Novel process for synthesizing high-purity metconazole

Abstract

The invention belongs to the technical field of pesticides and chemical engineering, and particularly relates to a novel process for synthesizing high-purity metconazole, which comprises the following steps: under the catalysis of alkali A, cyclopentanone and p-nitrobenzaldehyde are mixed for condensation reaction and dehydration to obtain 2-(4-nitrobenzylidene) cyclopentanone; and under the catalysis of an alkali B, mixing and stirring the 2-(4-nitrobenzal) cyclopentanone, a methylation reagent and a solvent B, and after the reaction is finished, dehydrating to obtain the 2, 2-dimethyl-5-(4-nitrobenzal) cyclopentanone. According to the method, cyclopentanone is used as a raw material, high-purity cis-metconazole is prepared through a condensation reaction, a reduction reaction, a Sandmeyer reaction, recrystallization and other modes, and compared with metconazole preparation modes in the prior art, the method has the advantages of being free of toxicity, low in danger coefficient, low in cost, high in preparation efficiency, simple in step, high in purity and the like, and is suitable for large-scale industrial production.

Description

Technical Field

[0001] The invention belongs to the technical field of pesticides and chemical industry, and specifically relates to a new process for synthesizing high-purity metconazole. Background Art

[0002] Metconazole, commonly known as Metconazole in English and traded as Caramba, is a new type of broad-spectrum systemic fungicide. Metconazole works by inhibiting the C-14 demethylase (cytochrome P4504pM) in the biochemical synthesis of ergosterol, a biofilm component of plant pathogens. Compared with the other three types of fungicides, the activity spectrum is quite different. Both isomers have fungicidal activity, but the cis isomer is higher than the trans. It is mainly used to control dwarf rust, leaf rust, yellow rust, crown rust, powdery mildew, glumes blight, as well as diseases caused by Septoria and Fusarium.

[0003] Most of the synthesis of metconazole involves the compound 2,2-dimethyl-5-(4-chlorobenzyl)-cyclopentane-1-one, so it is a very important intermediate in the synthesis of metconazole. There are many methods for the synthesis of 2,2-dimethyl-5-(4-chlorobenzyl)-cyclopentane-1-one: First, isobutyronitrile is used as the raw material, and lithium bis(trimethylsilyl)amide or lithium dimethylamide is needed in the process. Such compounds are not common and expensive. Secondly, sodium cyanide is also used, which is highly toxic and prone to accidents in industrial production, with a high risk factor. In addition, the purification of the intermediates requires too high equipment, which will greatly increase the production cost. Second, using 2,2-dimethylcyclopentanone as the raw material, although this route is shorter, its raw materials are relatively expensive, the synthesis process is longer, and it involves the use of sodium cyanide and methyl magnesium bromide, and there is a temperature requirement of -50°C. The production risk factor is also high and the production cost is high, so it is not suitable for industrial production; Third, using 2-ethoxycarbonylcyclopentanone as raw material, the order of unit operations such as methylation reaction, condensation reaction, hydrolysis decarboxylation reaction, reduction reaction, and epoxidation reaction in the preparation of metconazole has a great influence on the yield and purification of the final product. In particular, there are two-step methylation reactions in the process, which are highly toxic and difficult to operate. Therefore, the preparation method of metconazole still has difficulties.

[0004] In addition, studies have shown that metconazole has cis- and trans-isomers. Both isomers have fungicidal activity, but the cis is more active than the trans. However, to date, metconazole has appeared in the form of a mixture of cis- and trans-isomers. Summary of the invention

[0005] The invention aims to provide a new process for synthesizing high-purity metconazole, which uses cyclopentanone as a raw material and prepares high-purity cis-metconazole through condensation reaction, reduction reaction, Sandmeyer reaction, recrystallization and the like. Compared with the method for preparing metconazole in the prior art, the new process has the advantages of non-toxicity, low risk factor, low cost, high preparation efficiency, simple steps, high purity and the like, and is suitable for large-scale industrial production.

[0006] The technical solution adopted by the present invention is as follows: A new process for synthesizing high-purity metconazole comprises the following steps: Step 1: Under the catalysis of base A, cyclopentanone and p-nitrobenzaldehyde are mixed for condensation reaction and dehydration to obtain 2-(4-nitrobenzylidene)cyclopentanone; Step 2: Under the catalysis of base B, the 2-(4-nitrobenzylidene)cyclopentanone, the methylating agent and the solvent B are mixed and stirred, and after the reaction is completed, dehydration is performed to obtain 2,2-dimethyl-5-(4-nitrobenzylidene)cyclopentanone; Step 3: Under the action of a catalyst, the 2,2-dimethyl-5-(4-nitrobenzyl)cyclopentanone is mixed with hydrogen to undergo a reduction reaction and dehydration to obtain 2,2-dimethyl-5-(4-aminobenzyl)cyclopentanone; Step 4: The 2,2-dimethyl-5-(4-aminobenzyl)cyclopentanone is subjected to a Sandmeyer reaction to obtain 2,2-dimethyl-5-(4-chlorobenzyl)cyclopentanone; Step 5: Recrystallize the crude metconazole synthesized from 2,2-dimethyl-5-(4-chlorobenzyl)cyclopentanone through a one-pot method to obtain high-purity metconazole.

