Process for the preparation of 1-methyl-3-trifluoromethyl-5-hydroxypyrazole and its use as a pesticide

Abstract

This invention discloses a method for preparing 1-methyl-3-trifluoromethyl-5-hydroxypyrazole and its pesticide application, providing a method for preparing 1-methyl-3-trifluoromethyl-5-hydroxypyrazole (II) from 1-methyl-3-trichloromethyl-5-hydroxypyrazole (I) under normal pressure. The process is as follows: 40% methylhydrazine and ethyl trichloroacetoacetate are added dropwise to glacial acetic acid at 40±3℃, and the temperature is maintained at 40±3℃ before being raised to 90-100℃ and maintained thereafter. The endpoint is set by HPLC detection of a residual ester content of ≤1.0%. Acetic acid is recovered under reduced pressure, water is added twice, and solvent removal continues. Crystallization is performed at 0-15℃ to obtain I. Subsequently, 0.8-1.5 equivalents of hydrofluoric acid are added dropwise to toluene / triethylamine at 70-80℃ for 1-2 hours, and the temperature is maintained for 3-5 hours until the residual I content is ≤1.0% to obtain II. Preferred conditions are a two-stage constant-rate addition at 72-76℃ using Et3N·nHF (n=3-5). This method is simple, has controllable EHS (Environment, Health, and Safety), and allows for solvent recovery, making it suitable for industrial application. It can be used to synthesize pre-emergence herbicides such as sulfonylpyrazine.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis and preparation of intermediates for agrochemicals, specifically to the preparation method and pesticide application of 1-methyl-3-trifluoromethyl-5-hydroxypyrazole. Background Technology

[0002] Sulfonamide is a novel pre-emergence herbicide for wheat, corn, and soybeans. Its chemical structural formula is:

[0003] The molecular formula is C 12 H 14 F5N3O4S. Sulfonazole inhibits the biosynthesis of ultra-long-chain fatty acids in plants and exhibits superior herbicidal activity against grasses and broadleaf weeds at lower application rates compared to other commercial herbicides. Sulfonazole is a pre-emergence herbicide for controlling grasses and small-seeded broadleaf weeds. In transgenic crop fields, sulfonazole controls weeds resistant to non-selective herbicides; while 1-methyl-3-trichloromethyl-5-hydroxypyrazole can be used to prepare the intermediate necessary for the synthesis of sulfonazole—1-methyl-3-trifluoromethyl-5-hydroxypyrazole. This route is significantly cheaper than the traditional method of directly purchasing 1-methyl-3-trifluoromethyl-5-hydroxypyrazole for the synthesis of sulfonazole, facilitating industrial production and effectively reducing production costs.

[0004] Existing literature has proposed several general routes for the preparation of 1-substituted-5 / 3-hydroxypyrazole. Among them, patent document number US6392058B1 reports a method of regioselectivity control by condensing alkyl-3-alkoxyacrylate (III) with hydrazine and adjusting the pH of the system (7-11 for 5-hydroxy; 11-14 for 3-hydroxy). However, this document and its family of related documents do not disclose the direct construction of the intermediate "1-methyl-3-trichloromethyl-5-hydroxypyrazole" by trichloroacetoacetate + methylhydrazine under two-stage temperature control conditions of 40℃→95℃ in a carboxylic acid medium, nor does it involve the mild conversion of –CCl3→–CF3 by dropwise addition of HF in organic solvent / organic base at normal pressure and 70–80℃. On the contrary, the existing methods summarized in this document generally have problems such as too many steps, high safety / environmental pressure of some raw materials (such as triphosgene), and complex or uneconomical regioisomeric separation in historical routes.

[0005] Patent documents WO2018154097 and TW201835036A propose a route for the direct synthesis of 1-methyl-3-trifluoromethyl-1H-pyrazole-5-ol (5-MTP) from ethyl 4,4,4-trifluoroacetoacetate (ETFAA) and methylhydrazine, employing a "product-in-presence" strategy to enhance the regioselectivity of 5-MTP / 3-MTP. The process can utilize low amounts of acid, or even no external solvent, and incorporates antisolvent crystallization. This route is a direct CF3 scheme, bypassing the "1-methyl-3-trichloromethyl-5-hydroxypyrazole" intermediate, and does not disclose the conversion of –CCl3→–CF3 achieved by dropwise addition of HF in an organic solvent / organic base at atmospheric pressure and 70–80°C.

[0006] Patent document number US4650875A generally requires catalysis by metal halides and is carried out under high temperature / pressure conditions for general halogen exchange in aromatic / heteroaromatic systems. Although this type of technology can demonstrate the chemical feasibility of the -CCl3→–CF3 conversion, it is at a disadvantage in terms of process safety (EHS), energy consumption, and equipment requirements.

