Process for preparing prothioconazole and intermediate thereof

Abstract

The invention belongs to the technical field of prothioconazole preparation, and particularly relates to a process for preparing prothioconazole and an intermediate thereof. According to the method, the production efficiency and the product purity are remarkably improved, one-pot chlorination-ring opening and ionic liquid catalyzed microchannel ring closing reaction are adopted, the reaction time of key intermediates is greatly shortened, the steps of separation and purification of the intermediates are reduced, and efficient linkage of the whole process from raw materials to the final product prothioconazole is achieved. And the conditions of each step are mild and controllable, the final product is high in yield and excellent in purity, and the production requirements of high-quality active compounds are met. According to the preparation method disclosed by the invention, the lithium bis (trifluoromethanesulfonimide), the carboxyl functionalized ionic liquid and the nano Fe2O3 / Al2O3 aerogel catalyst are reasonably applied, so that the purity and the yield of the product are improved, part of the product can be recycled, and the waste discharge and the production cost are reduced. And a feasible technical path is provided for large-scale, low-cost and high-quality production of prothioconazole.

Description

Technical Field

[0001] This invention belongs to the field of prothioconazole preparation technology, specifically relating to a process for preparing prothioconazole and its intermediates. Background Technology

[0002] Prothioconazole, a highly effective and broad-spectrum triazole thionyl fungicide, is widely used for disease control in important food crops and cash crops such as wheat, corn, and soybeans due to its excellent disease control efficacy and low toxicity to crops. With the increasing demand for green agricultural development, the market has set higher standards for the purity, production efficiency, and environmental friendliness of prothioconazole technical.

[0003] Existing synthetic processes often suffer from problems such as lengthy steps, use of toxic and hazardous solvents, expensive and difficult-to-recover catalysts, poor reaction selectivity, and low overall yield. For example, traditional cyclization reactions are inefficient, Grignard reactions require harsh conditions, and solvents and catalysts in multiple steps are not recycled, increasing production costs and environmental burden.

[0004] In summary, the existing prothioconazole preparation process is subject to multiple constraints in terms of efficiency, environmental protection, cost, and industrialization feasibility. There is an urgent need to develop a new process that is efficient, simple, produces less waste, and is easy to industrialize, in order to break through the existing technological bottlenecks and meet the market demand for large-scale production of high-quality prothioconazole technical. Summary of the Invention

[0005] The purpose of this invention is to address existing problems by providing a process for preparing prothioconazole and its intermediates.

[0006] This invention is achieved through the following technical solution: A process for preparing prothioconazole includes the following steps: S1. One-pot chlorination-ring-opening reaction for the preparation of 3,5-dichloro-2-pentanone: Using α-acetyl-γ-butyrolactone as a raw material, chlorination was carried out with thionyl chloride in the presence of lithium bis(trifluoromethanesulfonylimide), followed by direct addition of hydrochloric acid aqueous solution to carry out ring-opening reaction, to obtain 3,5-dichloro-2-pentanone. S2. Preparation of 1-chloro-1-acetylcyclopropane by ionic liquid-catalyzed cyclization: The 3,5-dichloro-2-pentanone obtained in step S1 was subjected to a cyclization reaction under alkaline conditions in the presence of the carboxyl-functionalized ionic liquid 1-carboxyethyl-3-methylimidazolium bromide to give 1-chloro-1-acetylcyclopropane. S3. Preparation of 2-chloro-1-(1-chlorocyclopropyl)acetone by secondary chlorination: The 1-chloro-1-acetylcyclopropane obtained in step S2 was reacted with chlorine gas under cyclopentylmethyl ether and ultraviolet light to give 2-chloro-1-(1-chlorocyclopropyl)ethyl ketone. S4. Grignard condensation to prepare 2-(1-chlorocyclopropyl)-3-chloro-1-(2-chlorophenyl)-2-propanol: A Grignard reagent was prepared by using o-chlorobenzyl chloride, and then condensed with 2-chloro-1-(1-chlorocyclopropyl)ethyl ketone obtained in step S3 to give 2-(1-chlorocyclopropyl)-3-chloro-1-(2-chlorophenyl)-2-propanol. S5. One-pot hydrazino-cyclization preparation of prothioconazole precursor: The 2-(1-chlorocyclopropyl)-3-chloro-1-(2-chlorophenyl)-2-propanol obtained in step S4 was reacted with hydrazine hydrate and sodium thiocyanate in a mixed solvent of aminosulfonic acid and ethanol-water to give the 1,2,4-triazolidine-5-thione precursor. S6. Oxidative dehydrogenation to prepare prothioconazole: The 1,2,4-triazolidine-5-thione precursor obtained in step S5 was reacted with an oxidant in the presence of a catalyst to oxidize and dehydrogenate prothioconazole.

[0007] A method for preparing the intermediate 3,5-dichloro-2-pentanone, comprising: adding α-acetyl-γ-butyrolactone and 1-2% by mass of lithium bis(trifluoromethanesulfonylimide) (LiNTf2) as a Lewis acid catalyst in a reactor; slowly adding sulfoxide (SOCl2) as a chlorinating agent at a rate of 5-8 mL / h; the molar ratio of sulfoxide to the raw material being 1.13:1; controlling the temperature at 0-5°C during the addition; after the addition is complete; raising the temperature to 60-70°C and reacting for 2-4 h; directly adding a 30% hydrochloric acid aqueous solution to the reaction system; and carrying out a ring-opening reaction at 90-95°C for 3-5 h; after the reaction is complete; cooling to room temperature; allowing to stand and separating the liquids; and washing the organic phase with water and distilling under reduced pressure to obtain 3,5-dichloro-2-pentanone.

[0008] A method for preparing the intermediate 1-chloro-1-acetylcyclopropane, the method comprising: mixing 3,5-dichloro-2-pentanone with a 20% sodium hydroxide solution (the mass ratio of 20% sodium hydroxide solution to 3,5-dichloro-2-pentanone is 2:1), adding 2-3% by mass of 3,5-dichloro-2-pentanone of a carboxyl-functionalized ionic liquid 1-carboxyethyl-3-methylimidazolium bromide as a catalyst and phase transfer agent, passing the mixture into a microchannel reactor, reacting at 85-90°C for 10-15 min, allowing the reaction solution to stand and separate into layers after outflow, the aqueous phase of the ionic liquid can be directly recycled, and the organic phase is washed with water and dried to obtain 1-chloro-1-acetylcyclopropane.

