A continuous flow green synthesis process of chlorothalonil technical

Abstract

The application discloses a continuous flow green synthesis process of chlorothalonil technical material. The process adopts micro-chemical technology of continuous flow, online in-situ neutralization and segmented temperature control. Firstly, hydroxylamine hydrochloride aqueous solution and liquid alkali are pumped into a first-stage micro-mixer for online in-situ neutralization, the neutralized solution is instantly introduced into a second-stage micro-channel reactor for rapid condensation reaction with methyl acetoacetate, then industrial hydrochloric acid is introduced and continuous acidification cyclization is completed in a tubular reactor, finally, high-purity chlorothalonil technical material is obtained through continuous vacuum flash distillation and cooling crystallization. The centrifugal mother liquor is recycled after desalination by electrodialysis and concentration by reverse osmosis. The system has extremely low liquid holdup, realizes the intrinsic safety of the process, uses large-diameter high-shear flow channels to make by-product salt in the form of microcrystalline suspension, solves the industry pain point of micro-channel blockage, realizes continuous process in the whole flow process, greatly shortens the reaction period, and has high purity, good yield and green environmental protection.

Description

Technical Field

[0001] This invention relates to the field of pesticide chemical synthesis technology, and in particular to a continuous flow green synthesis process for hymexazol technical grade. Background Technology

[0002] Hymexazol, chemically known as 3-hydroxy-5-methylisoxazole, is a systemic, highly effective, and low-toxicity soil fungicide and plant growth regulator. Traditional industrial synthesis of hymexazol often employs a batch reactor process: first, hydroxylamine hydrochloride is neutralized with alkali in a reactor; then, a large amount of sodium chloride solid is removed by centrifugation or filtration to obtain a free hydroxylamine solution; this solution is then placed in a storage tank as a raw material and pumped into a reactor to undergo a condensation reaction with methyl acetoacetate at low temperature; finally, acid is added at high temperature for cyclization.

[0003] However, the aforementioned existing processes have the following serious defects and inconveniences in actual production and industrial applications:

[0004] Significant safety hazard: Free hydroxylamine (in its free radical state) exhibits extremely high thermal instability. Under strongly alkaline environments, localized heating, or catalysis by residual metal ions, it is highly susceptible to violent exothermic decomposition, leading to intense thermal runaway explosions. The large-scale preparation and storage of high-concentration free hydroxylamine solutions in traditional processes constitutes a major Level 1 safety risk, making it extremely difficult to pass modern chemical safety assessments.

[0005] The equipment is highly susceptible to crystallization and clogging: the inorganic salt (NaCl) crystals produced during neutralization are extremely small and very difficult to filter out completely in high-viscosity hydroxylamine solutions. If introduced into a continuous flow microreactor, the residual salt crystals can easily accumulate and grow within the 0.5-2 mm microchannels, leading to system pressure buildup and tube rupture, thus disrupting continuous production.

[0006] Low cyclization efficiency and numerous side reactions: The traditional batch acidification cyclization stage has a long reaction time (usually more than 2 hours). The intermediates will undergo side reactions such as self-polymerization when they remain in the high temperature and acidic environment for a long time, producing isomer impurities. This makes it difficult to stabilize the purity of the original drug at more than 98.5%, and the number of times the mother liquor can be recycled is extremely limited.

[0007] In order to solve the problems existing in the synthesis process of the above-mentioned hymexazol technical, relevant manufacturers have tried their best to find a solution, but for a long time no suitable design that can perfectly balance "intrinsic safety" and "anti-salt clogging" has been developed. Summary of the Invention

[0008] The main objective of this invention is to overcome the shortcomings of existing hymexazol synthesis processes, such as high safety risks, easy clogging, and long reaction cycles, and to provide a novel continuous flow green synthesis process for hymexazol technical. The technical problem to be solved is to achieve on-demand use of free hydroxylamine and continuous flow operation with salt in the system, which is more suitable for practical use and has high safety and industrial application value.

[0009] A continuous flow green synthesis process for hymexazol technical grade includes the following process steps:

[0010] (1) Hydroxylamine hydrochloride aqueous solution and alkaline solution are continuously introduced into the first-stage micro mixer for in-situ neutralization reaction, and free hydroxylamine mixture is continuously output;

[0011] (2) Without solid-liquid separation to remove by-product inorganic salts, the free hydroxylamine mixture and pure methyl acetoacetate are directly and continuously fed into the second-stage microchannel reactor for continuous condensation reaction, and the condensation intermediate is output.

