Fluorination preparation process of pesticide intermediate
By directly activating the C-H bond at the 3-position of the pyrazole ring, reacting with a trifluoromethyl reagent, and utilizing the N-protecting group reagent TMSCl and a catalyst, the problem of poor selectivity in the synthesis of 3-trifluoromethylpyrazole in the prior art is solved, and a high-yield and low-cost synthesis is achieved.
Patent Information
- Application Number
- CN202510813903.X
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-06-18
- Publication Date
- 2025-09-23
AI Technical Summary
The synthesis route of 3-trifluoromethylpyrazole in the prior art has poor regioselectivity, resulting in high by-product content, low product yield, and high cost.
Pyrazole was protected by the N-protecting group reagent TMSCl, and reacted with a trifluoromethylating agent in an inert solvent in combination with a catalyst and an oxidant to achieve highly selective synthesis of 3-trifluoromethylpyrazole through C-H bond activation.
The method improves product yield, reduces by-product content, simplifies process flow, reduces production cost, and has industrial application value.
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Figure CN120682148A_ABST
Abstract
Description
Technical Field
[0001] The present invention relates to the technical field of pesticide chemicals, and in particular to a fluorination preparation process for a pesticide intermediate. Background Art
[0002] Pyroxasulfone is a new, broad-spectrum, highly active pre-emergence soil treatment herbicide developed by Kumihiko Chemical Co., Ltd. of Japan. This herbicide belongs to the isoxazole class and is a potential inhibitor of very-long-chain fatty acid (VLCFAs) biosynthesis in plants. Pyroxasulfone is primarily used as a pre-emergence blocking agent, primarily targeting grasses and supplemented by broadleaf weeds. It can be used in crops such as wheat, corn, peanuts, rice, soybeans, and cotton. It has the advantages of being applicable to a wide range of crops, being environmentally friendly, and safe for both the current and subsequent crops. Its effectiveness lasts for approximately 28 days. The structure of pyroxasulfone is as follows:
[0003] Its chemical formula is C 12 H 14 F5N3O4S, molecular weight is 391.31, chemical name is 3-(((5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)methyl)sulfonyl)-5,5-dimethyl-4,5-dihydroisoxazole.
[0004] 3-Trifluoromethylpyrazole, with a molecular weight of 136.08 and a chemical formula of C4H3F3N2, is an intermediate in the synthesis of sulfonepyrazoline using a fluorination preparation process. Its structure is as follows:
[0005] Currently, there are few studies on the synthesis of 3-trifluoromethylpyrazole, which is mainly synthesized by ethyl trifluoroacetoacetate and hydrazine hydrate cyclization. This synthesis route has the disadvantage of poor regioselectivity, resulting in a high content of by-products in the product, and high product separation costs, resulting in low product yield. Summary of the Invention
[0006] In view of this, the present invention provides a fluorination preparation process for a pesticide intermediate. The process has high selectivity for 3-position substitution, directly activates the C-H bond at the 3-position of the pyrazole ring, and reacts with an electrophilic trifluoromethyl reagent to obtain the target product, 3-trifluoromethylpyrazole. The high selectivity of the process effectively reduces the content of by-products and improves the product yield. In addition, the preparation process has mild reaction conditions, high safety, and easy to handle by-products, which effectively reduces process costs.
[0007] The technical solutions of the present invention are as follows: A fluorination preparation process for a pesticide intermediate comprises the following steps: protecting the starting material pyrazole with an N-protecting group reagent, then adding a trifluoromethylating agent and an oxidizing agent under the action of a catalyst, and finally deprotecting the product to precipitate in an inert solvent; wherein the N-protecting group reagent is TMSCl (trimethylsilyl chloride); and the catalyst is a copper salt.