[0009] A method for preparing the intermediate 2-chloro-1-(1-chlorocyclopropyl)ethyl ketone, the method comprising: dissolving 1-chloro-1-acetylcyclopropane in cyclopentylmethyl ether (CPME) at a mass-to-volume ratio of 1:3; slowly introducing chlorine gas (flow rate 0.5 g / min) under ultraviolet light (wavelength 254 nm) at 10-15 °C until the reaction is complete; after the reaction is complete, washing with 10% sodium sulfite solution to remove residual chlorine gas; allowing the mixture to stand and separating the liquids; recovering the CPME solvent by vacuum distillation of the organic phase to obtain 2-chloro-1-(1-chlorocyclopropyl)ethyl ketone.

[0010] A method for preparing the intermediate 2-(1-chlorocyclopropyl)-3-chloro-1-(2-chlorophenyl)-2-propanol, wherein the method comprises: under N2 protection, using 2-methyltetrahydrofuran (2-MeTHF) as solvent, reacting o-chlorobenzyl chloride with magnesium shavings to prepare o-chlorobenzyl magnesium chloride Grignard reagent in situ, wherein the molar ratio of o-chlorobenzyl chloride to magnesium shavings is 1:(1~1.05); Then, at -10 to -5°C, a 2-MeTHF solution of 2-chloro-1-(1-chlorocyclopropyl)ethyl ketone (total volume being 2.5 to 3 times the total mass of o-chlorobenzyl chloride and 2-chloro-1-(1-chlorocyclopropyl)ethyl ketone) was slowly added dropwise to Grignard reagent (dropping rate 8 to 12 mL / h). The molar ratio of Grignard reagent to ethyl ketone was 1.03:1. After the addition was complete, the reaction was kept at this temperature for 1 to 2 hours. After the reaction was completed, the solution was quenched with 10% dilute hydrochloric acid, separated, and the organic phase was concentrated under reduced pressure to recover 2-MeTHF, yielding the crude product.

[0011] A method for preparing the intermediate 1,2,4-triazolidine-5-thione precursor, the method comprising: adding 2-(1-chlorocyclopropyl)-3-chloro-1-(2-chlorophenyl)-2-propanol, hydrazine hydrate, and sodium thiocyanate in a molar ratio of 1:(1.1~1.3):(1.05~1.2) to a mixed solvent of ethanol-water (volume ratio 1:1), wherein the mass-volume ratio of the chlorool to the ethanol-water mixed solvent is 1 g:(2~4) mL; reacting at 75~80℃ for 4~6 h under the catalysis of aminosulfonic acid (mass 0.01~0.03 times that of the chlorool); after the reaction is completed, cooling and crystallizing, filtering, and distilling the filtrate to recover ethanol and excess hydrazine hydrate; and drying the filter cake to obtain the 1,2,4-triazolidine-5-thione precursor.

[0012] Furthermore, the catalyst mentioned in step S6 is a supported nano-iron oxide / alumina catalyst, which is added at a mass of 5-8% of the 1,2,4-triazolidine-5-thione precursor; The oxidant is an aqueous solution of tert-butyl hydrogen peroxide, which is added at 34-39% by mass of the 1,2,4-triazolidine-5-thione precursor; The reaction was carried out in ethyl acetate solvent at 25–40 °C.

[0013] Furthermore, the preparation of the supported nano-iron oxide / alumina (Fe2O3 / Al2O3) catalyst includes the following steps: (1) Disperse boehmite (AlO(OH)) in deionized water at a mass-to-volume ratio of 1g:(5~7)mL, stir and mix at 60~70℃, add 65% nitric acid dropwise until the solution is clear, and continue stirring for 1~1.5h to obtain boehmite (γ-AlOOH) sol; Ferric chloride hexahydrate (FeCl3·6H2O) was dissolved in a mixed solvent of anhydrous ethanol and acetylacetone (volume ratio 3:1) at a mass-to-volume ratio of 1g:(4~5)mL, and stirred for 30~40min to obtain an iron source solution. According to the mass ratio of Fe2O3:Al2O3=1:10, the boehmite sol was slowly added to the iron source solution and stirred at 500~600rpm for 25~35min to obtain a mixed sol for later use. (2) Pluronic P123 (triblock copolymer) and 1-butyl-3-methylimidazolium tetrafluoroborate were added to the above mixed sol at a mass ratio of 2:1. After stirring for 10-20 min, the mixture was transferred to the reaction tank of an ultrasonic cell disruptor, cooled in an ice-water bath, and ultrasonically treated for 30-35 min at a power of 400W. Then the mixture was transferred to a glass culture dish and placed in an oven at 40-45℃ for 10-12 h to form a wet gel. The gel was then transferred to an oven at 60-65℃ for aging for 20-26 h. (3) Place the aged wet gel in an autoclave, seal it, and introduce liquid CO2 until the gel is submerged. Heat the gel to 40-45°C, pressurize it to 12 MPa, and maintain it for 2-2.5 h. Then release CO2 at a rate of 0.4-0.6 MPa / h until atmospheric pressure is reached to obtain Fe-Al composite aerogel. (4) Transfer the aerogel to a corundum crucible, place it in a muffle furnace, calcine it by programmed heating, and then cool it naturally to room temperature to obtain a supported nano Fe2O3 / Al2O3 catalyst. Grind it through a 100-mesh sieve for later use.

[0014] Furthermore, the programmed temperature rise is specifically as follows: the temperature is increased to 350℃ at a rate of 1~2℃ / min and held for 2~2.5h; then the temperature is increased to 500℃ at a rate of 4~5℃ / min and held for 2.5~3.5h.

[0015] Further, after the reaction in step S6 is completed, the catalyst is recovered by hot filtration. The filtrate is washed with water, concentrated under reduced pressure, and then n-heptane is added to crystallize. After filtration and drying, high-purity prothioconazole technical is obtained.