[0012] (3) The condensation intermediate liquid and hydrochloric acid are continuously introduced into the third-stage micro mixer for mixing, and then continuously injected into the high-temperature tubular reactor for continuous acidification cyclization reaction, and the cyclized mixture is output.

[0013] (4) After removing the byproduct methanol from the cyclized mixture, the mixture is cooled, crystallized, and centrifuged to obtain the technical grade of hymexazol.

[0014] Preferably, in step (1), the mass concentration of the aqueous hydroxylamine hydrochloride solution is 20%~30%; the alkaline solution is a liquid alkaline solution with a mass concentration of 25%~35%; the two components are pre-cooled to -5℃~0℃ by a pre-cooling module before entering the first-stage micro-mixer, and the molar ratio of hydroxylamine hydrochloride to alkaline solution is 1:1.

[0015] Preferably, in step (2), the molar ratio of methyl acetoacetate to hydroxylamine hydrochloride is 1.02~1.15:1. The internal channel diameter of the second-stage microchannel reactor is 1.5 mm~2.5 mm, and it has a high-shear-force topology to prevent crystallization and aggregation. The reaction temperature in the second-stage microchannel reactor is controlled at -5℃~0℃, the reaction pressure is 0.1~0.3 MPa, and the total residence time of the material is 1~4 min.

[0016] Preferably, in step (3), the hydrochloric acid is industrial hydrochloric acid with a mass concentration of 31%~35%, and the molar ratio of the hydrochloric acid to the condensation intermediate is 1.05~1.2:1. The high-temperature tubular reactor is a plug flow reactor (PFR), and its material is pressureless sintered silicon carbide (SSiC) or Hastelloy; the cyclization reaction temperature in the high-temperature tubular reactor is controlled at 60℃~75℃, and the residence time of the material in the tube is 15 min~40 min.

[0017] Preferably, in step (4), the cyclized mixture is continuously degraded from the byproduct methanol by means of a vacuum flash evaporator or a thin film evaporator at 50°C to 65°C; the residual liquid after methanol removal is continuously cooled to 5°C to 10°C and allowed to stand for crystallization for 2 hours, and then centrifuged to obtain white crystalline granular hymexazol technical.

[0018] By employing the above technical solution, the continuous flow green synthesis process for hymexazol technical material of the present invention has at least the following advantages:

[0019] By employing the above technical solution, the present invention has at least the following advantages:

[0020] 1. The process achieves "intrinsic safety" and completely eliminates major safety hazards: The "online in-situ neutralization" design allows free hydroxylamine to be used as soon as it is produced. The instantaneous liquid holding capacity of free hydroxylamine at any time in the entire system is at the micro level and is completely encapsulated in a microchannel reactor with strong heat transfer capacity, which fundamentally eliminates the possibility of thermal runaway explosion caused by the large-scale accumulation of hydroxylamine.

[0021] 2. Successfully overcame the industry engineering pain point of "inorganic salt solid blockage" in microchemical systems: by utilizing limited microchannel materials, large inner diameter structures and high shear force flow channel design, the generated NaCl crystals are forced to pass through at high speed as a micron-sized suspension by using strong fluid dynamic shear force, realizing long-term continuous and stable operation of the fluid system without blockage while "running with salt".

[0022] 3. Significantly improved production efficiency and equipment capacity, and shortened reaction cycle: By making full use of the extremely high mass and heat transfer efficiency of the microreactor, the condensation reaction time was shortened from several hours to 1-4 minutes, and the acidification cyclization reaction was shortened to 15-40 minutes, realizing a fully continuous flow operation throughout the entire process and significantly improving space-time yield.

[0023] 4. Product purity and yield are significantly improved, and the impurity profile is fundamentally optimized: heat and mass transfer are completed instantly and the reaction ratio is precisely controlled, effectively suppressing isomer byproducts and raw material hydrolysis caused by local overheating and excessive local alkalinity. The chromatographic content of hymexazol technical is stable at ≥98.6% (up to 99.4%).

