Synthesis process of meconazole
The optimized synthesis process for clofoconazole addresses the issues of high by-products and low yield by using 2-bromo-5-fluorobenzotrifluoride and acetaldehyde to prepare 4-fluorobenzotriazine, achieving higher yields and safer, cost-effective industrial production.
Patent Information
- Application Number
- CN202411160935.6
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-08-22
- Publication Date
- 2024-12-24
AI Technical Summary
The existing synthesis process of clofoconazole produces a large number of by-products and has a low yield, which limits its industrial application and is associated with high production costs and safety issues due to the use of expensive and difficult-to-recycle reagents like Grignard reagents and acetyl chloride.
The process optimizes the synthesis route by using 2-bromo-5-fluorobenzotrifluorobenzotriazine as a raw material, reacting it with a Grignard reagent and acetaldehyde to prepare 1-(4-fluorophenyl)ethan-1-ol, then oxidizing it to prepare 4-fluorobenzotriazine as a raw material, a Grignard reagent and acetaldehyde to prepare 4-fluorobenzotrifluorobenzotriazine, and then oxidizing it to prepare 4-fluorobenzotriazine, and then oxidizing it to prepare 4-fluorobenzotriazine, which has fewer by-products and a higher yield.
The optimized process reduces reaction by-products, improves yield, lowers production costs, and enhances safety by using safer and more cost-effective reagents, making it suitable for industrial large-scale production.
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Abstract
Description
Technical Field
[0001] The invention relates to the technical field of C07D249 / 08, in particular to a synthesis process of clofothiazolinone. Background Art
[0002] Chlorofluanidazole is a triazole fungicide and a C14-demethylation inhibitor in sterol biosynthesis. It has broad-spectrum, high-efficiency, systemic, eradication and protection effects, especially outstanding biological activity against a variety of fungal diseases that are difficult to control. It can significantly enhance the prevention and control of more than 60 field and economic crop diseases, such as field crops such as corn, cereals, and soybeans, as well as economic crops such as green peppers and grapes. It can also be used for lawn and seed treatment.
[0003] At present, clofoconazole is synthesized by the following process:
[0004]
[0005] 4-Fluoro-2-(trifluoromethyl)acetophenone is obtained by reacting a Grignard reagent with acetyl chloride under copper catalysis, but many by-products are produced and the yield is low. In addition, the reagents for etherification reaction, epoxidation reaction and ring-opening reaction are expensive and difficult to recycle, and there are certain safety issues. For example, in the fungicidal substituted 2-[2-haloalkyl-4-phenoxyphenyl]-1-[1,2,4]triazol-1-ylethanol compound disclosed in a Chinese patent (publication number CN103649057A), 2-bromo-4-fluoro-trifluorotoluene is used as a raw material to prepare a Grignard reagent in a tetrahydrofuran solution, and then acetyl chloride is added dropwise. After the reaction is completed, 4-fluoro-2-trifluoromethylacetophenone is prepared through extraction, water washing and other processes, and then reacted with 4-chlorophenol to synthesize 4-(4-chlorophenoxy)-2-trifluoromethylacetophenone. However, many reaction by-products and low yield limit its large-scale industrial application. Summary of the invention
[0006] In order to solve the above problems, the present invention provides a synthesis process of clofoconazole, which optimizes the synthesis process route, reduces reaction by-products, improves yield, and effectively reduces production costs, has low toxicity and higher safety.
[0007] The present invention provides a synthesis process of chlorfenapyr, which comprises at least the following steps:
[0008] (1) Using 2-bromo-5-fluorobenzotrifluoride as a raw material, a Grignard reagent and acetaldehyde are reacted to prepare 1-(4-fluoro-2-(trifluoromethyl)phenyl)ethan-1-ol, and then oxidizing 1-(4-fluoro-2-(trifluoromethyl)phenyl)ethan-1-ol to prepare 4-fluoro-2-(trifluoromethyl)acetophenone;
[0009] (2) using 4-fluoro-2-(trifluoromethyl)acetophenone and p-chlorophenol as raw materials to carry out etherification reaction to prepare 4-(4-chlorophenoxy)-2-(trifluoromethyl)acetophenone;
[0010] (3) subjecting 4-(4-chlorophenoxy)-2-(trifluoromethyl)acetophenone to epoxidation to prepare 1-(4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl)-2-methyl-oxirane;
[0011] (4) 1-(4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl)-2-methyl-oxirane is subjected to a ring-opening reaction to obtain clofodimazole.
[0012] As a preferred technical solution, the preparation method of 1-(4-fluoro-2-(trifluoromethyl)phenyl)ethan-1-ol is as follows: under the condition of 10-35°C, magnesium chips are added to tetrahydrofuran to obtain a Grignard reagent, nitrogen protection is replaced, 2-bromo-5-fluorobenzotrifluoride is diluted with tetrahydrofuran, and then slowly added dropwise to the reaction, the temperature is controlled to be 20-30°C, and the mixture is stirred for 1-3h, and no 2-bromo-5-fluorobenzotrifluoride remains in the gas phase; the reaction temperature is cooled to 0-5°C, acetaldehyde solution is slowly added dropwise to the reaction, the temperature is controlled to be 5-10°C, and the mixture is stirred for 1-3h, and the Grignard reagent in the gas phase is controlled to react completely; after the reaction is complete, the reaction is filtered, water is added to the filtrate and stirred, and the mixture is allowed to stand for phase separation, and the yellow oil obtained after the solvent is evaporated under reduced pressure is 1-(4-fluoro-2-(trifluoromethyl)phenyl)ethan-1-ol.
