CN115490612A - Synthesis method of trifloxystrobin - Google Patents
Synthesis method of trifloxystrobin Download PDFInfo
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- CN115490612A CN115490612A CN202211314388.3A CN202211314388A CN115490612A CN 115490612 A CN115490612 A CN 115490612A CN 202211314388 A CN202211314388 A CN 202211314388A CN 115490612 A CN115490612 A CN 115490612A
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- 239000005857 Trifloxystrobin Substances 0.000 title claims abstract description 51
- ONCZDRURRATYFI-TVJDWZFNSA-N trifloxystrobin Chemical compound CO\N=C(\C(=O)OC)C1=CC=CC=C1CO\N=C(/C)C1=CC=CC(C(F)(F)F)=C1 ONCZDRURRATYFI-TVJDWZFNSA-N 0.000 title claims abstract description 51
- 238000001308 synthesis method Methods 0.000 title claims description 11
- 238000006243 chemical reaction Methods 0.000 claims abstract description 61
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 54
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims abstract description 42
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 30
- 238000000034 method Methods 0.000 claims abstract description 24
- QQGVWMIRCZEUBB-UHFFFAOYSA-N n-[1-[3-(trifluoromethyl)phenyl]ethylidene]hydroxylamine Chemical compound ON=C(C)C1=CC=CC(C(F)(F)F)=C1 QQGVWMIRCZEUBB-UHFFFAOYSA-N 0.000 claims abstract description 18
- 239000003960 organic solvent Substances 0.000 claims abstract description 17
- 238000006482 condensation reaction Methods 0.000 claims abstract description 13
- 239000000126 substance Substances 0.000 claims abstract description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 30
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 18
- 239000002994 raw material Substances 0.000 claims description 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- 238000002425 crystallisation Methods 0.000 claims description 12
- 230000008025 crystallization Effects 0.000 claims description 12
- 238000001816 cooling Methods 0.000 claims description 11
- 238000005886 esterification reaction Methods 0.000 claims description 11
- 239000012074 organic phase Substances 0.000 claims description 11
- 238000001035 drying Methods 0.000 claims description 10
- 238000001914 filtration Methods 0.000 claims description 10
- 238000003756 stirring Methods 0.000 claims description 10
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 5
- 239000012312 sodium hydride Substances 0.000 claims description 5
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 5
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 230000002194 synthesizing effect Effects 0.000 claims 7
- 238000010189 synthetic method Methods 0.000 abstract description 5
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 4
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- 239000012295 chemical reaction liquid Substances 0.000 abstract description 2
- 230000007062 hydrolysis Effects 0.000 abstract description 2
- 238000006460 hydrolysis reaction Methods 0.000 abstract description 2
- 238000005406 washing Methods 0.000 abstract description 2
- 239000007788 liquid Substances 0.000 abstract 6
- 230000003472 neutralizing effect Effects 0.000 abstract 1
- 239000002904 solvent Substances 0.000 description 6
- 230000000844 anti-bacterial effect Effects 0.000 description 5
- 239000003899 bactericide agent Substances 0.000 description 4
- 238000004821 distillation Methods 0.000 description 3
- 208000005156 Dehydration Diseases 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 230000018044 dehydration Effects 0.000 description 2
- 238000006297 dehydration reaction Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 208000003643 Callosities Diseases 0.000 description 1
- 241000221785 Erysiphales Species 0.000 description 1
- 244000068988 Glycine max Species 0.000 description 1
- 235000010469 Glycine max Nutrition 0.000 description 1
- 206010020649 Hyperkeratosis Diseases 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- 229930182692 Strobilurin Natural products 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 244000052616 bacterial pathogen Species 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 235000013339 cereals Nutrition 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 239000002274 desiccant Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 235000012055 fruits and vegetables Nutrition 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 150000002611 lead compounds Chemical class 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- BSDQITJYKQHXQR-UHFFFAOYSA-N methyl prop-2-eneperoxoate Chemical compound COOC(=O)C=C BSDQITJYKQHXQR-UHFFFAOYSA-N 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 230000001151 other effect Effects 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000002689 soil Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C249/00—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton
- C07C249/04—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton of oximes
- C07C249/12—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton of oximes by reactions not involving the formation of oxyimino groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C249/00—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton
- C07C249/04—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton of oximes
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C249/00—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton
- C07C249/04—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton of oximes
- C07C249/14—Separation; Purification; Stabilisation; Use of additives
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to the technical field of organic synthesis, in particular to a synthetic method of trifloxystrobin. The method comprises the steps of enabling (E) -2- (2' -bromomethylphenyl) -2-carbonyl methyl acetate-O-methyl ketoxime and m-trifluoromethyl acetophenone oxime to carry out condensation reaction in an organic solvent in the presence of an alkaline substance, neutralizing and concentrating first reaction liquid obtained through the condensation reaction to obtain first concentrated liquid, washing the first concentrated liquid with water, concentrating the first concentrated liquid to obtain second concentrated liquid, further mixing the second concentrated liquid with methanol and thionyl chloride, and reesterifying a hydrolysis product of trifloxystrobin in the second concentrated liquid to obtain the trifloxystrobin. The method has the advantages of tolerant requirements on used reagents, mild reaction conditions, simple reaction steps, good yield of the obtained trifloxystrobin and high purity.