[0024] 5. Green and environmentally friendly with high resource recycling rate: The introduction of continuous flash evaporation for efficient recovery of by-product methanol, and the pretreatment of centrifugal mother liquor through electrodialysis desalination and reverse osmosis membrane concentration and enrichment technology, can increase the cumulative comprehensive yield to 96.8%, which greatly reduces the discharge of "three wastes" wastewater and inorganic salt residue.

[0025] Compared with the prior art, the present invention has significant advantages and beneficial effects. As can be seen from the above technical solution, in order to achieve the aforementioned objectives, the main technical contents of the present invention are as follows:

[0026] This invention proposes a continuous flow green synthesis process for hymexazol technical grade. The process primarily involves continuously pumping an aqueous solution of hydroxylamine hydrochloride and liquid alkali into a first-stage micromixer for online in-situ neutralization using a high-pressure constant flow pump. The neutralized solution is then immediately introduced into a second-stage microchannel reactor for efficient continuous flow condensation with methyl acetoacetate. Subsequently, hydrochloric acid is introduced into a third-stage micromixer and continuously fed into a tubular reactor to complete rapid and continuous acidification and cyclization. Finally, high-purity hymexazol technical grade is obtained through continuous de-alcoholization and cooling crystallization.

[0027] As described above, this invention relates to a continuous flow green synthesis process for hymexazol technical grade. This process utilizes microchemical technology of "continuous flow, in-situ neutralization, and segmented temperature control" to instantaneously neutralize hydroxylamine hydrochloride aqueous solution with liquid alkali online and directly perform continuous condensation, followed by continuous acidification, cyclization, solvent removal, and crystallization. This achieves a fully continuous flow operation throughout the entire process, featuring intrinsic safety, non-clogging of flow channels, high production efficiency, good product purity, and environmental friendliness.

[0028] By employing the above technical solution, the continuous flow green synthesis process for hymexazol technical material of the present invention has at least the following advantages:

[0029] 1. The process achieves "inherent safety" and completely eliminates major safety hazards: The "online in-situ neutralization" design allows free hydroxylamine to be used as soon as it is produced. The instantaneous liquid holding capacity of free hydroxylamine at any time in the entire system is at the micro level and is completely encapsulated in a microchannel reactor with strong heat transfer capacity, which fundamentally eliminates the possibility of thermal runaway explosion caused by the large-scale accumulation of hydroxylamine.

[0030] 2. Successfully overcame the industry engineering pain point of "inorganic salt solid blockage" in microchemical systems: by utilizing limited microchannel materials, large inner diameter structures and high shear force flow channel design, the generated NaCl crystals are forced to pass through at high speed as a micron-sized suspension by using strong fluid dynamic shear force, realizing long-term continuous and stable operation of the fluid system without blockage while "running with salt".

[0031] 3. Significantly improved production efficiency and equipment capacity, and shortened reaction cycle: By making full use of the extremely high mass and heat transfer efficiency of the microreactor, the condensation reaction time was shortened from several hours to 1-4 minutes, and the acidification cyclization reaction was shortened to 15-40 minutes, realizing a fully continuous flow operation throughout the entire process and significantly improving space-time yield.

[0032] 4. Product purity and yield are significantly improved, and the impurity profile is fundamentally optimized: heat and mass transfer are completed instantaneously, and the reaction ratio is precisely controlled, effectively suppressing isomer byproducts and raw material hydrolysis caused by local overheating and excessive alkalinity. The chromatographic content of hymexazol technical grade is stable at... (Up to 99.4%).

[0033] 5. Green and environmentally friendly with high resource recycling rate: The introduction of continuous flash evaporation for efficient recovery of by-product methanol, and the pretreatment of centrifugal mother liquor through electrodialysis desalination and membrane concentration enrichment technology, can increase the cumulative comprehensive recovery rate to 96.8%, which greatly reduces the discharge of wastewater and inorganic salt residue.

[0034] In summary, the unique continuous flow green synthesis process for hymexazol technical material of this invention effectively solves the technical problems of unstable and explosive free hydroxylamine, easy clogging of microchannels by inorganic salts, long reaction cycle, numerous isomer impurities, and difficulty in recycling mother liquor in traditional batch synthesis or existing continuous flow processes. This achieves the invention's objective of providing a safe, efficient, high-purity, high-yield, and environmentally friendly continuous flow green synthesis process. It possesses numerous advantages and practical value, and no similar design has been publicly disclosed or used in similar synthesis processes, thus it is truly innovative. It represents a significant improvement in both the synthesis method and functionality, demonstrating substantial technological advancement and producing user-friendly and practical effects. Compared to existing continuous flow green synthesis processes for hymexazol technical material, it offers several enhanced benefits, making it more suitable for practical application and possessing broad industrial value. It is indeed a novel, progressive, and practical new design.