[0016] The present invention has the following advantages over the prior art: 1. This invention provides a process for preparing prothioconazole and its intermediates, which significantly improves upon existing technologies, substantially enhancing production efficiency and product purity. It employs a one-pot chlorination-ring-opening and ionic liquid-catalyzed microchannel ring-closure reaction, drastically shortening the reaction time of key intermediates and reducing intermediate separation and purification steps. This achieves highly efficient integration of the entire process from raw materials to the final product, prothioconazole. Furthermore, the conditions at each step are mild and controllable, resulting in a high final product yield and superior purity, meeting the production requirements of high-quality technical grade pesticide.

[0017] 2. This invention rationally utilizes lithium bis(trifluoromethanesulfonylimide), carboxyl-functionalized ionic liquid, and a self-made nano-Fe2O3 / Al2O3 aerogel catalyst. These catalysts not only possess high activity and selectivity but are also partially recyclable, reducing waste emissions and production costs to a certain extent. Furthermore, green solvents such as cyclopentylmethyl ether and 2-methyltetrahydrofuran are preferred to replace traditional toxic and harmful solvents, making the process safer and more environmentally friendly.

[0018] 3. This invention achieves efficient utilization of materials and reduces the generation of waste through strategies such as in-situ preparation of Grignard reagents, one-pot hydrazination-cyclization, and catalytic oxidation, providing a practical and feasible technical path for the large-scale, low-cost, and high-quality production of prothioconazole. Attached Figure Description

[0019] Figure 1 This is a comparison chart of the total yield results of the various embodiments and comparative examples of the present invention; Figure 2 The graph shows a comparison of the HPLC purity results of the final product, prothioconazole, in each example and comparative example. Detailed Implementation

[0020] To further explain the present invention, the following specific embodiments are described.

[0021] The raw material product information involved in this invention is shown in Table 1 below.

[0022] Table 1

[0023] Note: Unless otherwise specified, the raw materials used in this invention are all from commercially available conventional products.

[0024] Example 1 A process for preparing prothioconazole includes the following steps: S1. One-pot chlorination-ring-opening reaction for the preparation of 3,5-dichloro-2-pentanone: In a reactor, α-acetyl-γ-butyrolactone and 1% by mass of lithium bis(trifluoromethanesulfonyl)imide were added, and sulfoxide was slowly added dropwise at a rate of 5 mL / h. The molar ratio of sulfoxide to the raw material was 1.13:1. The temperature was controlled at 0℃ during the dropwise addition. After the dropwise addition was completed, the temperature was raised to 60℃ and reacted for 2 h. Then, 30% hydrochloric acid aqueous solution was added directly to the reaction system, and the ring-opening reaction was carried out at 90℃ for 3 h. After the reaction was completed, the mixture was cooled to room temperature, allowed to stand, and separated. The organic phase was washed with water and distilled under reduced pressure to obtain 3,5-dichloro-2-pentanone. S2. Preparation of 1-chloro-1-acetylcyclopropane by ionic liquid-catalyzed cyclization: The 3,5-dichloro-2-pentanone obtained in step S1 was mixed with a 20% sodium hydroxide solution (the mass ratio of the 20% sodium hydroxide solution to 3,5-dichloro-2-pentanone was 2:1). 2% by mass of the carboxyl-functionalized ionic liquid 1-carboxyethyl-3-methylimidazolium bromide of 3,5-dichloro-2-pentanone was added. The mixture was then fed into a microchannel reactor and reacted at 85°C for 10 min. After the reaction liquid flowed out, it was allowed to stand and separate into layers. The aqueous phase of the ionic liquid could be directly recycled. The organic phase was washed with water and dried to obtain 1-chloro-1-acetylcyclopropane. S3. Preparation of 2-chloro-1-(1-chlorocyclopropyl)acetone by secondary chlorination: The 1-chloro-1-acetylcyclopropane obtained in step S2 was dissolved in cyclopentylmethyl ether at a mass-to-volume ratio of 1:3. Chlorine gas was slowly introduced (flow rate 0.5 g / min) under ultraviolet light (wavelength 254 nm) at 10 °C until the reaction was complete. After the reaction was completed, the residual chlorine gas was removed by washing with 10% sodium sulfite solution. The mixture was allowed to stand and separated. The organic phase was