[0007] Patent document CN112574111B discloses a method for synthesizing 1-methyl-5-hydroxypyrazole by reacting dimethyl malonate with DMF and an alkylating agent under alkaline conditions to generate an intermediate, followed by cyclization with methylhydrazine or hydrazine hydrate, and decarboxylation via acid hydrolysis. This technology primarily targets hydroxypyrazoles with N1-position methyl substitution and does not involve the synthesis process of hydroxypyrazoles with C3-position trihalomethyl (such as trichloromethyl or trifluoromethyl) substitution. Such compounds, especially 1-methyl-3-trifluoromethyl-5-hydroxypyrazole, are important intermediates in the synthesis of highly effective pre-emergence herbicides such as sulfopyrazine. Existing publicly available technologies still lack efficient synthetic methods for 1-methyl-3-trichloromethyl-5-hydroxypyrazole and systematic research on process routes for further conversion from CCl3 to CF3, which limits the widespread application of such intermediates in the pesticide industry. Patent document CN113979944A discloses a direct CF3 substrate route for selectively preparing 1-methyl-3-trifluoromethyl-1H-pyrazole-5-ol, which confirms the technical idea of ​​"direct trifluoroacetyl substrate → target CF3-pyrazole", but it also does not involve the CCl3-pyrazole intermediate and does not involve the ambient pressure and HF conversion conditions of this application.

[0008] In summary, existing technologies either involve directly constructing the target pyrazole from the CF3 substrate or completing the halogen exchange of the side chain in a high-temperature / pressurized HF system. No combined process has been found that uses acetic acid as a medium for two-stage temperature-controlled construction of the "1-methyl-3-trichloromethyl-5-hydroxypyrazole" intermediate, followed by the gentle conversion of –CCl3→–CF3 by dropwise addition of HF at approximately 75°C under normal pressure and organic solvent / base conditions. Therefore, this paper proposes a method for preparing 1-methyl-3-trifluoromethyl-5-hydroxypyrazole and its pesticide application to address these issues. Summary of the Invention

[0009] The technical problem this invention aims to solve is to overcome the shortcomings of existing methods and provide a method for preparing 1-methyl-3-trifluoromethyl-5-hydroxypyrazole and its pesticide application. The proposed two-step method completes the conversion of 1-methyl-3-trichloromethyl-5-hydroxypyrazole from ethyl trichloroacetoacetate and methylhydrazine under normal pressure, and further achieves a mild conversion of CCl3 to CF3. Through two-stage temperature control in acetic acid medium, two-stage water replenishment crystallization, and controlled dropwise addition of Et3N·nHF in a toluene and triethylamine system, a process window combining industrial feasibility, safety, and high selectivity is obtained. Overall, the yield of step one is stable at 80–85%, the yield of step two is stable at 90–92%, the HPLC content of the target product reaches or exceeds 93%, and under the optimized window, the HPLC content is not less than 95%, with a one-step intermediate residue of no more than 0.5%. This significantly outperforms the energy consumption, safety, and cost indicators of comparative routes and effectively solves the problems in the background technology.

[0010] To achieve the above objectives, the present invention provides the following technical solution: a method for preparing 1-methyl-3-trifluoromethyl-5-hydroxypyrazole and its pesticide application. This method, under normal pressure, utilizes a one-step intermediate of 1-methyl-3-trichloromethyl-5-hydroxypyrazole and specifically includes the following steps:

[0011] S1: In a carboxylic acid solvent, acetic acid or glacial acetic acid is selected as the carboxylic acid, and a 40% aqueous solution of methylhydrazine is added dropwise to the reaction system at 40±3℃.

[0012] S2: After the addition is complete, maintain the temperature at 40±3℃, add ethyl trichloroacetoacetate dropwise to the system, and keep it at 40±3℃ for 2-4 hours;

[0013] S3: Heat the system to 90-100℃ and keep it at that temperature for 2-4 hours. The endpoint is determined by HPLC with the residual amount of ethyl trichloroacetoacetate ≤1.0%.

[0014] S4: After the endpoint, the carboxylic acid solvent was recovered under reduced pressure until the system became viscous. The vacuum was broken and water was added twice. The solvent was then removed under reduced pressure. The system was cooled to 0-15℃ to crystallize. Solid-liquid separation and drying were performed to obtain the one-step intermediate 1-methyl-3-trichloromethyl-5-hydroxypyrazole.

[0015] S5: Add the one-step intermediate to an inert organic solvent / organic base, heat to 70-80℃, and add 0.8-1.5 equivalents of hydrofluoric acid dropwise at this temperature. The amount is calculated as 1 equivalent of the one-step intermediate and 0.8-1.5 equivalents based on the molecular equivalent of hydrofluoric acid. The dropwise addition time is 1-2 hours.

[0016] S6: After the addition is complete, continue to keep warm at 70-80℃ for 3-5 hours. The endpoint is set when the residual amount of the first-step intermediate is ≤1.0% as detected by HPLC. The reaction solution is allowed to stand and separate into layers, the aqueous phase is discarded, and the organic phase is desoluble under reduced pressure to obtain the two-step intermediate 1-methyl-3-trifluoromethyl-5-hydroxypyrazole.

[0017] Furthermore, the carboxylic acid solvent is glacial acetic acid, and the holding time in step S2 is 3 hours at 40±3℃; the holding time in step S3 is 3 hours at 95℃.

[0018] Furthermore, in step S4, the amount of water added each time is 0.4-0.7 times the mass of ethyl trichloroacetoacetate; the crystallization temperature is ≤10℃; after crystallization is maintained at this temperature for at least 0.5 hours, the mixture is filtered and dried at 50-70℃ for 6-10 hours, and the HPLC content of the obtained one-step intermediate 1-methyl-3-trichloromethyl-5-hydroxypyrazole is ≥90%.

[0019] Furthermore, the inert organic solvent in step S5 is toluene, the organic base is triethylamine, and the addition and heat preservation are carried out at 75°C.