[0035] The above description is merely an overview of the technical solution of the present invention. In order to better understand the technical means of the present invention and to implement it in accordance with the contents of the specification, the preferred embodiments of the present invention are described in detail below with reference to the accompanying drawings.

[0036] The specific synthesis process and structure of the present invention are given in detail in the following embodiments and accompanying drawings. Attached Figure Description

[0037] Figure 1 : A schematic diagram of the fully continuous green synthesis process of hymexazol technical grade in this invention;

[0038] Figure 2 Schematic diagram of the anti-clogging flow channel structure of a microchannel reactor. Detailed Implementation

[0039] To further illustrate the technical means and effects adopted by the present invention to achieve the intended purpose, the following detailed description, in conjunction with the accompanying drawings and preferred embodiments, details the specific implementation methods, steps, structures, features, and effects of a continuous flow green synthesis process for hymexazol technical material proposed according to the present invention.

[0040] Please see Figure 1 , Figure 2 As shown in the figure, a continuous flow green synthesis process for hymexazol technical material according to a preferred embodiment of the present invention mainly includes the following steps:

[0041] 1. Continuous flow material preparation and precooling

[0042] Preparation of material A (hydroxylamine hydrochloride aqueous solution): Dissolve solid hydroxylamine hydrochloride in deionized water to prepare a hydroxylamine hydrochloride aqueous solution with a mass concentration of 20% to 30%, which is then continuously transported by high-pressure constant flow pump A.

[0043] Preparation of material B (liquid alkali solution): Prepare a sodium hydroxide (NaOH) aqueous solution with a mass concentration of 25% to 35%, and continuously deliver it through a high-pressure constant flow pump B.

[0044] Preparation of C-path material (pure methyl acetoacetate): Prepare industrial-grade methyl acetoacetate (purity...) The pure material is continuously transported by a high-pressure constant flow pump C.

[0045] Material precooling: Activate the cooling circulation system to precool the materials from routes A, B, and C during the conveying process to a temperature that is sufficient before they enter the reactor. .

[0046] 2. Continuous flow in-situ neutralization and microchannel condensation reaction

[0047] Online in-situ neutralization: Pre-cooled material from route A is mixed with material from route B using... The molar ratio is continuously injected into the first-stage micromixer for in-situ neutralization, instantaneously releasing hydroxylamine. The reaction temperature in the neutralization section is controlled at... The pH of the neutralized material effluent system is maintained between 7.2 and 8.8.

[0048] High-efficiency continuous condensation: The neutralized mixture is used immediately after production without any delay. It is then fed into the second-stage microchannel reactor together with the C-channel material (calculated as hydroxylamine hydrochloride, with a molar equivalent of methyl acetoacetate of 1.02 to 1.15) delivered by constant flow pump C to carry out a rapid condensation reaction.

[0049] Combined parameter control: The reaction temperature inside the second-stage microchannel reactor is controlled to be... Adjust the total flow rate to control the total residence time of the material in the condensation section to 1-4 minutes. After the condensation reaction is completed, a suspension microemulsion containing condensation intermediates is generated.

[0050] Anti-clogging structure limitation: The microchannel reactor is made of pressureless sintered silicon carbide (SSiC) or Hastelloy. Its internal flow channel adopts a heart-shaped flow channel or split-recombination (SAR) flow channel with high shear force and an inner diameter of 1.5-2.5 mm. The strong shear force of fluid dynamics forces the sodium chloride (NaCl) produced by neutralization to pass through at high speed in a micron-sized fine crystal suspension state with the material, so as to achieve stable operation with salt.

[0051] 3. Continuous flow acidification cyclization reaction

[0052] Continuous mixing of acid materials: The condensation intermediate liquid continuously flowing out from step 2 is introduced into the third-stage micro mixer together with industrial hydrochloric acid with a mass concentration of 31% to 35% (calculated as hydroxylamine hydrochloride, HCl molar equivalent of 1.05 to 1.20) delivered by high-pressure constant flow pump D for online continuous flow mixing.