[0008] Preferably, the above fluorination preparation process is as follows: Step 1: dissolve pyrazole in a first solvent, cool to low temperature, add an acid-binding agent and TMSCl, stir for 2-3 hours, filter, and collect the filtrate; concentrate the filtrate to obtain intermediate 1; Step 2, reaction stage A, adding the second solvent to the intermediate 1, adding water, adding a catalyst, adding sodium trifluoromethanesulfinate, adding an oxidant, and reacting at room temperature for 10-12 hours; Extraction stage A: After the reaction is complete, water is added to the reaction solution, followed by extraction with an extractant, and the organic phase is collected; the organic phase is concentrated to obtain intermediate 2; Step 3, reaction stage B, adding the third solvent to the intermediate 2, adding TBAF (tetrabutylammonium fluoride), and reacting at room temperature for 1 hour; Extraction stage B: After the reaction is complete, saturated ammonium chloride solution is added to the reaction solution, and an extractant is added for extraction; the organic phases are combined, washed with saturated brine, dried, and concentrated; then an inert solvent is added for low-temperature crystallization to obtain the white target product 3-trifluoromethylpyrazole.
[0009] Preferably, in step 1, the first solvent comprises one or more of dichloromethane, chloroform, and dichloroethane; the mass ratio of the first solvent to pyrazole is 3-7:1; The molar ratio of TMSCl to pyrazole is 1.1-1.5:1; The acid binding agent is triethylamine, and the molar ratio of triethylamine to TMSCl is 1.5-2:1.
[0010] Preferably, in the reaction stage A of step 2, the second solvent is one or more combinations of ethyl acetate, DMF, and acetonitrile; The mass ratio of the second solvent to pyrazole is 20-30:1; the mass ratio of water to the second solvent is 1-3:10.
[0011] Preferably, in the reaction stage A of step 2, the molar ratio of sodium trifluoromethanesulfinate to pyrazole is 1.1-1.5:1; The catalyst is one or more combinations of cuprous iodide, cupric chloride, and cupric acetate; the mass ratio of the catalyst to pyrazole is 10-20:100; The oxidant is a peroxide; sodium trifluoromethanesulfinate is added as a CF3 free radical source through the oxide, and finally the protecting group is removed to obtain the target product.
[0012] Preferably, the oxidant is potassium persulfate and / or potassium hydrogen persulfate; and the molar ratio of the oxidant to pyrazole is 1.1-1.5:1.
[0013] Preferably, in the reaction stage B of step 3, the third solvent is tetrahydrofuran, and the mass ratio of tetrahydrofuran to pyrazole is 2-5:1; the molar ratio of TBAF to pyrazole is 1.3-2:1; In the extraction stage B, the inert solvent is one or a combination of n-hexane, cyclohexane, and n-heptane; the mass ratio of the inert solvent to pyrazole is 5-8:1; the low-temperature crystallization temperature is -20~-10°C. Crystallization within this temperature range can obtain a high-purity white solid.
[0014] Compared with the prior art, the present invention has the following beneficial effects: the starting raw material pyrazole is protected by an N-protecting group reagent, and then a trifluoromethylation reagent and an oxidant are added under the action of a catalyst, and finally deprotection is carried out, and the product is precipitated at low temperature in an inert solvent; in this process, the N-protecting group reagent TMSCl is used to protect the 1st position of pyrazole, a catalyst is added to activate the 3rd position of pyrazole, sodium trifluoromethylsulfinate is added as a CF3 free radical source, and TBAF is used for deprotection.
[0015] The fluorination preparation process provided by the present invention avoids the use of a trifluoromethylation reagent with high cost, greatly simplifies the process, saves production costs, and has important industrial application value. BRIEF DESCRIPTION OF THE DRAWINGS
[0016] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the following briefly introduces the drawings required for use in the embodiments or the description of the prior art. Obviously, for ordinary technicians in this field, other drawings can be obtained based on these drawings without any creative work.
[0017] Figure 1 1 is a reaction flow chart of the preparation process of the present invention. DETAILED DESCRIPTION
[0018] In order to enable those skilled in the art to better understand the technical solutions of the present invention, the technical solutions of the present invention will be clearly and completely described below in conjunction with the embodiments of the present invention. Obviously, the embodiments described are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative efforts should fall within the scope of protection of the present invention.