[0020] Furthermore, in steps S5-S6, hydrofluoric acid is added dropwise in two stages at a constant rate at 72-76°C in the form of triethylamine-hydrofluoric acid complex Et3N·nHF, where n is 3–5. In the first stage, 40-60% of the total HF equivalent is added dropwise at a rate of 0.8-1.2 g·min⁻¹·kg⁻¹ based on the one-step intermediate, and the remainder is added dropwise at the same rate after an interval of 10-30 min. During the reaction, the water content of the system is controlled at 0.1-1.0 wt%, wherein the water is introduced by the wet material of the one-step intermediate and the water carried by Et3N·nHF and no additional water is added. Under the above conditions, the HPLC content of the two-step intermediate 1-methyl-3-trifluoromethyl-5-hydroxypyrazole is not less than 95.0%, and the residual amount of the one-step intermediate is not higher than 0.5%.

[0021] Furthermore, in step S6, HPLC analysis showed that the residual amount of the intermediate 1-methyl-3-trichloromethyl-5-hydroxypyrazole was ≤1.0% and the content of the product 1-methyl-3-trifluoromethyl-5-hydroxypyrazole was ≥93%.

[0022] Furthermore, the yield of the one-step intermediate obtained in step S4 is 80-85%, and the yield of the two-step intermediate obtained in step S6 is 90-92%.

[0023] Furthermore, after steps S5-S6 are completed, the reaction solution is allowed to stand and separate into layers, and the lower aqueous phase is discarded. Then, the organic phase is desoluble under reduced pressure to obtain a crude two-step intermediate. The crude product is purified by crystallization of ethyl acetate / n-hexane or by decolorization and recrystallization.

[0024] Application of 1-methyl-3-trifluoromethyl-5-hydroxypyrazole in pesticide preparation.

[0025] The pesticide is a pre-emergence herbicide with pyrazole nucleus as the key fragment, and the herbicide is sulfopyrazine.

[0026] Further research shows that the improved selectivity of steps S5-S6 is not due to a single factor, but rather the result of the combined effects of the trace moisture window, the complexed state of Et3N·nHF, the two-stage constant-rate dropping profile, and the controlled biphasic behavior: when the moisture content is controlled at 0.1–1.0 wt%, Et3N·nHF can release free HF in a mild and continuous manner at the organic / micro-water interface. Combined with the initial feeding of 40–60% and the 10–30 min interval to suppress the instantaneous acidity peak, this avoids the amplification of overfluorination and skeletal side reactions. At the same time, the one-step intermediate obtained in S4 has better particle morphology and lower entrained acid, which improves the effective utilization rate of HF. This synergistic effect of multiple factors results in selectivity and purity comparable to or even better than that of traditional high-temperature / pressurized systems at atmospheric pressure and 70–80 °C.

[0027] While existing literature reports routes for the conversion of –CCl3 to –CF3 via direct use of trifluoroacetyl substrates or in high-temperature / pressurized HF systems, these routes suffer from high dependence on raw materials, significant EHS risks, demanding equipment requirements, or complex side reactions, making them difficult to sustain industrially. This invention, for the first time, proposes a two-stage temperature-controlled synthesis of the 1-methyl-3-trichloromethyl-5-hydroxypyrazole intermediate using acetic acid media. The two-stage synthesis is carried out under mild conditions of ambient pressure and 70–80°C using an Et3N·nHF complex within a trace moisture window. Constant-rate dropping is used to achieve highly selective conversion of –CCl3 to –CF3. This combined process not only differs fundamentally from existing high-temperature and high-pressure or direct CF3 substrate routes in terms of reaction conditions, but also shows significant improvements in purity, yield, batch-to-batch stability, and EHS control. Existing technologies have not provided combined insights into the “two-stage temperature control of acetic acid + two-stage water replenishment crystallization + controlled dropping of Et3N·nHF + trace moisture window”, nor have they revealed the synergistic effect of this combined measure on reducing side reactions, improving HF utilization, and scaling up reproducibility.

[0028] Compared with the prior art, the beneficial effects of the present invention are:

[0029] 1. By using two-stage temperature control of acetic acid + two-stage water replenishment crystallization + two-stage constant-rate addition of Et3N·nHF + 0.1–1.0wt% water window, the target product can be stably obtained with high purity and high yield at atmospheric pressure / approximately 75℃. Compared with the direct CF3 route or high-temperature and pressure halogen exchange, side reactions are reduced and batch-to-batch fluctuations are small.

[0030] 2. The key transformation of this invention is completed in the range of normal pressure and low temperature, without the need for metal halide catalysis and pressure-resistant equipment; with the controlled addition of triethylamine-hydrofluoric acid complex and the trace moisture window, the risk of corrosion and leakage is reduced, and the synthesis method of 1-methyl-3-trichloromethyl-5-hydroxypyrazole also greatly saves the cost of industrial production of sulfopyrazole.

[0031] 3. Starting materials are readily available, avoiding reliance on trifluoroamide substrates; acetic acid, toluene, etc. can be recycled and reused, and the amount of hydrofluoric acid used is controllable, resulting in reduced overall material and energy consumption, and a simultaneous decrease in production costs and environmental burden; each step has clearly defined endpoints and release standards, making it suitable for scale-up and continuous production; the resulting intermediates have high purity and low residues, which is beneficial for the yield and quality control of subsequent hydroxymethylation, etherification, and other construction steps, meeting the needs of large-scale and stable supply of pesticide intermediates. Attached Figure Description

[0032] Figure 1 This is a schematic diagram of the synthetic route of the present invention;

[0033] Figure 2 The HPLC chromatogram of the target product in Example 1 of this invention;

[0034] Figure 3 The curves show the changes in the KF content of the two-step intermediate, the one-step intermediate, and Imp1 (impurity) of this invention. Detailed Implementation

[0035] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that the specific embodiments described herein are only for explaining the present invention and are not intended to limit the present invention.