[0013] As a preferred technical solution, the preparation method of 1-(4-fluoro-2-(trifluoromethyl)phenyl)ethan-1-ol is as follows: under the condition of 20-30°C, 10-20g of magnesium chips are added to 200mL of tetrahydrofuran to obtain a Grignard reagent, and 80-120g of 2-bromo-5-fluorobenzotrifluoride is diluted with 200 mL of tetrahydrofuran, and then slowly added dropwise to the reaction, the temperature is controlled at 20-30° C., stirred for 1-3 hours, and no 2-bromo-5-fluorobenzotrifluoride remains in the gas phase; the reaction temperature is cooled to 0-5° C., 80-120 mL of 3-6 M acetaldehyde-tetrahydrofuran solution is slowly added dropwise to the reaction, the temperature is controlled at 5-10° C., stirred for 1-3 hours, and the reaction of the Grignard reagent in the gas phase is controlled to be complete; after the reaction is complete, it is filtered, water is added to the filtrate and stirred, and the phases are separated. The yellow oil obtained after the solvent is evaporated under reduced pressure is 1-(4-fluoro-2-(trifluoromethyl)phenyl)ethan-1-ol.
[0014] Preferably, the preparation method of 1-(4-fluoro-2-(trifluoromethyl)phenyl)ethan-1-ol is as follows: under the condition of 20-30°C, 15g of magnesium chips are added to 200mL of tetrahydrofuran to obtain a Grignard reagent, nitrogen protection is replaced, 100g of 2-bromo-5-fluorobenzotrifluoride is diluted with 200mL of tetrahydrofuran, and then slowly added dropwise to the reaction, the temperature is controlled to be 20-30°C, and stirred for 2h, and no 2-bromo-5-fluorobenzotrifluoride remains in the gas phase; the reaction is reduced to The mixture was heated to 0-5°C, 100 mL of 5 M acetaldehyde-tetrahydrofuran solution was slowly added dropwise to the reaction mixture, the temperature was controlled to be 5-10°C, and the mixture was stirred for 2 h. The reaction of the Grignard reagent in the gas phase was controlled to be complete. After the reaction was complete, the mixture was filtered, 200 mL of water was added to the filtrate and stirred, and the mixture was allowed to stand for phase separation. The solvent was evaporated under reduced pressure to obtain 81.5 g of a yellow oil (1-(4-fluoro-2-(trifluoromethyl)phenyl)ethan-1-ol) with a purity of 96.3% and a yield of 91.6%.
[0015] As a preferred technical solution, the process for preparing 4-fluoro-2-(trifluoromethyl)acetophenone by oxidizing 1-(4-fluoro-2-(trifluoromethyl)phenyl)ethan-1-ol is as follows: 1-(4-fluoro-2-(trifluoromethyl)phenyl)ethan-1-ol and manganese dioxide are added to dichloromethane in sequence under the condition of 10-35° C., and after stirring for at least 24 hours, no 1-(4-fluoro-2-(trifluoromethyl)phenyl)ethan-1-ol is detected, and the reaction is terminated; filtering, and distilling the filtrate under reduced pressure to remove the solvent to obtain a yellow oily substance, namely 4-fluoro-2-(trifluoromethyl)acetophenone.
[0016] As a preferred technical solution, the process for preparing 4-fluoro-2-(trifluoromethyl)acetophenone by oxidizing 1-(4-fluoro-2-(trifluoromethyl)phenyl)ethan-1-ol is as follows: 15-25 g of 1-(4-fluoro-2-(trifluoromethyl)phenyl)ethan-1-ol and 35-45 g of manganese dioxide are added to 200 mL of dichloromethane at 10-35° C., and after stirring for at least 48 hours, HPLC detection shows that there is no 1-(4-fluoro-2-(trifluoromethyl)phenyl)ethan-1-ol, and the reaction is completed; filtering, and distilling the filtrate under reduced pressure to remove the solvent to obtain a yellow oily substance, namely 4-fluoro-2-(trifluoromethyl)acetophenone.
[0017] Preferably, the process for preparing 4-fluoro-2-(trifluoromethyl)acetophenone by oxidizing 1-(4-fluoro-2-(trifluoromethyl)phenyl)ethan-1-ol is as follows: 20 g of 1-(4-fluoro-2-(trifluoromethyl)phenyl)ethan-1-ol and 41.8 g of manganese dioxide are added to 200 mL of dichloromethane at 10-35° C., and after stirring for 48 hours, HPLC detection shows that there is no 1-(4-fluoro-2-(trifluoromethyl)phenyl)ethan-1-ol, and the reaction is completed; filtering, and the filtrate is evaporated under reduced pressure to remove the solvent to obtain 18.2 g of a yellow oil (4-fluoro-2-(trifluoromethyl)acetophenone) with a purity of 94.8% and a yield of 87.1%.
[0018] The invention is based on the problem that a large number of by-products and a low yield are produced by using a Grignard reagent and acetyl chloride to obtain 4-fluoro-2-(trifluoromethyl)acetophenone in the existing synthesis process of clofosconazole under copper catalysis, and an optimization design is carried out. The Grignard reagent is reacted with acetaldehyde and then oxidized to obtain 4-fluoro-2-(trifluoromethyl)acetophenone, which has fewer by-products and a higher yield.