[0007] In a preferred embodiment, the Step 1 is specifically as follows: Cyclopentanone, p-nitrobenzaldehyde and base A are mixed and stirred for condensation reaction at a reaction temperature of 0°C to 150°C for a reaction time of 1h to 15h to obtain a mixed solution A, and the mixed solution A is sequentially extracted, separated and dehydrated to obtain 2-(4-nitrobenzyl)cyclopentanone, wherein the molar ratio of the cyclopentanone, p-nitrobenzaldehyde and base A is 1:(0.8-1.2):(0.01-0.5).

[0008] In a preferred embodiment, in Step 1, the condensation reaction is carried out in the presence of an organic solvent A or in the absence of a solvent. Optionally, the organic solvent A is a mixture of one or more of acetone, methanol, tetrahydrofuran, dichloroethane, ethanol, isopropanol, dioxane, toluene, dimethyl sulfoxide, N-methylpyrrolidone, and N,N-dimethylformamide, and the base A is one of sodium hydroxide, potassium hydroxide, sodium methoxide, sodium hydride, and tert-butyl lithium.

[0009] In a preferred embodiment, the Step 2 is specifically as follows: Adding base B and a methylating agent to the 2-(4-nitrobenzyl)cyclopentanone in batches, reacting in the presence of an organic solvent B, the reaction temperature is 0°C to 150°C, the reaction time is 1h to 15h, and a mixed solution B is obtained. The mixed solution B is sequentially extracted, separated and dehydrated to obtain 2,2-dimethyl-5-(4-nitrobenzyl)cyclopentanone, wherein the molar ratio of the 2-(4-nitrobenzyl)cyclopentanone, the base B and the methylating agent is 1:(2.0-4.0):(2.0-5.0).

[0010] In a preferred embodiment, the base B is one of sodium hydride, sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide, sodium tert-butoxide, potassium tert-butoxide, potassium carbonate, sodium carbonate, cesium carbonate, and butyl lithium; the methylating agent is one of methyl iodide, methyl bromide, dimethyl sulfate, and dimethyl carbonate; the organic solvent B is one of dichloromethane, acetone, methanol, tetrahydrofuran, ethyl acetate, ethanol, isopropanol, dioxane, toluene, chlorobenzene, dimethyl sulfoxide, and N,N-dimethylformamide, or a mixture of several thereof.

[0011] In a preferred embodiment, the Step 3 is specifically as follows: In the presence of an organic solvent C, the 2,2-dimethyl-5-(4-nitrobenzyl)cyclopentanone and a catalyst of palladium carbon or Raney nickel are added to a reaction kettle, hydrogen is introduced into the reaction kettle until the hydrogen pressure in the reaction kettle is 1ATM to 100ATM, and a reduction reaction is carried out with stirring. The reaction temperature is 0°C to 100°C, and the reaction time is 1h to 20h to obtain a mixed solution C. The mixed solution C is dehydrated to obtain 2,2-dimethyl-5-(4-aminobenzyl)cyclopentanone, wherein the molar ratio of the 2,2-dimethyl-5-(4-nitrobenzyl)cyclopentanone to the catalyst is 1:(0.0001 to 0.05).

[0012] In a preferred embodiment, the organic solvent C is one or a mixture of dichloromethane, acetone, methanol, tetrahydrofuran, ethyl acetate, ethanol, isopropanol, dioxane, toluene, chlorobenzene, dimethyl sulfoxide, and N,N-dimethylformamide.

[0013] In a preferred embodiment, the Step 4 is specifically as follows: The 2,2-dimethyl-5-(4-aminobenzyl)cyclopentanone and 10% hydrochloric acid are mixed and cooled to 0°C to 10°C, a sodium nitrite aqueous solution is added dropwise, and the mixture is kept warm at below 5°C for 1h to 3h, and a cuprous chloride hydrochloric acid solution is added dropwise to carry out a Sandmeyer reaction for 4h to 10h. After the reaction is completed, a sodium carbonate aqueous solution is added dropwise to adjust the pH to 7 to 8 to obtain a mixed solution D, and the mixed solution D is filtered to obtain a filter cake, and the filter cake is washed with water and dried to obtain 2,2-dimethyl-5-(4-chlorobenzyl)cyclopentanone, wherein the molar ratio of the 2,2-dimethyl-5-(4-nitrobenzyl)cyclopentanone, sodium nitrite, and cuprous chloride is 1:(1.0 to 2.0):(1.5 to 3).

[0014] In a preferred embodiment, the Step 5 is specifically as follows: The recrystallization process is specifically as follows: dissolving the cis-trans isomer mixture of metconazole obtained by the reaction in an organic solvent D at 40°C to 189°C, then cooling to 0°C to 30°C, washing the precipitated crystals with a cold recrystallization solvent and drying to obtain high-purity metconazole.

[0015] In a preferred embodiment, the organic solvent D is one or a mixture of dichloromethane, acetone, methanol, tetrahydrofuran, ethyl acetate, acetonitrile, ethanol, isopropanol, dioxane, toluene, chlorobenzene, dimethyl sulfoxide, N,N-dimethylformamide.