subjected to vacuum distillation to recover the CPME solvent, yielding 2-chloro-1-(1-chlorocyclopropyl)ethyl ketone. S4. Grignard condensation to prepare 2-(1-chlorocyclopropyl)-3-chloro-1-(2-chlorophenyl)-2-propanol: Under N2 protection, using 2-methyltetrahydrofuran as solvent, o-chlorobenzyl chloride magnesium chloride Grignard reagent was prepared in situ by reacting o-chlorobenzyl chloride with magnesium shavings, wherein the molar ratio of o-chlorobenzyl chloride to magnesium shavings was 1:1. Then, at -10℃, the 2-MeTHF solution of 2-chloro-1-(1-chlorocyclopropyl)ethyl ketone obtained in step S3 (total volume being 2.5 times the total mass of o-chlorobenzyl chloride and 2-chloro-1-(1-chlorocyclopropyl)ethyl ketone) was slowly added dropwise to Grignard reagent (dropping rate 8 mL / h). The molar ratio of Grignard reagent to ethyl ketone was 1.03:1. After the addition was complete, the reaction was kept at this temperature for 1 h. After the reaction was completed, the solution was quenched with 10% dilute hydrochloric acid, separated, and the organic phase was concentrated under reduced pressure to recover 2-MeTHF, yielding the crude product. S5. One-pot hydrazino-cyclization preparation of prothioconazole precursor: The chlorool, hydrazine hydrate, and sodium thiocyanate obtained in step S4 were added in a single batch to a mixed solvent of ethanol and water (volume ratio 1:1) at a molar ratio of 1:1.1:1.05. The mass-volume ratio of chlorool to the ethanol-water mixed solvent was 1 g: 2 mL. The reaction was carried out at 75 °C for 4 h under the catalysis of aminosulfonic acid (mass of 0.01 times that of chlorool). After the reaction was completed, the mixture was cooled and crystallized. The mixture was filtered, and the filtrate was distilled to recover ethanol and excess hydrazine hydrate. The filter cake was dried to obtain the 1,2,4-triazolidine-5-thione precursor. S6. Oxidative dehydrogenation to prepare prothioconazole: The triazolidine-5-thione precursor obtained in step S5 was dissolved in ethyl acetate, and a supported nano-iron oxide / alumina catalyst of 5% by mass of the precursor was added. At 35°C, an aqueous solution of tert-butyl hydrogen peroxide of 34% by mass of the triazolidine-5-thione precursor was slowly added dropwise. After the reaction was completed, the catalyst was recovered by hot filtration. The filtrate was washed with water, concentrated under reduced pressure, and then crystallized by adding n-heptane. After filtration and drying, high-purity prothioconazole technical was obtained. The preparation of the supported nano-iron oxide / alumina catalyst includes the following steps: (1) Disperse boehmite in deionized water at a mass-volume ratio of 1g:5mL, stir and mix at 60℃, add 65% nitric acid dropwise until the solution is clear, and continue stirring for 1h to obtain boehmite sol; Ferric chloride hexahydrate was dissolved in a mixed solvent of anhydrous ethanol and acetylacetone (volume ratio 3:1) at a mass-to-volume ratio of 1 g: 4 mL, and stirred for 30 min to obtain an iron source solution. According to the mass ratio of Fe2O3:Al2O3=1:10, the boehmite sol was slowly added to the iron source solution and stirred at 500 rpm for 25 min to obtain a mixed sol for later use. (2) Pluronic P123 (triblock copolymer) and 1-butyl-3-methylimidazolium tetrafluoroborate were added to the above mixed sol at a mass ratio of 2:1. After stirring for 10 min, the mixture was transferred to the reaction tank of an ultrasonic cell disruptor, cooled in an ice-water bath, and ultrasonically treated for 30 min at a power of 400 W. Then the mixture was transferred to a glass culture dish and placed in a 40°C oven for 10 h to form a wet gel. The gel was then transferred to a 60°C oven and aged for 20 h. The template agent is a polyoxyethylene-polyoxypropylene-polyoxyethylene triblock copolymer with the general formula HO-(CH2CH2O). a -[CH(CH3)CH2O] b -(CH2CH2O) a -H, wherein the average molecular weight (M) of the polyoxypropylene block n The concentration of the polyoxyethylene group is 3,000~5,000 g / mol, and the polyoxyethylene segment accounts for 30%±5% of the total weight. (3) Place the aged wet gel in an autoclave, seal it, and introduce liquid CO2 until the gel is submerged. Heat the gel to 40°C, pressurize it to 12 MPa, maintain it for 2 hours, and then release CO2 at a rate of 0.4 MPa / h until atmospheric pressure is reached to obtain Fe-Al composite aerogel. (4) Transfer the aerogel to a corundum crucible, place it in a muffle furnace, calcine it by programmed heating, and then cool it naturally to room temperature to obtain a supported nano Fe2O3 / Al2O3 catalyst. Grind it through a 100-mesh sieve for later use.