[0019] As a preferred technical solution, the etherification reaction is specifically as follows: 4-fluoro-2-(trifluoromethyl)acetophenone, p-chlorophenol, and a base are added to an organic solvent in sequence at 10-35°C, the temperature is raised to 80-120°C, and the mixture is stirred for 2-5h. After no 4-fluoro-2-(trifluoromethyl)acetophenone is detected, the reaction is completed, the reaction solution is cooled to 10-35°C, water is added and stirred, and the mixture is allowed to stand for phase separation. After the aqueous phase is discarded, a sodium hydroxide aqueous solution is added and stirred. After the mixture is allowed to stand for phase separation, the organic phase is transferred to a rotary evaporator and concentrated in vacuo to obtain 4-(4-chlorophenoxy)-2-(trifluoromethyl)acetophenone.
[0020] As a preferred technical solution, the organic solvent is at least one of acetone, toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, methanol, ethanol, isopropanol, tert-butanol, and n-butanol, preferably xylene.
[0021] As a preferred technical solution, the base is at least one of potassium carbonate, lithium hydroxide, sodium hydroxide and potassium hydroxide, preferably sodium hydroxide.
[0022] As a preferred technical solution, the etherification reaction is specifically as follows: under the condition of 20-30° C., 8-12 g 4-fluoro-2-(trifluoromethyl)acetophenone, 5-8 g p-chlorophenol, and 2-4 g sodium hydroxide are added to 50 mL of xylene in sequence, the temperature is raised to 80-120° C. and stirred for 2-5 hours, and no 4-fluoro-2-(trifluoromethyl)acetophenone is detected, the reaction is completed, the reaction solution is cooled to 20-30° C., water is added and stirred, and the phases are allowed to stand for separation. After the aqueous phase is discarded, a sodium hydroxide aqueous solution is added and stirred, and after the phases are allowed to stand for separation, the organic phase is transferred to a rotary evaporator and concentrated in vacuo to obtain 4-(4-chlorophenoxy)-2-(trifluoromethyl)acetophenone.
[0023] As a preferred technical solution, the etherification reaction is specifically as follows: under the condition of 20-30° C., 10 g of 4-fluoro-2-(trifluoromethyl)acetophenone, 6.9 g of p-chlorophenol and 2.9 g of sodium hydroxide are added to 50 mL of xylene in sequence, the temperature is raised to 100° C. and stirred for 4 hours, and no 4-fluoro-2-(trifluoromethyl)acetophenone is detected, the reaction is completed, the reaction solution is cooled to 20-30° C., 20 mL of water is added and stirred for 10 minutes, and the phases are allowed to stand for separation. After the aqueous phase is discarded, 20 mL of 10 wt% sodium hydroxide aqueous solution is added and stirred for 20 minutes. After the phases are allowed to stand for separation, the organic phase is transferred to a rotary evaporator and concentrated in vacuo to obtain 14.2 g of 4-(4-chlorophenoxy)-2-(trifluoromethyl)acetophenone, with a yield of 93.0%.
[0024] Furthermore, by optimizing the organic solvent in the etherification reaction to xylene, the solvent cost is effectively reduced and xylene is easy to recycle, which is more suitable for industrial large-scale production.
[0025] As a preferred technical solution, the epoxidation reaction is specifically as follows: at 10-35° C., 30-50 g of concentrated sulfuric acid is slowly added dropwise to 50-70 g of dimethyl sulfide, and after stirring for 0.3-1 h, 5-8 g of methanol is slowly added dropwise, and after continuing to stir for at least 5 h, 200 mL of tetrahydrofuran and 25-35 g of 4-(4-chlorophenoxy)-2-(trifluoromethyl)acetophenone are added in sequence, and 80-110 g of potassium hydroxide solid is added in batches, and the mixture is heated to 40-50° C. and reacted for 4-7 hours; the reaction solution is filtered to remove inorganic salts, tetrahydrofuran is evaporated under reduced pressure, methanol is added for recrystallization, and a white solid is obtained by suction filtration. After drying, 1-(4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl)-2-methyl-oxirane is obtained.
[0026] As a preferred technical solution, the epoxidation reaction is specifically as follows: at 20-30° C., 39.3 g of concentrated sulfuric acid is slowly added dropwise to 62.2 g of dimethyl sulfide, and after stirring for 0.5 h, 6.4 g of methanol is slowly added dropwise, and after continuing to stir for 6 h, 200 mL of tetrahydrofuran and 31.5 g of 4-(4-chlorophenoxy)-2-(trifluoromethyl)acetophenone are added in sequence, and 89.9-101.1 g of potassium hydroxide solid is added in batches, and the mixture is heated to 40° C. for 6 hours; the reaction solution is filtered to remove inorganic salts, tetrahydrofuran is evaporated under reduced pressure, methanol is added for recrystallization, and a white solid is obtained by suction filtration. After drying, 29.0-29.3 g of 1-(4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl)-2-methyl-oxirane is obtained, with a yield of 88.0-89.0%.
[0027] Furthermore, by optimizing the epoxidation reaction process, 1-(4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl)-2-methyl-oxirane is prepared by reacting concentrated sulfuric acid and dimethyl sulfide as raw materials with 25-35g of 4-(4-chlorophenoxy)-2-(trifluoromethyl)acetophenone, thereby avoiding the problems of high production cost, high toxicity and low safety in the existing process of using dimethyl sulfate as raw material. In particular, the amount of potassium hydroxide solid added in batches during the reaction is controlled to be 80-110g, ensuring that the yield of 1-(4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl)-2-methyl-oxirane is 88.0-89.0%.