[0019] Example 1 A fluorination preparation process for a pesticide intermediate is as follows: Step 1: Under nitrogen protection, 0.68 kg of pyrazole and 2.7 kg of dichloromethane were added to a reaction kettle to dissolve the pyrazole; after dissolution, the temperature was lowered to 2°C, 1.58 kg of triethylamine was added, and then 0.96 kg of TMSCl was added dropwise. The mixture was stirred at room temperature for 3 hours. After the reaction was complete, the reaction solution was filtered and the filtrate was collected; the filtrate was concentrated to obtain intermediate 1; Step 2, reaction stage A, under nitrogen protection, 20.4 kg of acetonitrile was added to the intermediate 1, and after thorough stirring, 4.0 kg of water was added; after thorough stirring, 105 g of copper acetate was added, and after stirring for 10 minutes, 1.7 kg of sodium trifluoromethanesulfinate was added, followed by 2.9 kg of potassium persulfate, and the reaction was carried out at room temperature for 10 hours; Extraction stage A: After the reaction is complete, 7 kg of water is added to the reaction solution, and then ethyl acetate is added for extraction three times, with 15 kg of ethyl acetate added during each extraction process. The organic phases are collected and combined; the organic phases are washed with water and saturated brine, and then magnesium sulfate is added as a desiccant, filtered, and concentrated to obtain intermediate 2; Step 3, reaction stage B, add 3 kg of tetrahydrofuran to intermediate 2, then add 3.4 kg of TBAF (tetrabutylammonium fluoride), and react at room temperature for 1 hour; Extraction stage B: After the reaction is complete, 8 kg of saturated ammonium chloride solution is added to the reaction solution, and ethyl acetate is added for extraction three times, adding 10 kg of ethyl acetate each time; after the organic phases are combined, they are washed with saturated brine, dried, and concentrated; then 4.1 kg of n-hexane is added to quickly disperse the concentrate, and the mixture is stirred at low speed for 2.5 hours under the condition of -15±5°C for crystallization to obtain 0.95 kg of the white target product 3-trifluoromethylpyrazole with a purity of 98.2% and a yield of 70.0%.
[0020] Comparative Example 1 The difference from Example 1 is that the N-protecting group reagent TMSCl is not added in step 1; the rest of the treatment is the same as in Example 1; In step 3, extraction stage B of this comparative example, the concentrate obtained was an oily substance. After 4.1 kg of n-hexane was added to quickly disperse the concentrate, it was stirred at a low speed for 2.5 hours under the condition of -15±5°C for crystallization, and no solid was precipitated.
[0021] During the reaction of Example 1 and Comparative Example 1, it was difficult to obtain the target product 3-trifluoromethylpyrazole without adding an N-protecting group reagent. Very little of the target product 3-trifluoromethylpyrazole was present in the monitored product of Comparative Example 1. If no protecting group was added, the N at position 1 would react directly with the trifluoromethyl group.
[0022] Comparative Example 2 The difference from Example 1 is that in the reaction stage A of step 2, 2.1 kg of trifluoroiodomethane is used instead of 1.7 kg of sodium trifluoromethanesulfinate, and the remaining steps are the same as in Example 1; Monitoring the reaction process of reaction stage A. The results show that the reaction in this stage is basically unreacted and there is no intermediate 2 in the product; When trifluoroiodomethane is used, the electrophilic substitution reaction requires ultra-low temperature of tert-butyl lithium to proceed, otherwise the reaction will produce a large amount of by-products, resulting in the ineffective reaction. In the present invention, after adding the N-protecting group reagent, pyrazole cannot be converted into a highly active carbon anion nucleophile, thereby failing to drive the reaction with CF3I.
[0023] Comparative Example 3 The difference from Example 1 is that no catalyst is added in the reaction stage A of step 2; The reaction process of reaction stage A was monitored. The results showed that the reaction in this stage was basically unreacted and part of the obtained 5-substituted trifluoromethylpyrazole was obtained.
[0024] Combining Example 1, Comparative Example 1, Comparative Example 2 and Comparative Example 3, it can be seen that in the present invention, the addition of an N-protecting group reagent and sodium trifluoromethylsulfinate can produce a synergistic effect, thereby improving the selectivity of substitution at the 3-position of the pyrazole ring during the substitution reaction, thereby reducing the production of by-products and improving the reaction accuracy.
[0025] Comparative Example 4 The difference from Example 1 is that in step 2, the mass ratio of water to the second solvent is 3.5:10; The reaction process of reaction stage A was monitored. The results showed that the reaction solution obtained in this stage contained more by-products and less intermediate 2.
[0026] Comparative Example 5 The difference from Example 1 is that in step 2, the mass ratio of water to the second solvent is 0.8:10.
