A method for continuously preparing 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid based on a series connection of cyclization-dealcoholization solvent exchange-wiped film fluorination

Abstract

This invention discloses a continuous method for preparing 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid based on a cascaded process of cyclization-de-alcoholization-scraped membrane fluorination, belonging to the field of continuous synthesis technology in fine chemicals. The method includes: cyclizing ethyl 2-ethoxymethylene-4,4-dichloroacetoacetate with methylhydrazine in a loop reactor with forced external circulation, controlling the circulation ratio boundary at 15:1 to 18:1 to improve the selectivity of the target isomer; continuously removing at least some ethanol from the cyclized liquid and adding sulfolane for solvent replacement, ensuring that the ethanol content in the system before entering the fluorination stage is no higher than 1.0% (wt) and the water content is 0.1-0.2% (wt); subsequently, the resulting intermediate material, along with anhydrous potassium fluoride and 18-crown-6 to form a heterogeneous slurry, is fed into a vertical scraped membrane reactor, with a residence time strictly controlled at 169-171°C for 80-100 seconds, and rapid cooling within 3 seconds after discharge; finally, the target product is obtained through hydrolysis and acidification. This specific combined process can achieve high 1,3-isomer selectivity, high fluorination conversion, low aldehyde byproduct levels, and good long-term continuous operation stability without separating the cyclization intermediate.

Description

Technical Field

[0001] This invention belongs to the field of continuous synthesis technology in fine chemicals, specifically relating to a method for the continuous preparation of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid (DFPA) using a loop reactor in the cyclization section, a continuous de-alcoholization and solvent replacement step between the cyclization section and the fluorination section, and a vertical scraped membrane reactor in the fluorination section. Background Technology

[0002] 3-Difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid (DFPA) is a key intermediate in the synthesis of various SDHI-based fungicides. Existing technologies have disclosed chemical routes starting with dichloroacetoacetate derivatives, including methylhydrazine cyclization, halogen exchange (Halex reaction), and hydrolysis-acidification; at the same time, there have also been continuous explorations of related ester intermediates.

[0003] However, existing disclosures do not provide a stable process for the specific material system described in this application that can complete the continuous series of "cyclization—de-alcoholization and solvent exchange—high-temperature short-time fluorination—hydrolysis and acidification" without separating the cyclization intermediate. When scaling up the production of this specific material system, at least three coupled engineering challenges exist: First, the heat transfer and mixing issues in the cyclization stage. This cyclization reaction is significantly exothermic; at ambient temperatures around 20°C, the macroscopic and microscopic mixing rates of conventional continuous equipment often cannot effectively match the exothermic rate, and the resulting local hot spots easily lead to an increase in undesirable 1,5-isomer byproducts. Second, the ethanol and trace amounts of water introduced in the cyclization stage significantly interfere with the subsequent Halex reaction, increasing the risk of hydrolysis and defluorination side reactions. Third, high-solids KF systems are prone to KCl deposition under high-temperature continuous fluorination conditions, leading to increased equipment pressure drop and deteriorated heat transfer. Summary of the Invention

[0004] The technical problem to be solved by this invention is to provide a continuous combined process for addressing the above three coupled engineering challenges. Without separating the cyclization intermediate, the stable and continuous preparation of DFPA is achieved through sequential synergy of external circulation-controlled mixing of the cyclization segment, alcohol removal and solvent exchange-controlled introduction, and high-temperature short-time fluorination and rapid quenching of the scraped film. This process also takes into account high 1,3-isomer selectivity, high fluorination conversion rate, low aldehyde byproduct level, and good long-term operational stability.