[0028] As a preferred technical solution, the ring-opening reaction is specifically as follows: under the condition of 10-35°C, 1, 2, 4-triazole and alkaline substances are added in sequence to the solvent, and 1-(4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl)-2-methyl-oxirane is added after stirring for 0.3-1h, and the temperature is raised to 60-65°C, and the reaction is refluxed for at least 6h. After detecting that there is no residual 1-(4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl)-2-methyl-oxirane, methanol is evaporated under reduced pressure, water and toluene are added in sequence, and the mixture is heated to 50-60°C for separation, the organic phase is reduced to 10-35°C for crystallization, and a white solid is obtained by suction filtration, and then chlorfluanidazole is obtained after drying.
[0029] Preferably, the solvent is selected from at least one of acetone, toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, methanol, ethanol, isopropanol, tert-butanol and n-butanol, preferably methanol.
[0030] Preferably, the alkaline substance is selected from at least one of potassium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, triethylamine, and 1,8-diazobispiro[5.4.0]undec-7-ene, preferably potassium carbonate.
[0031] As a preferred technical solution, the ring-opening reaction is specifically as follows: under the condition of 10-35° C., 80-100 g of 1, 2, 4-triazole and 70-230 g of potassium carbonate are added to 1000 mL of methanol in sequence, and after stirring for 0.3-1 h, 300-400 g of 1-(4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl)-2-methyl-oxirane is added, the temperature is raised to 60-65° C., and the reaction is refluxed for at least 6 h. After detecting that there is no residual 1-(4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl)-2-methyl-oxirane, methanol is evaporated under reduced pressure, 500 mL of water and 1000 mL of toluene are added in sequence, and the mixture is heated to 50-60° C. for separation, the organic phase is reduced to 10-35° C. for crystallization, and a white solid is obtained by suction filtration. After drying, chlorfluanidazole is obtained.
[0032] As a preferred technical solution, the ring-opening reaction is specifically as follows: under the condition of 20-30° C., 88.3 g of 1, 2, 4-triazole and 100-150 g of potassium carbonate are added to 1000 mL of methanol in sequence, and after stirring for 0.5 h, 350 g of 1-(4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl)-2-methyl-oxirane is added, the temperature is raised to 60-65° C., and the reaction is refluxed for 8 h. After detecting that there is no residual 1-(4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl)-2-methyl-oxirane, methanol is evaporated under reduced pressure, 500 mL of water and 1000 mL of toluene are added in sequence, and the mixture is heated to 50° C. for separation, the organic phase is reduced to 20-30° C. for crystallization, and a white solid is obtained by suction filtration. After drying, chlorfluanidazole is obtained.
[0033] As a preferred technical solution, the ring-opening reaction is specifically as follows: under the condition of 20-30° C., 88.3 g of 1, 2, 4-triazole and 110.4-147.1 g of potassium carbonate are added to 1000 mL of methanol in sequence, and after stirring for 0.5 h, 350 g of 1-(4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl)-2-methyl-oxirane is added, the temperature is raised to 60-65° C., and the reaction is refluxed for 8 h. After detecting that there is no residual 1-(4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl)-2-methyl-oxirane, methanol is evaporated under reduced pressure, 500 mL of water and 1000 mL of toluene are added in sequence, and the mixture is heated to 50° C. for separation. The organic phase is cooled to 20-30° C. for crystallization, and a white solid is obtained by suction filtration. After drying, 326.9-330.0 g of chlorfluanidazole is obtained, and the yield is 77.2-77.9%.
[0034] Furthermore, by optimizing the solvent in the ring-opening reaction to methanol, the cost is low and the recovery is easy compared to N,N-dimethylformamide in the existing process. In particular, the amount of potassium carbonate added during the reaction is controlled to be 100-150 g, thereby ensuring that the yield of the prepared chlorfluanidazole is 77.2-77.9%.
[0035] Beneficial Effects
[0036] 1. The present invention provides a synthesis process of clofoconazole, which optimizes the synthesis process route, reduces reaction by-products, improves yield, and effectively reduces production costs, has low toxicity, and is safer.
[0037] 2. The present invention optimizes the design based on the problem that the existing synthesis process of clofoconazole uses a Grignard reagent and acetyl chloride under copper catalysis to obtain 4-fluoro-2-(trifluoromethyl)acetophenone, which has a large number of by-products and a low yield. The Grignard reagent is reacted with acetaldehyde and then oxidized to obtain 4-fluoro-2-(trifluoromethyl)acetophenone, which has fewer by-products and a higher yield.
[0038] 3. The present invention optimizes the organic solvent in the etherification reaction to be xylene, thereby effectively reducing the solvent cost and making xylene easy to recycle, which is more suitable for industrial large-scale production.
[0039] 4. The present invention optimizes the epoxidation reaction process, specifically using concentrated sulfuric acid and dimethyl sulfide as raw materials to react with 25-35g of 4-(4-chlorophenoxy)-2-(trifluoromethyl) acetophenone to prepare 1-(4-(4-chlorophenoxy)-2-(trifluoromethyl) phenyl)-2-methyl-oxirane, thereby avoiding the problems of high production cost, high toxicity and low safety in the existing process of using dimethyl sulfate as raw material. In particular, the amount of potassium hydroxide solid added in batches during the reaction is controlled to be 80-110g, ensuring that the yield of 1-(4-(4-chlorophenoxy)-2-(trifluoromethyl) phenyl)-2-methyl-oxirane is 88.0-89.0%.