[0027] Monitoring the reaction process of reaction stage A showed that the reaction time was prolonged. This may be due to the high amount of salt in the system, which prevented the reaction from proceeding in a homogeneous phase and led to a slower reaction. This indicates that water content below a certain level is not conducive to the reaction.
[0028] Comparative Example 6 The difference from Example 1 is that in step 2, the molar ratio of the oxidant to pyrazole is 1.0:1; The reaction process of reaction stage A was monitored, and the results showed that the reaction time was prolonged, and the purity and yield of the intermediate 2 obtained after treatment were low.
[0029] Example 2 The difference from Example 1 is that in step 1, the first solvent was reacted separately for comparison as follows: Example 2.1: Step 1: Under nitrogen protection, 0.68 kg of pyrazole and 4.1 kg of dichloroethane were added to a reaction kettle to dissolve the pyrazole; after dissolution, the temperature was lowered to 2°C, 1.46 kg of triethylamine was added, and then 0.89 kg of TMSCl was added dropwise. The mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was filtered and the filtrate was collected; the filtrate was concentrated to obtain intermediate 1; Example 2.2: Step 1: Under nitrogen protection, 0.68 kg of pyrazole and 4.7 kg of chloroform were added to a reactor to dissolve the pyrazole; after dissolution, the temperature was lowered to 2°C, 1.3 kg of triethylamine was added, and then 0.89 kg of TMSCl was added dropwise. The mixture was stirred at room temperature for 3 hours. After the reaction was complete, the reaction solution was filtered and the filtrate was collected; the filtrate was concentrated to obtain intermediate 1; Example 2.3: Step 1: Under nitrogen protection, 0.68 kg of pyrazole and 2.0 kg of dichloroethane were added to a reaction kettle to dissolve the pyrazole; after dissolution, the temperature was lowered to 2°C, 1.3 kg of triethylamine was added, and then 0.89 kg of TMSCl was added dropwise. The mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was filtered and the filtrate was collected; the filtrate was concentrated to obtain intermediate 1; Examples 1, 2.1, 2.2, and 2.3 demonstrate that, in step 1, the reaction conditions result in a faster reaction rate in dichloroethane. Therefore, dichloroethane was selected as the first solvent and the reaction solvent for step 1. Furthermore, in combination with Examples 1 and 2, when the amount of pyrazole added was 0.68 kg, an input amount of 0.89 kg of TMSCl (trimethylsilyl chloride) satisfied the reaction conditions, and the excess amount needed to be removed by the solvent, otherwise it would affect subsequent feeding.
[0030] Example 3 A fluorination preparation process for a pesticide intermediate is as follows: Step 1: Under nitrogen protection, 0.68 kg of pyrazole and 2.0 kg of dichloroethane were added to a reaction kettle to dissolve the pyrazole; after dissolution, the temperature was lowered to 3°C, 1.3 kg of triethylamine was added, and then 0.89 kg of TMSCl was added dropwise. The mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was filtered and the filtrate was collected; the filtrate was concentrated to obtain intermediate 1; Step 2, reaction stage A, under nitrogen protection, 20.4 kg DMF was added to intermediate 1, and after thorough stirring, 6.1 kg water was added; after thorough stirring, 136 g copper acetate was added, and after stirring for 10 minutes, 1.74 kg sodium trifluoromethanesulfinate was added, followed by 2.97 kg potassium persulfate, and the reaction was carried out at room temperature for 12 hours; Extraction stage A: After the reaction is complete, 10 kg of water is added to the reaction solution, and then ethyl acetate is added for extraction three times, adding 20 kg of ethyl acetate for extraction during each extraction process. The organic phase is collected and combined; the organic phase is washed with water and saturated brine, and a desiccant magnesium sulfate is added. The reaction mixture is filtered and concentrated to obtain intermediate 2; Step 3, reaction stage B, add 4.1 kg of tetrahydrofuran to intermediate 2, then add 3.6 kg of TBAF (tetrabutylammonium fluoride), and react at room temperature for 1 hour; Extraction stage B: After the reaction is complete, 16 kg of saturated ammonium chloride solution is added to the reaction solution, and ethyl acetate is added for extraction three times, with 10 kg of ethyl acetate added each time. After the organic phases are combined, they are washed with saturated brine, dried, and concentrated. Then, 5.4 kg of n-hexane is added to quickly disperse the concentrate, and the concentrate is stirred at low speed for 2 hours under the condition of -15±5°C for crystallization to obtain 0.71 kg of the white target product 3-trifluoromethylpyrazole with a purity of 97.3% and a yield of 52.3%.