[0053] Rapid tubular cyclization: The mixed strong acidic liquid is directly and continuously injected into a high-temperature insulated tubular reactor (PFR) lined with Teflon (PFA) to carry out the cyclization reaction.

[0054] Cycloning parameter control: The temperature inside the tubular reactor is controlled at 60℃~75℃, and the residence time of the material inside the tube is adjusted to 15~40 minutes by adjusting the tube length. After the reaction is completed, the generated cyclization reaction liquid flows out continuously and enters the collection system.

[0055] 4. Continuous deethanolination, crystallization, and mother liquor pretreatment are recycled.

[0056] Continuous de-alcoholization under reduced pressure: The cyclization reaction solution is continuously fed into a flash evaporator or thin-film evaporator, and the reaction is carried out at a temperature of 50℃~65℃ and a vacuum level of... Under certain conditions, methanol produced as a reaction byproduct is rapidly removed, and the removed methanol is collected by condensation and recycled as a solvent.

[0057] Cooling crystallization and separation: The residual liquid after alcohol removal is continuously fed into the crystallization vessel, and the cooling rate is controlled at 1.5℃~2℃ / min. The liquid is cooled to 5℃~10℃ and allowed to stand for crystallization for 1.5~3 hours. Then, it is sent to a continuous centrifuge for solid-liquid separation. The filter cake is washed with a small amount of ice water and dried with a double cone to obtain white crystalline granular hymexazol technical.

[0058] Mother liquor pretreatment and recycling: The mother liquor obtained by centrifugation is sent to a continuous electrodialysis unit for desalination to control the desalination rate. The desalted mother liquor is then concentrated through a reverse osmosis membrane module to enrich unreacted methyl acetoacetate and residual hymexazol to obtain a recycled compound solution. The recycled compound solution is used as a diluent or as a partial raw material to be recycled in step 1 for more than 5 batches.

[0059] Example 1

[0060] The fully continuous flow reaction process in this embodiment is as follows:

[0061] Material preparation: Add a 25% hydroxylamine hydrochloride aqueous solution (prepared by mixing 69.5 g (1.0 mol) of hydroxylamine hydrochloride and 208.5 g of deionized water) to material storage tank 10 (Route A). Prepare 133.3 g (containing 1.0 mol) of 30% liquid alkali (NaOH) solution to material storage tank 20 (Route B). Prepare 121.8 g (1.05 mol) of pure methyl acetoacetate to material storage tank 30 (Route C). Prepare 125.4 g (containing 1.1 mol) of 32% industrial hydrochloric acid solution to material storage tank 40 (Route D).

[0062] Continuous flow reaction process: The fully continuous flow microreactor system is activated and the flow channel is pre-cooled to -5℃. Materials from pathway A and pathway B are simultaneously and continuously pumped into the first-stage silicon carbide micromixer 101 at a flow ratio of 1.83:1 via a high-pressure constant flow pump for online in-situ neutralization. The neutralization temperature is controlled at -5℃, and the pH of the effluent is 7.8. The neutralized liquid flows out continuously without retention and immediately enters the second-stage pressureless sintered silicon carbide microchannel reactor 102 together with the material from pathway C, which is pumped in by a constant flow pump, for a continuous condensation reaction. The temperature of reactor 102 is controlled at 0℃, and the total flow rate is adjusted so that the total residence time of the material in the internal heart-shaped collision shear zone 1021 and the condensation flow channel section is 2 minutes. The sodium chloride crystals produced during neutralization are pulverized into micron-sized crystals under the high shear force of the heart-shaped collision shear zone 1021, passing through at high speed with the fluid without clogging.

[0063] The condensation intermediate liquid continuously flowing out from the condensation section is continuously mixed with the 32% hydrochloric acid solution from channel D in the third-stage micromixer 103, and then directly injected into the PFA-lined insulated tubular reactor (PFR) 104. The temperature of the tubular reactor 104 is controlled at 68°C, and the material residence time in the tube is 25 minutes to complete the continuous acidification cyclization.