[0040] 5. By optimizing the solvent in the ring-opening reaction to methanol, the cost is low and the recovery is easy compared to N,N-dimethylformamide in the existing process. In particular, the amount of potassium carbonate added during the reaction is controlled to be 100-150 g, ensuring that the yield of the prepared chlorfluanidazole is 77.2-77.9%. BRIEF DESCRIPTION OF THE DRAWINGS
[0041] Figure 1 This is the hydrogen nuclear magnetic resonance spectrum of 4-(4-chlorophenoxy)-2-(trifluoromethyl)acetophenone prepared in Example 1.
[0042] Figure 2 This is the liquid phase mass spectrum of 4-(4-chlorophenoxy)-2-(trifluoromethyl)acetophenone prepared in Example 1.
[0043] Figure 3 This is the hydrogen nuclear magnetic resonance spectrum of 1-(4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl)-2-methyl-oxirane prepared in Example 1.
[0044] Figure 4 This is the liquid phase mass spectrum of 1-(4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl)-2-methyl-oxirane prepared in Example 1.
[0045] Figure 5 This is the hydrogen nuclear magnetic resonance spectrum of the chlorpyrifos prepared in Example 1.
[0046] Figure 6 This is the liquid phase mass spectrum of the chlorpyrifos prepared in Example 1. DETAILED DESCRIPTION
[0047] Example 1
[0048] Embodiment 1 of the present invention provides a synthesis process of clofoconazole, comprising the following steps:
[0049] (1) Using 2-bromo-5-fluorobenzotrifluoride as a raw material, a Grignard reagent and acetaldehyde are reacted to prepare 1-(4-fluoro-2-(trifluoromethyl)phenyl)ethan-1-ol, and then oxidizing 1-(4-fluoro-2-(trifluoromethyl)phenyl)ethan-1-ol to prepare 4-fluoro-2-(trifluoromethyl)acetophenone;
[0050] (2) using 4-fluoro-2-(trifluoromethyl)acetophenone and p-chlorophenol as raw materials to carry out etherification reaction to prepare 4-(4-chlorophenoxy)-2-(trifluoromethyl)acetophenone;
[0051] (3) subjecting 4-(4-chlorophenoxy)-2-(trifluoromethyl)acetophenone to epoxidation to prepare 1-(4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl)-2-methyl-oxirane;
[0052] (4) 1-(4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl)-2-methyl-oxirane is subjected to a ring-opening reaction to obtain clofodimazole.
[0053] The preparation method of 1-(4-fluoro-2-(trifluoromethyl)phenyl)ethan-1-ol is as follows: under the condition of 25±2°C, 15g of magnesium chips are added to 200mL of tetrahydrofuran to obtain a Grignard reagent, and nitrogen protection is replaced. 100g 2-Bromo-5-fluorobenzotrifluoride was diluted with 200 mL of tetrahydrofuran and slowly added dropwise to the reaction, the temperature was controlled at 25±2° C., stirred for 2 h, and no 2-bromo-5-fluorobenzotrifluoride remained in the gas phase; the reaction temperature was cooled to 2±2° C., 100 mL of 5M acetaldehyde-tetrahydrofuran solution was slowly added dropwise to the reaction, the temperature was controlled at 8±2° C., stirred for 2 h, and the reaction of the Grignard reagent in the gas phase was controlled to be complete; after the reaction was complete, it was filtered, 200 mL of water was added to the filtrate and stirred, and the mixture was allowed to stand for phase separation, and the solvent was evaporated under reduced pressure to obtain 81.5 g of a yellow oil (1-(4-fluoro-2-(trifluoromethyl)phenyl)ethan-1-ol), the purity of which was 96.3% as determined by HPLC, and the yield was 91.6% based on 2-bromo-5-fluorobenzotrifluoride.
[0054] The process for preparing 4-fluoro-2-(trifluoromethyl)acetophenone by oxidizing 1-(4-fluoro-2-(trifluoromethyl)phenyl)ethan-1-ol is as follows: under the condition of 25±2° C., 20 g of 1-(4-fluoro-2-(trifluoromethyl)phenyl)ethan-1-ol and 41.8 g of manganese dioxide are added in sequence to 200 mL of dichloromethane; after stirring for 48 hours, HPLC detection shows that there is no 1-(4-fluoro-2-(trifluoromethyl)phenyl)ethan-1-ol, and the reaction is completed; filtering, and the filtrate is evaporated under reduced pressure to remove the solvent to obtain 18.2 g of a yellow oil (4-fluoro-2-(trifluoromethyl)acetophenone); the purity detected by HPLC is 94.8%, and the yield is 87.1% based on 1-(4-fluoro-2-(trifluoromethyl)phenyl)ethan-1-ol.