[0031] Example 4 A fluorination preparation process for a pesticide intermediate is as follows: Step 1: Under nitrogen protection, 0.68 kg of pyrazole and 2.0 kg of dichloroethane were added to a reaction kettle to dissolve the pyrazole; after dissolution, the temperature was lowered to 2°C, 1.3 kg of triethylamine was added, and then 0.89 kg of TMSCl was added dropwise. The mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was filtered and the filtrate was collected; the filtrate was concentrated to obtain intermediate 1; Step 2, reaction stage A, under nitrogen protection, 20.4 kg DMF was added to the intermediate 1, and after thorough stirring, 6.1 kg water was added; after thorough stirring, 100 g copper chloride and 100 g cuprous iodide were added, and after stirring for 10 minutes, 1.89 kg sodium trifluoromethanesulfinate was added, followed by 3.24 kg potassium persulfate, and the reaction was carried out at room temperature for 12 h; Extraction stage A: After the reaction is complete, 10 kg of water is added to the reaction solution, and then ethyl acetate is added for extraction three times, with 20 kg of ethyl acetate added during each extraction process. The organic phases are collected and combined; the organic phases are washed with water and saturated brine, and magnesium sulfate as a desiccant is added. The mixture is filtered and concentrated to obtain intermediate 2; Step 3, reaction stage B, add 4.1 kg of tetrahydrofuran to intermediate 2, then add 3.4 kg of TBAF (tetrabutylammonium fluoride), and react at room temperature for 1 hour; Extraction stage B: After the reaction is complete, 12 kg of saturated ammonium chloride solution is added to the reaction solution, and ethyl acetate is added for extraction three times, adding 10 kg of ethyl acetate each time; after the organic phases are combined, they are washed with saturated brine, dried, and concentrated; then 4.7 kg of n-hexane is added to quickly disperse the concentrate, and the mixture is stirred at a low speed for 2.5 hours under the condition of -15±5°C for crystallization to obtain 0.66 kg of the white target product 3-trifluoromethylpyrazole with a purity of 97.5% and a yield of 48.6%.
[0032] Example 5 A fluorination preparation process for a pesticide intermediate is as follows: Step 1: Under nitrogen protection, 0.68 kg of pyrazole and 2.0 kg of dichloroethane were added to a reaction kettle to dissolve the pyrazole; after dissolution, the temperature was lowered to 3°C, 1.3 kg of triethylamine was added, and then 0.89 kg of TMSCl was added dropwise. The mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was filtered and the filtrate was collected; the filtrate was concentrated to obtain intermediate 1; Step 2, reaction stage A, under nitrogen protection, 20.4 kg of ethyl acetate was added to the intermediate 1, and after thorough stirring, 4.1 kg of water was added; after thorough stirring, 102 g of copper acetate was added, and after stirring for 10 minutes, 1.74 kg of sodium trifluoromethanesulfinate was added, followed by 2.97 kg of potassium persulfate, and the reaction was carried out at room temperature for 12 hours; Extraction stage A: After the reaction is complete, 10 kg of water is added to the reaction solution, and then ethyl acetate is added for extraction twice, with 20 kg of ethyl acetate added during each extraction process. The organic phases are collected and combined; the organic phases are washed with water and saturated brine, and magnesium sulfate as a desiccant is added. The mixture is filtered and concentrated to obtain intermediate 2; Step 3, reaction stage B, add 6.8 kg of tetrahydrofuran to intermediate 2, then add 3.4 kg of TBAF (tetrabutylammonium fluoride), and react at room temperature for 1 hour; Extraction stage B: After the reaction is complete, 12 kg of saturated ammonium chloride solution is added to the reaction solution, and ethyl acetate is added for extraction three times, adding 10 kg of ethyl acetate each time; after the organic phases are combined, they are washed with saturated brine, dried, and concentrated; then 4.0 kg of n-hexane is added to quickly disperse the concentrate, and the mixture is stirred at low speed for 2 hours under the condition of -15±5°C for crystallization to obtain 1.05 kg of the white target product 3-trifluoromethylpyrazole with a purity of 98.7% and a yield of 77%.