Description
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a synthetic method of trifloxystrobin.
Background
Trifloxystrobin, common english name: trifloxystrobin belongs to methoxy acrylate bactericides and is also a bactericide developed by taking natural Strobilurin bactericides as lead compounds, and the specific structure of the bactericide is shown as follows:
the trifloxystrobin not only has a wide bactericidal spectrum, but also has good protection, treatment, shoveling, permeation, systemic activity and other effects, can still maintain the drug effect after being washed by rainwater, has a surface evaporation redistribution function, is quickly decomposed in soil and underground water, and has high environmental safety. Trifloxystrobin almost has good activity on fungous diseases, and has special efficacy on preventing and treating powdery mildew and leaf spot; the method has strong pertinence on preventing and controlling germs, does not cause adverse effect on non-target tissues, and is suitable for crops such as soybeans, grains, corns, rice, fruits and vegetables.
Currently, the synthesis of trifloxystrobin mostly uses (E) -2- (2' -bromomethylphenyl) -2-carbonyl methyl acetate-O-methyl ketoxime and m-trifluoromethyl acetophenone oxime as raw materials, and the raw materials are subjected to condensation reaction in the presence of alkaline substances and organic solvents to obtain the trifloxystrobin, but the solvents used in the synthesis methods inevitably contain trace moisture, and a small amount of water is generated in the reaction process, and the moisture easily enables the generated trifloxystrobin to be hydrolyzed into corresponding acid under alkaline conditions, so that the yield of the trifloxystrobin is low, and the purity is low.
In order to improve the yield of the trifloxystrobin, the prior art has a method for carrying out reaction on raw materials in a container containing a water separation device and removing water in time, and also has a method for removing water generated in the reaction process by distillation or adding a drying agent and then adding a second raw material for carrying out esterification, but the condensation reaction in the methods needs to be carried out step by step, and even though the individual methods obtain considerable yield and purity, the defects of extremely high requirements on the used reagents or the need of carrying out dehydration treatment on the used reagents in advance still exist, so that the reaction process is complex, the reaction cost is increased, and the method is not beneficial to practical large-scale application.
Disclosure of Invention
Aiming at the technical problems, the invention provides the synthetic method of trifloxystrobin, which has the advantages of simple steps, convenience and feasibility, and the synthetic trifloxystrobin has good yield and high purity.
In order to solve the technical problem, the embodiment of the invention adopts the following technical scheme:
in a first aspect, the invention provides a synthetic method of trifloxystrobin, which specifically comprises the following synthetic steps:
s1, in the presence of an alkaline substance, carrying out condensation reaction on raw materials (E) -2- (2' -bromomethylphenyl) -2-carbonyl methyl acetate-O-methyl ketoxime and m-trifluoromethyl acetophenone oxime in a first organic solvent to obtain a first reaction solution, adjusting the pH of the first reaction solution to 6.5-7.5 by using dilute hydrochloric acid, and then concentrating to obtain a first concentrated solution;
s2, adding a second organic solvent insoluble in water and water into the first concentrated solution obtained in the step S1, stirring, standing for layering, removing the water, and concentrating an organic phase to obtain a second concentrated solution;
and S3, adding methanol and thionyl chloride into the second concentrated solution obtained in the step S2 to perform esterification reaction, cooling and crystallizing after the reaction is completed, filtering, and drying to obtain trifloxystrobin.
