH of the acid adjustment is pH≤3, and the reaction temperature is 20-30℃.

[0047] By adopting the technical scheme, a large amount of heat is released during the reaction of concentrated hydrochloric acid, and maintaining a low reaction temperature can improve the safety of the reaction.

[0048] More specifically, the method of the present application is recommended to be carried out according to the following steps:

[0049] S1, 246.5-291.3g (diethoxy) phosphorus ethyl acetate and 434.0-651.0g DMF are put into a dry and clean reactor, stirred and cooled to 0-30℃, 115.3-134.5g sodium tert-butoxide is added in batches, and the addition is completed in 30-60min, and the stirring is continued for 10-30min, 217.0g 2,4-dichlorobenzophenone is dissolved in 217.0g DMF, and the 2,4-dichlorobenzophenone DMF solution is added dropwise into the mixture, and the dropping is completed in 30-60min, and the stirring is continued for 60min, to generate 3-(2,4-dichlorophenyl)-2-alkenyl-hexanoic acid ethyl ester, after the reaction is completed, the solvent is removed under negative pressure and heating at 135-140℃ / -0.098MPa, the temperature is lowered to 80-90℃, and toluene and water are added, stirred for 15min, separated into layers, the water layer is extracted with toluene twice, the toluene layers are combined, and the toluene layer is washed with water, and the layers are separated to obtain the toluene solution of 3-(2,4-dichlorophenyl)-2-alkenyl-hexanoic acid ethyl ester.

[0050] S2, 217g deionized water and 92.4-100.8g sodium bicarbonate are added to the toluene solution of 3-(2,4-dichlorophenyl)-2-alkenyl-hexanoic acid ethyl ester obtained in step S1, the temperature is lowered to -5-10℃, 226.5-248.1g of 80% m-chloroperbenzoic acid is dissolved in 150g ethanol, and the m-chloroperbenzoic acid ethanol solution is slowly added dropwise, the dropping is completed in 30-60min, and the temperature is maintained for 6-8h, the low temperature is maintained to make 3-(2,4-dichlorophenyl)-2-alkenyl-hexanoic acid ethyl ester react with m-chloroperbenzoic acid to generate Prilezhaev epoxidation reaction, after the reaction is completed, 10% sodium hydroxide aqueous solution is added dropwise into the mixture, the pH is adjusted to≥9, the water layer is separated, the toluene is extracted twice, the toluene layers are combined, and the toluene layer is washed once with 5% sodium hydroxide aqueous solution to obtain the toluene solution of 3-(2,4-dichlorophenyl)-2,3-epoxy-hexanoic acid ethyl ester.

[0051] S3, to the toluene solution of 3-(2,4-dichlorophenyl)-2,3-epoxy-hexanoic acid ethyl ester obtained in step S2, 173.3-213.2 g of 30% sodium hydroxide solution was added, the temperature was raised to 75-80°C, and the alkaline hydrolysis was carried out for 2-5 hours, the temperature was lowered, and the control temperature was 20-30°C, 194.6-218.9 g of 30% hydrochloric acid was added dropwise for neutralization until the pH was ≤3, and the mixture was allowed to stand for separation, the water layer was extracted with toluene twice, the toluene layers were combined, and the toluene was removed under negative pressure to obtain 2-(2,4-dichlorophenyl)pentanal.

[0052] The synthetic method described in the present application has the beneficial effects that the present application does not use 1-bromopropane, a high-toxicity substance dimethyl sulfate in the list of 2B carcinogens, and does not use the dangerous processes of hydrogenation reduction and alkylation, so that the present application is safer. The present application does not use dimethyl sulfide, which has a low boiling point, is volatile, and has a foul odor, so that the present application is more environmentally friendly and environmentally friendly. The present application adopts the process route that 2,4-dichlorobutyrophenone is first subjected to witting-horner reaction, then subjected to Prilezhaev epoxidation reaction, and then subjected to alkaline hydrolysis and acidification reaction to obtain 2-(2,4-dichlorophenyl)pentanal. This route is efficient and clean, has few side reactions, and has high content and yield of the obtained 2-(2,4-dichlorophenyl)pentanal. The raw and auxiliary materials used in this route are all easily purchased chemicals. DETAILED DESCRIPTION

[0053] The present application will be further described below through specific embodiments, but the protection scope of the present application is not limited thereto.