[0033] Example 6 A fluorination preparation process for a pesticide intermediate is as follows: Step 1: Under nitrogen protection, 0.68 kg of pyrazole and 2.0 kg of dichloroethane were added to a reaction kettle to dissolve the pyrazole; after dissolution, the temperature was lowered to 0°C, 1.3 kg of triethylamine was added, and then 0.89 kg of TMSCl was added dropwise. The mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was filtered and the filtrate was collected; the filtrate was concentrated to obtain intermediate 1; Step 2, reaction stage A, under nitrogen protection, 20.4 kg of ethyl acetate was added to the intermediate 1, and after thorough stirring, 6.1 kg of water was added; after thorough stirring, 136 g of copper acetate was added, and after stirring for 10 minutes, 1.74 kg of sodium trifluoromethanesulfinate was added, followed by 6.7 kg of potassium persulfate, and the reaction was carried out at room temperature for 12 hours; Extraction stage A: After the reaction is complete, 20 kg of water is added to the reaction solution, and then ethyl acetate is added for extraction twice, adding 10 kg of ethyl acetate each time, and the organic phase is collected; the organic phase is washed with water and saturated brine, and magnesium sulfate is added as a desiccant, filtered, and the organic phase is concentrated until no fraction flows down to obtain intermediate 2; Step 3, reaction stage B, add 6.8 kg of tetrahydrofuran to intermediate 2, then add 3.1 kg of TBAF (tetrabutylammonium fluoride), and react at room temperature for 1 hour; Extraction stage B: After the reaction is complete, 10 kg of saturated ammonium chloride solution is added to the reaction solution, and ethyl acetate is added for extraction three times, adding 10 kg of ethyl acetate each time. The organic phases are combined, washed with saturated brine, dried, and concentrated. 4.0 kg of n-heptane is then added to quickly disperse the concentrate. Crystallization is carried out by low-speed stirring at -15 ± 5 ° C for 2.5 hours to obtain 0.54 kg of the white target product 3-trifluoromethylpyrazole with a purity of 96.7% and a yield of 40.1%. In step 2 of this embodiment, too much potassium persulfate solid was added and could not be completely dissolved, resulting in a slow reaction and a correspondingly prolonged reaction time.
[0034] Example 7 A fluorination preparation process for a pesticide intermediate is as follows: Step 1: Under nitrogen protection, 0.68 kg of pyrazole and 2.0 kg of dichloroethane were added to a reaction kettle to dissolve the pyrazole; after dissolution, the temperature was lowered to 3°C, 1.3 kg of triethylamine was added, and then 0.89 kg of TMSCl was added dropwise. The mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was filtered and the filtrate was collected; the filtrate was concentrated to obtain intermediate 1; Step 2, reaction stage A, under nitrogen protection, 13.6 kg of ethyl acetate was added to the intermediate 1, and after thorough stirring, 1.36 kg of water was added; after thorough stirring, 100 g of copper chloride and 100 g of cuprous iodide were added, and after stirring for 10 minutes, 1.74 kg of sodium trifluoromethanesulfinate was added, followed by 2.97 kg of potassium persulfate, and the reaction was carried out at room temperature for 12 hours; Extraction stage A: After the reaction is complete, 10 kg of water is added to the reaction solution, and then ethyl acetate is added for extraction twice, with 10 kg of ethyl acetate added during each extraction process. The organic phases are collected and combined; the organic phases are washed with water and saturated brine, and magnesium sulfate as a desiccant is added. The mixture is filtered and concentrated to obtain intermediate 2; Step 3, reaction stage B, add 6.8 kg of tetrahydrofuran to intermediate 2, then add 3.1 kg of TBAF (tetrabutylammonium fluoride), and react at room temperature for 1 hour; Extraction stage B: After the reaction is complete, 10 kg of saturated ammonium chloride solution is added to the reaction solution, and ethyl acetate is added for extraction three times, adding 10 kg of ethyl acetate each time; after the organic phases are combined, they are washed with saturated brine, dried, and concentrated; then 4.0 kg of n-heptane is added to quickly disperse the concentrate, and the mixture is stirred at low speed for 3 hours under the condition of -15±5°C for crystallization to obtain 0.75 kg of the white target product 3-trifluoromethylpyrazole with a purity of 98.2% and a yield of 55.3%.
