Fully continuous flow production process of hymexazol
By using a fully continuous flow production process and a fixed-bed reactor with micro-mixers and solid acid catalysts, the production of hymexazol is achieved in a highly efficient and environmentally friendly manner. This solves the problems of poor safety, low yield, high cost and environmental pollution in existing technologies, making it suitable for industrial applications.
Patent Information
- Application Number
- CN202510970291.5
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-07-15
- Publication Date
- 2025-10-31
AI Technical Summary
The existing hymexazol production process suffers from poor safety, environmental unfriendliness, low yield, high cost, high energy consumption, and large wastewater volume, and has not achieved fully continuous production throughout the entire process.
The fully continuous flow production process of hymexazol is achieved by using multiple micro-mixers, continuous reactors and fixed-bed reactors loaded with solid acid catalysts connected in sequence. The hydroxylation and cyclization reactions are carried out in the continuous tubular reactor, and the post-treatment uses solid acid catalysts instead of hydrochloric acid.
It improves reaction yield, reduces impurity formation, lowers energy consumption and production costs, and reduces wastewater and exhaust gas pollution, making it suitable for industrial production.
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Figure CN120865114A_ABST
Abstract
Description
Technical Field
[0001] This invention belongs to the field of pesticide technology. More specifically, it relates to a fully continuous flow production process for hymexazol. Background Technology
[0002] Hymexazol (3-hydroxy-5-methylisoxazole) is a highly effective, low-toxicity, and residue-free soil fungicide with strong systemic properties, long-lasting efficacy, no phytotoxicity, and no pollution. It is mainly used to control rice damping-off, soil-borne diseases of vegetables and other crops, and has significant effects on damping-off, seedling rot, anthracnose, and sclerotinia rot.
[0003] The existing synthetic routes for hymexazol technical grade are as follows:
[0004] Route 1 uses ethyl β-chlorocrotonate as raw material, which is hydroxylated with hydroxylamine hydrochloride and sodium hydroxide, then cyclized by reflux and post-processing to obtain hymexazol technical powder.
[0005] Route 2 uses ethyl β-butynate as a raw material, which is hydroxylated with hydroxylamine hydrochloride and sodium hydroxide, then cyclized, and post-processed to obtain hymexazol technical powder.
[0006] Route 3 uses ethoxyxamic acid as a raw material, which is hydroxylated with hydroxylamine hydrochloride and sodium hydroxide, then cyclized, and post-processed to obtain hymexazol technical powder.
[0007] Route 4 uses methyl (ethyl) acetoacetate as raw material, protects the β-keto group with ethylene glycol, hydroxylates it with hydroxylamine hydrochloride and potassium carbonate, then cyclizes it with hydrochloric acid, and finally processes it to obtain hymexazol raw powder.
[0008] Route 5 uses methyl (ethyl) acetoacetate as raw material, which is hydroxylated with hydroxylamine hydrochloride and sodium hydroxide, then cyclized with hydrochloric acid, and post-processed to obtain hymexazol raw powder.
[0009] The raw material β-chlorocrotonate used in Route 1 must be synthesized using phosphorus pentachloride, which has poor production safety, strong material corrosivity, high requirements for production environment and equipment, and is not environmentally friendly.
[0010] Route 2 has a lower yield, resulting in lower purity of the obtained hymexazol technical grade.
[0011] Route 3 uses more organic solvents, which is more expensive and environmentally unfriendly.
[0012] The protective reagent used in Route 4, ethylene glycol, is expensive and difficult to recycle, resulting in a higher overall cost.
[0013] Route 5 involves synthesis in an aqueous phase, which has very strict requirements on the pH of the reaction system. If the pH of the reaction system fluctuates too much during the feeding process, it will lead to an increase in by-products and a low yield. Hot hydrochloric acid is used as the cyclization reagent in the cyclization process, which causes severe corrosion to the equipment, causes great pollution, and is not environmentally friendly.
[0014] Patent CN106946809 improved Route 5 by using a buffer salt system of sodium bicarbonate and sodium carbonate, and simultaneously adding sodium hydroxide solution and methyl acetoacetate at low temperature. This can more stably control the pH of the reaction system during the hydroxylation reaction, but the dropping rate must be strictly controlled. During the production scale-up process, the dropping time is too long, which leads to a significant increase in impurities, a decrease in yield, and high energy consumption.
