Synthesis method of cycloxaprid

Abstract

The invention discloses a cycloxaprid synthesis method which comprises the following steps: adding a solvent, tert-butyl diphenyl siloxane butyraldehyde, nitroimidazolidine and acid into a reaction container, and carrying out heat preservation reaction; raising the temperature, keeping the temperature for reaction, and deprotecting; cooling to room temperature, carrying out suction filtration, adding an oxidizing agent into the filtrate, and carrying out heat preservation reaction at 50-60 DEG C; adding acid until the pH value is 2-3, keeping the temperature to a reaction end point, adjusting the pH value, carrying out suction filtration, and drying a filter cake; and dissolving the filter cake in a solvent, adding sodium hydroxide, dropwise adding a 2-chloro-5-chloromethylpyridine solution, carrying out a thermal reaction, filtering to remove a sodium chloride solid after the reaction is finished, crystallizing, and carrying out suction filtration to obtain a cycloxaprid finished product. According to the method disclosed by the invention, tert-butyl diphenyl siloxane butyraldehyde adopted by the method is easily obtained through selective protection and oxidation reaction of butanediol, and the use of butanedialdehyde is avoided, so that a hydrogenation process for synthesizing butanedialdehyde is avoided, and the production of cycloxaprid is safer; the raw materials are cheap, so that the production cost is greatly reduced.

Description

Technical Field

[0001] The present invention relates to the technical field of epoxiconazole synthesis, and particularly relates to a method for synthesizing epoxiconazole. Background Art

[0002] Epoxiconazole is a broad-spectrum triazole fungicide used in agriculture to control various fungal diseases. It exerts its fungicidal effect by inhibiting the synthesis of ergosterol in the fungal cell membrane, thereby affecting the formation and function of the fungal cell membrane. Its molecular structure is shown as follows:

[0003]

[0004] The usual synthesis route of epoxiconazole (such as Patent CN112010873A) is the synthesis of intermediate CMNI and succinaldehyde under acidic conditions. However, since both succinaldehyde and intermediate CMNI contain two active sites, when succinaldehyde cyclizes with intermediate CMNI, side reactions of head-to-tail connection are likely to occur, forming various high-molecular compounds, which not only clog pipelines and reaction kettles, but also seriously affect the yield of epoxiconazole. Therefore, an economical and environmentally friendly method for synthesizing epoxiconazole is needed. Summary of the Invention

[0005] The purpose of the present invention is to provide a method for synthesizing epoxiconazole in view of the deficiencies in the prior art.

[0006] To achieve the above purpose, the technical solution adopted by the present invention is:

[0007] Provide a method for synthesizing epoxiconazole, including the following steps:

[0008] Step 1, add a solvent, tert-butyl diphenylsilyloxy butyraldehyde, nitroimidazolidine and an acid into a reaction vessel, control the temperature to be kept at 40 - 45 °C for reaction, and obtain compound (I) after the reaction ends;

[0009]

[0010] Step 2, raise the temperature to 60 - 70 °C and keep it for 2 - 5 hours for reaction to remove the protection and obtain compound (II);

[0011]

[0012] Step 3, after the reaction in Step 2 ends, cool down to room temperature, carry out suction filtration, add an oxidant to the filtrate, keep it at 50 - 60 °C for 2 - 5 hours for reaction to obtain compound (III);

[0013] Step 4, add an acid to adjust the pH value to 2 - 3, keep it until the reaction end point, adjust the pH value to 8 - 9, carry out suction filtration, and dry the filter cake to obtain compound (IV);

[0014]

[0015] Step 5: Dissolve the filter cake in a solvent, add sodium hydroxide, dropwise add a 2-chloro-5-(chloromethyl)pyridine solution at a temperature of 20 - 30°C, keep the temperature for reaction for 3 - 6 hours. After the reaction is completed, directly filter to remove the sodium chloride solid. Cool the filtrate to 0 - 5°C for crystallization and then perform suction filtration to obtain the finished product of epoxifenprox.

[0016]

[0017] Further, in Step 1, the molar ratio of tert-butyldiphenylsilyloxybutyraldehyde to nitroimidazolidine is 1:(1 - 1.5).

[0018] Further, in Step 1, the molar ratio of tert-butyldiphenylsilyloxybutyraldehyde to hydrogen ions in the acid is 1:(2 - 2.5).

[0019] Further, the molar ratio of tert-butyldiphenylsilyloxybutyraldehyde to the oxidant is 1:(1 - 1.5); preferably, the oxidant is one or more of ammonium persulfate, potassium persulfate, sodium persulfate, sodium bisulfate persulfate, and potassium bisulfate persulfate.