According to the invention, (E) -2- (2' -bromomethylphenyl) -2-carbonyl methyl acetate-O-methyl ketoxime and m-trifluoromethyl acetophenone oxime are taken as raw materials, a condensation reaction is carried out in an organic solvent in the presence of an alkaline substance, the reaction conditions are mild, the reaction steps are simple, and after the condensation reaction is completed, the trifloxystrobin hydrolyzed in the reaction process and methanol are subjected to an esterification reaction in the presence of thionyl chloride, so that the reaction yield of the trifloxystrobin is improved, impurities in a reaction liquid are reduced, and the method is favorable for obtaining the high-purity trifloxystrobin through subsequent crystallization.
With reference to the first aspect, the first organic solvent in S1 is selected from tetrahydrofuran or N, N-dimethylformamide, a good solvent of the used raw materials is selected to enable the reaction to be more complete, the pH of the solution is adjusted to be neutral after the reaction is finished, and the obtained solvent can be recycled after reduced pressure distillation.
With reference to the first aspect, the second organic solvent in S2 is selected from dichloroethane, ethyl acetate, or dichloromethane, and the first concentrated trifloxystrobin solution is diluted with an organic solvent having a lower boiling point, and then the residual salts in the system are washed with water, so as to further reduce the content of impurities.
In combination with the first aspect, the alkaline substance in S1 is selected from sodium hydride, sodium methoxide, sodium ethoxide, sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate, and the alkaline substance can be removed by water washing at the end of the reaction.
In connection with the first aspect, the condensation reaction is carried out in S1 at a temperature of 0 to 40 ℃, preferably 20 to 30 ℃.
In connection with the first aspect, the esterification reaction is carried out in S3 at 20 to 50 ℃, preferably 30 to 40 ℃.
In combination with the first aspect, the temperature in S3 is reduced to 3-7 ℃ for crystallization, preferably 4-6 ℃.
The synthesis method provided by the invention has mild reaction temperature, does not need high-temperature or low-temperature reaction, and is convenient and feasible.
In combination with the first aspect, the molar ratio of the (E) -2- (2' -bromomethylphenyl) -2-carbonyl acetic acid methyl ester-O-methyl ketoxime, m-trifluoromethyl acetophenone oxime and basic substance in S1 is 1:1.0 to 1.1:1.2 to 1.6. In the synthesis method provided by the invention, the molar ratio of the raw material (E) -2- (2' -bromomethylphenyl) -2-carbonyl methyl acetate-O-methyl ketoxime to m-trifluoromethyl acetophenone oxime is close to 1:1, not only can ensure the complete reaction of the raw materials, but also can not leave excessive raw materials in a reaction system.
In combination with the first aspect, the mass ratio of the (E) -2- (2' -bromomethylphenyl) -2-carbonylacetic acid methyl ester-O-methylketoxime to the first organic solvent in S1 is 1:2 to 4, preferably 1:3. if the amount of the first organic solvent is too large, the concentration of the raw material in the reaction system is too low, which results in a decrease in the reaction rate, and if the amount of the first organic solvent is too small, the raw material cannot be completely dissolved, which results in insufficient reaction.
In combination with the first aspect, the molar ratio of the (E) -2- (2' -bromomethylphenyl) -2-carbonyl acetic acid methyl ester-O-methyl ketoxime to thionyl chloride is 1:0.1 to 0.5. The thionyl chloride can accelerate the esterification reaction of the hydrolyzed trifloxystrobin and methanol, and the synthetic method of the invention slowly and dropwise adds the thionyl chloride into a reaction system, so that the reaction can be prevented from being too violent.
In combination with the first aspect, the mass ratio of the (E) -2- (2' -bromomethylphenyl) -2-carbonyl acetic acid methyl ester-O-methyl ketoxime to methanol is 1: 2-4, directly crystallizing in methanol after the esterification reaction is finished to obtain the trifloxystrobin without adding other solvents.