[0016] The technical effects achieved by the present invention are: The invention uses cyclopentanone as a raw material and prepares high-purity cis-metconazole through condensation reaction, reduction reaction, Sandmeyer reaction, recrystallization and the like. Compared with the method for preparing metconazole in the prior art, the invention has the advantages of being non-toxic, having a low risk factor, low cost, high preparation efficiency, simple steps, high purity and the like, and is suitable for large-scale industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0017] Figure 1 It is a preparation route map of high-purity metconazole of the present invention; Figure 2 It is a schematic diagram of the gas chromatography detection results of high-purity metconazole of the present invention. DETAILED DESCRIPTION

[0018] In order to make the above-mentioned objects, features and advantages of the present invention more obvious and easy to understand, the specific implementation methods of the present invention are described in detail below in conjunction with the accompanying drawings.

[0019] In the following description, many specific details are set forth to facilitate a full understanding of the present invention, but the present invention may also be implemented in other ways different from those described herein, and those skilled in the art may make similar generalizations without violating the connotation of the present invention. Therefore, the present invention is not limited to the specific embodiments disclosed below.

[0020] Secondly, the term "one embodiment" or "embodiment" as used herein refers to a specific feature, structure or characteristic that may be included in at least one implementation of the present invention. The phrase "in a preferred embodiment" that appears in different places in this specification does not refer to the same embodiment, nor is it a separate or selective embodiment that is mutually exclusive with other embodiments.

[0021] Please see attached Figure 1 As shown, this embodiment provides a new process for synthesizing high-purity metconazole, comprising the following steps: Step 1: cyclopentanone, p-nitrobenzaldehyde and base A are mixed and stirred for condensation reaction at a reaction temperature of 0°C to 150°C for 1h to 15h to obtain a mixed solution A, and the mixed solution A is sequentially extracted, separated and dehydrated to obtain 2-(4-nitrobenzyl)cyclopentanone (II); The molar ratio of cyclopentanone, p-nitrobenzaldehyde and base A is 1: (0.8-1.2): (0.01-0.5), and optionally, the base A is one of sodium hydroxide, potassium hydroxide, sodium methoxide, sodium hydride and tert-butyl lithium; It should be noted that the condensation reaction is carried out in the presence of an organic solvent A or in the absence of a solvent. Optionally, the organic solvent A is a mixture of one or more of acetone, methanol, tetrahydrofuran, dichloroethane, ethanol, isopropanol, dioxane, toluene, dimethyl sulfoxide, N-methylpyrrolidone, and N,N-dimethylformamide.

[0022] Step 2: Adding base B and methylating agent to the 2-(4-nitrobenzylidene)cyclopentanone in batches, reacting in the presence of organic solvent B, the reaction temperature is 0°C to 150°C, the reaction time is 1h to 15h, to obtain a mixed solution B, extracting, separating and dehydrating the mixed solution B in sequence, to obtain 2,2-dimethyl-5-(4-nitrobenzylidene)cyclopentanone (III); The molar ratio of the 2-(4-nitrobenzylidene)cyclopentanone, the base B, and the methylating agent is 1:(2.0-4.0):(2.0-5.0), the base B is one of sodium hydride, sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide, sodium tert-butoxide, potassium tert-butoxide, potassium carbonate, sodium carbonate, cesium carbonate, and butyl lithium, the methylating agent is one of iodomethane, methyl bromide, dimethyl sulfate, and dimethyl carbonate, and the organic solvent B is one of dichloromethane, acetone, methanol, tetrahydrofuran, ethyl acetate, ethanol, isopropanol, dioxane, toluene, chlorobenzene, dimethyl sulfoxide, and N,N-dimethylformamide, or a mixture of several thereof.

[0023] Step 3: In the presence of an organic solvent C, the 2,2-dimethyl-5-(4-nitrobenzyl)cyclopentanone and the catalyst are added to a reaction kettle, hydrogen is introduced into the reaction kettle until the hydrogen pressure in the reaction kettle is 1ATM to 100ATM, and the mixture is stirred for reduction reaction at a reaction temperature of 0°C to 100°C for a reaction time of 1h to 20h to obtain a mixed solution C, and the mixed solution C is dehydrated to obtain 2,2-dimethyl-5-(4-aminobenzyl)cyclopentanone (IV); The catalyst is palladium carbon or Raney nickel, the organic solvent C is one or a mixture of dichloromethane, acetone, methanol, tetrahydrofuran, ethyl acetate, ethanol, isopropanol, dioxane, toluene, chlorobenzene, dimethyl sulfoxide, and N,N-dimethylformamide, and the molar ratio of the 2,2-dimethyl-5-(4-nitrobenzylidene)cyclopentanone to the catalyst is 1:(0.0001-0.05).

[0024] Step 4: The 2,2-dimethyl-5-(4-aminobenzyl)cyclopentanone and 10% hydrochloric acid are mixed and cooled to 0°C to 10°C, a metal nitrite aqueous solution is added dropwise, and the temperature is kept below 5°C for 1h to 3h, and a cuprous chloride hydrochloric acid solution is added dropwise to carry out a Sandmeyer reaction for 4h to 10h. After the reaction is completed, a sodium carbonate aqueous solution is added dropwise to adjust the pH to 7 to 8 to obtain a mixed solution D, and the mixed solution D is filtered to obtain a filter cake, and the filter cake is washed with water and dried to obtain 2,2-dimethyl-5-(4-chlorobenzyl)cyclopentanone (V); The molar ratio of the 2,2-dimethyl-5-(4-nitrobenzylidene)cyclopentanone, the metal nitrite and cuprous chloride is 1:(1.0-2.0):(1.5-3), and the metal nitrite is sodium nitrite.