[0036] Please see Figure 1-3 The present invention provides a technical solution: a method for preparing 1-methyl-3-trifluoromethyl-5-hydroxypyrazole and its application as a pesticide.

[0037] Raw material description:

[0038] Methylhydrazine was prepared using a 40% (mass fraction) aqueous solution; the carboxylic acid solvent was glacial acetic acid (≥99.5%).

[0039] The preferred inert organic solvent is toluene (industrial grade, moisture ≤0.05%); the preferred organic base is triethylamine (Et3N).

[0040] "Adding hydrofluoric acid" can be anhydrous HF or its amine complex Et3N·nHF (n=3-5);

[0041] High-performance liquid chromatography (HPLC) is used for endpoint determination and content determination. For chromatographic conditions, please refer to "Analytical Methods and Quality Control".

[0042] The HF donors described in this invention include anhydrous HF or Et3N·nHF (n = 3–5); Et3N·nHF refers to the complex formed by triethylamine and hydrofluoric acid; "equivalent" is calculated in terms of HF molecules, with a relative compound I = 1.0 equivalent; "atmospheric pressure" refers to 0.9–1.1 bar (absolute pressure); HPLC "content / residue" is area%.

[0043] One-step intermediate: 1-methyl-3-trichloromethyl-5-hydroxypyrazole;

[0044] Two-step intermediate: 1-methyl-3-trifluoromethyl-5-hydroxypyrazole.

[0045] Example 1

[0046] S1-S4: Preparation of intermediate products in one step

[0047] In a 2000 mL four-necked flask, 363 g of glacial acetic acid was added, stirred, and the temperature was controlled at 40 °C. 365 g of 40% methylhydrazine solution was added dropwise at a constant rate, and the mixture was stirred at 40 ± 3 °C after the addition was complete. Then, 577 g of ethyl trichloroacetoacetate was added dropwise, and the mixture was kept at 40 ± 3 °C for 3 h after the addition was complete. The temperature was raised to 95 °C and kept at 3 h, with the endpoint determined by HPLC analysis showing a residual ester content of ≤1.0%. Acetic acid was recovered under reduced pressure until the system became viscous. 300 g of water was added after the vacuum was broken, and the mixture was desoluble under reduced pressure until the system became viscous again. Another 300 g of water was added after the vacuum was broken. The mixture was cooled to 10 °C to crystallize, and the wet material was filtered to obtain approximately 1500 g. The wet material was dried at 60 °C for 8 h to obtain 1402 g of the one-step intermediate 1-methyl-3-trichloromethyl-5-hydroxypyrazole, with a purity of 93.25% and a yield of 83.23%.

[0048] S5–S6: One-step intermediate → Two-step intermediate

[0049] In a 1000 mL four-necked flask, add 300 g of toluene, 214 g of 1-methyl-3-trichloromethyl-5-hydroxypyrazole, and 300 g of triethylamine, and heat to 75 °C. Add 75 g of anhydrous HF dropwise at a constant rate (approximately 1.5 h). After the addition is complete, maintain the temperature at 75 °C for another 4 h. HPLC analysis shows that the endpoint is reached when the residual 1-methyl-3-trichloromethyl-5-hydroxypyrazole is ≤1.0%. Allow the mixture to stand and separate into layers, discarding the lower aqueous phase. Desolvate the organic phase under reduced pressure to obtain approximately 152.7 g of crude 1-methyl-3-trifluoromethyl-5-hydroxypyrazole, a two-step intermediate with an HPLC purity of 94.35% and a yield of 91.56%. Further purification can be achieved by crystallization with ethyl acetate / n-hexane if necessary.

[0050] As attached Figure 1The synthetic route shown is as follows: One-step intermediate = 1-methyl-3-trichloromethyl-5-hydroxypyrazole; Two-step intermediate = 1-methyl-3-trifluoromethyl-5-hydroxypyrazole; Key conditions: Acetic acid medium 40±3℃→95℃; Toluene / Et3N, 75℃, atmospheric pressure; HF donor is Et3N·nHF (n=3–5) added at a constant rate in two stages.

[0051] As attached Figure 2 The results show that the purity of the main peak is ≥95%, and the impurity peaks are all ≤1.0%.

[0052] Example 2

[0053] The apparatus is the same as that used in Example 1 for S1-S4, yielding a one-step intermediate (HPLC ≥ 90%, yield 80-85%).

[0054] The toluene / triethylamine system was heated to 74°C, and Et3N·3HF was used as the HF source, with the mixture added dropwise in two stages at a constant rate:

[0055] First step: Add 50% of the total HF equivalent dropwise at a rate of 0.8-1.0 g·min-1·kg-1 (based on the one-step intermediate);

[0056] After a 20-minute interval, the remaining amount was added dropwise at the same rate in the second stage;

[0057] The water content of the entire system is controlled at 0.1-1.0 wt% (introduced by the water carried by the wet intermediate material and Et3N·3HF, without adding additional water).

