A method for preparing flumioxazin

Abstract

The application provides a synthesis method of flumioxazin, and belongs to the technical field of pesticide synthesis. The application takes 2,4-difluoro nitrobenzene as a starting material, and obtains the product flumioxazin through hydrolysis, bromination, etherification, ring closure, propynylization and acylation. The method provided by the application solves the problems of complicated synthesis process, serious environmental pollution and low yield of flumioxazin, and the synthesis method of flumioxazin is suitable for industrial production.

Description

Technical Field

[0001] This invention relates to the technical field of pesticide synthesis, specifically to a method for preparing propyzamide. Background Technology

[0002] Flumioxazin, also known as Sumisoya, is a cyclic imide herbicide in chemical structure and a protoporphyrinogen oxidase inhibitor in mechanism of action. It is a leading herbicide among "other PPO inhibitor herbicides." Developed by Sumitomo Chemical Co., Ltd. of Japan in 1993, it effectively controls weeds that other herbicides (such as glyphosate) cannot control. It can also be used to control gramineous and broadleaf weeds on soybeans, cotton, grapes, and many other crops. Several methods for synthesizing flumioxazin are currently available:

[0003] (1) It is prepared by using m-fluorophenol as raw material and undergoing five steps of reaction: etherification, nitration, reduction cyclization, propyneation and acylation.

[0004]

[0005] The raw material m-fluorophenol used in this synthetic route is expensive; after hydrolysis, ether bonds are generated and then nitrated, but the nitration reaction is violent and easily causes the ether bonds to break; the hydrogenation reduction using iron powder has a low yield and produces a large amount of difficult-to-treat iron sludge.

[0006] (2) It is obtained by using 2,4-difluoronitrobenzene as raw material and undergoing 7 steps of reaction including hydrolysis, etherification, reduction, cyclization, nitration, propyneation, nitro reduction and acylation.

[0007]

[0008] The synthetic route requires two hydrogenation reductions, which greatly increases the cost and is not conducive to the development of the project. The intermediate is first attached with a propynyl group and then nitrated and reduced, which makes it difficult to selectively reduce the nitro group and easily generates impurities that are difficult to remove.

[0009] (3) It is obtained by using 2,4-difluoronitrobenzene as raw material and undergoing 7 steps of reaction including hydrolysis, etherification, cyclization, nitration, nitro reduction, phthalic anhydride acylation and propyneation.

[0010]

[0011] The synthetic route conditions are similar to those of route (2), but the final step of attaching the propyne group requires sodium hydride, resulting in low yield and difficulty in removing impurities. Therefore, there is still much room for improvement in the existing methods for synthesizing propyne fluroxypyr.

[0012] Therefore, it is necessary to study new methods for preparing propyzamide in view of the problems existing in the above synthesis methods. Summary of the Invention

[0013] In view of the above-mentioned methods for preparing propyzamide, which have technical problems such as many process steps, large environmental pollution and low yield, this invention provides a method for synthesizing propyzamide.

[0014] The synthetic route for propyzinamide provided by this invention is as follows:

[0015]

[0016] To achieve the above objectives, the present invention adopts the following technical solution:

[0017] One of the technical solutions of the present invention is a method for preparing propyzamide, comprising the following steps:

[0018] Step 1: 2,4-Difluoronitrobenzene is hydrolyzed in an inorganic alkaline aqueous solution to obtain 5-fluoro-2-nitrophenol;

[0019] Step 2: 5-Fluoro-2-nitrophenol reacts with a brominizing agent in a solvent to give 4-bromo-5-fluoro-2-nitrophenol;

[0020] Step 3: After removing the alcohol from an alcoholic solution of inorganic base, 4-bromo-5-fluoro-2-nitrophenol reacts with ethyl 2-bromoacetate in the presence of a solvent under an inert atmosphere to give ethyl 4-bromo-5-fluoro-2-nitrophenoxyacetate.

[0021] Step 4: Ethyl 4-bromo-5-fluoro-2-nitrophenoxyethyl reacts with hydrogen in a solvent, with a catalyst, under an inert atmosphere and at a certain pressure to give 7-fluoro-6-bromo-4-benzoxazine-3(4H)-one;

[0022] Step 5: In the presence of an inorganic base and solvent, 7-fluoro-6-bromo-2H-1,4-benzoxazine-3(4H)-one reacts with 3-bromopropyne to give 7-fluoro-6-bromo-4-propyne-2H-1,4-benzoxazine-3-one.