[0025] Step 5: dissolving the cis-trans isomer mixture of metconazole obtained by the reaction in an organic solvent D at 40°C to 189°C by a one-pot method, and then cooling to 0°C to 30°C. The precipitated crystals are washed with a cold recrystallization solvent and then dried to obtain high-purity metconazole (VI); Wherein, the organic solvent D is one or a mixture of dichloromethane, acetone, methanol, tetrahydrofuran, ethyl acetate, acetonitrile, ethanol, isopropanol, dioxane, toluene, chlorobenzene, dimethyl sulfoxide, N,N-dimethylformamide.

[0026] The following are embodiments of the present invention. Example 1 Synthesis of 2-(4-nitrobenzylidene)cyclopentanone (Ⅱ) Cyclopentanone (36 g, 0.428 mol), p-nitrobenzaldehyde (64 g, 0.424 mol), sodium hydroxide (17.2 g, 0.428 mol) and 300 ml toluene were added to a 500 mL dry four-necked bottle, stirred at 25 °C for 6 hours, and ethyl acetate was added for extraction and separation. After spin drying, 2-(4-nitrobenzylidene)cyclopentanone was obtained with a yield of 90%.

[0027] Example 2 Synthesis of 2-(4-nitrobenzylidene)cyclopentanone (Ⅱ) In a 500mL three-necked flask, add cyclopentanone (36g, 0.428mol), p-nitrobenzaldehyde (64g, 0.424mol), sodium methoxide (24.5g, 0.45mol) and 200mL of dioxane, heat to reflux temperature (about 101°C) and maintain the reaction for 10 hours. After the reaction is completed, cool to room temperature, add water and ethyl acetate for extraction, separate the liquids, dry the organic phase with anhydrous sodium sulfate, and remove the solvent by rotary evaporation to obtain 2-(4-nitrobenzylidene)cyclopentanone with a yield of 85%.

[0028] Example 3 Synthesis of 2-(4-nitrobenzylidene)cyclopentanone (Ⅱ) In a 500mL round-bottom flask, add cyclopentanone (36g, 0.428mol), p-nitrobenzaldehyde (64g, 0.424mol), potassium hydroxide (23.6g, 0.428mol) and 150mL of tetrahydrofuran, and stir at room temperature for 8 hours. After the reaction is completed, pour the mixture into a separatory funnel, add water and ethyl acetate for extraction, separate the organic phase, dry it with anhydrous magnesium sulfate, and remove the solvent by rotary evaporation to obtain 2-(4-nitrobenzylidene)cyclopentanone with a yield of 88%.

[0029] Example 4 Synthesis of 2-(4-nitrobenzylidene)cyclopentanone (Ⅱ) In a 500mL round-bottom flask, add cyclopentanone (36g, 0.428mol), p-nitrobenzaldehyde (64g, 0.424mol), potassium hydroxide (23.6g, 0.428mol) and 150mL of tetrahydrofuran, and stir at room temperature for 8 hours. After the reaction is completed, pour the mixture into a separatory funnel, add water and ethyl acetate for extraction, separate the organic phase, dry it with anhydrous magnesium sulfate, and remove the solvent by rotary evaporation to obtain 2-(4-nitrobenzylidene)cyclopentanone with a yield of 88%.

[0030] Example 5 Synthesis of 2,2-dimethyl-5-(4-nitrobenzylidene)cyclopentanone (Ⅲ) Under nitrogen protection, 2-(4-nitrobenzyl)cyclopentanone (25.2 g, 0.116 mol), potassium tert-butoxide (39 g, 0.348 mol), and 300 ml of tetrahydrofuran were added to a dry 500 ml four-necked bottle. After stirring at -5 °C for one hour, iodomethane (82.3 g, 0.58 mol) was added dropwise. After the addition was completed, the mixture was reacted at 60 °C for 6 hours. After the reaction was completed, water and ethyl acetate were added for separation. The organic layer was washed with water and dried. After the solvent was removed by rotation, 2,2-dimethyl-5-(4-nitrobenzyl)cyclopentanone was obtained with a yield of 90%.

[0031] Example 6 Synthesis of 2,2-dimethyl-5-(4-nitrobenzylidene)cyclopentanone (Ⅲ) Under nitrogen protection, 2-(4-nitrobenzylidene)cyclopentanone (25.2g, 0.116mol), sodium hydride (60% dispersed in mineral oil, 11.6g, 0.29mol) and 150ml of dimethylformamide were added to a dry 500ml four-necked bottle. After stirring at room temperature for 1 hour, iodomethane (41.15g, 0.29mol) was slowly added dropwise. After the addition was complete, the reaction temperature was raised to 40°C and the reaction was maintained for 4 hours. After the reaction was completed, the reaction mixture was poured into ice water, extracted with ethyl acetate, the organic phases were combined and washed with saturated brine, the organic phases were dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation to obtain 2,2-dimethyl-5-(4-nitrobenzylidene)cyclopentanone with a yield of 85%.