[0020] More preferably, the oxidant is ammonium persulfate:

[0021]

[0022] Further, the solvent is selected from one or more of toluene, methanol, ethanol, acetonitrile, ethylene glycol dimethyl ether, dichloromethane, dichloroethane, and n-hexane.

[0023] Further, the molar ratio of tert-butyldiphenylsilyloxybutyraldehyde to 2-chloro-5-(chloromethyl)pyridine is 1:(1 - 1.05).

[0024] The present invention adopts the above technical solutions, and compared with the prior art, has the following technical effects:

[0025] 1) The synthesis method of epoxifenprox provided by the present invention uses tert-butyldiphenylsilyloxybutyraldehyde and nitroimidazolidine to condense to obtain an epoxifenprox intermediate, and then through deprotection, oxidation, and cyclization to obtain epoxifenprox; tert-butyldiphenylsilyloxybutyraldehyde can be easily obtained through the selective protection of butanediol and oxidation reaction. The by-products generated after deprotection can be recovered and reused with a little treatment. This method avoids the use of succinaldehyde, thus avoiding the hydrogenation process of synthesizing succinaldehyde, making the production of epoxifenprox safer; since the raw materials are all very cheap, the production cost is greatly reduced.

[0026] 2) The traditional process uses succinaldehyde and CMNI for cyclization to obtain epoxifenvalerate, which easily generates macromolecular compounds connected end to end, thus forming tar, wasting a large amount of expensive raw materials and easily clogging pipelines. The tert-butyldiphenylsilyloxybutyraldehyde used in the present invention has only one reaction site and will not produce products connected end to end during condensation with the intermediate, so tar will not be generated, greatly improving the yield. Detailed implementation mode

[0027] The present invention will be further described below in conjunction with specific embodiments, but it is not intended to limit the present invention. It should be noted that, without conflict, the embodiments in the present invention and the features in the embodiments can be combined with each other.

[0028] Example 1

[0029] Add 300 mL of dichloromethane, 33.26 g (0.1 mol) of 98% tert-butyldiphenylsilyloxybutyraldehyde and 13.15 g (0.1 mol) of 99% nitroimidazolidine into a three-necked flask, then add 20.44 g (0.2 mol) of 36% hydrochloric acid, control the temperature at 40 - 45 °C and stir for 2.5 h while maintaining the temperature; raise the temperature to 60 °C and keep it for 2 hours to remove the protection; cool down to 25 °C, filter by suction, add 232.3 g (0.102 mol) of 10% ammonium persulfate aqueous solution to the filtrate, raise the temperature to 50 °C and keep it for 2 hours; add acid to adjust the pH value to 2 - 3, keep it until the reaction end point, after the reaction is completed, cool down to room temperature, adjust the pH to 8 - 9, filter by suction, and dry the filter cake; dissolve the filter cake in dichloromethane, add 5 g of sodium hydroxide, dropwise add a dichloromethane solution of 2-chloro-5-chloromethylpyridine (0.1 mol) at 20 - 30 °C, keep the reaction for 3 hours, filter by suction to obtain the filtrate, keep the filtrate at 0 - 5 °C for 3 hours, filter by suction, and dry the filter cake at 40 °C to obtain 32.2 g of epoxifenvalerate with a content of 99% and a yield of 99%.

[0030] Example 2

[0031] Add 300 mL of acetonitrile, 33.26 g (0.1 mol) of 98% tert-butyldiphenylsilyloxybutyraldehyde, and 13.15 g (0.1 mol) of 99% nitroimidazolidine into a three-necked flask. Then add 20.44 g (0.2 mol) of 36% hydrochloric acid. Control the temperature at 40 - 45 °C and stir for 2.5 h while keeping warm. Raise the temperature to 60 °C and keep warm for 2 hours to remove the protection. Cool down to 25 °C, filter by suction. Add 232.3 g (0.102 mol) of 10% aqueous sodium persulfate solution to the filtrate, raise the temperature to 50 °C and keep warm for 2 hours. Add acid to adjust the pH value to 2 - 3, keep warm until the reaction reaches the end point. After the reaction is completed, cool down to room temperature, adjust the pH to 8 - 9, filter by suction, and dry the filter cake. Dissolve the filter cake in acetonitrile, add 5 g of sodium hydroxide, and dropwise add a dichloromethane solution of 2-chloro-5-(chloromethyl)pyridine (0.1 mol) at 20 - 30 °C. Keep the reaction warm for 3 hours, filter by suction to obtain the filtrate. Keep the filtrate at 0 - 5 °C for 3 hours, filter by suction, and dry the filter cake at 40 °C to obtain 31.1 g of epoxifenidin with a content of 98% and a yield of 94.6%.