[0023] Step 6: 7-Fluoro-6-bromo-4-propyne-2H-1,4-benzoxazine-3-one reacts with 3,4,5,6-tetrahydrophthalimide in a solvent in the presence of a catalyst to give propyne fluroxypyr.

[0024] In step 2, step 3, and step 5, the inorganic base is independently selected from one of sodium hydroxide, potassium hydroxide, sodium carbonate, and potassium carbonate.

[0025] The inert atmospheres mentioned in steps 3 and 4 are each independently selected from either a nitrogen atmosphere or an argon atmosphere.

[0026] According to one embodiment of this application, in step 1, the selected inorganic alkaline aqueous solution is sodium hydroxide, potassium hydroxide, sodium carbonate, or potassium carbonate aqueous solution, preferably a sodium hydroxide aqueous solution. More preferably, it is a 30% sodium hydroxide aqueous solution.

[0027] According to one embodiment of this application, in step 1, the selected solvent is dimethyl sulfoxide, tetrahydrofuran, NMP, or water, preferably dimethyl sulfoxide.

[0028] According to one embodiment of this application, in step 2, the selected solvent is acetonitrile, chloroform, or carbon tetrachloride, preferably acetonitrile.

[0029] According to one embodiment of this application, in step 2, the selected brominating agent is bromine, NBS, pyridine tribromide, or hydrobromic acid, preferably pyridine tribromide or NBS.

[0030] According to one embodiment of this application, in step 2, the selected reaction temperature is 10℃-150℃, preferably 60℃-100℃. More preferably, it is 75℃-95℃.

[0031] According to one embodiment of this application, in step 2, the selected reaction time is 1-24 hours, preferably 5-15 hours, and more preferably 8-12 hours.

[0032] According to one embodiment of this application, in step 2, the molar ratio of the selected brominating agent to 5-fluoro-2-nitrophenol is 1.1:1 to 1.5:1.

[0033] According to one embodiment of this application, in step 3, the selected inorganic base is sodium hydroxide, potassium hydroxide, potassium carbonate or sodium carbonate, preferably potassium hydroxide.

[0034] According to one embodiment of this application, in step 3, the selected alcohol is ethanol, methanol, , , or , with ethanol being preferred.

[0035] According to one embodiment of this application, in step 3, the selected solvent is DMF, 1,4-dioxane, acetonitrile, or NMP, preferably DMF.

[0036] According to one embodiment of this application, in step 3, the selected inert atmosphere is a nitrogen atmosphere or an argon atmosphere, preferably a nitrogen atmosphere.

[0037] According to one embodiment of this application, in step 3, the selected post-treatment is extraction, washing, drying, and solvent removal to obtain ethyl 4-bromo-5-fluoro-2-nitrophenoxyethyl. Preferably, ethyl acetate is added for extraction, and the extraction solution is washed with distilled water. The organic layers are combined, dried with anhydrous sodium sulfate, and the solvent is recovered by vacuum distillation to obtain the product ethyl 4-bromo-5-fluoro-2-nitrophenoxyethyl.

[0038] According to one embodiment of this application, in step 3, the molar ratio of the selected ethyl 2-bromoacetate to 4-bromo-5-fluoro-2-nitrophenol is 1.1:1 to 3:1.

[0039] According to one embodiment of this application, in step 4, the selected solvent is N,N-dimethylformamide (DMF), dimethyl sulfoxide, N,N-dimethylacetamide or N-methylpyrrolidone (NMP), preferably N,N-dimethylformamide.

[0040] According to one embodiment of this application, in step 4, the selected catalyst is Raney nickel or palladium on carbon, preferably Raney nickel.

[0041] According to one embodiment of this application, in step 4, the selected inert atmosphere is a nitrogen atmosphere or an argon atmosphere, preferably a nitrogen atmosphere.

[0042] According to one embodiment of this application, in step 4, the selected pressure is 0.6MPa-1.2MPa, preferably 0.9MPa-1.1MPa.

[0043] According to one embodiment of this application, in step 4, the selected reaction temperature is 70℃-150℃, preferably 90℃-110℃.