[0032] Example 7 Synthesis of 2,2-dimethyl-5-(4-nitrobenzylidene)cyclopentanone (Ⅲ) Under nitrogen protection, 2-(4-nitrobenzylidene)cyclopentanone (25.2g, 0.116mol), potassium hydroxide (13.1g, 0.232mol) and 150ml of acetonitrile were added to a dry 500ml three-necked flask. After stirring at room temperature for 1 hour, dimethyl sulfate (34.8g, 0.29mol) was slowly added dropwise. After the addition was completed, the reaction temperature was raised to 50°C and the reaction was maintained for 5 hours. After the reaction was completed, the reaction mixture was poured into ice water, extracted with ethyl acetate, and the organic phases were combined and washed with saturated brine. After the organic phase was dried over anhydrous sodium sulfate, the solvent was removed by rotary evaporation to obtain 2,2-dimethyl-5-(4-nitrobenzylidene)cyclopentanone with a yield of 88%.

[0033] Example 8 Synthesis of 2,2-dimethyl-5-(4-nitrobenzylidene)cyclopentanone (Ⅲ) Under nitrogen protection, 2-(4-nitrobenzylidene)cyclopentanone (25.2 g, 0.116 mol), potassium tert-butoxide (39 g, 0.348 mol) and 200 ml of tetrahydrofuran were added to a dry 500 ml round-bottom flask. The reaction system was cooled to -10 °C, and methyl methanesulfonate (46.8 g, 0.411 mol) was slowly added dropwise at this temperature. After the addition was completed, the reaction temperature was gradually raised to room temperature, and the reaction was continued to stir for 8 hours. After the reaction was completed, the mixture was poured into a separatory funnel, and water and ethyl acetate were added for extraction. After separating the organic phase, it was dried with anhydrous sodium sulfate, and the solvent was removed by rotary evaporation to obtain 2,2-dimethyl-5-(4-nitrobenzylidene)cyclopentanone with a yield of 87%.

[0034] Example 9 Synthesis of 2,2-dimethyl-5-(4-aminobenzyl)cyclopentanone (Ⅳ) A dry 500mL reactor was added with 2,2-dimethyl-5-(4-nitrobenzyl)cyclopentanone (10 g, 0.058 mol) and Pd / C (5%) (0.122 g, 0.0058 mol), and the mixture was evacuated and replaced with hydrogen two to three times. After the replacement, 200 mL of methanol solvent was added under a hydrogen atmosphere, and hydrogen was filled to 1.5 ATM. The mixture was stirred at room temperature for 8 hours, and the solvent was removed by vortexing to obtain 2,2-dimethyl-5-(4-aminobenzyl)cyclopentanone with a yield of 86%.

[0035] Example 10 Synthesis of 2,2-dimethyl-5-(4-aminobenzyl)cyclopentanone (Ⅳ) A dry 500 mL reactor was added with 2,2-dimethyl-5-(4-nitrobenzyl)cyclopentanone (10 g, 0.058 mol), iron powder (16.2 g, 0.29 mol) and acetic acid (100 mL). The reaction mixture was heated to reflux temperature and stirred at this temperature for 6 hours. After the reaction was completed, the mixture was cooled to room temperature and filtered to remove the unreacted iron powder. The filtrate was poured into a separatory funnel, and water and ethyl acetate were added for extraction. After the organic phase was separated, it was washed with a saturated sodium bicarbonate solution and then dried over anhydrous sodium sulfate. After the solvent was removed by rotary evaporation, 2,2-dimethyl-5-(4-aminobenzyl)cyclopentanone was obtained with a yield of 82%.

[0036] Embodiment 11 Synthesis of 2,2-dimethyl-5-(4-aminobenzyl)cyclopentanone (Ⅳ) 2,2-dimethyl-5-(4-nitrobenzyl)cyclopentanone (10 g, 0.058 mol), hydrazine hydrate (85% purity, 10.5 g, 0.174 mol) and anhydrous ethanol (150 mL) were added to a dry 500 mL round-bottom flask. The reaction mixture was heated to reflux temperature and stirred at this temperature for 4 hours. After the reaction was completed, the mixture was cooled to room temperature and filtered to remove insoluble matter. The filtrate was poured into a separatory funnel, and water and ethyl acetate were added for extraction. After separating the organic phase, it was dried over anhydrous sodium sulfate. After the solvent was removed by rotary evaporation, 2,2-dimethyl-5-(4-aminobenzyl)cyclopentanone was obtained with a yield of 80%.

[0037] Example 12 Synthesis of 2,2-dimethyl-5-(4-aminobenzyl)cyclopentanone (Ⅳ) In a dry 500mL autoclave, add 2,2-dimethyl-5-(4-nitrobenzyl)cyclopentanone (10g, 0.058mol), iron powder (16.2g, 0.29mol), acetic acid (100mL) and a small amount of hydrochloric acid (10mL, 37%). Heat the reaction mixture to 100°C and stir at this temperature for 8 hours. After the reaction is completed, the mixture is cooled to room temperature and filtered to remove the unreacted iron powder. The filtrate is poured into a separatory funnel, and water and ethyl acetate are added for extraction. After separating the organic phase, wash it with a saturated sodium bicarbonate solution and then dry it with anhydrous sodium sulfate. After the solvent is removed by rotary evaporation, 2,2-dimethyl-5-(4-aminobenzyl)cyclopentanone is obtained with a yield of 84%.