The invention has the beneficial effects that: the method directly dissolves raw materials (E) -2- (2' -bromomethylphenyl) -2-carbonyl methyl acetate-O-methyl ketoxime and m-trifluoromethyl acetophenone oxime in an organic solvent containing alkaline substances for condensation reaction without dehydration pretreatment of the used solvent or stepwise condensation reaction; after the esterification reaction is finished, crystallization can be directly carried out without adding other solvents; and the reaction condition is mild, the reaction steps are simple, the feasibility is high, and the obtained trifloxystrobin has good yield and high purity and has wide application prospect.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to the following embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
In the synthesis method provided by the embodiment of the invention, the reaction process is monitored by using liquid chromatography, and in the condensation reaction process, when the content of the raw material (E) -2- (2' -bromomethylphenyl) -2-carbonyl methyl acetate-O-methyl ketoxime in the reaction system is less than 1%, the reaction is stopped, namely the reaction time is determined according to the actual reaction process; in the esterification reaction process, when the hydrolysis product of the trifloxystrobin cannot be detected in the reaction system, the reaction can be stopped.
In the embodiment of the invention, after the esterification reaction is finished, the thionyl chloride and part of methanol need to be distilled and removed, the residual methanol can be directly used for crystallizing the trifloxystrobin, and it needs to be noted that the distillation can be stopped when the weight of the distilled solution is about 2 times of the weight of the second concentrated solution.
The raw materials (E) -2- (2' -bromomethylphenyl) -2-carbonyl methyl acetate-O-methyl ketoxime and m-trifluoromethyl acetophenone oxime used in the examples of the present invention are commercially available chemicals.
Example 1
30.1g (0.1mo 1, 95%) (E) -2- (2' -bromomethylphenyl) -2-carbonylacetic acid methyl ester-O-methylketoxime, 22.4g (0.105mo 1, 95%) of m-trifluoromethylacetophenone oxime, 6g (0.15mo 1) of sodium hydride having a mass fraction of 60% and 120.4g of N, N-dimethylformamide were charged into a 250mL four-necked flask, and the reaction was stirred at 0 ℃ for 8 hours to stop the reaction. Adding a small amount of hydrochloric acid to adjust the pH value of the solution to 6.8, and concentrating under reduced pressure until the residual weight is 60.2g to obtain a first concentrated solution;
adding 120mL of dichloroethane and 120mL of water into the obtained first concentrated solution, stirring, standing, layering, removing water to obtain an organic phase, and concentrating under reduced pressure until the residual weight is 45.2g to obtain a second concentrated solution;
adding 60.2g of methanol into the obtained second concentrated solution, slowly dropwise adding 1.2g (0.01 mol) of thionyl chloride, reacting for 2 hours at 30 ℃ after dropwise adding, concentrating under reduced pressure to 89.5g (unreacted thionyl chloride is evaporated during concentration) after the reaction is finished, cooling to 5 ℃ for crystallization, filtering and drying to obtain 37.9g of trifloxystrobin (yield 91.3%, purity 98.2%).
Example 2
30.1g (0.1mo 1, 95%) of (E) -methyl 2- (2' -bromomethylphenyl) -2-carbonylacetate-O-methylketoxime, 22.4g (0.105mo 1, 95%) of m-trifluoromethylacetophenone oxime, 6.4g (0.1umo 1) of sodium hydroxide and 120.4g of N, N-dimethylformamide were charged into a 250mL four-necked flask, and the reaction was stirred at 30 ℃ for 3 hours to stop the reaction. Adding a small amount of hydrochloric acid to adjust the pH value of the solution to 7.0, and concentrating under reduced pressure until the residual weight is 59.8g to obtain a first concentrated solution;
adding 120mL of dichloroethane and 120mL of water into the obtained first concentrated solution, stirring, standing, layering, removing water to obtain an organic phase, and concentrating under reduced pressure until the residual weight is 44.8g to obtain a second concentrated solution;
adding 90.3g of methanol into the obtained second concentrated solution, slowly dropwise adding 4.8g (0.04 mol) of thionyl chloride, reacting for 2 hours at 30 ℃ after dropwise adding, concentrating under reduced pressure until the residual weight is 90.1g (unreacted thionyl chloride is evaporated in the concentration process) after the reaction is finished, cooling to 5 ℃ for crystallization, filtering and drying to obtain 37.8g of trifloxystrobin (yield 91.2% and purity 98.5%).