[0044] According to one embodiment of this application, in step 4, the molar ratio of the selected catalyst to ethyl 4-bromo-5-fluoro-2-nitrophenoxyacetate is 0.1:1 to 1:1.

[0045] According to one embodiment of this application, in step 4, the molar ratio of the selected hydrogen gas to ethyl 4-bromo-5-fluoro-2-nitrophenoxyacetate is 1.1:1 to 3:1.

[0046] According to one embodiment of this application, in step 4, the selected post-treatment is to take the supernatant and distill it under reduced pressure, then add methanol to the residue after distillation, heat to reflux, keep warm for 30-40 minutes, cool, filter and dry to obtain 7-fluoro-6-bromo-2H-1,4-benzoxazine-3(4H)-one solid.

[0047] According to one embodiment of this application, in step 5, the selected inorganic base is potassium carbonate, sodium carbonate, or sodium hydroxide, preferably potassium carbonate.

[0048] According to one embodiment of this application, in step 5, the selected solvent is toluene, acetone, chlorobenzene, ethyl acetate, acetonitrile, 1,2-dichloroethane, or xylene, preferably toluene.

[0049] According to one embodiment of this application, in step 5, the molar ratio of the selected 3-bromopropyne to 7-fluoro-6-bromo-2H-1,4-benzoxazine-3(4H)-one is 1.1:1 to 3:1.

[0050] According to one embodiment of this application, in step 5, 3-bromopropyne is added dropwise at a temperature below 5°C, and after the addition is complete, the temperature is raised to 50°C-70°C to react and obtain 7-fluoro-6-bromo-4-propyne-2H-1,4-benzoxazine-3-one; preferably, 3-bromopropyne is added dropwise at a temperature below 5°C, and the addition is completed within 0.5 hours, then the temperature is raised to 50-70°C, and the reaction is stopped after 4-5 hours to obtain 7-fluoro-6-bromo-4-propyne-2H-1,4-benzoxazine-3-one.

[0051] According to one embodiment of this application, in step 6, the selected solvent is ethylene glycol dimethyl ether, dioxane, anisole, or ethylene glycol diethyl ether, preferably ethylene glycol dimethyl ether.

[0052] According to one embodiment of this application, in step 6, the selected catalyst is palladium acetate, 1,1'-bis(diphenylphosphine)ferrocene and palladium dichloride or cuprous iodide, preferably palladium acetate.

[0053] According to one embodiment of this application, in step 6, the molar ratio of the selected catalyst to 7-fluoro-6-bromo-4-propynyl-2H-1,4-benzoxazin-3-one is 0.01:1 to 1:1, preferably 0.01:1 to 0.03:1.

[0054] According to one embodiment of this application, in step 6, the selected acylation reagent is 3,4,5,6-tetrahydrophthalimide.

[0055] According to one embodiment of this application, in step 6, the reaction temperature is 100℃-120℃.

[0056] According to one embodiment of this application, in step 6, the reaction time is 8 to 12 hours.

[0057] In some embodiments, a method for preparing propyzamide according to the present invention includes the following steps:

[0058] Step 1: Using 2,4-difluoronitrobenzene as the raw material, 30% sodium hydroxide aqueous solution as the hydrolysis reagent, and dimethyl sulfoxide as the solvent, the reaction yields 5-fluoro-2-nitrophenol;

[0059] Step 2: Add 5-fluoro-2-nitrophenol and the bromide reagent to the solvent, and heat to 75-95℃ for 8-12 hours. After the reaction is complete, filter, wash the filtrate with saturated sodium thiosulfate solution, extract the organic phase with petroleum ether, and distill under reduced pressure to obtain 4-bromo-5-fluoro-2-nitrophenol;

[0060] Step 3: Dissolve 4-bromo-5-fluoro-2-nitrophenol in an ethanol solution of potassium hydroxide (1 mol equivalent of KOH). After stirring at room temperature for 1 hour, remove the solvent ethanol under reduced pressure. Dissolve the resulting reactant in N,N-dimethylformamide (DMF) and add ethyl 2-bromoacetate. Stir under nitrogen for 24 hours. After the reaction is complete, extract with ethyl acetate and wash the extract five times with distilled water. Combine the organic layers, dry with anhydrous sodium sulfate, and recover the solvent by distillation under reduced pressure to obtain the product ethyl 4-bromo-5-fluoro-2-nitrophenoxyacetate.