[0054] Example 1:

[0055] S1: In a dry and clean reactor, 246.5 g of (diethoxy) phosphinoacetic acid ethyl ester and 434.0 g of DMF were added, and stirred to lower the temperature to 0°C, 115.3 g of sodium tert-butoxide was added in batches, and 217.0 g of 2,4-dichlorobutyrophenone dissolved in 217.0 g of DMF was added dropwise for 30 min, and stirred for 60 min, and the control detection of 2,4-dichlorobutyrophenone was ≤0.5%, which was qualified, the solvent was removed under negative pressure and heating to 135°C / -0.098 MPa, the temperature was lowered to 80°C, 434.0 g of toluene and 217.0 g of water were added, and stirred for 15 min, and the layers were separated, the water layer was extracted with 65.1 g of toluene twice, the toluene layers were combined, and the toluene layer was washed with 217.0 g of water, and the layers were separated to obtain a toluene solution of 3-(2,4-dichlorophenyl)-2-alkenyl-hexanoic acid ethyl ester.

[0056] S2: To the toluene solution obtained in step S2, 217.0 g of water and 92.4 g of sodium bicarbonate were added, and the temperature was lowered to -5°C. A solution of 226.5 g of m-chloroperbenzoic acid with a content of 80% in 150 g of ethanol was slowly added dropwise, and the dropping was completed in 30 min. The solution was kept at 6 h, and the content of ethyl 3-(2,4-dichlorophenyl)-2-alkenyl-hexanoate was ≤1%. The solution was qualified, and 217.0 g of 10% sodium hydroxide aqueous solution was added dropwise to adjust the pH to 9. The water layer was separated, and 43.4 g of toluene was added for extraction twice. The toluene layers were combined, and then washed once with 217.0 g of 5% sodium hydroxide aqueous solution to obtain a toluene solution of ethyl 3-(2,4-dichlorophenyl)-2,3-epoxy-hexanoate.

[0057] S3: To the toluene solution in step S2, 173.3 g of 30% sodium hydroxide aqueous solution was added, and the temperature was raised to 75°C. The solution was alkalized for 2-5 h, and then the temperature was lowered to 20°C. 194.6 g of 30% hydrochloric acid was added dropwise to neutralize the solution to pH=3. The solution was allowed to stand to separate into layers, and the water layer was extracted with 43.4 g of toluene twice. The toluene layers were combined, and then the toluene was removed under negative pressure to obtain 2-(2,4-dichlorophenyl)pentanal.

[0058] Examples 2-3 and Comparative Examples 1-2 differ from Example 1 in that the mass of ethyl (diethoxy)phosphorylacetate added in step S1 is different, as shown in the following table:

[0059] Mass of (diethoxy)phosphinylacetic acid ethyl ester (g) Example 1 246.5 Example 2 269.0 Example 3 291.3 Comparative Example 1 224.2 Comparative Example 2 331.9

[0060] Examples 4-5 and Comparative Examples 3-4 differ from Example 1 in that the mass of m-chloroperbenzoic acid added in step S2 is different, as shown in the following table:

[0061] Mass of 80% meta-chloroperoxybenzoic acid (g) Example 1 226.5 Example 4 237.4 Example 5 248.1 Comparative Example 3 215.8 Comparative Example 4 258.9

[0062] Comparative Example 5 differs from Example 1 in that Comparative Example 5 was synthesized according to process route (6), and the specific process is as follows: In a 2000 L enamel reaction kettle, 700 kg of toluene and 250 kg of 2,4-dichlorophenyl butanone were added, and the temperature was lowered to about 15°C by passing brine. Sodium methoxide was added for about 0.5 h, and then chloroacetic acid methyl ester was added dropwise for 2-2.5 h at a temperature of 15-25°C. After the dropping was completed, the solution was kept at 15-25°C for 2 h. After the sample was controlled and qualified, an alkali solution was added, the temperature was raised to 65-75°C, and the solution was alkalized for 3 h. After the alkalization was completed, the solution was neutralized to pH 3-4 with hydrochloric acid. The lower water layer was separated, and then 400 kg of water was added for washing once. Then, the toluene was removed under normal pressure and then under reduced pressure. The temperature was lowered to 50-60°C to obtain 2-(2,4-dichlorophenyl)pentanal.