[0025] The specific temperature ramp-up procedure is as follows: the temperature is increased to 350℃ at a rate of 1℃ / min and held for 2 hours; then the temperature is increased to 500℃ at a rate of 4℃ / min and held for 2.5 hours.

[0026] Example 2 A process for preparing prothioconazole includes the following steps: S1. One-pot chlorination-ring-opening reaction for the preparation of 3,5-dichloro-2-pentanone: In a reactor, α-acetyl-γ-butyrolactone and 1.5% (by mass) of lithium bis(trifluoromethanesulfonyl)imide were added. Sulfoxide was slowly added dropwise at a rate of 6 mL / h, with a molar ratio of sulfoxide to raw material of 1.13:1. The temperature was controlled at 3°C ​​during the dropwise addition. After the dropwise addition was completed, the temperature was raised to 65°C and reacted for 3 h. Then, 30% hydrochloric acid aqueous solution was added directly to the reaction system, and the ring-opening reaction was carried out at 92°C for 4 h. After the reaction was completed, the mixture was cooled to room temperature, allowed to stand, and separated. The organic phase was washed with water and distilled under reduced pressure to obtain 3,5-dichloro-2-pentanone. S2. Preparation of 1-chloro-1-acetylcyclopropane by ionic liquid-catalyzed cyclization: The 3,5-dichloro-2-pentanone obtained in step S1 was mixed with a 20% sodium hydroxide solution (the mass ratio of the 20% sodium hydroxide solution to 3,5-dichloro-2-pentanone was 2:1). 2.5% by mass of 3,5-dichloro-2-pentanone was added to the carboxyl-functionalized ionic liquid 1-carboxyethyl-3-methylimidazolium bromide. The mixture was then fed into a microchannel reactor and reacted at 88°C for 12 min. After the reaction liquid flowed out, it was allowed to stand and separate into layers. The aqueous phase of the ionic liquid could be directly recycled. The organic phase was washed with water and dried to obtain 1-chloro-1-acetylcyclopropane. S3. Preparation of 2-chloro-1-(1-chlorocyclopropyl)acetone by secondary chlorination: The 1-chloro-1-acetylcyclopropane obtained in step S2 was dissolved in cyclopentylmethyl ether at a mass-to-volume ratio of 1:3. Chlorine gas was slowly introduced (flow rate 0.5 g / min) at 12 °C and under ultraviolet light irradiation until the reaction was complete. After the reaction was completed, the residual chlorine gas was removed by washing with 10% sodium sulfite solution. The mixture was allowed to stand and separated. The organic phase was subjected to vacuum distillation to recover the CPME solvent, yielding 2-chloro-1-(1-chlorocyclopropyl)ethyl ketone. S4. Grignard condensation to prepare 2-(1-chlorocyclopropyl)-3-chloro-1-(2-chlorophenyl)-2-propanol: Under N2 protection, using 2-methyltetrahydrofuran as solvent, o-chlorobenzyl chloride magnesium chloride Grignard reagent was prepared in situ by reacting o-chlorobenzyl chloride with magnesium shavings, wherein the molar ratio of o-chlorobenzyl chloride to magnesium shavings was 1:1. Then, at -8℃, the 2-MeTHF solution of 2-chloro-1-(1-chlorocyclopropyl)ethyl ketone obtained in step S3 (total volume being 2.8 times the total mass of o-chlorobenzyl chloride and 2-chloro-1-(1-chlorocyclopropyl)ethyl ketone) was slowly added dropwise to Grignard reagent (dropping rate 10 mL / h). The molar ratio of Grignard reagent to ethyl ketone was 1.03:1. After the addition was complete, the reaction was kept at this temperature for 1.5 h. After the reaction was completed, the solution was quenched with 10% dilute hydrochloric acid, separated, and the organic phase was concentrated under reduced pressure to recover 2-MeTHF, yielding the crude product. S5. One-pot hydrazino-cyclization preparation of prothioconazole precursor: The chlorool, hydrazine hydrate, and sodium thiocyanate obtained in step S4 were added in a single batch to a mixed solvent of ethanol and water (volume ratio 1:1) at a molar ratio of 1:1.2:1.1. The mass-volume ratio of chlorool to the ethanol-water mixed solvent was 1 g:3 mL. The reaction was carried out at 77 °C for 5 h under the catalysis of aminosulfonic acid (mass 0.02 times that of chlorool). After the reaction was completed, the mixture was cooled and crystallized. The mixture was filtered, and the filtrate was distilled to recover ethanol and excess hydrazine hydrate. The filter cake was dried to obtain the 1,2,4-triazolidine-5-thione precursor. S6. Oxidative dehydrogenation to prepare prothioconazole: The triazolidine-5-thione precursor obtained in step S5 was dissolved in ethyl acetate, and a supported nano-iron oxide / alumina catalyst of 6% by mass of the precursor was added. At 38°C, an aqueous solution of tert-butyl hydrogen peroxide of 37% by mass of the triazolidine-5-thione precursor was slowly added dropwise. After the reaction was completed, the catalyst was recovered by hot filtration. The filtrate was washed with water, concentrated under reduced pressure, and then crystallized by adding n-heptane. After filtration and drying, high-purity prothioconazole technical was obtained. The preparation of the supported nano-iron oxide / alumina catalyst includes the following steps: (1) Disperse boehmite in deionized water at a mass-volume ratio of 1g:6mL, stir and mix at 65℃, add 65% nitric acid dropwise until the solution is clear, and continue stirring for 1.2h to obtain boehmite (γ-AlOOH) sol; Ferric chloride hexahydrate was dissolved in a mixed solvent of anhydrous ethanol and acetylacetone (volume ratio 3:1) at a mass-to-volume ratio of 1 g: 4.5 mL, and stirred for 35 min to obtain an iron source solution. According to the mass ratio of Fe2O3:Al2O3=1:10, the boehmite sol was slowly added to the iron source solution and stirred at 550 rpm for 30 min to obtain a mixed sol for later use. (2) Pluronic P123 (triblock copolymer) and 1-butyl-3-methylimidazolium tetrafluoroborate were added to the above mixed sol at a mass ratio of 2:1. After stirring for 15 min, the mixture was transferred to the reaction tank of an ultrasonic cell disruptor, cooled in an ice-water bath, and ultrasonically treated for 33 min at a power of 400 W. Then the mixture was transferred to a glass culture dish and placed in an oven at 43 °C for 11 h to form a wet gel. The gel was then transferred to an oven at 62 °C for aging for 23 h. (3) Place the aged wet gel in an autoclave, seal it, and introduce liquid CO2 until the gel is submerged. Heat the gel to 43°C, pressurize it to 12 MPa, maintain it for 2 hours, and then release CO2 at a rate of 0.5 MPa / h until atmospheric pressure is reached to obtain Fe-Al composite aerogel. (4) Transfer the aerogel to a corundum crucible, place it in a muffle furnace, calcine it by programmed heating, and then cool it naturally to room temperature to obtain a supported nano Fe2O3 / Al2O3 catalyst. Grind it through a 100-mesh sieve for later use.

[0027] The specific temperature ramp-up procedure is as follows: the temperature is increased to 350℃ at a rate of 1.5℃ / min and held for 2 hours; then the temperature is increased to 500℃ at a rate of 5℃ / min and held for 3 hours.