[0061] Step 4: Add ethyl 4-bromo-5-fluoro-2-nitrophenoxyethyl acetate, N,N-dimethylformamide, and Raney nickel to the reaction vessel. Seal the reaction vessel, replace the air with nitrogen, then replace the nitrogen with hydrogen, and finally purge with hydrogen to 0.9-1.1 MPa. Start stirring and heat to 90-110℃. When the pressure inside the vessel is lower than 0.6 MPa, add hydrogen to 0.9-1.1 MPa and react for 3-4 hours. After the reaction is complete, take the supernatant and distill under reduced pressure. Add methanol to the residue after distillation, heat to reflux, maintain the temperature for 30-40 minutes, cool, filter and dry to obtain 7-fluoro-6-bromo-2H-1,4-benzoxazine-3(4H)-one solid.

[0062] Step 5: Add potassium carbonate and toluene to a dry reactor, start stirring, and control the temperature below 5°C. Add 7-fluoro-6-bromo-2H-1,4-benzoxazine-3(4H)-one in batches until the addition is complete. Add 3-bromopropyne dropwise below 5°C, completing the addition within 0.5-1 hour. Raise the temperature to 50-70°C and maintain the reaction for 4-5 hours. After the reaction is complete, filter the solution. Distill the filtrate under normal pressure and then under reduced pressure to obtain the solid product 7-fluoro-6-bromo-4-propyne-2H-1,4-benzoxazine-3-one.

[0063] Step 6: Add ethylene glycol dimethyl ether as solvent and palladium acetate as catalyst to the reaction flask of 7-fluoro-6-bromo-4-propyne-2H-1,4-benzoxazine-3-one, stir to dissolve, add 3,4,5,6-tetrahydrophthalimide, heat to 100-120℃ and react for 8-12 hours, filter, and distill under reduced pressure to obtain propyne fluroxypyr.

[0064] This invention uses inexpensive 2,4-difluoronitrobenzene as raw material and synthesizes propyne fluroxypyr through reaction steps such as fluorination, bromination, etherification, cyclization, propyneation, and acylation.

[0065] Compared with existing synthesis methods, the present invention has the following advantages:

[0066] 1) No steps such as nitration are required; a safe bromination reaction is used instead, which is mild, safe, and environmentally friendly.

[0067] 2) Brominating reagents are solid reagents; avoid using hazardous reagents such as bromine and hydrobromic acid.

[0068] 3) The reduction-ring-closure reaction uses H2 / Raney nickel, which has higher selectivity and reaction efficiency, and is also more environmentally friendly;

[0069] 4) Using 3,4,5,6-tetrahydrophthalimide as an acylation reagent, propyzamide was obtained in a high yield of 97%.

[0070] In the description of this invention, it should be understood that the terms "first" and "second" are used for descriptive purposes only and should not be construed as indicating or implying relative importance or implicitly specifying the number of indicated technical features. Therefore, a feature defined as "first" or "second" may explicitly or implicitly include one or more of that feature. In the description of this invention, "a plurality of" means two or more, unless otherwise explicitly specified.

[0071] In the description of this specification, the references to terms such as "one embodiment," "some embodiments," "example," "specific example," or "some examples," etc., indicate that a specific feature, structure, material, or characteristic described in connection with that embodiment or example is included in at least one embodiment or example of the present invention. In this specification, the illustrative expressions of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in one or more embodiments or examples. Moreover, without contradiction, those skilled in the art can combine and integrate the different embodiments or examples described in this specification, as well as the features of different embodiments or examples. Detailed Implementation

[0072] To enable those skilled in the art to better understand the technical solutions of the present invention, some non-limiting embodiments are further disclosed below to provide a more detailed description of the present invention.

[0073] All reagents used in this invention can be purchased commercially or prepared by the methods described in this invention.

[0074] In this invention, min represents minutes; h represents hours; g represents grams; mL represents milliliters; and mg represents milligrams.