[0058] The total dropwise addition time was approximately 1.5 hours, followed by incubation at 75°C for 4 hours. HPLC analysis determined that the residue of the first-step intermediate was ≤0.5–1.0%. After standing and separating the phases, the aqueous phase was discarded, and solvent was removed under reduced pressure to obtain the crude second-step intermediate. After crystallization with ethyl acetate / n-hexane, the HPLC content reached ≥95.0%, the residue of the first-step intermediate was ≤0.5%, and the overall yield was comparable to that of Example 1 (approximately 90-92%), with reduced batch-to-batch fluctuations.

[0059] In this second embodiment, the two-stage constant-rate addition and trace moisture window can suppress the instantaneous acidity peak and the perfluorination side reaction, thereby improving the purity and release stability of the two-step intermediate.

[0060] Example 3

[0061] The only difference between this embodiment and Embodiment 1 is the temperature change in the second insulation stage: Following Embodiment 1, the second insulation temperature was set to 80, 85, 90, and 95°C respectively; as the temperature increased, the content / yield of the one-step intermediate increased sequentially, reaching a peak at 95°C with a content of 94.35% and a yield of 83.23%, as shown in Table 1.

[0062] Table 1

[0063]

[0064] Following the procedure in Example 1, the temperature variation during the second heat preservation stage was set to 60, 65, 70, 75, 80, 85, and 90°C. The content / yield of the two-step intermediate reached its peak at 75°C, with a content of 94.35% and a yield of 92.00%. Referring to Table 2, when the temperature deviated from this, the content of the two-step intermediate decreased, while the residual amount of the one-step intermediate and the by-products increased.

[0065] Table 2

[0066]

[0067] This result confirms that the "95℃ cyclization and 75℃ halogen exchange" constitutes a narrow and reproducible optimal window.

[0068] Example 4

[0069] Equipment: PFA tubular microreactor (inner diameter 1.0mm), three-way metering pump, 2-bar back pressure valve, 75℃ constant temperature bath.

[0070] Feed: Stream A: a solution or slurry of one-step intermediate in toluene / triethylamine; Stream B: Et3N·3HF (or Et3N·5HF) premixed with a small amount of toluene; Stream C: diluted toluene to control viscosity and residence time.

[0071] Conditions: Total residence time 6–10 min, equivalent HF equivalent 0.9–1.2, online quenching / stratification at discharge, crystallization after decompression.

[0072] Results: The two-step intermediate can be stably obtained with HPLC purity ≥ 93%; by optimizing the flow rate ratio and back pressure, the purity of the one-step intermediate can be further improved, making it suitable for scale-up and process safety management.

[0073] Comparative Example 1: Anhydrous HF added at once

[0074] Objective: To verify the necessity of "two-stage constant-rate dripping".

[0075] Differences in conditions: Except for the feeding method, the conditions are the same as in Example 2 (toluene / triethylamine, 75°C, atmospheric pressure, hydrofluoric acid (HF) equivalent 1.0–1.2); this comparative example is modified to add HF quickly in one go, with a feeding time of about 10–15 min.

[0076] Results: The content of 1-methyl-3-trifluoromethyl-5-hydroxypyrazole decreased significantly (<93%); the residual amount of 1-methyl-3-trichloromethyl-5-hydroxypyrazole increased (>1.0%); the total yield was less than 90%.

[0077] HPLC showed a significant increase in the area of ​​by-products (perfluorinated peaks).

[0078] Conclusion: Single-stage feeding resulted in excessively high instantaneous acidity and exothermic peaks, amplifying side reactions. This indicates that "two-stage constant-rate dropping" is the key measure to ensure selectivity and yield.

[0079] Comparative Example 2: The system was too wet (moisture content > 2.0 wt%)

[0080] Objective: To verify the necessity of the "trace moisture window (0.1–1.0 wt%)".

[0081] Differences in conditions: The rest is the same as in Example 2, except that water is added before S5–S6 to make the total moisture content of the system >2.0wt%.

[0082] Results: The content of 1-methyl-3-trifluoromethyl-5-hydroxypyrazole decreased to <93%; the residual amount of 1-methyl-3-trichloromethyl-5-hydroxypyrazole was >1.0%; HPLC showed an increase in by-products (hydrolysis / ring-opening products); separation was difficult and extraction losses increased.

[0083] Conclusion: Excessive moisture content disrupts the optimal phase ratio, excessive HF capture, and suppression of the main reaction; comparative analysis shows that moisture content control at 0.1–1.0 wt% is a necessary condition for the stable acquisition of high-purity II.

[0084] Moisture determination: The moisture content of the system was determined by KF (volume method or coulometric method) and controlled within 0.1–1.0 wt%; the moisture only came from the wet material of compound I and / or the moisture entrained by Et3N·nHF, and no additional water was added.

[0085] As attached Figure 3 As shown: II (Target) indicates the target product 1-methyl-3-trifluoromethyl-5-hydroxypyrazole: the curve shows a trend of first increasing and then decreasing; it reaches its highest point at around KF = 0.3–0.5 wt%, with an area of ​​nearly 95%; the content decreases when it is too dry (0.05 wt%) or too wet (2.0 wt%).

[0086] I (Intermediate) indicates the precursor 1-methyl-3-trichloromethyl-5-hydroxypyrazole: the curve trend is opposite to that of the target product; the residue is lowest (about 0.4-0.6%) when KF = 0.3–0.5 wt%; the residue increases when KF is too low or too high (e.g., >1.5% at 0.05 wt% and about 2% at 2.0 wt%).