[0032] Example 3

[0033] Add 300 mL of dichloromethane, 33.26 g (0.1 mol) of 98% tert-butyldiphenylsilyloxybutyraldehyde, and 13.15 g (0.1 mol) of 99% nitroimidazolidine into a three-necked flask. Then add 20.44 g (0.2 mol) of 36% hydrochloric acid. Control the temperature at 40 - 45 °C and stir for 2.5 h while keeping warm. Raise the temperature to 70 °C and keep warm for 5 hours to remove the protection. Cool down to 25 °C, filter by suction. Add 232.3 g (0.102 mol) of 10% aqueous ammonium persulfate solution to the filtrate, raise the temperature to 60 °C and keep warm for 5 hours. Add acid to adjust the pH value to 2 - 3, keep warm until the reaction reaches the end point. After the reaction is completed, cool down to room temperature, adjust the pH to 8 - 9, filter by suction, and dry the filter cake. Dissolve the filter cake in dichloromethane, add 5 g of sodium hydroxide, and dropwise add a dichloromethane solution of 2-chloro-5-(chloromethyl)pyridine (0.1 mol) at 20 - 30 °C. Keep the reaction warm for 3 hours, filter by suction to obtain the filtrate. Keep the filtrate at 0 - 5 °C for 3 hours, filter by suction, and dry the filter cake at 40 °C to obtain 32.2 g of epoxifenidin with a content of 99% and a yield of 99%.

[0034] The above are only the preferred embodiments of the present invention, and do not limit the implementation manners and protection scope of the present invention. For those skilled in the art, it should be realized that all the equivalent replacements and obvious changes made by using the content of the specification of the present invention should be included in the protection scope of the present invention.

Claims

1. A method for synthesizing cycloheximide, characterized in that: The steps include: Step 1, adding a solvent, tert-butyldiphenylsiloxane butyraldehyde, nitroimidazole and an acid into a reaction vessel, controlling the temperature to be kept at 40-45° C. to react, and after the reaction is completed, obtaining compound (I); Step 2, raising the temperature to 60-70°C and maintaining the reaction for 2-5 hours, and deprotecting to obtain compound (II); Step 3: After the reaction in step 2 is completed, the temperature is lowered to room temperature, filtered, an oxidant is added to the filtrate, and the mixture is kept at 50-60° C. for 2-5 hours to obtain compound (III); Step 4, adding acid to a pH value of 2-3, keeping warm until the reaction end point, adjusting the pH value to 8-9, filtering with suction, and drying the filter cake to obtain compound (IV); Step 5, dissolving the filter cake in a solvent, adding sodium hydroxide, and dropping 2-chloro-5-chloromethylpyridine solution at a temperature of 20-30° C., and reacting by heat preservation for 3-6 hours. After the reaction is completed, directly filtering to remove the sodium chloride solid, cooling the filtrate to 0-5° C., crystallizing, and then filtering to obtain the cycloheximide product; 2. The method for synthesizing cycloheximide according to claim 1, characterized in that: In step 1, the molar ratio of the tert-butyldiphenylsiloxane butyraldehyde to nitroimidazole is 1:(1-1.5).

3. The method for synthesizing cycloheximide according to claim 1, characterized in that: In step 1, the molar ratio of the tert-butyldiphenylsiloxane butyraldehyde to the hydrogen ions in the acid is 1:(2-2.5).

4. The method for synthesizing cycloheximide according to claim 1, characterized in that: The molar ratio of the tert-butyldiphenylsiloxane-based butyraldehyde to the oxidant is 1:(1-1.5).

5. The method for synthesizing cycloheximide according to claim 4, characterized in that: The oxidant is one or more of ammonium persulfate, potassium persulfate, sodium persulfate, sodium hydrogen persulfate, and potassium hydrogen persulfate.

6. The method for synthesizing cycloheximide according to claim 1, characterized in that: The solvent is selected from one or more of toluene, methanol, ethanol, acetonitrile, ethylene glycol dimethyl ether, dichloromethane, dichloroethane and n-hexane.

7. The method for synthesizing cycloheximide according to claim 1, characterized in that: The molar ratio of the tert-butyldiphenylsilylbutyraldehyde to 2-chloro-5-chloromethylpyridine is 1:(1-1.05).

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