[0015] The team led by Du Xiaohua at Zhejiang University of Technology adopted a continuous flow approach (Org. Process Res.Dev.2019,23,1152-1158), integrating the hydroxylation and cyclization reactions into a tubular reactor. This approach avoids uneven temperature distribution and pH fluctuations during material mixing, but it does not achieve a fully continuous process. In addition, this approach generates a large amount of wastewater, and the post-treatment process requires the use of a large amount of organic solvents for extraction and concentration, resulting in a relatively high overall cost. Summary of the Invention
[0016] The technical problem this invention aims to solve is to overcome the defects and shortcomings of existing technologies and provide a fully continuous flow production process for hymexazol. The process includes: continuously feeding hydroxylamine hydrochloride aqueous solution, sodium hydroxide aqueous solution, and acetoacetate-based raw materials through a first micro-mixer into a first continuous tubular reactor for hydroxylation reaction; subsequently, the reaction solution enters a second continuous fixed-bed reactor, where a cyclization reaction is catalyzed by a solid acid catalyst; and post-treatment yields the target product. This invention provides a stable, rapid, and scale-up suitable solution that effectively reduces impurity generation, increases reaction yield, and significantly reduces energy consumption; the use of a solid acid catalyst instead of hydrochloric acid reduces wastewater and exhaust gas pollution, lowers requirements for production equipment, is environmentally friendly, and is suitable for industrial production.
[0017] The purpose of this invention is to provide a fully continuous flow production process for hymexazol.
[0018] The above-mentioned objective of this invention is achieved through the following technical solution:
[0019] A fully continuous flow production process for hymexazol utilizes a fully continuous flow production system consisting of multiple sequentially connected micro-mixers, continuous reactors, and fixed-bed reactors loaded with solid acid catalysts. The specific steps are as follows:
[0020] (i) Acetoacetate (1), hydroxylamine hydrochloride aqueous solution and sodium hydroxide aqueous solution are continuously passed through the first micro mixer and then enter the first continuous tubular reactor to carry out hydroxylamine reaction to obtain a solution of hydroxyoxime acid product (2).
[0021] (ii) The hydroxamic acid product (2) solution was fed into the second continuous fixed bed reactor and cyclized by a solid acid catalyst. The reaction solution was cooled and crystallized to obtain the final product hymexazol (3).
[0022] Its chemical reaction formula is:
[0023]
[0024] R1 is selected from any one of methyl, ethyl and isopropyl.
[0025] Preferably, in step (i), the concentration of the hydroxylamine hydrochloride aqueous solution is 15wt% to 40wt%, and more preferably, the concentration of the hydroxylamine hydrochloride aqueous solution is 30wt% to 35wt%. The concentration of the sodium hydroxide aqueous solution is 10wt% to 40wt%, and more preferably, the concentration of the sodium hydroxide aqueous solution is 30wt% to 35wt%. The acetoacetate (1) is any one of methyl acetoacetate, ethyl acetoacetate, and isopropyl acetoacetate, and more preferably, the acetoacetate (1) is methyl acetoacetate.
[0026] Preferably, in step (a), the flow rate ratio of acetoacetate (1), hydroxylamine hydrochloride aqueous solution and sodium hydroxide aqueous solution delivered to the first mixer is controlled such that the molar ratio of acetoacetate (1), hydroxylamine hydrochloride and sodium hydroxide is 1:(0.9~1.2):(1.5~3.0), and further, the molar ratio of acetoacetate (1), hydroxylamine hydrochloride and sodium hydroxide is 1:(0.98~1.02):(1.8~2.2).
[0027] Preferably, in step (i): the temperature in the first continuous tubular reactor is controlled within the range of -10 to 50°C, and further, the temperature is controlled within the range of -5 to 15°C; the residence time of the mixed reactants in the first continuous tubular reactor is 0.1 to 30 minutes, and further, the residence time is 1 to 5 minutes.
[0028] Preferably, the solid acid catalyst is selected from any one of silicotungstic acid, phosphotungstic acid, and strong acid ion exchange resin; further, the solid acid catalyst is silicotungstic acid.
[0029] Preferably, in step (ii), the mass ratio of the solid acid catalyst to acetoacetate (1) is (0.01-1.5):1, and further, the mass ratio of the solid acid catalyst to acetoacetate (1) is (0.5-0.8):1.
[0030] Preferably, in step (ii), the temperature in the second continuous fixed bed reactor is controlled in the range of 20 to 80°C, and further, the temperature is controlled in the range of 50 to 70°C; the residence time of the hydroxamic acid product (2) solution in the second continuous fixed bed reactor is 0.1 to 30 minutes, and further, the residence time is 1 to 5 minutes.
[0031] Preferably, in step (ii), the temperature for cooling and crystallization is controlled within the range of -10 to 30°C, and further, the temperature is controlled within the range of 0 to 10°C.
[0032] Preferably, the micro mixer is any one of a static mixer, a T-type micro mixer, a Y-type micro mixer, a cross-type micro mixer, a coaxial flow micro mixer, and a flow focusing micro mixer; further, the micro mixer is any one of a static mixer, a T-type micro mixer, and a Y-type micro mixer.