[0063] Detection method

[0064] The 2-(2,4-dichlorophenyl)pentanal obtained in step S3 was analyzed by liquid chromatography to obtain the content (%) of 2-(2,4-dichlorophenyl)pentanal and the yield (%) of 2-(2,4-dichlorophenyl)pentanal. The test results are shown in the following table:

[0065]

[0066]

[0067] Conclusion: From the data of Examples 1-3 and Comparative Examples 1-2 in the above table, it can be seen that the yield of the reaction is higher when the molar ratio of 2,4-dichlorobutyrophenone to (diethoxy) phosphonoacetic acid ethyl ester is 1:1.1-1:1.3. When the molar ratio of 2,4-dichlorobutyrophenone to (diethoxy) phosphonoacetic acid ethyl ester is less than 1:1.1, the yield decreases significantly. When the molar ratio of 2,4-dichlorobutyrophenone to (diethoxy) phosphonoacetic acid ethyl ester is greater than 1:1.3, the yield does not increase significantly. When the molar ratio of 2,4-dichlorobutyrophenone to (diethoxy) phosphonoacetic acid ethyl ester is 1:1, the reaction is not complete. When the molar ratio of 2,4-dichlorobutyrophenone to (diethoxy) phosphonoacetic acid ethyl ester is less than 1:1.1, 2,4-dichlorobutyrophenone does not react completely, and the yield decreases significantly. When the molar ratio of 2,4-dichlorobutyrophenone to (diethoxy) phosphonoacetic acid ethyl ester is greater than 1:1.3, 2,4-dichlorobutyrophenone reacts completely. Increasing the amount of (diethoxy) phosphonoacetic acid ethyl ester has little effect. It is shown that the suitable molar ratio of 2,4-dichlorobutyrophenone to (diethoxy) phosphonoacetic acid ethyl ester for the reaction is 1:1.1-1:1.3.

[0068] Conclusion: From the data of the above table, Example 1, 4, 5 and Comparative Example 3-4, it can be seen that when the molar ratio of 2,4-dichlorobutyrophenone to meta-chloroperbenzoic acid is 1:1.05-1:1.15, the yield is higher, when the molar ratio of 2,4-dichlorobutyrophenone to meta-chloroperbenzoic acid is less than 1:1.05, the yield is greatly reduced, when the molar ratio of 2,4-dichlorobutyrophenone to meta-chloroperbenzoic acid is greater than 1:1.15, the yield does not increase significantly, 3-(2,4-dichlorophenyl)-2-alkene-hexanoic acid ethyl ester reacts with meta-chloroperbenzoic acid to undergo Prilezhaev epoxidation reaction, the molar ratio is 1:1, but the reaction is not complete, when the molar ratio of 2,4-dichlorobutyrophenone to meta-chloroperbenzoic acid is less than 1:1.05, 3-(2,4-dichlorophenyl)-2-alkene-hexanoic acid ethyl ester does not react completely, the yield is greatly reduced, when the molar ratio of 2,4-dichlorobutyrophenone to meta-chloroperbenzoic acid is greater than 1:1.15, 3-(2,4-dichlorophenyl)-2-alkene-hexanoic acid ethyl ester is basically completely reacted, and further increasing the amount of meta-chloroperbenzoic acid has little effect, indicating that the suitable molar ratio of 2,4-dichlorobutyrophenone to meta-chloroperbenzoic acid for the reaction is 1:1.05-1:1.15.

[0069] Conclusion: From the data of the above table, Example 1 and Comparative Example 5, it can be seen that in the synthesis of the target product 2-(2,4-dichlorophenyl)pentanal, the yield and content are both greater than the existing process route (6), process route (6) uses Darzens condensation to prepare 2-(2,4-dichlorophenyl)pentanal, which is a condensation reaction of 2,4-dichlorobutyrophenone and chloroacetic acid ethyl ester under strong base conditions, which generates byproduct hydrochloric acid, which reacts with the base to reduce the basicity of the reaction environment, thereby reducing the reaction degree and the yield of the product, and under the action of strong base, chloroacetic acid ethyl ester is hydrolyzed to generate more byproducts, thereby reducing the purity of the product, in the present technical solution, 2,4-dichlorobutyrophenone first reacts with (diethoxy) phosphoacetic acid ethyl ester to undergo Witting-Horner reaction, the acidity of the byproduct (diethoxy) phosphoric acid of this reaction is greatly reduced compared with hydrochloric acid, and has less effect on the basicity of the reaction environment, thereby improving the reaction degree and increasing the yield, then 3-(2,4-dichlorophenyl)-2-alkene-hexanoic acid ethyl ester reacts with meta-chloroperbenzoic acid to undergo Prilezhaev epoxidation reaction, meta-chloroperbenzoic acid has strong oxidizing property, which makes the reaction of 3-(2,4-dichlorophenyl)-2-alkene-hexanoic acid ethyl ester more complete, thereby improving the yield of the final product.