[0028] Example 3 A process for preparing prothioconazole includes the following steps: S1. One-pot chlorination-ring-opening reaction for the preparation of 3,5-dichloro-2-pentanone: In a reactor, α-acetyl-γ-butyrolactone and 2% (by mass) of lithium bis(trifluoromethanesulfonyl)imide were added. Sulfoxide was slowly added dropwise at a rate of 8 mL / h, with a molar ratio of sulfoxide to the raw material of 1.13:1. The temperature was controlled at 5°C during the dropwise addition. After the dropwise addition was completed, the temperature was raised to 70°C and reacted for 4 h. Then, 30% hydrochloric acid aqueous solution was added directly to the reaction system, and the ring-opening reaction was carried out at 95°C for 5 h. After the reaction was completed, the mixture was cooled to room temperature, allowed to stand, and separated. The organic phase was washed with water and distilled under reduced pressure to obtain 3,5-dichloro-2-pentanone. S2. Preparation of 1-chloro-1-acetylcyclopropane by ionic liquid-catalyzed cyclization: The 3,5-dichloro-2-pentanone obtained in step S1 was mixed with a 20% sodium hydroxide solution (the mass ratio of the 20% sodium hydroxide solution to 3,5-dichloro-2-pentanone was 2:1). 3% by mass of the carboxyl-functionalized ionic liquid 1-carboxyethyl-3-methylimidazolium bromide of 3,5-dichloro-2-pentanone was added. The mixture was then fed into a microchannel reactor and reacted at 90°C for 15 min. After the reaction liquid flowed out, it was allowed to stand and separate into layers. The aqueous phase of the ionic liquid could be directly recycled. The organic phase was washed with water and dried to obtain 1-chloro-1-acetylcyclopropane. S3. Preparation of 2-chloro-1-(1-chlorocyclopropyl)acetone by secondary chlorination: The 1-chloro-1-acetylcyclopropane obtained in step S2 was dissolved in cyclopentylmethyl ether at a mass-to-volume ratio of 1:3. Chlorine gas was slowly introduced (flow rate 0.5 g / min) at 15 °C and under ultraviolet light irradiation until the reaction was complete. After the reaction was completed, the residual chlorine gas was removed by washing with 10% sodium sulfite solution. The mixture was allowed to stand and separated. The organic phase was subjected to vacuum distillation to recover the CPME solvent, yielding 2-chloro-1-(1-chlorocyclopropyl)ethyl ketone. S4. Grignard condensation to prepare 2-(1-chlorocyclopropyl)-3-chloro-1-(2-chlorophenyl)-2-propanol: Under N2 protection, using 2-methyltetrahydrofuran as solvent, o-chlorobenzyl chloride magnesium chloride Grignard reagent was prepared in situ by reacting o-chlorobenzyl chloride with magnesium shavings, wherein the molar ratio of o-chlorobenzyl chloride to magnesium shavings was 1:1.05. Then, at -5℃, the 2-MeTHF solution of 2-chloro-1-(1-chlorocyclopropyl)ethyl ketone obtained in step S3 (total volume being 3 times the total mass of o-chlorobenzyl chloride and 2-chloro-1-(1-chlorocyclopropyl)ethyl ketone) was slowly added dropwise to Grignard reagent (dropping rate 12 mL / h). The molar ratio of Grignard reagent to ethyl ketone was 1.03:1. After the addition was complete, the reaction was kept at this temperature for 2 h. After the reaction was completed, the solution was quenched with 10% dilute hydrochloric acid, separated, and the organic phase was concentrated under reduced pressure to recover 2-MeTHF, yielding the crude product. S5. One-pot hydrazino-cyclization preparation of prothioconazole precursor: The chlorool, hydrazine hydrate, and sodium thiocyanate obtained in step S4 were added in a single batch to a mixed solvent of ethanol and water (volume ratio 1:1) at a molar ratio of 1:1.3:1.2. The mass-volume ratio of chlorool to the ethanol-water mixed solvent was 1 g:4 mL. The reaction was carried out at 80 °C for 6 h under the catalysis of aminosulfonic acid (mass 0.03 times that of chlorool). After the reaction was completed, the mixture was cooled and crystallized. The mixture was filtered, and the filtrate was distilled to recover ethanol and excess hydrazine hydrate. The filter cake was dried to obtain the 1,2,4-triazolidine-5-thione precursor. S6. Oxidative dehydrogenation to prepare prothioconazole: The triazolidine-5-thione precursor obtained in step S5 was dissolved in ethyl acetate, and 8% by mass of the precursor of a supported nano-iron oxide / alumina catalyst was added. At 40°C, 39% by mass of the triazolidine-5-thione precursor of an aqueous solution of tert-butyl hydrogen peroxide was slowly added dropwise. After the reaction was completed, the catalyst was recovered by hot filtration. The filtrate was washed with water, concentrated under reduced pressure, and then crystallized by adding n-heptane. After filtration and drying, high-purity prothioconazole technical was obtained. The preparation of the supported nano-iron oxide / alumina catalyst includes the following steps: (1) Disperse boehmite in deionized water at a mass-volume ratio of 1g:7mL, stir and mix at 70℃, add 65% nitric acid dropwise until the solution is clear, and continue stirring for 1.5h to obtain boehmite sol; Ferric chloride hexahydrate was dissolved in a mixed solvent of anhydrous ethanol and acetylacetone (volume ratio 3:1) at a mass-to-volume ratio of 1 g: 5 mL, and stirred for 40 min to obtain an iron source solution. According to the mass ratio of Fe2O3:Al2O3=1:10, the boehmite sol was slowly added to the iron source solution and stirred at 600 rpm for 35 min to obtain a mixed sol for later use. (2) Pluronic P123 (triblock copolymer) and 1-butyl-3-methylimidazolium tetrafluoroborate were added to the above mixed sol at a mass ratio of 2:1. After stirring for 20 min, the mixture was transferred to the reaction tank of an ultrasonic cell disruptor, cooled in an ice-water bath, and ultrasonically treated for 35 min at a power of 400 W. Then the mixture was transferred to a glass culture dish and placed in a 45°C oven for 12 h to form a wet gel. The gel was then transferred to a 65°C oven and aged for 26 h. (3) Place the aged wet gel in an autoclave, seal it, and introduce liquid CO2 until the gel is submerged. Heat to 45°C, pressurize to 12 MPa, maintain for 2.5 h, and then release CO2 at a rate of 0.6 MPa / h until atmospheric pressure is reached to obtain Fe-Al composite aerogel. (4) Transfer the aerogel to a corundum crucible, place it in a muffle furnace, calcine it by programmed heating, and then cool it naturally to room temperature to obtain a supported nano Fe2O3 / Al2O3 catalyst. Grind it through a 100-mesh sieve for later use.

[0029] The specific temperature ramp-up procedure is as follows: the temperature is increased to 350℃ at a rate of 2℃ / min and held for 2.5 hours; then the temperature is increased to 500℃ at a rate of 5℃ / min and held for 3.5 hours.

[0030] Comparative Example 1 Compared with Example 2, in Comparative Example 1, lithium bis(trifluoromethanesulfonylimide) (LiNTf2) in step S1 was replaced with an equimolar amount of the conventional Lewis acid catalyst aluminum trichloride (AlCl3), and the remaining steps and conditions were the same as in Example 2.

[0031] Comparative Example 2 (Microchannel Reactor) Compared with Example 2, Comparative Example 2 does not use the carboxyl-functionalized ionic liquid 1-carboxyethyl-3-methylimidazolium bromide in step S2. Instead, it uses tetrabutylammonium bromide (TBAB) as a conventional phase transfer catalyst. The ring-closing reaction is carried out in a conventional stirred tank reactor at a reaction temperature of 85°C and the reaction time is extended to 2 hours. The remaining steps and conditions are the same as in Example 2.

[0032] Comparative Example 3 Compared with Example 2, in Comparative Example 3, the ultraviolet lamp was turned off in step S3, and chlorine gas was introduced only under dark conditions at 10°C. The remaining steps and conditions were the same as in Example 2.

[0033] Comparative Example 4 Compared with Example 2, Comparative Example 4 replaces 2-methyltetrahydrofuran in step S4 with an equal volume of the conventional solvent tetrahydrofuran, while the remaining steps and conditions are the same as in Example 2.

[0034] Comparative Example 5 Compared with Example 2, Comparative Example 5 replaces aminosulfonic acid in step S5 with an equimolar amount of concentrated hydrochloric acid, while the remaining steps and conditions are the same as in Example 2.