[0038] Embodiment 13 Synthesis of 2,2-dimethyl-5-(4-chlorobenzyl)cyclopentanone (V) 2,2-dimethyl-5-(4-aminobenzyl)cyclopentanone (24.5g, 0.1mol) and 200ml of 10% hydrochloric acid were added to a 500mL four-necked bottle and cooled to 0°C. An aqueous solution of sodium nitrite (8.3g, 0.12mol) was slowly added dropwise, and the temperature was kept below 5°C for two hours. Then a hydrochloric acid solution of cuprous chloride (24.8, 0.25mol) was added dropwise to react for 6 hours. After the reaction, an aqueous solution of sodium carbonate was added dropwise to adjust the pH to 7-8, and the filter cake was washed with water and dried to obtain 2,2-dimethyl-5-(4-chlorobenzyl)cyclopentanone with a yield of 90%.

[0039] Embodiment 14 Synthesis of 2,2-dimethyl-5-(4-chlorobenzyl)cyclopentanone (V) 2,2-dimethyl-5-(4-aminobenzyl)cyclopentanone (24.5 g, 0.1 mol) was dissolved in 150 mL of dichloromethane and placed in a dry 1 L three-necked flask. The reaction mixture was cooled to 0 °C under nitrogen protection. Subsequently, a dichloromethane solution (50 mL) of thionyl chloride (14.2 g, 0.12 mol) was slowly added dropwise, and the drop rate was controlled to keep the reaction temperature no higher than 5 °C. After the addition was completed, the reaction mixture was gradually warmed to room temperature and stirred for 4 hours. After the reaction was completed, the mixture was poured into ice water and extracted three times with dichloromethane. The organic phases were combined and washed with saturated sodium bicarbonate solution and then dried over anhydrous sodium sulfate. After the solvent was removed by rotary evaporation, the residue was purified by silica gel column chromatography to obtain 2,2-dimethyl-5-(4-chlorobenzyl)cyclopentanone with a yield of 89%.

[0040] Embodiment 15 Synthesis of 2,2-dimethyl-5-(4-chlorobenzyl)cyclopentanone (V) In a dry 500mL round-bottom flask, 2,2-dimethyl-5-(4-aminobenzyl)cyclopentanone (24.5g, 0.1mol), sodium chloride (11.7g, 0.2mol) and 150mL of water were added. Under stirring, concentrated hydrochloric acid (37%, about 20mL) was slowly added until the pH value of the reaction mixture dropped to 1-2. Subsequently, the reaction mixture was heated to reflux temperature and stirred at this temperature for 6 hours. After the reaction was completed, the mixture was cooled to room temperature and extracted three times with ethyl acetate. The organic phases were combined and washed with saturated sodium bicarbonate solution and then dried over anhydrous sodium sulfate. After the solvent was removed by rotary evaporation, the residue was purified by silica gel column chromatography to obtain 2,2-dimethyl-5-(4-chlorobenzyl)cyclopentanone with a yield of 88%.

[0041] Example 16 Synthesis of 2,2-dimethyl-5-(4-chlorobenzyl)cyclopentanone (V) In a dry 500mL three-necked flask, 2,2-dimethyl-5-(4-aminobenzyl)cyclopentanone (24.5g, 0.1mol), sodium chloride (11.7g, 0.2mol) and 150mL of water were added. Under stirring, concentrated hydrochloric acid (37%, about 20mL) was slowly added until the pH value of the reaction mixture dropped to 1-2. Subsequently, the reaction mixture was heated to reflux temperature and stirred at this temperature for 6 hours. After the reaction was completed, the mixture was cooled to room temperature and extracted three times with ethyl acetate. The organic phases were combined and washed with saturated sodium bicarbonate solution and then dried over anhydrous sodium sulfate. After the solvent was removed by rotary evaporation, the residue was purified by silica gel column chromatography to obtain 2,2-dimethyl-5-(4-chlorobenzyl)cyclopentanone with a yield of 88%.

[0042] Embodiment 17 Synthesis of Metconazole (VI) In a 250ml four-necked bottle, add trimethyl sulfoxide iodide (25.4g, 0.115mol), 60% sodium hydride (7.18g, 0.299mol), evacuate, replace nitrogen three times, add 150ml dimethyl sulfoxide, and after the reaction has no bubbles, add 2,2-dimethyl-5-(4-chlorobenzyl) cyclopentanone (25g, 0.106mol), and then react at 90℃ for 24h. After the reaction, add water and toluene, extract and layer, extract the aqueous phase with toluene twice, wash the toluene phase with water, desolventize, remove the toluene, reduce the pressure of the oil pump, remove the high boiling point impurities, recrystallize with 5 times methanol, obtain metconazole, dry, the yield is 90.5%, the sample is tested by high performance gas chromatography, the cis content is 98.31%, and the trans content is 0.97%. For the test results, please refer to Figure 2 shown.

[0043] Test Case Through the above examples, we have successfully synthesized metconazole compounds and optimized the yield and the ratio of cis-trans isomers through different synthetic routes. In order to further verify the biological activity of these compounds, we conducted the following biological test experiments.

[0044] Test Example 1 Experimental Materials and Methods 1. Experimental Materials: The metconazole samples used were the metconazole synthesized in Example 17 and a commercially available metconazole reference substance.

[0045] Experimental subjects: Common plant pathogens were selected, such as Gibberella zeae, Rhizoctonia solani and Botrytis cinerea.