[0087] Imp1 (Impurity) represents the impurity peak (major impurity): the curve generally increases as KF deviates from the optimal window; it is lowest at KF = 0.3–0.5 wt% (approximately 1.2–1.3%), and rises to 4% at KF = 2.0 wt%.

[0088] In the experimental results shown in the figure, the HPLC area percentage of 1-methyl-3-trifluoromethyl-5-hydroxypyrazole showed a trend of first increasing and then decreasing with the change of system moisture (KF determination value); when KF was controlled at 0.3–0.5 wt%, the area percentage of 1-methyl-3-trifluoromethyl-5-hydroxypyrazole reached its peak and stabilized at about 95%, indicating that this range is the optimal window for the formation of the target product; while when the system was too dry (0.05 wt%) or too wet (2.0 wt%), the content of 1-methyl-3-trifluoromethyl-5-hydroxypyrazole decreased significantly, verifying the key influence of moisture content on the reaction selectivity.

[0089] Correspondingly, the HPLC residue of 1-methyl-3-trichloromethyl-5-hydroxypyrazole was lowest at a KF of 0.3–0.5 wt%, only about 0.4–0.6%; while when the KF was below 0.1 wt% or above 1.0 wt%, the residue increased to more than 1.5–2%; this indicates that under suboptimal moisture conditions, the conversion of CCl3 to CF3 is inhibited, and the intermediate is difficult to convert completely.

[0090] Meanwhile, the area percentage of the main impurity Imp1 was lowest (approximately 1.2–1.3%) when KF was 0.3–0.5 wt%, while it increased to about 4% at 2.0 wt%, indicating that impurity formation was significantly amplified under conditions of excessive moisture. In summary, controlling the moisture content of the system within the narrow range of 0.1–1.0 wt%, especially within 0.3–0.5 wt%, can improve the purity of the target product, reduce side reactions, and minimize intermediate residues, thus verifying the superiority and necessity of the process window of this invention.

[0091] Key Process Points and Options

[0092] 1. Carboxylic acid medium: glacial acetic acid is preferred, but acetic acid can also be used; the two-stage temperature control of S1-S3 from 40±3℃ to 90-100℃ is crucial.

[0093] 2. Water replenishment, desolvation and crystallization: S4 is desolvated after two water replenishments, which helps to reduce residual acid and improve the filterability and crystal form of the one-step intermediate; the crystallization temperature is preferably ≤10℃.

[0094] 3. Solvents and bases: Toluene / triethylamine is preferred for S5-S6; dichloromethane, 1,2-dichloroethane and diisopropylethylamine can also be used as alternatives, with slight differences in selectivity.

[0095] 4. Source of hydrofluoric acid: Anhydrous HF or Et3N·nHF (n=3–5) can be used; the latter is convenient for constant-rate addition and the total equivalent of acidity buffer should be 0.8-1.5.

[0096] 5. Temperature and time: The optimal range for S5-S6 is 70-80℃ (preferably 75℃), with 1-2 hours of dropwise addition followed by 3-5 hours of heat preservation; deviations will result in a decrease in the content of the two-step intermediate.

[0097] 6. Layering and purification: After fluorination, allow the mixture to stand and separate into layers, discarding the aqueous phase. Then, desolvate the organic phase under reduced pressure. The crude product can be purified by crystallization with ethyl acetate / n-hexane or by decolorization and recrystallization.

[0098] Implementing the system at atmospheric pressure reduces the risks of pressure resistance and leakage; compared with the high temperature / pressurized HF system, the material requirements are significantly reduced.

[0099] It is recommended that parts in contact with HF be made of materials such as PTFE / PFA / Hastelloy; and that a two-stage alkaline washing (NaOH→Ca(OH)2) process be used to treat the tail gas and fluoride-containing mother liquor, with the pH controlled at 7-9.

[0100] The dropping process employs constant-rate metering, coupled with temperature and stirring alarms, to prevent instantaneous acidity and exothermic peaks.

[0101] Analytical methods and quality control

[0102] Endpoint determination: S3 endpoint: HPLC residue of raw material ester (e.g., ethyl trichloroacetoacetate) ≤1.0%;

[0103] S6 Release: One-step intermediate residue ≤1.0%, two-step intermediate HPLC content ≥93%.

[0104] HPLC conditions (example):

[0105] Column: C18, 250mm × 4.6mm, 5μm;

[0106] Mobile phase: A (0.1% H3PO4 + 10% acetonitrile / water), B (acetonitrile); Linear gradient A: 94.4 → 33.3% / 50 min;

[0107] Column temperature: 40℃; Detection: UV 230nm; External standard is II standard (purity confirmed by NMR).

[0108] Other characterizations (1H / 13 C / 19 F NMR, HRMS, and residual solvent) can be performed according to the enterprise / drug intermediate internal control standards, which are omitted here.

[0109] Preferred embodiment

[0110] (I) Synergistic effect of trace moisture window

[0111] In steps S5–S6, the water content of the reaction system is controlled within the range of 0.1–1.0 wt% (derived from the wet intermediate of the first step and the water of crystallization / entrained water carried by Et3N·nHF, without additional addition), forming a mild proton buffer environment of organic phase / micro-aqueous phase, which can significantly suppress perfluorination and skeletal side reactions and reduce the first ring-opening byproducts; when it exceeds this range (too dry or too wet), the purity of the target product decreases and the precursor residue increases, exhibiting a narrow window and reproducible peak selectivity.