[0055] The etherification reaction is specifically as follows: under the condition of 25±2° C., 10 g of 4-fluoro-2-(trifluoromethyl)acetophenone, 6.9 g of p-chlorophenol and 2.9 g of sodium hydroxide are added to 50 mL of xylene in sequence, the temperature is raised to 100° C. and stirred for 4 hours, and after detecting that there is no 4-fluoro-2-(trifluoromethyl)acetophenone, the reaction is completed, the reaction solution is cooled to 25±2° C., 20 mL of water is added and stirred for 10 minutes, and the mixture is allowed to stand for phase separation, the aqueous phase is discarded, 20 mL of 10 wt% sodium hydroxide aqueous solution is added and stirred for 20 minutes, and the organic phase is allowed to stand for phase separation and then transferred to a rotary evaporator, and concentrated in vacuo to obtain 14.2 g of 4-(4-chlorophenoxy)-2-(trifluoromethyl)acetophenone, the purity of which is 98.5% as determined by HPLC, and the yield is 91.6% based on 4-fluoro-2-(trifluoromethyl)acetophenone; 1 H NMR (400MHz, Chloroform-d) δ7.50 (d, J = 8.5 Hz, 1H), 7.40–7.35 (m, 2H), 7.31 (d, J = 2.5 Hz, 1H), 7.12 (dd, J = 8.5, 2.5 Hz, 1H), 7.02–6.98 (m, 2H), 2.57 (s, 3H). MS (ESI) calcd for C15H10ClF3O2[MH] 313, found: 313. H NMR spectrum see Figure 1 , HPLC mass spectrometry see Figure 2 .
[0056] The epoxidation reaction is specifically as follows: at 25±2° C., 39.3 g of concentrated sulfuric acid is slowly added dropwise to 62.2 g of dimethyl sulfide, and 6.4 g of methanol is slowly added dropwise after stirring for 0.5 h. After continuing to stir for 6 h, 200 mL of tetrahydrofuran, 31.5 g of 4-(4-chlorophenoxy)-2-(trifluoromethyl)acetophenone, and 89.9 g of potassium hydroxide solid are added in sequence, and the mixture is heated to 40° C. and reacted for 6 hours; the reaction solution is filtered to remove inorganic salts, tetrahydrofuran is evaporated under reduced pressure, methanol is added for recrystallization, and a white solid is filtered to obtain a white solid, which is dried to obtain 29.3 g of 1-(4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl)-2-methyl-oxirane, and the purity is 99.6% as determined by HPLC, and the yield is 88.6% based on 4-(4-chlorophenoxy)-2-(trifluoromethyl)acetophenone; 1 H NMR (400 MHz, Chloroform-d) δ7.63 (d, J = 8.6 Hz, 1H), 7.36–7.31 (m, 2H), 7.22 (d, J = 2.6 Hz, 1H), 7.12 (dd, J = 8.7, 2.5 Hz, 1H), 6.98–6.94 (m, 2H), 3.02 (d, J = 4.9 Hz, 1H), 2.95 (d, J = 4.9 Hz, 1H), 1.64 (s, 3H). MS (ESI) calcd for C16H12ClF3O2[MH] 327, found: 327. H NMR spectrum see Figure 3 , HPLC mass spectrometry see Figure 4 .
[0057] The ring-opening reaction is specifically as follows: at 25±2°C, 88.3 g of 1,2,4-triazole and 110.4 g of potassium carbonate are added to 1000 mL of methanol in sequence, stirred for 0.5 h, and then 350 g of 1-(4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl)-2-methyl-oxirane, heated to 62°C, refluxed for 8h, detected no 1-(4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl)-2-methyl-oxirane residue, then distilled off methanol under reduced pressure, added 500mL of water and 1000mL of toluene in sequence, heated to 50°C for separation, the organic phase was cooled to 25±2°C for crystallization, filtered to obtain a white solid, and dried to obtain 330.0g of chlorfenapyr, the purity of which was 99.4% as determined by HPLC, and the yield was 76.9% based on 1-(4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl)-2-methyl-oxirane; 1H NMR (400 MHz, Chloroform-d) δ8.02 (s, 1H), 7.89 (s, 1H), 7.60 (d, J = 8.9 Hz, 1H), 7.37 (d, J = 2.7 Hz, 1H), 7.36–7.31 (m, 2H), 7.02 (dd, J = 8.9, 2.7 Hz, 1H), 6.97–6.92 (m, 2H), 4.65 (d, J = 14.2 Hz, 1H), 4.45 (d, J = 14.2 Hz, 1H), 1.63 (s, 3H). MS (ESI) calcd for C18H15ClF3N3O2[MH] 396, found: 396. H NMR spectrum see Figure 5 , HPLC mass spectrometry see Figure 6 .
[0058] Example 2
[0059] Example 2 of the present invention provides a synthesis process of chlorfluanidazole, and its specific implementation method is the same as that of Example 1, except that the ring-opening reaction is specifically as follows: under the condition of 25±2°C, 88.3g of 1,2,4-triazole and 73.6g of potassium carbonate are added to 1000mL of methanol in sequence, and 350g of 1-(4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl)-2-methyl-oxirane was heated to 62°C and refluxed for 8h. After detecting that there was no residual 1-(4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl)-2-methyl-oxirane, methanol was evaporated under reduced pressure. 500mL of water and 1000mL of toluene were added in sequence. The mixture was heated to 50°C for separation. The organic phase was cooled to 25±2°C for crystallization. A white solid was filtered out and dried to obtain 295.6g of chlorfluanidazole. The purity was 98.6% according to HPLC. The yield was 68.8% based on 1-(4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl)-2-methyl-oxirane.
[0060] Example 3
[0061] Example 3 of the present invention provides a synthesis process of chlorfluanidazole, and its specific implementation method is the same as that of Example 1, except that the ring-opening reaction is specifically as follows: under the condition of 25±2°C, 88.3g of 1,2,4-triazole and 147.1g of potassium carbonate are added to 1000mL of methanol in sequence, and 350g of 1-(4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl)-2-methyl-oxirane was heated to 62°C and refluxed for 8h. After detecting that there was no residual 1-(4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl)-2-methyl-oxirane, methanol was evaporated under reduced pressure. 500mL of water and 1000mL of toluene were added in sequence. The mixture was heated to 50°C for separation. The organic phase was cooled to 25±2°C for crystallization. A white solid was filtered out and dried to obtain 326.9g of chlorfenapyr. The purity was 99.5% according to HPLC. The yield was 76.8% based on 1-(4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl)-2-methyl-oxirane.