Example 3
30.1g (0.1mo 1, 95%) of (E) -methyl 2- (2' -bromomethylphenyl) -2-carbonylacetate-O-methylketoxime, 22.4g (0.105mo 1, 95%) of m-trifluoromethylacetophenone oxime, 6.4g (0.1umo 1) of sodium hydroxide and 120.4g of N, N-dimethylformamide were charged into a 250mL four-necked flask, and the reaction was stirred at 25 ℃ for 4 hours to stop the reaction. Adding a small amount of hydrochloric acid to adjust the pH value of the solution to 7.0, and concentrating under reduced pressure until the residual weight is 59.6g to obtain a first concentrated solution;
adding 120mL of dichloroethane and 120mL of water into the obtained first concentrated solution, stirring, standing, layering, removing water to obtain an organic phase, and concentrating under reduced pressure until the residual weight is 45.3g to obtain a second concentrated solution;
adding 90.3g of methanol into the obtained second concentrated solution, slowly dropwise adding 3.6g (0.03 mol) of thionyl chloride, reacting for 2 hours at 30 ℃ after dropwise adding, concentrating under reduced pressure until the residual weight is 90.5g (unreacted thionyl chloride is evaporated in the concentration process) after the reaction is finished, cooling to 5 ℃ for crystallization, filtering and drying to obtain 37.6g of trifloxystrobin (yield is 90.9%, purity is 98.7%).
Example 4
30.1g (0.1mo 1, 95%) (E) -methyl 2- (2' -bromomethylphenyl) -2-carbonylacetate-O-methylketoxime, 23.5g (0.11mo 1, 95%) of m-trifluoromethylacetophenone oxime, 6.8g (0.12mo 1) of potassium hydroxide and 90.3g of N, N-dimethylformamide were charged into a 250mL four-necked flask, and the reaction was stirred at 40 ℃ for 2 hours to stop the reaction. Adding a small amount of hydrochloric acid to adjust the pH value of the solution to 7.3, and concentrating under reduced pressure until the residual weight is 60.5g to obtain a first concentrated solution;
adding 120mL of ethyl acetate and 120mL of water into the obtained first concentrated solution, stirring, standing, layering, removing water to obtain an organic phase, and concentrating under reduced pressure until the residual weight is 45.7g to obtain a second concentrated solution;
adding 120.4g of methanol into the obtained second concentrated solution, slowly dropwise adding 6.0g (0.05 mol) of thionyl chloride, reacting at 30 ℃ for 2 hours after dropwise adding, concentrating under reduced pressure until the residual weight is 91.2g (unreacted thionyl chloride is evaporated in the concentration process) after the reaction is finished, cooling to 4 ℃ for crystallization, filtering and drying to obtain 37.3g of trifloxystrobin (the yield is 90.2%, and the purity is 98.6%).
Example 5
30.1g (0.1mo 1, 95%) (E) -methyl 2- (2' -bromomethylphenyl) -2-carbonylacetate-O-methylketoxime, 23.5g (0.11mo 1, 95%) of m-trifluoromethylacetophenone oxime, 20.7g (0.15mo 1) of potassium carbonate and 120.4g of N, N-dimethylformamide were charged into a 250mL four-necked flask, and the reaction was stirred at 25 ℃ for 4 hours to stop the reaction. Adding a small amount of hydrochloric acid to adjust the pH value of the solution to 7.1, and concentrating under reduced pressure until the residual weight is 61.1g to obtain a first concentrated solution;
adding 120mL of ethyl acetate and 120mL of water into the obtained first concentrated solution, stirring, standing for layering, removing water to obtain an organic phase, and concentrating under reduced pressure until the residual weight is 45.1g to obtain a second concentrated solution;
adding 120.4g of methanol into the obtained second concentrated solution, slowly dropwise adding 2.4g (0.02 mol) of thionyl chloride, reacting for 2 hours at 30 ℃ after dropwise adding, concentrating under reduced pressure until the residual weight is 90.9g (unreacted thionyl chloride is evaporated in the concentration process) after the reaction is finished, cooling to 6 ℃ for crystallization, filtering and drying to obtain 37.4g of trifloxystrobin (yield is 90.3%, purity is 98.4%).