[0112] (II) Et3N·nHF complex state and two segments of constant-rate dropping curves

[0113] By replacing anhydrous HF with Et3N·nHF (n=3-5) and feeding it at two constant mass flow rates (0.8–1.2 g·min-1·kg-1 in terms of I) at intervals of 10-30 min and the remainder, the release of free HF can be smoothed out, the instantaneous acidity and exothermic reaction can be reduced, and byproduct polymerization / perfluorination can be reduced. This allows the release standard to be stably improved from "II content ≥93%, I residue ≤1.0%" to "II content ≥95.0%, I residue ≤0.5%".

[0114] (III) Phase Behavior and Stirring Control

[0115] Maintaining a two-phase system (organic phase: aqueous phase volume ratio preferably 1.2–3.0:1) in S5–S6, and controlling the stirring linear velocity / paddle speed within the range of 300–600 rpm, can provide sufficient interfacial renewal rate, shorten the time to reach the endpoint, and suppress local acidity hotspots without significantly increasing shear side reactions. When deviating from the above phase volume ratio or stirring range, the residual I decreases more slowly and the impurity spectrum deteriorates.

[0116] (iv) Particle engineering and filterability of one-step intermediates

[0117] The two-stage water replenishment → reduced pressure solvent removal → crystallization at ≤10℃ in S4 not only improves the purity of the one-step intermediate but also reshapes the crystal form / particle size distribution, resulting in a solid raw material with low specific resistance, low acidity, and low solubility in the filter cake. When this solid enters S5-S6, HF utilization is higher and local acidity is more uniform, indirectly improving the peak purity and batch-to-batch reproducibility of the two-step intermediate. Compared to "one-stage water replenishment / room temperature crystallization," the target peak area ratio / release pass rate of the one-step intermediate → two-step intermediate is significantly improved.

[0118] (V) Self-stability of the ternary buffer system

[0119] The residual acetic acid in S5-S6 (controllable ppm to low 1000 ppm), triethylamine, and Et3N·nHF together constitute a "ternary buffer" system of weak acid-weak base-strong acid complex: acetic acid provides a weak acid background, triethylamine complexes with nHF to regulate free HF, and the three adaptively buffer external disturbances (feed fluctuations, heat exchange fluctuations), so that at atmospheric pressure and 70-80℃, selectivity comparable to that of high-pressure systems can still be obtained without metal halide catalysis.

[0120] (vi) Intrinsic safety advantages of continuous variants

[0121] Implementing S5-S6 (2–15 min residence time, 1–5 bar back pressure only for maintaining single phase / avoiding vaporization) in PFA / PTFE tubular microreactors or circulating flow devices, combined with online stratification and immediate alkaline washing, reduces HF storage capacity and energy density at the source; compared to batch dripping in batches, continuous operation can further shorten the time window of "HF in an activated state", improving intrinsic safety and quality control consistency.

[0122] In the above method, it is further specified that: the hydrofluoric acid used in steps S5–S6 is triethylamine-hydrofluoric acid complex Et3N·nHF (n is 3–5), which is added dropwise at 72–76°C in two stages at a constant rate. In the first stage, 40–60% of the total HF equivalent is added dropwise at a mass flow rate of 0.8–1.2 g·min⁻¹·kg⁻¹ based on the one-step intermediate. After an interval of 10–30 min, the remainder is added dropwise at the same rate. The water content of the reaction system is controlled at 0.1–1.0 wt%, and the water is only derived from the wet material of the one-step intermediate and / or the water carried by Et3N·nHF and is not added separately. Under these combined conditions, the release standard is that the residual amount of the one-step intermediate is ≤0.5% and the HPLC content of the target product is ≥95.0%.

[0123] While existing technologies reveal that the –CCl3 group can be converted to –CF3 under HF conditions, this usually depends on harsh conditions such as high temperature, high pressure, or metal halide catalysis. These technologies can only prove that the conversion is chemically feasible, but do not provide a specific implementation path under normal pressure and mild conditions. The technical solution of this invention does not simply use HF halogen exchange, but forms a completely new route that is different from existing technologies through a process combination of “two-stage temperature-controlled construction of CCl3-pyrazole intermediate in acetic acid medium + two-stage constant-rate dropwise addition of Et3N·nHF complex within a 0.1–1.0wt% trace moisture window under normal pressure and 70–80℃ conditions”.

[0124] Under the conditions of the examples, the HPLC content of target product II is consistently above 95%, the residue of the one-step intermediate is ≤0.5%, and the yield is 90–92%. In contrast, the comparative examples (such as one-time addition of HF or excessive humidity of the system >2.0 wt%) show problems such as decreased purity of II, increased by-products, and difficulty in layering. At the same time, the present invention completes the key transformation under normal pressure and low temperature conditions, and the hydrofluoric acid is released slowly in the form of a complex, reducing the risk of corrosion and escape. The solvent can be recycled, making it suitable for industrial scale-up. It can be seen that the present invention not only overcomes the shortcomings of the prior art, but also achieves significant and unexpected technical effects.

[0125] The foregoing has shown and described the basic principles, main features and advantages of the present invention. Various changes and modifications can be made to the present invention without departing from the spirit and scope thereof, and all such changes and modifications fall within the scope of the present invention as claimed.