[0005] To achieve the above objectives, the technical solution of the present invention is as follows: A continuous method for preparing 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid based on a cascade of cyclization-de-alcoholization-scraped fluorination comprises the following sequential steps: (1) Cyclic reaction: An ethanol solution of ethyl 2-ethoxymethylene-4,4-dichloroacetoacetate and an ethanol solution of methylhydrazine are continuously fed into a loop reactor with forced external circulation and jacket heat exchange in parallel. The molar ratio of ethyl 2-ethoxymethylene-4,4-dichloroacetoacetate to methylhydrazine is controlled at 1:1.00 to 1.05, the reaction temperature is 20°C, the average residence time is 3 minutes, and the volume ratio of the circulation flow rate to the total feed flow rate of the loop reactor is 15:1 to 18:1, to obtain a cyclized reaction mixture containing ethyl 3-dichloromethyl-1-methyl-1H-pyrazole-4-carboxylate. (2) Continuous de-alcoholization and solvent replacement: The cyclized reaction mixture obtained in step (1) is continuously subjected to de-alcoholization under reduced pressure, and sulfolane is added for solvent replacement. The ethanol content in the system before entering step (3) is controlled to be no higher than 1.0% (wt) and the water content is 0.1-0.2% (wt) to obtain the intermediate material for subsequent fluorination. (3) Fluorination reaction: The intermediate material obtained in step (2) is mixed with anhydrous potassium fluoride and 18-crown-6 to form a solid-liquid heterogeneous slurry. The amount of anhydrous potassium fluoride added is 2.9 to 3.1 times the molar amount of ethyl 3-dichloromethyl-1-methyl-1H-pyrazole-4-carboxylate, and the amount of 18-crown-6 added is 0.08 to 0.12 times the molar amount of ethyl 3-dichloromethyl-1-methyl-1H-pyrazole-4-carboxylate. The solid content of the slurry is 25 to 32 wt%. The slurry is continuously fed into a vertical scraped film reactor, and the inner wall temperature is controlled at 169 to 171°C and the mechanical scraper rotation speed is 330 to 380 rpm. The average residence time of the material in the reactor is 80-100 seconds. The reaction effluent is quenched in a 0-10°C quenching liquid within 3 seconds after leaving the heating zone, and the volume ratio of the reaction effluent to the quenching liquid is not less than 1:2, to obtain an effluent containing ethyl 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylate. (4) Hydrolysis and acidification: After filtering out inorganic salts from the effluent obtained in step (3), the effluent is hydrolyzed with a sodium hydroxide aqueous solution of 25% to 32% by mass at 55 to 65°C. Then, the effluent is acidified with hydrochloric acid to pH 2.0 to 2.5 to separate 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid.

[0006] Preferably, in step (1), the molar ratio of ethyl 2-ethoxymethylene-4,4-dichloroacetoacetate to methylhydrazine is 1:1.03 to 1.05.

[0007] Preferably, the ethanol content in the system after continuous de-alcoholization and solvent replacement treatment in step (2) and before entering step (3) is not higher than 0.8% (wt), and the water content is 0.15 to 0.20% (wt).

[0008] Preferably, the quenching liquid in step (3) is water or a water / ethanol mixture, and the average residence time is calibrated to be 85-95 seconds using a tracer method.

[0009] Preferably, in step (3), the contents of anhydrous potassium fluoride, 18-crown-6 and slurry solids are controlled to be 3.0 times, 0.10 times and 28% (wt) of the molar amount of ethyl 3-dichloromethyl-1-methyl-1H-pyrazole-4-carboxylate, respectively; and the pH of the acidification endpoint in step (4) is 2.2 to 2.5.

[0010] Compared with conventional batch reactor or ordinary continuous tubular process, this application achieves the following technical effects by locking the process parameters within a specific narrow window: During the cyclization stage, the micro-mixing environment was improved under the coupling of 20°C, 3-minute residence time, and a specific cycle ratio of 15:1 to 18:1, which significantly enhanced the selectivity of the 1,3-isomer.

[0011] Before the fluorination stage, the ethanol and water content in the cyclization liquid are controlled to an acceptable range for subsequent halogen exchange through continuous de-alcoholization and solvent replacement. On this basis, a vertical scraped membrane reactor is used to strictly control the residence time in the high-temperature zone of 169-171℃ to 80-100 seconds, and combined with rapid quenching within 3 seconds, which effectively reduces the formation of water-induced aldehyde byproducts.

[0012] In long-term continuous operation tests, the parameter scheme showed stable heat transfer efficiency and pressure drop under the given conditions in the embodiments of this application, effectively suppressing the phenomenon of scale deposition on pipe walls that is prone to occur in high solid content systems. Attached Figure Description Figure 1 This is the chemical structural formula of the target product of this invention. Figure 2 This is a schematic diagram of a continuous process equipment according to an embodiment of the present invention.