[0075] Example 1

[0076] Synthesis of 5-fluoro-2-nitrophenol

[0077] 16 g (0.1 mol) of 2,4-difluoronitrobenzene and 100 mL of dimethyl sulfoxide (DMSO) were added to a 250 mL round-bottom flask. The mixture was heated to 55 °C, and 40 g of a 30% (w / w) NaOH aqueous solution was added dropwise with stirring. The reaction was allowed to proceed for 2 hours, during which the reaction was monitored by TLC. After the reaction was complete, 10 mL of water was added, and the pH was adjusted to 1–2 with hydrochloric acid. The mixture was then extracted twice with ethyl acetate. The organic phases were combined, and the solvent was removed by vacuum distillation to obtain 13.9 g of a yellow liquid, with a yield of 86% and a purity of 98%.

[0078] Synthesis of 4-bromo-5-fluoro-2-nitrophenol

[0079] 15.7 g (0.1 mol) of 5-fluoro-2-nitrophenol and 200 mL of chloroform were added to a 1000 mL three-necked flask equipped with a reflux condenser. The mixture was stirred to dissolve, and then 19.6 g (0.11 mol) of N-bromosuccinimide (NBS) was added in portions. The mixture was heated to 75 °C and reacted for 8 hours. The reaction solution was filtered, and the filtrate was washed with saturated sodium thiosulfate solution until the solution changed from deep red to colorless. The organic phase was extracted with petroleum ether, and the solution was distilled under reduced pressure to give 17.7 g of yellow crystals, with a yield of 75% and a purity of 95%.

[0080] Synthesis of ethyl 4-bromo-5-fluoro-2-nitrophenoxyacetate

[0081] 23.6 g (0.1 mol) of 4-bromo-5-fluoro-2-nitrophenol was dissolved in a 0.1 M potassium hydroxide solution in ethanol (1 mol equivalent of KOH). After stirring at room temperature for 1 hour, the solvent ethanol was removed by vacuum distillation. The resulting reaction mixture was dissolved in 150 mL of N,N-dimethylformamide (DMF), and 1.2 mol equivalent of ethyl 2-bromoformamide was added. The reaction mixture was stirred under nitrogen for 24 hours. After the reaction was completed, 50 mL of ethyl acetate was added for extraction, and the extract was washed five times with distilled water. The organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was recovered by vacuum distillation to give 31.5 g of a yellow solid, with a yield of 98% and a purity of 99%.

[0082] Synthesis of 7-fluoro-6-bromo-2H-1,4-benzoxazine-3(4H)-one

[0083] 32.2 g (0.1 mol) of ethyl 4-bromo-5-fluoro-2-nitrophenoxyethyl acetate, 200 mL of N,N-dimethylformamide, and 1.2 g of Raney nickel were added to a high-pressure reactor. The reactor was sealed, and the air was purged with nitrogen, followed by the nitrogen purging with hydrogen. Finally, hydrogen was added to 0.9 MPa, stirring was started, and the temperature was raised to 90 °C. When the pressure inside the reactor dropped below 0.6 MPa, hydrogen was added to bring the pressure back to 0.9 MPa, and the reaction was carried out for 3 hours. After the reaction was completed, the supernatant was collected and distilled under reduced pressure. Methanol was added to the distillate residue, and the mixture was heated to reflux and held at that temperature for 30 minutes. After cooling, the mixture was filtered and dried to obtain 22.6 g of solid 7-fluoro-6-bromo-2H-1,4-benzoxazine-3(4H)-one, with a yield of 92% and a purity of 95%.

[0084] Synthesis of 7-fluoro-6-bromo-4-propynyl-2H-1,4-benzoxazin-3-one

[0085] 20.73 g (0.15 mol) of potassium carbonate and 100 mL of toluene were added to a dry reactor. Stirring was started, and the temperature was controlled below 5 °C. 24.6 g (0.1 mol) of 7-fluoro-6-bromo-2H-1,4-benzoxazine-3(4H)-one was added in portions until the addition was complete. 1.3 g (0.11 mol) of 3-bromopropyne was added dropwise over 0.5 hours below 5 °C. The temperature was then raised to 50 °C and the reaction was maintained for 4 hours. After the reaction was complete, the mixture was filtered. The filtrate was first distilled under normal pressure and then under reduced pressure to obtain 23.8 g of the solid product 7-fluoro-6-bromo-4-propyne-2H-1,4-benzoxazine-3-one, with a yield of 84% and a purity of 93%.