Example 6
30.1g (0.1mo 1, 95%) (E) -2- (2' -bromomethylphenyl) -2-carbonylacetic acid methyl ester-O-methylketoxime, 23.5g (0.11mo 1, 95%) m-trifluoromethylacetophenone oxime, 6.0g (0.15mo 1) of sodium hydride with a mass fraction of 60% and 120.4g of N, N-dimethylformamide were charged into a 250mL four-necked flask, and the reaction was stirred at 25 ℃ for 4 hours to stop the reaction. Adding a small amount of hydrochloric acid to adjust the pH value of the solution to 7.4, and concentrating under reduced pressure until the residual weight is 59.4g to obtain a first concentrated solution;
adding 120mL of ethyl acetate and 120mL of water into the obtained first concentrated solution, stirring, standing, layering, removing water to obtain an organic phase, and concentrating under reduced pressure until the residual weight is 44.9g to obtain a second concentrated solution;
adding 120.4g of methanol into the obtained second concentrated solution, slowly dropwise adding 2.4g (0.02 mol) of thionyl chloride, reacting at 30 ℃ for 2 hours after dropwise adding, concentrating under reduced pressure until the residual weight is 89.4g (unreacted thionyl chloride is evaporated in the concentration process) after the reaction is finished, cooling to 6 ℃ for crystallization, filtering and drying to obtain 37.9g of trifloxystrobin (the yield is 91.2%, and the purity is 98.3%).
Comparative example 1
30.1g (0.1mo 1, 95%) of (E) -methyl 2- (2' -bromomethylphenyl) -2-carbonylacetate-O-methylketoxime, 22.4g (0.105mo 1, 95%) of m-trifluoromethylacetophenone oxime, 6.4g (0.1umo 1) of sodium hydroxide and 120.4g of N, N-dimethylformamide were charged into a 250mL four-necked flask, and the reaction was stirred at 25 ℃ for 4 hours to stop the reaction. Adding a small amount of hydrochloric acid to adjust the pH value of the solution to 7.2, and concentrating under reduced pressure until the residual weight is 59.9g to obtain a first concentrated solution;
adding 120mL of dichloroethane and 120mL of water into the obtained first concentrated solution, stirring, standing, layering, removing water to obtain an organic phase, and concentrating under reduced pressure until the residual weight is 42.9g to obtain a second concentrated solution;
and adding 45g of methanol into the obtained second concentrated solution, cooling to 5 ℃ for crystallization, filtering and drying to obtain 33.6g of trifloxystrobin (yield is 78.5%, purity is 95.2%).
Comparative example 2
30.1g (0.1mo 1, 95%) (E) -methyl 2- (2' -bromomethylphenyl) -2-carbonylacetate-O-methylketoxime, 23.5g (0.11mo 1, 95%) of m-trifluoromethylacetophenone oxime, 6.0g (0.15mo 1) of sodium hydride with a mass fraction of 60% and 120.4g of N, N-dimethylformamide were charged into a 250mL four-necked flask, and the reaction was stirred at 25 ℃ for 4 hours to stop. Adding a small amount of hydrochloric acid to adjust the pH value of the solution to 6.9, and concentrating under reduced pressure until the residual weight is 59.7g to obtain a first concentrated solution;
adding 120mL of ethyl acetate and 120mL of water into the obtained first concentrated solution, stirring, standing, layering, removing water to obtain an organic phase, and concentrating under reduced pressure until the weight of the organic phase is 43.5g to obtain a second concentrated solution;
and adding 45g of methanol into the obtained second concentrated solution, cooling to 5 ℃ for crystallization, filtering and drying to obtain 37.7g of trifloxystrobin (yield 88.9% and purity 96.3%).
The synthesis method of trifloxystrobin provided by the invention has the advantages of wide reagent requirements, mild reaction conditions and simple reaction steps, optimizes the reaction steps on the premise of not reducing the yield and purity of trifloxystrobin, and is simple, convenient and feasible. The trifloxystrobin synthesis method provided by the invention is more suitable for large-scale production.