Detailed Implementation Methods

[0013] Key testing and evaluation methods To ensure the reproducibility of the experimental data and the consistency of the judgment criteria in this application, the following definitions are made: Component content: Conversion rate, isomer ratio and aldehyde impurities were determined by high performance liquid chromatography (HPLC, normalization method).

[0014] Initial moisture content: The moisture content of the material after slurry preparation and before entering the thin-film reactor is determined using a Karl Fischer moisture titrator.

[0015] Residual ethanol: The ethanol content in the intermediate material before entering the fluorination section after continuous alcohol removal and solvent replacement was determined by gas chromatography.

[0016] Average residence time: The average residence time in the loop section is obtained by dividing the effective volume of the reactor by the feed volumetric flow rate; the average residence time in the thin-film reactor section is calibrated using a dye tracer method combined with a mass flow meter.

[0017] Quenching time difference: It is calculated by dividing the length of the connecting pipe from the edge of the discharge port at the bottom of the thin film reactor to the liquid surface in the quenching tank by the actual average flow velocity of the material.

[0018] System pressure drop (ΔP): Calculated by reading the pressure difference between the WFE inlet and outlet pressure transmitters from the DCS system.

[0019] Heat transfer coefficient (K value): The DCS system automatically calculates and records the data every hour based on the temperature difference between the jacket inlet and outlet, the flow rate, and the heat load on the feed side.

[0020] Equipment cleaning and scale determination: After shutdown and evacuation, use methanol of twice the system volume to perform standard circulation flushing for 1 hour at room temperature. After evacuation, open the flange and use an industrial endoscope to inspect the heating surface. If no continuous white solid deposit layer is seen, it is determined that there is no obvious salt scale adhesion.

[0021] Examples and Effect Verification The following examples all use a loop reactor with an effective volume of 50 L (with built-in static mixing components) and a vertical scraped film reactor with an effective heat transfer area of ​​0.5 m².

[0022] Example 1 Cyclization reaction: The molar ratio of ethyl 2-ethoxymethylene-4,4-dichloroacetoacetate to methylhydrazine was 1:1.03. The reaction temperature was 20℃, the average residence time was 3 minutes, and the circulation ratio was controlled at 15:1 using a variable frequency pump.

[0023] Intermediate material preparation and fluorination reaction: The cyclized liquid was continuously depressurized to remove ethanol, and sulfolane was added for solvent replacement, controlling the ethanol content to be 0.8 wt% and water content to be 0.15 wt% before entering the fluorination section; then anhydrous KF (3.0 molar amounts) and 18-crown-6 (0.1 molar amounts) were added to prepare a slurry with a solid content of 28 wt%. The inner wall temperature of the WFE heating element was 170℃, the scraper rotation speed was 350 rpm, and the average residence time was 90 seconds. After discharge, the material was quenched in water at 5℃ (volume ratio 1:2) within 2.5 seconds.

[0024] Hydrolysis and acidification: After separating the inorganic salts, hydrolysis was performed using a 28% NaOH aqueous solution at 60℃, followed by acidification with hydrochloric acid to pH 2.2.

[0025] Test results: 1,3-isomer selectivity of cyclization segment 97.6%; fluorination conversion rate 98.5%; aldehyde impurities 0.4%.

[0026] Example 2 Cyclic section: molar ratio 1:1.00, temperature 20℃, residence time 3 minutes, circulation ratio 18:1.

[0027] Intermediate material preparation and fluorination section: The cyclization liquid is continuously depressurized to remove ethanol, and sulfolane is added for solvent replacement. The ethanol content is controlled to be no higher than 1.0 wt% and the water content to be 0.1 wt% before entering the fluorination section. Subsequently, anhydrous KF (2.9 molar amounts) and 18-crown-6 (0.08 molar amounts) are added to prepare a slurry with a solid content of 25 wt%. WFE temperature is 169℃, scraper speed is 330 rpm, and residence time is 100 seconds. Quenching occurs within 2.8 seconds of discharge.