[0064] Post-processing and analysis: The cyclized feed solution continuously flowed into a vacuum flash evaporator 201, where it was rapidly flash-evaporated at 55℃ and -0.08 MPa to remove the byproduct methanol, which was then condensed and recovered. The residue after methanol removal continuously flowed into a continuous cooling crystallizer 202, where it was cooled to 8℃ at a cooling rate of 2℃ / min and allowed to crystallize for 2 hours. The suspension was then sent to a continuous centrifuge 203 for separation. The filter cake was washed with a small amount of ice water and dried using a double-cone dryer to obtain 91.2 g of white crystalline granular hymexazol technical grade. Analysis showed that the chromatographic content of the hymexazol technical grade was 99.2%, the yield (based on hydroxylamine hydrochloride) was 92.1%, the melting point was 86.4–86.9℃, the water content was 0.2%, and the water-insoluble matter was < 0.05%.

[0065] Example 2

[0066] This embodiment is used to verify the process feasibility of low concentration and low flow rate lower limit parameters:

[0067] Material preparation: A-path 10 is a 20% hydroxylamine hydrochloride aqueous solution (containing 1.0 mol of hydroxylamine hydrochloride); B-path 20 is a 25% liquid alkali solution (containing 1.0 mol of NaOH); C-path 30 is pure methyl acetoacetate (1.02 mol); D-path 40 is 31% industrial hydrochloric acid (1.05 mol).

[0068] Continuous flow reaction process: The temperature of the first-stage micromixer 101 is controlled at -10℃, and the A and B streams are neutralized in situ, with an outlet pH of 7.2. The mixed solution and the material from the C stream enter the second-stage microchannel reactor 102, where the reaction temperature is controlled at -5℃, and the pump flow rate is adjusted to extend the residence time of the material in the condensation section to 4 minutes. The intermediate solution is mixed with hydrochloric acid from the D stream in the third-stage micromixer 103 and continuously injected into the tubular reactor 104, where the temperature is controlled at 60℃ and the residence time is 40 minutes. After continuous outflow, the reaction solution enters the vacuum flash evaporator 201 for de-alcoholization. The residual liquid continuously flows into the crystallizer 202, is cooled to 5℃, crystallized for 3 hours, centrifuged in centrifuge 203, washed with water, and dried.

[0069] The solid technical grade of hymexazol was obtained. The yield was 90.5%, the chromatographic content was 98.8%, and the melting point was 86.1-86.7℃.

[0070] Example 3

[0071] This embodiment is used to verify the process feasibility of high concentration and high flow rate upper limit parameters:

[0072] Material preparation: Route A 10 is a 30% hydroxylamine hydrochloride aqueous solution (containing 1.0 mol of hydroxylamine hydrochloride); Route B 20 is a 35% liquid alkali solution (containing 1.05 mol of NaOH); Route C 30 is pure methyl acetoacetate (1.15 mol); Route D 40 is 35% concentrated hydrochloric acid (1.20 mol).

[0073] Continuous flow reaction process: The temperature of the first-stage micromixer 101 is controlled at 5℃, and the A and B streams are neutralized in situ, with an outlet pH of 8.8. The mixed liquid and the material from the C stream enter the second-stage microchannel reactor 102, where the reaction temperature is controlled at 5℃, and the total pump flow rate is increased to shorten the residence time of the material in the condensation section to 1 minute. The condensation intermediate flowing out of 102 is continuously mixed with hydrochloric acid from the D stream in the third-stage micromixer 103 and injected into the tubular reactor 104, where the temperature is increased to 75℃ and the residence time is shortened to 15 minutes. The cyclic liquid is continuously fed into a thin-film evaporator (replacing 201) for rapid flash evaporation and de-alcoholization at 65℃ and -0.09 MPa. The residual liquid is cooled to 10℃ and crystallized for 1.5 hours, then centrifuged, washed, and dried using centrifuge 203.

[0074] The technical grade solid of hymexazol was obtained. The yield was 93.2%, the chromatographic content was 98.6%, and the melting point was 86.0-86.5℃.

[0075] Example 4

[0076] This embodiment uses the optimized median process parameters as the core comparison reference:

[0077] Material preparation: Route A 10 is a 25% hydroxylamine hydrochloride aqueous solution (containing 1.0 mol of hydroxylamine hydrochloride); Route B 20 is a 32% liquid alkali solution (containing 1.01 mol of NaOH); Route C 30 is pure methyl acetoacetate (1.08 mol); Route D 40 is 32% industrial hydrochloric acid (1.10 mol).