[0035] Comparative Example 6 Compared with Example 2, Comparative Example 6 replaces the supported nano-iron oxide / alumina catalyst in step S6 with an equal mass of ordinary Fe2O3 / Al2O3 catalyst (prepared by conventional impregnation method without aerogel process), while the other steps and conditions are the same as in Example 2.

[0036] Comparative Example 7 Compared with Example 2, Comparative Example 7 omits the supported nano-iron oxide / alumina catalyst in step S6, while the other steps and conditions are the same as in Example 2.

[0037] To compare the technical effects of the present invention, prothioconazole and its intermediates were prepared using the methods of Examples 1-3 and Comparative Examples 1-7, respectively. Then, the total yield and the HPLC purity of the final product prothioconazole were calculated and statistically analyzed.

[0038] In this application, the yield of step S4 is calculated based on the quality of the crude product and the theoretical yield. The yields of all steps S1 to S6 are calculated based on the actual product obtained in that step. The total yield is the product of the yields of each step. The calculation basis is consistent and can be repeatedly verified.

[0039] Note: Total yield = S1 yield × S2 yield × S3 yield × S4 yield × S5 yield × S6 yield The experimental comparison results are as follows Figure 1 and 2 As shown.

[0040] Depend on Figure 1 and 2 As can be seen from the comparison of the proportions and examples, LiNTf2 exhibits superior stability and catalytic efficiency compared to traditional AlCl3. The carboxyl-functionalized ionic liquid combines catalysis and phase transfer functions, achieving highly efficient and rapid ring-closing reactions when combined with a microchannel reactor, far superior to traditional batch and TBAB systems. Compared to concentrated hydrochloric acid, the use of aminosulfonic acid in this invention improves product purity, possibly because aminosulfonic acid is a mild protic acid that only catalyzes the condensation of chloroalcohols with hydrazine hydrate. Concentrated hydrochloric acid, being too acidic, causes sodium thiocyanate to decompose, producing thiocyanate, which further reacts with hydrazine to generate impurities, thus reducing the purity of the precursor. The supported nano-iron oxide / alumina catalyst prepared by the method of this invention exhibits significantly higher catalytic activity and selectivity than conventional impregnated catalysts due to its high specific surface area and uniform nanostructure, making it key to achieving mild and efficient oxidative dehydrogenation.

[0041] Replacing 2-methyltetrahydrofuran with tetrahydrofuran (THF) reduced the overall yield from 80.2% to 78.1% and the purity from 99.6% to 99.2%. Although the effects of the two solvents did not change significantly, 2-MeTHF, while ensuring the reaction effect, has a higher boiling point and lower toxicity than traditional THF, which is more in line with the requirements of modern green chemistry.

[0042] As can be seen from the bar chart, UV photoinitiation is the key to achieving selective chlorination, which can efficiently generate chlorine radicals and avoid byproducts caused by ionic reaction pathways. The microchannel reactor provides excellent mass and heat transfer efficiency, which greatly shortens the reaction time and improves the selectivity and safety of the reaction.

[0043] The specific embodiments described above further illustrate the purpose, technical solution, and beneficial effects of the present invention. It should be understood that the above description is only a specific embodiment of the present invention and is not intended to limit the scope of protection of the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A process for preparing prothioconazole, characterized in that, Includes the following steps: S1. One-pot chlorination-ring-opening reaction for the preparation of 3,5-dichloro-2-pentanone: Using α-acetyl-γ-butyrolactone as a raw material, chlorination was carried out with thionyl chloride in the presence of lithium bis(trifluoromethanesulfonylimide), followed by direct addition of hydrochloric acid aqueous solution to carry out ring-opening reaction, to obtain 3,5-dichloro-2-pentanone. S2. Preparation of 1-chloro-1-acetylcyclopropane by ionic liquid-catalyzed cyclization: The 3,5-dichloro-2-pentanone obtained in step S1 was subjected to a cyclization reaction under alkaline conditions in the presence of the carboxyl-functionalized ionic liquid 1-carboxyethyl-3-methylimidazolium bromide to give 1-chloro-1-acetylcyclopropane. S3. Preparation of 2-chloro-1-(1-chlorocyclopropyl)acetone by secondary chlorination: The 1-chloro-1-acetylcyclopropane obtained in step S2 was reacted with chlorine gas under cyclopentylmethyl ether and ultraviolet light to give 2-chloro-1-(1-chlorocyclopropyl)ethyl ketone. S4. Grignard condensation to prepare 2-(1-chlorocyclopropyl)-3-chloro-1-(2-chlorophenyl)-2-propanol: A Grignard reagent was prepared by using o-chlorobenzyl chloride, and then condensed with 2-chloro-1-(1-chlorocyclopropyl)ethyl ketone obtained in step S3 to give 2-(1-chlorocyclopropyl)-3-chloro-1-(2-chlorophenyl)-2-propanol. S5. One-pot hydrazino-cyclization preparation of prothioconazole precursor: The 2-(1-chlorocyclopropyl)-3-chloro-1-(2-chlorophenyl)-2-propanol obtained in step S4 was reacted with hydrazine hydrate and sodium thiocyanate in a mixed solvent of aminosulfonic acid and ethanol-water to give the 1,2,4-triazolidine-5-thione precursor. S6. Oxidative dehydrogenation to prepare prothioconazole: The 1,2,4-triazolidine-5-thione precursor obtained in step S5 was reacted with an oxidant in the presence of a catalyst to oxidize and dehydrogenate prothioconazole.

2. A method for preparing the intermediate 3,5-dichloro-2-pentanone in the process of claim 1, characterized in that, The method is as follows: In a reactor, α-acetyl-γ-butyrolactone and 1-2% (by mass) of lithium bis(trifluoromethanesulfonyl)imide are added. Sulfoxide is added dropwise at a rate of 5-8 mL / h, with a molar ratio of sulfoxide to raw material of 1.13:

1. The temperature is controlled at 0-5℃ during the dropwise addition. After the dropwise addition is completed, the temperature is raised to 60-70℃ and reacted for 2-4 h. Then, 30% hydrochloric acid aqueous solution is added directly to the reaction system, and the ring-opening reaction is carried out at 90-95℃ for 3-5 h. After the reaction is completed, the mixture is cooled to room temperature, allowed to stand, and separated. The organic phase is washed with water and distilled under reduced pressure to obtain 3,5-dichloro-2-pentanone.