[0028] Test results: 1,3-isomer selectivity 97.8%; fluorination conversion rate 98.2%; aldehyde impurities 0.5%.

[0029] Example 3 Cyclic section: molar ratio 1:1.05, temperature 20℃, residence time 3 minutes, circulation ratio 16:1.

[0030] Intermediate material preparation and fluorination section: The cyclization liquid is continuously depressurized to remove ethanol and sulfolane is added for solvent replacement, controlling the ethanol content to be no higher than 1.0% (wt) and the water content to be 0.2% (wt) before entering the fluorination section; then anhydrous KF 3.1 molar amounts and 18-crown-6 0.12 molar amounts are added to prepare a slurry with a solid content of 32 wt%. WFE temperature 171℃, scraper 380 rpm, residence time 80 seconds. Quenching occurs within 2.1 seconds of discharge.

[0031] Test results: 1,3-isomer selectivity 97.4%; fluorination conversion rate 97.8%; aldehyde impurities 0.6%.

[0032] Comparative Study To verify the improvements brought about by specific reactor characteristics, a comparative example with the same heat history was set up: Comparative Example 1 (Ring Section Comparison - Conventional Tubular Reactor): All other conditions were the same as in Example 1, using a conventional plug flow tubular reactor (without external circulation), maintaining an average temperature of 20°C and a residence time of 3 minutes. Radial mixing was limited, and the selectivity for the 1,3-isomer was measured to be 86.2%.

[0033] Comparative Example 2 (Ring Section Comparison - Intermittent Reactor): Same formulation as Example 1, using a conventional reactor. Due to limitations in the macroscopic heat transfer rate, microscopic hot spots appeared (the highest locally measured temperature was 42.5℃), and the selectivity of the 1,3-isomer was only 81.4%. The comparison shows that the 15:1 cycle ratio of Example 1 exhibited an unexpected improvement.

[0034] Comparative Example 3 (Fluorination Section Comparison - Static Mixing Tube): All other conditions were the same as in Example 1, using a static mixing continuous tube reaction. The fluorination conversion rate was only 68.2% with a residence time of 90 seconds. If the residence time was extended to 45 minutes to improve the conversion rate, the hydrolysis side reaction intensified, resulting in aldehyde impurities as high as 18.5%.

[0035] The comparative results above demonstrate that the technical effect of this application does not stem from the conventional replacement of any single step or single piece of equipment, but rather from the continuous combination and parameter coupling of "external circulation controlled mixing in the cyclization stage—de-alcoholization and solvent exchange controlled introduction—vertical scraping film high-temperature short-time fluorination—rapid quenching." For the specific material system described in this application, the sequence of the above steps and the parameter window jointly determine the target isomer selectivity, fluorination conversion rate, aldehyde byproduct level, and long-term operational stability.

[0036] DCS Long-Term Stability Verification

[0037] Under the process conditions of Example 1, the platform operated continuously for 168 hours, and the timing data of key DCS nodes were recorded: t=1h: Inlet and outlet pressure drop 2.1 kPa, scraper torque load rate 45.2%, heat transfer coefficient K=865 W / (m²·K).

[0038] t=48h: Inlet and outlet pressure drop 2.2 kPa, scraper torque load rate 45.5%, heat transfer coefficient K=862 W / (m²·K).

[0039] t=120h: Inlet and outlet pressure drop 2.4 kPa, scraper torque load rate 46.2%, heat transfer coefficient K=854 W / (m²·K).

[0040] t=168h: Inlet and outlet pressure drop 2.5 kPa, scraper torque load rate 46.8%, heat transfer coefficient K=848 W / (m²·K).

[0041] At the end of the test, the pressure drop throughout the process remained stable, and no pipe blockage occurred; the calculated K-value decay was 1.96%. After shutdown according to the aforementioned "cleaning and scaling determination method", endoscopic inspection confirmed that there was no obvious salt scale adhering to the inner wall of the heating element.