[0062] Example 4
[0063] Example 4 of the present invention provides a synthesis process of chlorfluanidazole, and its specific implementation method is the same as that of Example 1, except that the ring-opening reaction is specifically as follows: under 25±2°C, 88.3g of 1,2,4-triazole and 220.7g of potassium carbonate are added to 1000mL of methanol in sequence, and 350g of 1-(4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl)-2-methyl-oxirane, heated to 62°C, refluxed for 8h, detected that there was no residual 1-(4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl)-2-methyl-oxirane, and then evaporated the methanol under reduced pressure. 500mL of water and 1000mL of toluene were added in sequence, and the mixture was heated to 50°C for separation. The organic phase was cooled to 25±2°C for crystallization, and a white solid was filtered out. After drying, 321.2g of chlorfenapyr was obtained. The purity was 99.4% according to HPLC, and the yield was 75.4% based on 1-(4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl)-2-methyl-oxirane.
[0064] Example 5
[0065] Example 5 of the present invention provides a synthesis process of chlorfluanidazole, and its specific implementation method is the same as that of Example 1, except that the epoxidation reaction is specifically as follows: under the condition of 25±2°C, 39.3g of concentrated sulfuric acid is slowly added dropwise to 62.2g of dimethyl sulfide, and after stirring for 0.5h, 6.4g of methanol is slowly added dropwise, and after continuing to stir for 6h, 200mL of tetrahydrofuran, 31.5g of 4-(4-chlorophenoxy)-2-(trifluoromethyl)acetophenone and 67.4 g (divided into several batches, the number of grams in each batch must be specified) potassium hydroxide solid are heated to 40°C for reaction for 6 hours; the reaction solution is filtered to remove inorganic salts, tetrahydrofuran is evaporated under reduced pressure, methanol is added for recrystallization, and a white solid is filtered to obtain a white solid. After drying, 27.5 g of 1-(4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl)-2-methyl-oxirane is obtained, and the purity detected by HPLC is 99.3%, and the yield is 83.0% based on 4-(4-chlorophenoxy)-2-(trifluoromethyl)acetophenone; no subsequent ring-opening reaction is performed.
[0066] Example 6
[0067] Example 6 of the present invention provides a synthesis process of chlorfluanidazole, and its specific implementation method is the same as that of Example 1, except that the epoxidation reaction is specifically as follows: under 25±2°C, 39.3g of concentrated sulfuric acid is slowly added dropwise to 62.2g of dimethyl sulfide, and after stirring for 0.5h, 6.4g of methanol is slowly added dropwise, and after continuing to stir for 6h, 200mL of tetrahydrofuran, 31.5g of 4-(4-chlorophenoxy)-2-(trifluoromethyl)acetophenone and 78.6 g (divided into several batches, the number of grams in each batch must be specified) potassium hydroxide solid are heated to 40°C for reaction for 6 hours; the reaction solution is filtered to remove inorganic salts, tetrahydrofuran is evaporated under reduced pressure, methanol is added for recrystallization, and a white solid is filtered to obtain a white solid. After drying, 28.1 g of 1-(4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl)-2-methyl-oxirane is obtained, and the purity detected by HPLC is 99.5%, and the yield is 85.0% based on 4-(4-chlorophenoxy)-2-(trifluoromethyl)acetophenone; no subsequent ring-opening reaction is performed.
[0068] Example 7
[0069] Example 7 of the present invention provides a synthesis process of chlorfluanidazole, and its specific implementation method is the same as that of Example 1, except that the epoxidation reaction is specifically as follows: under the condition of 25±2°C, 39.3g of concentrated sulfuric acid is slowly added dropwise to 62.2g of dimethyl sulfide, and after stirring for 0.5h, 6.4g of methanol is slowly added dropwise, and after continuing to stir for 6h, 200mL of tetrahydrofuran, 31.5g of 4-(4-chlorophenoxy)-2-(trifluoromethyl)acetophenone and 101.1 g (divided into several batches, the number of grams in each batch must be specified) potassium hydroxide solid are heated to 40°C for reaction for 6 hours; the reaction solution is filtered to remove inorganic salts, tetrahydrofuran is evaporated under reduced pressure, methanol is added for recrystallization, and a white solid is filtered to obtain a white solid. After drying, 29.0 g of 1-(4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl)-2-methyl-oxirane is obtained, and the purity detected by HPLC is 99.7%, and the yield is 87.7% based on 4-(4-chlorophenoxy)-2-(trifluoromethyl)acetophenone; no subsequent ring-opening reaction is performed.
Claims
1. A synthesis process of clofoconazole, characterized in that: At least the following steps are included: (1) Using 2-bromo-5-fluorobenzotrifluoride as a raw material, a Grignard reagent and acetaldehyde are reacted to prepare 1-(4-fluoro-2-(trifluoromethyl)phenyl)ethan-1-ol, and then oxidizing 1-(4-fluoro-2-(trifluoromethyl)phenyl)ethan-1-ol to prepare 4-fluoro-2-(trifluoromethyl)acetophenone; (2) using 4-fluoro-2-(trifluoromethyl)acetophenone and p-chlorophenol as raw materials to carry out etherification reaction to prepare 4-(4-chlorophenoxy)-2-(trifluoromethyl)acetophenone; (3) subjecting 4-(4-chlorophenoxy)-2-(trifluoromethyl)acetophenone to epoxidation to prepare 1-(4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl)-2-methyl-oxirane; (4) 1-(4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl)-2-methyl-oxirane is subjected to a ring-opening reaction to obtain clofodimazole.