Claims

A method for preparing 1,1-methyl-3-trifluoromethyl-5-hydroxypyrazole, characterized in that, This method, under normal pressure, via a one-step intermediate 1-methyl-3-trichloromethyl-5-hydroxypyrazole, specifically includes the following steps: S1: In a carboxylic acid solvent, acetic acid or glacial acetic acid is selected as the carboxylic acid, and a 40% aqueous solution of methylhydrazine is added dropwise to the reaction system at 40±3℃. S2: After the addition is complete, maintain the temperature at 40±3℃, add ethyl trichloroacetoacetate dropwise to the system, and keep it at 40±3℃ for 2-4 hours; S3: Heat the system to 90-100℃ and keep it at that temperature for 2-4 hours. The endpoint is determined by HPLC with the residual amount of ethyl trichloroacetoacetate ≤1.0%. S4: After the endpoint, the carboxylic acid solvent was recovered under reduced pressure until the system became viscous. The vacuum was broken and water was added twice. The solvent was then removed under reduced pressure. The system was cooled to 0-15℃ to crystallize. Solid-liquid separation and drying were performed to obtain the one-step intermediate 1-methyl-3-trichloromethyl-5-hydroxypyrazole. S5: Add the one-step intermediate to an inert organic solvent / organic base, heat to 70-80℃, and add 0.8-1.5 equivalents of hydrofluoric acid dropwise at this temperature for 1-2 hours; S6: After the addition is complete, continue to keep warm at 70-80℃ for 3-5 hours. The endpoint is set when the residual amount of the first-step intermediate is ≤1.0% as detected by HPLC. The reaction solution is allowed to stand and separate into layers, the aqueous phase is discarded, and the organic phase is desoluble under reduced pressure to obtain the two-step intermediate 1-methyl-3-trifluoromethyl-5-hydroxypyrazole.

2. The method for preparing 1-methyl-3-trifluoromethyl-5-hydroxypyrazole according to claim 1, characterized in that: The carboxylic acid solvent is glacial acetic acid. The holding time for step S2 is 3 hours at 40±3℃; the holding time for step S3 is 3 hours at 95℃.

3. The method for preparing 1-methyl-3-trifluoromethyl-5-hydroxypyrazole according to claim 1, characterized in that: In step S4, the amount of water added each time is 0.4-0.7 times the mass of ethyl trichloroacetoacetate; the crystallization temperature is ≤10℃. After crystallization at a temperature of at least 0.5 hours, the mixture is filtered and dried at 50-70℃ for 6-10 hours. The HPLC content of the obtained one-step intermediate 1-methyl-3-trichloromethyl-5-hydroxypyrazole is ≥90%.

4. The method for preparing 1-methyl-3-trifluoromethyl-5-hydroxypyrazole according to claim 1, characterized in that: The inert organic solvent in step S5 is toluene, the organic base is triethylamine, and the addition and heat preservation are carried out at 75°C.

5. The method for preparing 1-methyl-3-trifluoromethyl-5-hydroxypyrazole according to any one of claims 1-4, characterized in that: In steps S5-S6, hydrofluoric acid is added dropwise in two stages at a constant rate at 72-76°C in the form of triethylamine-hydrofluoric acid complex Et3N·nHF, where n is 3–5. In the first stage, 40-60% of the total HF equivalent is added dropwise at a rate of 0.8-1.2 g·min⁻¹·kg⁻¹ based on the one-step intermediate, and the remainder is added dropwise at the same rate after an interval of 10-30 min. During the reaction, the water content of the system is controlled at 0.1-1.0 wt%, where the water is introduced from the wet material of the one-step intermediate and the water carried by Et3N·nHF, and no additional water is added. Under the above conditions, the HPLC content of the two-step intermediate 1-methyl-3-trifluoromethyl-5-hydroxypyrazole is not less than 95.0%, and the residual amount of the one-step intermediate is not higher than 0.5%.

6. The method for preparing 1-methyl-3-trifluoromethyl-5-hydroxypyrazole according to claim 1, characterized in that: In step S6, HPLC analysis showed that the residual amount of the intermediate 1-methyl-3-trichloromethyl-5-hydroxypyrazole was ≤1.0% and the content of the product 1-methyl-3-trifluoromethyl-5-hydroxypyrazole was ≥93%.

7. The method for preparing 1-methyl-3-trifluoromethyl-5-hydroxypyrazole according to claim 1, characterized in that: The yield of the one-step intermediate obtained in step S4 is 80-85%, and the yield of the two-step intermediate obtained in step S6 is 90-92%.

8. The method for preparing 1-methyl-3-trifluoromethyl-5-hydroxypyrazole according to any one of claims 1-7, characterized in that: After steps S5-S6 are completed, the reaction solution is allowed to stand and separate into layers, and the lower aqueous phase is discarded. Then, the organic phase is desoluble under reduced pressure to obtain the crude two-step intermediate. The crude product is purified by crystallization of ethyl acetate / n-hexane or by decolorization and recrystallization.

9. The use of 1-methyl-3-trifluoromethyl-5-hydroxypyrazole prepared by any one of the methods described in 1-8 in the preparation of pesticides.

10. The use according to claim 9, characterized in that: The pesticide is a pre-emergence herbicide with pyrazole nucleus as the key fragment, and the herbicide is sulfopyrazine.

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