Claims

1. A method for the continuous preparation of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid based on a tandem sequence of cyclization-de-alcoholization solvent exchange-scraped film fluorination, characterized in that, Includes the following sequential steps: (1) Cyclic reaction: An ethanol solution of ethyl 2-ethoxymethylene-4,4-dichloroacetoacetate and an ethanol solution of methylhydrazine are continuously fed into a loop reactor with forced external circulation and jacket heat exchange in parallel. The molar ratio of ethyl 2-ethoxymethylene-4,4-dichloroacetoacetate to methylhydrazine is controlled at 1:1.00 to 1.05, the reaction temperature is 20°C, the average residence time is 3 minutes, and the volume ratio of the circulation flow rate to the total feed flow rate of the loop reactor is 15:1 to 18:1, to obtain a cyclized reaction mixture containing ethyl 3-dichloromethyl-1-methyl-1H-pyrazole-4-carboxylate. (2) Continuous de-alcoholization and solvent replacement: The cyclized reaction mixture obtained in step (1) is continuously subjected to de-alcoholization under reduced pressure, and sulfolane is added for solvent replacement. The ethanol content in the system before entering step (3) is controlled to be no higher than 1.0% (wt) and the water content is 0.1-0.2% (wt) to obtain the intermediate material for subsequent fluorination. (3) Fluorination reaction: The intermediate material obtained in step (2) is mixed with anhydrous potassium fluoride and 18-crown-6 to form a solid-liquid heterogeneous slurry. The amount of anhydrous potassium fluoride added is 2.9 to 3.1 times the molar amount of ethyl 3-dichloromethyl-1-methyl-1H-pyrazole-4-carboxylate, and the amount of 18-crown-6 added is 0.08 to 0.12 times the molar amount of ethyl 3-dichloromethyl-1-methyl-1H-pyrazole-4-carboxylate. The solid content of the slurry is 25 to 32 wt%. The slurry is continuously fed into a vertical scraped film reactor, and the inner wall temperature is controlled at 169 to 171°C and the mechanical scraper rotation speed is 330 to 380 rpm. The average residence time of the material in the reactor is 80-100 seconds. The reaction effluent is quenched in a 0-10°C quenching liquid within 3 seconds after leaving the heating zone, and the volume ratio of the reaction effluent to the quenching liquid is not less than 1:2, to obtain an effluent containing ethyl 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylate. (4) Hydrolysis and acidification: After filtering out inorganic salts from the effluent obtained in step (3), the effluent is hydrolyzed with a sodium hydroxide aqueous solution of 25% to 32% by mass at 55 to 65°C. Then, the effluent is acidified with hydrochloric acid to pH 2.0 to 2.5 to separate 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid.

2. The method according to claim 1, characterized in that: The molar ratio of ethyl 2-ethoxymethylene-4,4-dichloroacetoacetate to methylhydrazine in step (1) is 1:1.03 to 1.

05.

3. The method according to claim 1, characterized in that: In step (1), a static mixing component is installed in the loop reactor, and the volume ratio of the circulating flow rate to the total feed flow rate is adjusted by a variable frequency circulating pump.

4. The method according to claim 1, characterized in that: After the continuous de-alcoholization and solvent replacement treatment in step (2) and before entering step (3), the ethanol content in the system is no higher than 0.8% (wt), and the water content is 0.15-0.20% (wt).

5. The method according to claim 1, characterized in that: The quenching liquid mentioned in step (3) is water or a water / ethanol mixture.

6. The method according to claim 1, characterized in that: The average dwell time mentioned in step (3) is calibrated to 85-95 seconds using the tracer method.

7. The method according to claim 1, characterized in that: After the inorganic salts are removed from the quenched reaction effluent obtained in step (3), it is directly fed into a continuous or semi-continuous hydrolysis tank for the hydrolysis reaction in step (4).

8. The method according to claim 1, characterized in that: The acidification endpoint pH in step (4) is 2.2 to 2.

5.

9. The method according to claim 1, characterized in that: In step (3), the content of anhydrous potassium fluoride, 18-crown-6 and slurry solids is controlled to be 3.0 times, 0.10 times and 28% (wt) of the molar amount of ethyl 3-dichloromethyl-1-methyl-1H-pyrazole-4-carboxylate, respectively.

Images