2. The synthesis process of chlorfenapyr according to claim 1, characterized in that: The preparation method of 1-(4-fluoro-2-(trifluoromethyl)phenyl)ethan-1-ol is as follows: under the condition of 10-35° C., magnesium chips are added to tetrahydrofuran to obtain a Grignard reagent, nitrogen protection is replaced, 2-bromo-5-fluorobenzotrifluoride is diluted with tetrahydrofuran, and then slowly added dropwise to the reaction, the temperature is controlled to be 20-30° C., stirring is performed for 1-3 hours, and no 2-bromo-5-fluorobenzotrifluoride remains in the gas phase; the reaction temperature is cooled to 0-5° C., acetaldehyde solution is slowly added dropwise to the reaction, the temperature is controlled to be 5-10° C., stirring is performed for 1-3 hours, and the Grignard reagent in the gas phase is controlled to react completely; after the reaction is completed, filtering is performed, water is added to the filtrate and stirred, and the phases are separated by standing, and the solvent is evaporated under reduced pressure to obtain a yellow oily substance, which is 1-(4-fluoro-2-(trifluoromethyl)phenyl)ethan-1-ol.
3. The synthesis process of chlorfenapyr according to claim 1, characterized in that: The process for preparing 4-fluoro-2-(trifluoromethyl)acetophenone by oxidizing 1-(4-fluoro-2-(trifluoromethyl)phenyl)ethan-1-ol is specifically as follows: 1-(4-fluoro-2-(trifluoromethyl)phenyl)ethan-1-ol and manganese dioxide are added to dichloromethane in sequence at 10-35° C., and after stirring for at least 24 hours, no 1-(4-fluoro-2-(trifluoromethyl)phenyl)ethan-1-ol is detected, and the reaction is terminated; filtering, and distilling the filtrate under reduced pressure to remove the solvent to obtain a yellow oily substance, namely 4-fluoro-2-(trifluoromethyl)acetophenone.
4. The synthesis process of chlorfenapyr according to claim 1, characterized in that: The etherification reaction is specifically as follows: 4-fluoro-2-(trifluoromethyl)acetophenone, p-chlorophenol and alkali are added to an organic solvent in sequence at 10-35° C., the temperature is raised to 80-120° C., the mixture is stirred for 2-5 hours, and no 4-fluoro-2-(trifluoromethyl)acetophenone is detected, the reaction is completed, the reaction solution is cooled to 10-35° C., water is added and stirred, the mixture is allowed to stand for phase separation, the aqueous phase is discarded, a sodium hydroxide aqueous solution is added and stirred, the organic phase is allowed to stand for phase separation, and then the organic phase is transferred to a rotary evaporator and concentrated in vacuo to obtain 4-(4-chlorophenoxy)-2-(trifluoromethyl)acetophenone.
5. The synthesis process of chlorfenapyr according to claim 4, characterized in that: The organic solvent is at least one of acetone, toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, methanol, ethanol, isopropanol, tert-butanol and n-butanol.
6. The synthesis process of chlorfenapyr according to claim 4, characterized in that: The base is at least one of potassium carbonate, lithium hydroxide, sodium hydroxide and potassium hydroxide.
7. The synthesis process of chlorfenapyr according to claim 1, characterized in that: The epoxidation reaction is specifically as follows: slowly drop 30-50g of concentrated sulfuric acid into 50-70g of dimethyl sulfide at 10-35°C, stir for reaction for 0.3-1h, then slowly drop 5-8g of methanol, continue stirring for at least 5h, then sequentially add 200mL of tetrahydrofuran and 25-35g of 4-(4-chlorophenoxy)-2-(trifluoromethyl)acetophenone, add 80-110g of potassium hydroxide solid in batches, heat to 40-50°C and react for 4-7 hours; filter the reaction solution to remove inorganic salts, evaporate tetrahydrofuran under reduced pressure, add methanol for recrystallization, filter to obtain a white solid, and dry to obtain 1-(4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl)-2-methyl-oxirane.
8. The synthesis process of chlorfenapyr according to claim 1, characterized in that: The ring-opening reaction is specifically as follows: at 10-35° C., 1, 2, 4-triazole and an alkaline substance are sequentially added to a solvent, stirred for 0.3-1h, and then 1-(4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl)-2-methyl-oxirane is added, the temperature is raised to 60-65° C., and the reaction is refluxed for at least 6h. After detecting that no 1-(4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl)-2-methyl-oxirane remains, methanol is evaporated under reduced pressure, water and toluene are sequentially added, and the mixture is heated to 50-60° C. for separation, the organic phase is cooled to 10-35° C. for crystallization, and a white solid is obtained by suction filtration. After drying, chlorfluanidazole is obtained.
9. The synthesis process of chlorfenapyr according to claim 8, characterized in that: The solvent is selected from at least one of acetone, toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, methanol, ethanol, isopropanol, tert-butanol and n-butanol.
10. The synthesis process of mefenamic acid according to claim 8, characterized in that: The alkaline substance is selected from at least one of potassium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, triethylamine, and 1,8-diazobispiro[5.4.0]undec-7-ene.