[0078] Continuous flow reaction process: The neutralization temperature in the first-stage micromixer 101 is controlled at 0℃, and the neutralization pH is 7.8. The mixed liquid and the C-path material enter the second-stage microchannel reactor 102, where the condensation reaction temperature is controlled at 0℃, and the total residence time of the materials is controlled at 2 minutes. The intermediate and the D-path hydrochloric acid are continuously mixed in the third-stage micromixer 103 and injected into the tubular reactor 104, where the temperature is controlled at 68℃ and the residence time is 25 minutes. The cyclic liquid is continuously de-alcoholized in the vacuum flash evaporator 201 (55℃), and the residual liquid is cooled to 8℃ for crystallization for 2 hours, then centrifuged, washed, and dried in centrifuge 203.

[0079] The solid technical grade of hymexazol was obtained. The results showed that the yield was 94.5%, the chromatographic content was 99.4%, the melting point was 86.5-87.0℃, the moisture content was 0.15%, and the water-insoluble matter was <0.01%.

[0080] Example 5

[0081] This embodiment is used to verify the stability of pretreatment and recycling of centrifuged mother liquor:

[0082] Mother liquor pretreatment: 1000 mL of the high-salt organic mother liquor separated and discharged from the continuous centrifuge 203 in Example 4 was collected. This mother liquor was continuously fed into a continuous electrodialysis unit 301 for desalination, with the current controlled to achieve a desalination rate of 96%. The byproduct sodium chloride inorganic salt flowed out of the system with the concentrated brine. Subsequently, the desalinated aqueous phase mother liquor was continuously passed through a reverse osmosis membrane concentration module 302 for dehydration, intercepting and enriching the organic matter. Excess water was discharged as wastewater, and finally, a recovered compound solution rich in unreacted raw materials and trace amounts of hymexazol was collected at the outlet of 302. Testing revealed that the recovered compound solution contained 0.05 mol of unreacted methyl acetoacetate.

[0083] Applying the flow reaction process:

[0084] The recovered compound solution prepared above was introduced into the front-end system as a dilution solvent. The ratio of new materials was adjusted during feeding: A-channel 10 remained a 25% hydroxylamine hydrochloride aqueous solution (1.0 mol); B-channel 20 contained a 32% liquid alkali solution (1.01 mol); C-channel 30 was pumped with the above-mentioned recovered compound solution, and new pure methyl acetoacetate was added to bring the total to 1.08 mol; D-channel 40 contained 32% industrial hydrochloric acid (1.10 mol).

[0085] The operating parameters of Example 4 (neutralization 0°C, condensation 0°C / 2 min, cyclization 68°C / 25 min, crystallization 8°C / 2 h) were completely repeated for continuous flow reaction and post-treatment. The above-described cycle of "separation of mother liquor - electrodialysis desalination - reverse osmosis concentration - re-combination and feeding" was completely repeated for 5 batches. After the 5th batch cycle, the filter cake in centrifuge 203 was collected and dried. Testing showed that the chromatographic content of the 5th generation hymexazol technical product remained at 98.7%, the melting point was 86.2–86.7°C, the moisture content was 0.3%, and the product appearance was white granules with no obvious impurity enrichment or discoloration. Because the residual raw materials in the mother liquor of the first 4 batches were recycled, the cumulative overall yield of hymexazol in the 5th batch was significantly increased to 96.8%.

[0086] The parameters and results of the implementation examples are summarized in Table 1:

[0087] Example 1 25% -5℃ / 2 min 68℃ / 25 min Reduced pressure flash evaporation 92.1% 99.2% Example 2 20% -10℃ / 4 min 60℃ / 40 min Reduced pressure flash evaporation 90.5% 98.8% Example 3 30% 5℃ / 1 min 75℃ / 15 min Thin film evaporation 93.2% 98.6% Example 4 25% 0℃ / 2 min 68℃ / 25 min Reduced pressure flash evaporation 94.5% 99.4% Example 5 25% 0℃ / 2 min 68℃ / 25 min Reduced pressure flash evaporation 96.8% 98.7%

[0088] Table 1 Summary of Experimental Data from Embodiments of the Invention

[0089] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention in any way. Although the present invention has been disclosed above with reference to preferred embodiments, it is not intended to limit the present invention. Any person skilled in the art can make some modifications or alterations to the methods and techniques disclosed above without departing from the scope of the present invention to create equivalent embodiments. Any simple modifications, equivalent changes and alterations made to the above embodiments based on the technical essence of the present invention without departing from the scope of the present invention shall still fall within the scope of the present invention.