[0033] Preferably, the first continuous tubular reactor and the second continuous fixed-bed reactor are made of any one of 304L, 316L, 904L stainless steel, Hastelloy, silicon carbide, PTFE, and PEEK. Further, the first continuous tubular reactor and the second continuous fixed-bed reactor are made of any one of 304L, 316L stainless steel, and PTFE. The inner diameter of the pipes ranges from 0.1 to 20 mm. Further, the inner diameter of the pipes ranges from 2 to 8 mm.
[0034] The present invention has the following beneficial effects:
[0035] (1) The fully continuous flow production process provided by the present invention has excellent mass transfer, heat transfer and material molecule mixing performance, which greatly shortens the reaction time and greatly improves the reaction efficiency, reducing the time of traditional batch reactor reaction from several days to twenty minutes to complete the synthesis of hymexazol.
[0036] (2) Continuous mixing and quenching of the reaction solution are easy to operate in continuous flow processes. Due to the significantly improved heat transfer efficiency compared to batch reactors, the stability of the reaction temperature and the overall safety are greatly improved for the hydroxylation reaction section and the cyclization reaction section, which have fast reaction rates and significant exothermic reactions.
[0037] (3) The continuous flow process shortens the hydroxylamine reaction time and the pH requirement of the hydroxylamine reaction system can be relaxed to 9.5-12.0. Compared with the strict pH control range (9.5-10.0) of the traditional batch reactor production, it is easier to operate. The unstable hydroxamic acid intermediate is acidified and cyclized in time after generation, which will not generate more impurities, resulting in higher product purity and higher yield.
[0038] (4) Using solid acid catalysts instead of hydrochloric acid as cyclization reagents can reduce the amount of water in the reaction, increase the acid concentration, promote the forward cyclization reaction, reduce wastewater discharge, and avoid the volatilization of hydrogen chloride gas during hydrochloric acid heating, which can corrode equipment and pollute the environment.
[0039] (5) The fully continuous flow synthesis process is carried out without interruption, with a high degree of automation. No external intervention is required in the middle, resulting in high time and space efficiency, greatly reducing the number of operators and labor intensity, and significantly reducing production costs. Attached Figure Description
[0040] Figure 1 : Figure 1 This is a schematic diagram of a fully continuous flow manufacturing process. Detailed Implementation
[0041] The present invention will be further illustrated below with reference to specific embodiments, but the embodiments do not limit the present invention in any way. Unless otherwise specified, the reagents, methods, and equipment used in the present invention are conventional reagents, methods, and equipment in this technical field.
[0042] Unless otherwise specified, all reagents and materials used in the following examples are commercially available.
[0043] Example 1
[0044] A fully continuous flow production process for hymexazol includes the following steps: A 30wt% hydroxylamine hydrochloride aqueous solution (flow rate 20.0 g / min, 1.0 equivalent) and a 32wt% sodium hydroxide aqueous solution (flow rate 21.5 g / min, 2.0 equivalent) are fed to a first T-type mixer for mixing. Then, a methyl acetoacetate solution (flow rate 10.0 g / min, 1.0 equivalent) is fed together with this solution to a T-type mixer for further mixing. The mixture then enters a first continuous tubular reactor (75 m long, 235 mL volume, 2 mm inner diameter). The temperature of the first continuous tubular reactor is controlled... At 0℃, after reacting for 5 minutes (i.e., the residence time of the mixture in the tube is 5 minutes), the solution of hydroxamic acid product (2) flows out from the outlet. After preheating to 60℃, it enters the second continuous fixed-bed reactor (tube length 0.1m, volume 31.4mL, inner diameter 20mm). The packing material in the fixed-bed reactor is 40g silicotungstic acid. After reacting for 0.6 minutes (i.e., the residence time of the mixture in the tube is 0.6 minutes), the solution of hymexazol flows out from the outlet. After running for 2 hours, the reaction solution is cooled to 5℃ to crystallize, and a solid is precipitated to obtain the hymexazol product, which is off-white in appearance. After drying, 689g of product is obtained, with a purity of 99.7% and a yield of 67%.
[0045] Example 2
[0046] This embodiment is the same as Example 1, except that an equal mass of phosphotungstic acid is used instead of silicotungstic acid. The resulting product is 626g, with a purity of 99.6% and a yield of 61%.
[0047] Example 3
[0048] This embodiment is the same as Example 1, except that an equal mass of 732 type strong acid cation exchange resin is used to replace silicotungstic acid. The resulting product is 575g, with a purity of 99.5% and a yield of 56%.