[0035] Example 8 A fluorination preparation process for a pesticide intermediate is as follows: Step 1: Under nitrogen protection, 0.68 kg of pyrazole and 2.0 kg of dichloroethane were added to a reaction kettle to dissolve the pyrazole; after dissolution, the temperature was lowered to 3°C, 1.3 kg of triethylamine was added, and then 0.89 kg of TMSCl was added dropwise. The mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was filtered and the filtrate was collected; the filtrate was concentrated to obtain intermediate 1; Step 2, reaction stage A, under nitrogen protection, 20.4 kg of ethyl acetate was added to the intermediate 1, and after thorough stirring, 6.1 kg of water was added; after thorough stirring, 136 g of copper acetate was added, and after stirring for 10 minutes, 2.3 kg of sodium trifluoromethanesulfinate was added, followed by 4.0 kg of potassium persulfate, and the reaction was carried out at room temperature for 12 hours; Extraction stage A: After the reaction is complete, 10 kg of water is added to the reaction solution, and then ethyl acetate is added for extraction twice, with 10 kg of ethyl acetate added during each extraction process. The organic phase is collected; the organic phase is washed with water and saturated brine, and magnesium sulfate as a desiccant is added. The mixture is filtered and concentrated to obtain intermediate 2; Step 3, reaction stage B, add 6.8 kg of tetrahydrofuran to intermediate 2, then add 3.1 kg of TBAF (tetrabutylammonium fluoride), and react at room temperature for 1 hour; Extraction stage B: After the reaction is complete, 10 kg of saturated ammonium chloride solution is added to the reaction solution, and ethyl acetate is added for extraction three times, adding 10 kg of ethyl acetate each time; after the organic phases are combined, they are washed with saturated brine, dried, and concentrated; then 5.4 kg of n-heptane is added to quickly disperse the concentrate, and the mixture is stirred at low speed for 3 hours under the condition of -15±5°C for crystallization to obtain 1.07 kg of the white target product 3-trifluoromethylpyrazole with a purity of 98.6% and a yield of 78.6%.
[0036] Example 9 A fluorination preparation process for a pesticide intermediate is as follows: Step 1: Under nitrogen protection, 0.68 kg of pyrazole and 2.0 kg of dichloroethane were added to a reaction kettle to dissolve the pyrazole; after dissolution, the temperature was lowered to 2°C, 1.3 kg of triethylamine was added, and then 0.89 kg of TMSCl was added dropwise. The mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was filtered and the filtrate was collected; the filtrate was concentrated to obtain intermediate 1; Step 2, reaction stage A, under nitrogen protection, 17 kg of ethyl acetate was added to the intermediate 1, and after thorough stirring, 3.4 kg of water was added; after thorough stirring, 68 g of copper acetate was added, and after stirring for 10 minutes, 2.1 kg of sodium trifluoromethanesulfinate was added, followed by 3.5 kg of potassium persulfate, and the reaction was carried out at room temperature for 14 hours; Extraction stage A: After the reaction is complete, 10 kg of water is added to the reaction solution, and then ethyl acetate is added for extraction twice, with 10 kg of ethyl acetate added during each extraction process. The organic phases are collected and combined; the organic phases are washed with water and saturated brine, and magnesium sulfate is added as a desiccant. The organic phase is filtered and concentrated until no fractions are left to obtain intermediate 2; Step 3, reaction stage B, add 4.1 kg of tetrahydrofuran to intermediate 2, then add 3.1 kg of TBAF (tetrabutylammonium fluoride), and react at room temperature for 1 hour; Extraction stage B: After the reaction is complete, 10 kg of saturated ammonium chloride solution is added to the reaction solution, and ethyl acetate is added for extraction three times, adding 10 kg of ethyl acetate each time; after the organic phases are combined, they are washed with saturated brine, dried, and concentrated; then 5.4 kg of n-hexane is added to quickly disperse the concentrate, and the mixture is stirred at a low speed for 2.5 hours under the condition of -15±5°C for crystallization to obtain 1.1 kg of the white target product 3-trifluoromethylpyrazole with a purity of 98.1% and a yield of 81%.