3. A method for preparing the intermediate 1-chloro-1-acetylcyclopropane in the process of claim 1, characterized in that, The method is as follows: 3,5-dichloro-2-pentanone is mixed with 20% sodium hydroxide solution, and 2-3% by mass of 1-carboxyethyl-3-methylimidazolium bromide, a carboxyl-functionalized ionic liquid, is added. The mixture is then passed into a microchannel reactor and reacted at 85-90°C for 10-15 min. After the reaction liquid flows out, it is allowed to stand and separate into layers. The organic phase is washed with water and dried to obtain 1-chloro-1-acetylcyclopropane.

4. A method for preparing the intermediate 2-chloro-1-(1-chlorocyclopropyl)ethyl ketone in the process of claim 1, characterized in that, The method is as follows: 1-chloro-1-acetylcyclopropane is dissolved in cyclopentylmethyl ether at a mass-to-volume ratio of 1:

3. Chlorine gas is introduced under ultraviolet light at 10-15°C until the reaction is complete. After the reaction is complete, residual chlorine gas is removed by washing with 10% sodium sulfite solution. The mixture is allowed to stand and separated. The organic phase is subjected to vacuum distillation to recover the CPME solvent, yielding 2-chloro-1-(1-chlorocyclopropyl)ethyl ketone.

5. A method for preparing the intermediate 2-(1-chlorocyclopropyl)-3-chloro-1-(2-chlorophenyl)-2-propanol in the process of claim 1, characterized in that, The method is as follows: under N2 protection, using 2-methyltetrahydrofuran as solvent, o-chlorobenzyl chloride magnesium chloride Grignard reagent is prepared in situ by reacting o-chlorobenzyl chloride with magnesium shavings, wherein the molar ratio of o-chlorobenzyl chloride to magnesium shavings is 1:(1~1.05). Then, at -10 to -5℃, a 2-MeTHF solution of 2-chloro-1-(1-chlorocyclopropyl)ethyl ketone was added dropwise to a Grignard reagent at a rate of 8 to 12 mL / h. The molar ratio of Grignard reagent to ethyl ketone was 1.03:

1. After the addition was complete, the reaction was maintained at this temperature for 1 to 2 h. After the reaction was completed, the solution was quenched with 10% dilute hydrochloric acid, separated, and the organic phase was concentrated under reduced pressure to recover 2-MeTHF, yielding the crude product.

6. A method for preparing the intermediate 1,2,4-triazolidine-5-thione precursor in the process of claim 1, characterized in that, The method is as follows: 2-(1-chlorocyclopropyl)-3-chloro-1-(2-chlorophenyl)-2-propanol, hydrazine hydrate, and sodium thiocyanate are added to a mixed solvent of ethanol and water in a molar ratio of 1:(1.1~1.3):(1.05~1.2). The mass-volume ratio of the chloroalcohol to the ethanol-water mixed solvent is 1 g:(2~4) mL. The reaction is carried out at 75~80℃ for 4~6 h under the catalysis of aminosulfonic acid. After the reaction is completed, the mixture is cooled and crystallized, filtered, and the filtrate can be distilled to recover ethanol and excess hydrazine hydrate. The filter cake is dried to obtain the 1,2,4-triazolidine-5-thione precursor.

7. The process according to claim 1, characterized in that, The catalyst mentioned in step S6 is a supported nano-iron oxide / alumina catalyst, which is added at a mass of 5-8% of the 1,2,4-triazolidine-5-thione precursor; The oxidant is an aqueous solution of tert-butyl hydrogen peroxide, which is added at 34-39% by mass of the 1,2,4-triazolidine-5-thione precursor. The reaction was carried out in ethyl acetate solvent at 25–40 °C.

8. The process according to claim 7, characterized in that, The preparation of the supported nano-iron oxide / alumina catalyst includes the following steps: (1) Disperse boehmite in deionized water at a mass-to-volume ratio of 1g:(5~7)mL, stir and mix at 60~70℃, add 65% nitric acid dropwise until the solution is clear, and continue stirring for 1~1.5h to obtain boehmite sol; Ferric chloride hexahydrate was dissolved in a mixed solvent of anhydrous ethanol and acetylacetone at a mass-to-volume ratio of 1 g:(4~5) mL and stirred for 30~40 min to obtain an iron source solution. According to the mass ratio of Fe2O3:Al2O3=1:10, boehmite sol was added to the iron source solution and stirred at 500~600rpm for 25~35min to obtain a mixed sol for later use. (2) Pluronic P123 and 1-butyl-3-methylimidazolium tetrafluoroborate were added to the above mixed sol at a mass ratio of 2:

1. After stirring for 10-20 min, the mixture was transferred to the reaction tank of an ultrasonic cell disruptor, cooled in an ice-water bath, and ultrasonically treated for 30-35 min at a power of 400W. Then, it was transferred to an oven at 40-45℃ and allowed to stand for 10-12 h to form a wet gel. Finally, it was transferred to an oven at 60-65℃ and aged for 20-26 h. (3) Place the aged wet gel in an autoclave, seal it, and introduce liquid CO2 until the gel is submerged. Heat the gel to 40-45°C, pressurize it to 12 MPa, and maintain it for 2-2.5 h. Then release CO2 at a rate of 0.4-0.6 MPa / h until atmospheric pressure is reached to obtain Fe-Al composite aerogel. (4) Transfer the aerogel to a corundum crucible, place it in a muffle furnace, calcine it by programmed heating, and then cool it naturally to room temperature to obtain a supported nano Fe2O3 / Al2O3 catalyst. Grind it through a 100-mesh sieve for later use.

9. The process according to claim 8, characterized in that, The specific temperature program described in step (4) is as follows: heat up to 350℃ at 1~2℃ / min and hold for 2~2.5h; then heat up to 500℃ at 4~5℃ / min and hold for 2.5~3.5h.

10. The process according to claim 1, characterized in that, After the reaction in step S6 is completed, the catalyst is recovered by hot filtration. The filtrate is washed with water, concentrated under reduced pressure, and then n-heptane is added to crystallize. After filtration and drying, high-purity prothioconazole technical is obtained.

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