[0049] Example 4
[0050] The continuous stability of the silicotungstic acid catalyst was verified according to the process of Example 1. The catalyst was continuously fed for 24 hours, with each batch consisting of 4 hours. The product yield of each batch is shown in Table 1 below.
[0051] Table 1 Catalyst stability test
[0052] batch time Product Quality purity yield 1 0～4h 1417g 99.7％ 69％ 2 4～8h 1380g 99.7％ 67％ 3 8～12h 1361g 99.5％ 66％ 4 12～16h 1355g 99.6％ 66％ 5 16～20h 1358g 99.5％ 66％ 6 20～24h 1343g 99.5％ 65％
[0053] As can be seen from Examples 1-3, using a solid acid catalyst instead of hydrochloric acid as the cyclization reagent can reduce the amount of water in the reaction, increase the acid concentration, promote the forward cyclization reaction, reduce wastewater discharge, avoid the volatilization of hydrogen chloride gas during hydrochloric acid heating, prevent equipment corrosion and environmental pollution, and obtain products with higher purity and yield.
[0054] As can be seen from Example 4, the fully continuous flow production process of the present invention is stable, and the resulting product has high purity and yield.
[0055] The above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above embodiments. Any changes, modifications, substitutions, combinations, or simplifications made without departing from the spirit and principle of the present invention shall be considered equivalent substitutions and shall be included within the protection scope of the present invention.
Claims
1. A fully continuous flow production process for hymexazol, characterized in that, A fully continuous flow production system consisting of multiple sequentially connected micromixers, continuous reactors, and fixed-bed reactors loaded with solid acid catalysts comprises the following steps: (i) Acetoacetate (1), hydroxylamine hydrochloride aqueous solution and sodium hydroxide aqueous solution are continuously passed through the first micro mixer and then enter the first continuous tubular reactor to carry out hydroxylamine reaction to obtain a solution of hydroxyoxime acid product (2). (ii) The hydroxamic acid product (2) solution was fed into the second continuous fixed bed reactor and cyclized by a solid acid catalyst. The reaction solution was cooled and crystallized to obtain the final product hymexazol (3). Its chemical reaction formula is: R1 is selected from any one of methyl, ethyl and isopropyl.
2. The fully continuous flow production process for hymexazol according to claim 1, characterized in that, In step (i), the concentration of the hydroxylamine hydrochloride aqueous solution is 15wt% to 40wt%, the concentration of the sodium hydroxide aqueous solution is 10wt% to 40wt%, and the acetoacetate (1) is any one of methyl acetoacetate, ethyl acetoacetate, and isopropyl acetoacetate.
3. The fully continuous flow production process for hymexazol according to claim 1, characterized in that, In step (a), the flow rate ratio of acetoacetate (1), hydroxylamine hydrochloride aqueous solution and sodium hydroxide aqueous solution delivered to the first mixer is controlled so that the molar ratio of acetoacetate (1), hydroxylamine hydrochloride and sodium hydroxide is 1:(0.9~1.2):(1.5~3.0).
4. The fully continuous flow production process for hymexazol according to any one of claims 1-3, characterized in that, In step (1): the temperature in the first continuous tubular reactor is controlled within the range of -10 to 50°C; the residence time of the mixed reactants in the first continuous tubular reactor is 0.1 to 30 minutes.
5. The fully continuous flow production process of hymexazol according to claim 1, characterized in that, In step (ii), the solid acid catalyst is selected from any one of silicotungstic acid, phosphotungstic acid, and strong acid ion exchange resin.
6. The fully continuous flow production process of hymexazol according to claim 1 or 5, characterized in that, In step (ii), the mass ratio of the solid acid catalyst to acetoacetate (1) is (0.01-1.5):
1.
7. The fully continuous flow production process for hymexazol according to claim 6, characterized in that, In step (ii), the temperature in the second continuous fixed bed reactor is controlled within the range of 20 to 80°C; the residence time of the hydroxamic acid product (2) solution in the second continuous fixed bed reactor is 0.1 to 30 minutes.
8. The fully continuous flow production process of hymexazol according to claim 7, characterized in that, In step (ii), the temperature for cooling and crystallization is controlled within the range of -10 to 30°C.
9. The fully continuous flow production process of hymexazol according to claim 1, characterized in that, The micro mixer can be any one of a static mixer, a T-type micro mixer, a Y-type micro mixer, a cross-type micro mixer, a coaxial flow micro mixer, or a flow focusing micro mixer.
10. The fully continuous flow production process of hymexazol as described in claim 1, characterized in that, The first continuous tubular reactor and the second continuous fixed-bed reactor are made of any one of 304L, 316L, 904L stainless steel, Hastelloy, silicon carbide, PTFE, and PEEK; the inner diameter of the pipes ranges from 0.1 to 20 mm.