The above description is intended to be illustrative of the preferred embodiment of the present invention and should not be taken as limiting the invention, but rather, the invention is intended to cover all modifications, equivalents, and alternatives falling within the spirit and scope of the invention.
Claims (10)
1. The synthesis method of trifloxystrobin is characterized by comprising the following steps:
s1, in the presence of an alkaline substance, carrying out condensation reaction on raw materials (E) -2- (2' -bromomethylphenyl) -2-carbonyl methyl acetate-O-methyl ketoxime and m-trifluoromethyl acetophenone oxime in a first organic solvent to obtain a first reaction solution, adjusting the pH of the first reaction solution to 6.5-7.5 by using dilute hydrochloric acid, and then concentrating to obtain a first concentrated solution;
s2, adding a second organic solvent insoluble in water and water into the first concentrated solution obtained in the step S1, stirring, standing for layering, removing the water, and concentrating an organic phase to obtain a second concentrated solution;
and S3, adding methanol and thionyl chloride into the second concentrated solution obtained in the step S2 to carry out esterification reaction, cooling and crystallizing after the reaction is completed, filtering, and drying to obtain trifloxystrobin.
2. The method for synthesizing trifloxystrobin according to claim 1, wherein the first organic solvent in S1 is selected from tetrahydrofuran or N, N-dimethylformamide.
3. The method for synthesizing trifloxystrobin according to claim 1, wherein the second organic solvent in S2 is selected from dichloroethane, ethyl acetate or dichloromethane.
4. The method for synthesizing trifloxystrobin according to claim 1, wherein the alkaline substance in S1 is selected from sodium hydride, sodium methoxide, sodium ethoxide, sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate.
5. The method for synthesizing trifloxystrobin according to claim 1, wherein the condensation reaction is performed at 0-40 ℃ in S1.
6. The method for synthesizing trifloxystrobin according to claim 1, wherein the esterification reaction is performed at 20-50 ℃ in S3; and/or
And (3) cooling to 3-7 ℃ for crystallization.
7. The method for synthesizing trifloxystrobin according to any one of claims 1 to 6, wherein the molar ratio of the (E) -2- (2' -bromomethylphenyl) -2-carbonyl acetic acid methyl ester-O-methyl ketoxime, m-trifluoromethyl acetophenone oxime and alkaline substance in S1 is 1:1.0 to 1.1:1.2 to 1.6.
8. The synthesis method of trifloxystrobin according to any one of claims 1 to 6, wherein the mass ratio of the (E) -2- (2' -bromomethylphenyl) -2-carbonyl methyl acetate-O-methyl ketoxime in S1 to the first organic solvent is 1:2 to 4.
9. The method for synthesizing trifloxystrobin according to any one of claims 1 to 6, wherein the molar ratio of (E) -2- (2' -bromomethylphenyl) -2-carbonyl methyl acetate-O-methyl ketoxime to thionyl chloride is 1:0.1 to 0.5.
10. The synthesis method of trifloxystrobin according to any one of claims 1 to 6, wherein the mass ratio of (E) -2- (2' -bromomethylphenyl) -2-carbonyl methyl acetate-O-methyl ketoxime to methanol is 1:2 to 4.
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| CN1560027A (en) * | 2004-03-05 | 2005-01-05 | 同济大学 | Preparation process of oxime strain ester |
| CN1793115A (en) * | 2005-11-18 | 2006-06-28 | 上海同纳环保科技有限公司 | Tech. for synthesizing high productivity oxime kresoxim |
| CN105294490A (en) * | 2015-09-10 | 2016-02-03 | 江苏长青农化股份有限公司 | Trifloxystrobin synthesizing method |
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| CN1560027A (en) * | 2004-03-05 | 2005-01-05 | 同济大学 | Preparation process of oxime strain ester |
| CN1793115A (en) * | 2005-11-18 | 2006-06-28 | 上海同纳环保科技有限公司 | Tech. for synthesizing high productivity oxime kresoxim |
| CN105294490A (en) * | 2015-09-10 | 2016-02-03 | 江苏长青农化股份有限公司 | Trifloxystrobin synthesizing method |
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