[0046] Experimental method: The mycelium growth rate method was used to test the biological activity. The metconazole sample was dissolved in an appropriate organic solvent, and then diluted with sterile water to different concentrations of the solution. The solution was evenly applied on the PDA culture medium. After the solvent evaporated, the pathogen cake was inoculated. The culture medium without the solution was used as the control group. Three replicates were set for each treatment. The inoculated culture dish was placed in a constant temperature incubator for culture, and the colony diameter was measured regularly to calculate the inhibition rate.

[0047] Experimental Results 1. Inhibitory effect on wheat fusarium sphaeroides: The metconazole synthesized in Example 17 has a significant inhibitory effect on wheat fusarium sphaeroides, wherein the inhibition rate can reach more than 90% at a concentration of 100 mg / L.

[0048] Inhibitory effect on rice sheath blight: The metconazole synthesized in Example 17 showed good inhibitory activity against rice sheath blight, with an inhibition rate of 88% at a concentration of 100 mg / L.

[0049] Inhibitory effect on tomato gray mold: The metconazole samples showed good inhibitory activity against tomato gray mold. The inhibition rate of the metconazole synthesized in Example 17 could reach more than 95% at a concentration of 50 mg / L.

[0050] Test Example 2 Experimental Materials and Methods 1. Experimental Materials: The metconazole samples used were metconazole (VI) synthesized in Example 17 and a commercially available metconazole reference substance.

[0051] Experimental subjects: Several important crop pests were selected, including cotton aphid (Aphis gossypii), rice planthopper (Nilaparvata lugens) and cabbage worm (Pieris rapae).

[0052] Experimental method: The biological activity test was conducted by leaf immersion method. Dissolve the metconazole sample in an appropriate organic solvent and then dilute it with sterile water to different concentrations. Soak fresh plant leaves in the solution for a few seconds, then take them out and dry them naturally. Place the treated leaves in a petri dish and inoculate hungry pests. Leaves without the solution were used as the control group. Three replicates were set for each treatment. The petri dish was placed under constant temperature conditions, and the mortality rate and feeding conditions of the pests were regularly observed and recorded.

[0053] Experimental Results 1. Insecticidal effect on cotton aphids: The metconazole synthesized in Example 17 showed high insecticidal activity against cotton aphids, wherein at a concentration of 100 mg / L, the mortality rate after 24 hours could reach more than 85%, while the mortality rate of the commercially available reference product at the same concentration was about 75%.

[0054] Insecticidal effect on rice planthoppers: The metconazole synthesized in Example 17 has a good inhibitory effect on rice planthoppers. At a concentration of 100 mg / L, the mortality rate can reach 80% after 48 hours.

[0055] Insecticidal effect on cabbage loopers: The metconazole samples synthesized in Example 17 all showed significant insecticidal activity against cabbage loopers. At a concentration of 50 mg / L, the mortality rate after 72 hours could reach more than 90%, while the mortality rate of the commercially available reference product at the same concentration was about 80%.

[0056] In summary, high-purity cis-metconazole is prepared by using cyclopentanone as a raw material through condensation reaction, reduction reaction, Sandmeyer reaction, recrystallization and the like. Compared with the method of preparing metconazole in the prior art, it has the advantages of non-toxicity, low risk factor, low cost, high preparation efficiency, simple steps, high purity, etc., and is suitable for large-scale industrial production. The synthesized metconazole sample has a significant inhibitory effect on plant pathogens and has good insecticidal activity against a variety of crop pests. Moreover, the samples obtained by different synthetic routes all perform well, among which Example 17 is the best. The optimized synthetic route greatly improves the purity of metconazole and has a good market prospect.

[0057] The above is only a preferred embodiment of the present invention. It should be noted that, for those skilled in the art, several improvements and modifications can be made without departing from the principles of the present invention, and these improvements and modifications should also be considered as the protection scope of the present invention. The structures, devices and operating methods not specifically described and explained in the present invention shall be implemented according to the conventional means in the art unless otherwise specified and limited.

Claims

1. A new process for synthesizing high-purity metconazole, characterized in that: The following steps are involved: Step 1: Under the catalysis of base A, cyclopentanone and p-nitrobenzaldehyde are mixed for condensation reaction and dehydration to obtain 2-(4-nitrobenzylidene)cyclopentanone; Step 2: Under the catalysis of base B, the 2-(4-nitrobenzylidene)cyclopentanone, the methylating agent and the solvent B are mixed and stirred, and after the reaction is completed, dehydration is performed to obtain 2,2-dimethyl-5-(4-nitrobenzylidene)cyclopentanone; Step 3: Under the action of a catalyst, the 2,2-dimethyl-5-(4-nitrobenzyl)cyclopentanone is mixed with hydrogen to undergo a reduction reaction and dehydrate to obtain 2,2-dimethyl-5-(4-aminobenzyl)cyclopentanone; Step 4: The 2,2-dimethyl-5-(4-aminobenzyl)cyclopentanone is subjected to a Sandmeyer reaction to obtain 2,2-dimethyl-5-(4-chlorobenzyl)cyclopentanone; Step 5: Recrystallize the crude metconazole synthesized from 2,2-dimethyl-5-(4-chlorobenzyl)cyclopentanone through a one-pot method to obtain high-purity metconazole.