[0070] The above are preferred embodiments of the present application, and do not limit the protection scope of the present application, therefore: any equivalent changes made according to the structure, shape, principle of the present application should be covered within the protection scope of the present application.

Claims

1. A method for synthesizing a key intermediate of tebuconazole, characterized in that, Includes the following steps: S1. Dissolve ethyl (diethoxy)phosphoethyl acetate in DMF, add strong base in batches, and after the addition is complete, continue stirring and add a DMF solution of 2,4-dichlorophenylbutanone dropwise. Continue stirring to allow 2,4-dichlorophenylbutanone and ethyl (diethoxy)phosphoethyl acetate to undergo a witting-horner reaction under the action of strong base to generate ethyl 3-(2,4-dichlorophenyl)-2-en-hexanoate. After the reaction is complete, dry the product under vacuum at a temperature of 135-140℃ and a pressure of -0.090 MPa to -0.099 MPa. Extract the dried product in a mixture of toluene and water to obtain a toluene solution of ethyl 3-(2,4-dichlorophenyl)-2-en-hexanoate. S2. Add deionized water and sodium bicarbonate to the toluene solution of ethyl 3-(2,4-dichlorophenyl)-2-en-hexanoate obtained in step S1. Slowly add an ethanol solution of m-chloroperoxybenzoic acid at low temperature. Maintain the low temperature to allow ethyl 3-(2,4-dichlorophenyl)-2-en-hexanoate to undergo a Prilezhaev epoxidation reaction with m-chloroperoxybenzoic acid. After the reaction is completed, add 10% sodium hydroxide solution to the mixture to adjust the pH. Separate the aqueous layer to obtain a toluene solution of ethyl 3-(2,4-dichlorophenyl)-2,3-epoxy-hexanoate. S3. Add 30% sodium hydroxide solution to the toluene solution of ethyl 3-(2,4-dichlorophenyl)-2,3-epoxy-hexanoate obtained in step S2, hydrolyze at high temperature for 2-5 hours, cool down and add 30% hydrochloric acid solution dropwise to adjust pH, separate the aqueous layer to obtain a toluene solution of 2-(2,4-dichlorophenyl)pentanal, and vacuum dry the solution to remove toluene to obtain the target product 2-(2,4-dichlorophenyl)pentanal; In step S1, the molar ratio of 2,4-dichlorophenylbutanone to (diethoxy)phosphoethyl acetate is 1:1.1-1:1.

3. In step S1, the temperature for the witting-horner reaction between 2,4-dichlorophenylbutanone and (diethoxy)phosphoethyl acetate is 0-30°C, and the reaction time is 1-2 hours. The strong base in step S1 is one or a combination of sodium methoxide, potassium tert-butoxide, and sodium tert-butoxide.

2. The method for synthesizing a key intermediate of tebuconazole according to claim 1, characterized in that: In step S2, the molar ratio of 2,4-dichlorophenylbutanone to m-chloroperoxybenzoic acid is 1:1.05-1:1.

15.

3. The method for synthesizing a key intermediate of tebuconazole according to claim 1, characterized in that: In step S2, the Prilezhaev epoxidation reaction of ethyl 3-(2,4-dichlorophenyl)-2-en-hexanoate with m-chloroperoxybenzoic acid occurs at a temperature of -5 to 10°C and for a reaction time of 6 to 8 hours.

4. The method for synthesizing a key intermediate of tebuconazole according to claim 1, characterized in that: In step S2, the final pH value for adjusting the alkali with sodium hydroxide is pH ≥ 9.

5. The method for synthesizing a key intermediate of tebuconazole according to claim 1, characterized in that: In step S3, the molar ratio of 2,4-dichlorophenylbutanone to added sodium hydroxide is 1:1.3-1:1.6, the hydrolysis time is 2-5 hours, and the hydrolysis temperature is 75-80℃.

6. The method for synthesizing a key intermediate of tebuconazole according to claim 1, characterized in that: In step S3, the molar ratio of 2,4-dichlorophenylbutanone to added hydrochloric acid is 1:1.6-1:1.8, the final pH of acid adjustment is pH≤3, and the reaction temperature is 20-30℃.

Images