[0037] Although the present invention has been described in detail with reference to preferred embodiments, the present invention is not limited thereto. Without departing from the spirit and essence of the present invention, a person of ordinary skill in the art may make various equivalent modifications or substitutions to the embodiments of the present invention, and such modifications or substitutions shall be within the scope of the present invention. Any person skilled in the art who can easily conceive of changes or substitutions within the technical scope disclosed in the present invention shall be included within the scope of protection of the present invention. Therefore, the scope of protection of the present invention shall be based on the scope of protection of the claims.
Claims
1. A fluorination preparation process for a pesticide intermediate, characterized in that: The process is as follows: the starting material pyrazole is protected by an N-protecting group reagent, then a trifluoromethylation reagent and an oxidant are added under the action of a catalyst, and finally deprotection is performed to precipitate the product in an inert solvent; wherein the N-protecting group reagent is TMSCl; and the catalyst is a copper salt.
2. The fluorination preparation process for the pesticide intermediate according to claim 1, characterized in that: The specific process is as follows: Step 1: dissolve pyrazole in a first solvent, cool to low temperature, add an acid-binding agent and TMSCl, stir for 2-3 hours, filter, and collect the filtrate; concentrate the filtrate to obtain intermediate 1; Step 2, reaction stage A, adding the second solvent to the intermediate 1, adding water, adding a catalyst, adding sodium trifluoromethanesulfinate, adding an oxidant, and reacting at room temperature for 10-12 hours; Extraction stage A: After the reaction is complete, water is added to the reaction solution, followed by extraction with an extractant, and the organic phase is collected; the organic phase is concentrated to obtain intermediate 2; Step 3, reaction stage B, adding the third solvent to the intermediate 2, adding TBAF, and reacting at room temperature for 1 hour; Extraction stage B: After the reaction is complete, saturated ammonium chloride solution is added to the reaction solution, and an extractant is added for extraction; the organic phases are combined, washed with saturated brine, dried, and concentrated; then an inert solvent is added for low-temperature crystallization to obtain the white target product 3-trifluoromethylpyrazole.
3. The fluorination preparation process of the pesticide intermediate according to claim 2, characterized in that: In step 1, the first solvent includes one or more of dichloromethane, chloroform, and dichloroethane; the mass ratio of the first solvent to pyrazole is 3-7:1; the molar ratio of TMSCl to pyrazole is 1.1-1.5:1; The acid binding agent is triethylamine, and the molar ratio of triethylamine to TMSCl is 1.5-2:
1.
4. The fluorination preparation process for the pesticide intermediate according to claim 2, characterized in that: In the reaction stage A of step 2, the second solvent is one or more combinations of ethyl acetate, DMF, and acetonitrile; The mass ratio of the second solvent to pyrazole is 20-30:1; the mass ratio of water to the second solvent is 1-3:
10.
5. The fluorination preparation process for the pesticide intermediate according to claim 2, characterized in that: In the reaction stage A of step 2, the molar ratio of sodium trifluoromethanesulfinate to pyrazole is 1.1-1.5:1; The catalyst is one or more combinations of cuprous iodide, cupric chloride, and cupric acetate; the mass ratio of the catalyst to pyrazole is 10-20:100; The oxidizing agent is a peroxide.
6. The fluorination preparation process for the pesticide intermediate according to claim 5, characterized in that: The oxidant is potassium persulfate and / or potassium hydrogen persulfate; the molar ratio of the oxidant to pyrazole is 1.1-1.5:
1.
7. The fluorination preparation process for a pesticide intermediate according to claim 2, characterized in that: In the reaction stage B of step 3, the third solvent is tetrahydrofuran, and the mass ratio of tetrahydrofuran to pyrazole is 2-5:1; the molar ratio of TBAF to pyrazole is 1.3-2:1; In the extraction stage B, the inert solvent is one or a combination of n-hexane, cyclohexane, and n-heptane; the mass ratio of the inert solvent to pyrazole is 5-8:1; and the temperature of the low-temperature crystallization is -20 to -10°C.