2. A new process for synthesizing high-purity metconazole according to claim 1, characterized in that: The Step 1 is specifically as follows: Cyclopentanone, p-nitrobenzaldehyde and base A are mixed and stirred for condensation reaction at a reaction temperature of 0°C to 150°C for a reaction time of 1h to 15h to obtain a mixed solution A, and the mixed solution A is sequentially extracted, separated and dehydrated to obtain 2-(4-nitrobenzyl)cyclopentanone, wherein the molar ratio of the cyclopentanone, p-nitrobenzaldehyde and base A is 1:(0.8-1.2):(0.01-0.5).

3. A new process for synthesizing high-purity metconazole according to claim 2, characterized in that: In the Step 1, the condensation reaction is carried out in the presence of an organic solvent A or in the absence of a solvent. Optionally, the organic solvent A is a mixture of one or more of acetone, methanol, tetrahydrofuran, dichloroethane, ethanol, isopropanol, dioxane, toluene, dimethyl sulfoxide, N-methylpyrrolidone, and N,N-dimethylformamide, and the base A is one of sodium hydroxide, potassium hydroxide, sodium methoxide, sodium hydride, and tert-butyl lithium.

4. A new process for synthesizing high-purity metconazole according to claim 1, characterized in that: The Step 2 is specifically as follows: Adding base B and a methylating agent to the 2-(4-nitrobenzyl)cyclopentanone in batches, reacting in the presence of an organic solvent B, the reaction temperature is 0°C to 150°C, the reaction time is 1h to 15h, and a mixed solution B is obtained. The mixed solution B is sequentially extracted, separated and dehydrated to obtain 2,2-dimethyl-5-(4-nitrobenzyl)cyclopentanone, wherein the molar ratio of the 2-(4-nitrobenzyl)cyclopentanone, the base B and the methylating agent is 1:(2.0-4.0):(2.0-5.0).

5. A new process for synthesizing high-purity metconazole according to claim 5, characterized in that: The base B is one of sodium hydride, sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide, sodium tert-butoxide, potassium tert-butoxide, potassium carbonate, sodium carbonate, cesium carbonate, and butyl lithium; the methylating agent is one of methyl iodide, methyl bromide, dimethyl sulfate, and dimethyl carbonate; the organic solvent B is one of dichloromethane, acetone, methanol, tetrahydrofuran, ethyl acetate, ethanol, isopropanol, dioxane, toluene, chlorobenzene, dimethyl sulfoxide, and N,N-dimethylformamide, or a mixture of several thereof.

6. A new process for synthesizing high-purity metconazole according to claim 1, characterized in that: The Step 3 is specifically as follows: In the presence of an organic solvent C, the 2,2-dimethyl-5-(4-nitrobenzyl)cyclopentanone and a catalyst of palladium carbon or Raney nickel are added to a reaction kettle, hydrogen is introduced into the reaction kettle until the hydrogen pressure in the reaction kettle is 1ATM to 100ATM, and a reduction reaction is carried out with stirring. The reaction temperature is 0°C to 100°C, and the reaction time is 1h to 20h to obtain a mixed solution C. The mixed solution C is dehydrated to obtain 2,2-dimethyl-5-(4-aminobenzyl)cyclopentanone, wherein the molar ratio of the 2,2-dimethyl-5-(4-nitrobenzyl)cyclopentanone to the catalyst is 1:(0.0001 to 0.05).

7. A new process for synthesizing high-purity metconazole according to claim 9, characterized in that: The organic solvent C is one or a mixture of dichloromethane, acetone, methanol, tetrahydrofuran, ethyl acetate, ethanol, isopropanol, dioxane, toluene, chlorobenzene, dimethyl sulfoxide, and N,N-dimethylformamide.

8. A new process for synthesizing high-purity metconazole according to claim 1, characterized in that: The Step 4 is specifically as follows: The 2,2-dimethyl-5-(4-aminobenzyl)cyclopentanone and 10% hydrochloric acid are mixed and cooled to 0°C to 10°C, a sodium nitrite aqueous solution is added dropwise, and the mixture is kept warm at below 5°C for 1h to 3h, and a cuprous chloride hydrochloric acid solution is added dropwise to carry out a Sandmeyer reaction for 4h to 10h. After the reaction is completed, a sodium carbonate aqueous solution is added dropwise to adjust the pH to 7 to 8 to obtain a mixed solution D, and the mixed solution D is filtered to obtain a filter cake, and the filter cake is washed with water and dried to obtain 2,2-dimethyl-5-(4-chlorobenzyl)cyclopentanone, wherein the molar ratio of the 2,2-dimethyl-5-(4-nitrobenzyl)cyclopentanone, sodium nitrite, and cuprous chloride is 1:(1.0 to 2.0):(1.5 to 3).

9. A new process for synthesizing high-purity metconazole according to claim 1, characterized in that: In the Step 5, the recrystallization process is specifically as follows: dissolving the cis-trans isomer mixture of metconazole obtained by the reaction in an organic solvent D at 40°C to 189°C, then cooling to 0°C to 30°C, washing the precipitated crystals with a cold recrystallization solvent and then drying to obtain high-purity metconazole.

10. A new process for synthesizing high-purity metconazole according to claim 14, characterized in that: The organic solvent D is one or a mixture of dichloromethane, acetone, methanol, tetrahydrofuran, ethyl acetate, acetonitrile, ethanol, isopropanol, dioxane, toluene, chlorobenzene, dimethyl sulfoxide, and N,N-dimethylformamide.

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