Claims

1. A continuous flow green synthesis process for hymexazol technical grade, characterized in that, The process includes the following steps: (1) Hydroxylamine hydrochloride aqueous solution and alkaline solution are continuously introduced into the first-stage micro mixer for in-situ neutralization reaction, and free hydroxylamine mixture is continuously output; (2) Without solid-liquid separation to remove by-product inorganic salts, the free hydroxylamine mixture and pure methyl acetoacetate are directly and continuously fed into the second-stage microchannel reactor for continuous condensation reaction, and the condensation intermediate is output. (3) The condensation intermediate liquid and hydrochloric acid are continuously introduced into the third-stage micro mixer for mixing, and then continuously injected into the high-temperature tubular reactor for continuous acidification cyclization reaction, and the cyclized mixture is output. (4) After removing the byproduct methanol from the cyclized mixture, the mixture is cooled, crystallized, and centrifuged to obtain the technical grade of hymexazol.

2. The continuous flow green synthesis process for hymexazol technical grade according to claim 1, characterized in that: In step (1), the mass concentration of the aqueous hydroxylamine hydrochloride solution is 20%~30%; the alkaline solution is a liquid alkaline solution with a mass concentration of 25%~35%.

3. The continuous flow green synthesis process for hymexazol technical grade according to claim 1, characterized in that: In step (1), the aqueous solution of hydroxylamine hydrochloride and the alkaline solution are pre-cooled to -5℃~0℃ before entering the first-stage micro-mixer; the molar ratio of hydroxylamine hydrochloride to alkaline solution is 1:

1.

4. The continuous flow green synthesis process for hymexazol technical grade according to claim 1, characterized in that: In step (2), the free hydroxylamine mixture is immediately mixed with pure methyl acetoacetate without stopping after flowing out of the first-stage micro mixer, wherein the molar ratio of methyl acetoacetate to hydroxylamine hydrochloride is 1.02~1.15 :

1.

5. The continuous flow green synthesis process for hymexazol technical grade according to claim 1, characterized in that: In step (2), the inner diameter of the internal channel of the second-stage microchannel reactor is 1.5 mm to 2.5 mm, and the internal structure has a high shear force topology to prevent crystallization and accumulation.

6. The continuous flow green synthesis process for hymexazol technical grade according to claim 1, characterized in that: In step (2), the reaction temperature in the second-stage microchannel reactor is controlled to be -5℃ to 0℃, the reaction pressure is 0.1 to 0.3 MPa, and the total residence time of the material is 1 to 4 min.

7. The continuous flow green synthesis process for hymexazol technical grade according to claim 1, characterized in that: In step (3), the hydrochloric acid is industrial hydrochloric acid with a mass concentration of 31% to 35%, and the molar ratio of the hydrochloric acid to the condensation intermediate is 1.05 to 1.2:

1.

8. The continuous flow green synthesis process for hymexazol technical grade according to claim 1, characterized in that: In step (3), the high-temperature tubular reactor is a plunger flow reactor (PFR) made of silicon carbide or Hastelloy; the cyclization reaction temperature in the high-temperature tubular reactor is controlled at 60℃~75℃, and the residence time of the material in the tube is 15 min~40 min.

9. The continuous flow green synthesis process for hymexazol technical grade according to claim 1, characterized in that: In step (4), the cyclized mixture is continuously degraded by methanol at 50°C to 65°C using a vacuum flash evaporator or a thin-film evaporator; the residual liquid after methanol removal is continuously cooled to 5°C to 10°C and allowed to stand for crystallization for 2 hours, and then centrifuged to obtain white crystalline granular hymexazol technical.

10. The continuous flow green synthesis process for hymexazol technical grade according to claim 1, characterized in that: In step (4), the mother liquor obtained by centrifugation is desalted by an electrodialysis device, then concentrated and enriched by a reverse osmosis membrane module. After removing inorganic salts and recovering unreacted raw materials and residual products, it is recycled and reused in the material preparation of step (1) or the crystallization process of step (4).

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