[0086] Synthesis of propyzamide

[0087] 200 mL of ethylene glycol dimethyl ether solvent and 0.001 mol of palladium acetate catalyst were added to a reaction flask containing 28.4 g (0.1 mol) of 7-fluoro-6-bromo-4-propyne-2H-1,4-benzoxazine-3-one. The mixture was stirred to dissolve the precipitate, and then 16.6 g (0.11 mol) of 3,4,5,6-tetrahydrophthalimide was added. The mixture was heated to 100 °C and reacted for 8 hours. After filtration and vacuum distillation, 27.6 g of propyzamide was obtained, with a yield of 78% and a purity of 97%.

[0088] Example 2

[0089] Synthesis of 5-fluoro-2-nitrophenol

[0090] 16 g (0.1 mol) of 2,4-difluoronitrobenzene and 100 mL of water were added to a 250 mL round-bottom flask and heated to 55 °C. 40 g of a 30% NaOH aqueous solution was added dropwise with stirring, and the reaction was allowed to proceed for 6 hours. After the reaction was complete, hydrochloric acid was added to adjust the pH to 1–2. The mixture was then extracted twice with dichloromethane. The organic phases were combined and distilled under reduced pressure to obtain 13.2 g of a yellow liquid, with a yield of 84% and a purity of 98%.

[0091] Synthesis of 4-bromo-5-fluoro-2-nitrophenol

[0092] 15.7 g (0.1 mol) of 5-fluoro-2-nitrophenol and 200 mL of acetonitrile were added to a 1000 mL three-necked flask equipped with a reflux condenser. The mixture was stirred until dissolved, and then 48 g (0.15 mol) of pyridine tribromide was added in portions. The mixture was heated to 95 °C and reacted for 12 hours. The reaction solution was filtered, and the filtrate was washed with saturated sodium thiosulfate solution until the solution changed from dark red to colorless. The organic phase was extracted with petroleum ether, and the solution was distilled under reduced pressure to give 17.2 g of yellow crystals, with a yield of 73% and a purity of 92%.

[0093] Synthesis of ethyl 4-bromo-5-fluoro-2-nitrophenoxyacetate

[0094] 23.6 g (0.1 mol) of 4-bromo-5-fluoro-2-nitrophenol was dissolved in a 0.1 M potassium hydroxide solution in ethanol (1 mol equivalent of KOH). After stirring at room temperature for 1 hour, the solvent ethanol was removed by vacuum distillation. The resulting reaction mixture was dissolved in 150 mL of N,N-dimethylformamide (DMF), and 1.2 mol equivalent of ethyl 2-bromoformamide was added. The reaction mixture was stirred under nitrogen for 24 hours. After the reaction was completed, 50 mL of ethyl acetate was added for extraction, and the extract was washed five times with distilled water. The organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was recovered by vacuum distillation to give 31.3 g of a yellow solid, with a yield of 97% and a purity of 99%.

[0095] Synthesis of 7-fluoro-6-bromo-2H-1,4-benzoxazine-3(4H)-one

[0096] 32.2 g (0.1 mol) of ethyl 4-bromo-5-fluoro-2-nitrophenoxyethyl acetate, 200 mL of N,N-dimethylformamide, and 1.2 g of Raney nickel were added to a high-pressure reactor. The reactor was sealed, and the air was replaced with nitrogen, followed by the replacement of nitrogen with hydrogen. Finally, hydrogen was added to 1.1 MPa, stirring was started, and the temperature was raised to 110 °C. When the pressure inside the reactor dropped below 0.6 MPa, hydrogen was added to bring the pressure back to 1.1 MPa, and the reaction was carried out for 4 hours. After the reaction was completed, the supernatant was collected and distilled under reduced pressure. Methanol was added to the residue after distillation, and the mixture was heated to reflux and held at that temperature for 40 minutes. After cooling, the mixture was filtered and dried to obtain 20.6 g of solid 7-fluoro-6-bromo-2H-1,4-benzoxazine-3(4H)-one, with a yield of 91% and a purity of 95%.

[0097] Synthesis of 7-fluoro-6-bromo-4-propynyl-2H-1,4-benzoxazin-3-one

[0098] 20.73 g (0.15 mol) of potassium carbonate and 100 mL of toluene were added to a dry reactor. Stirring was started, and the temperature was controlled below 5 °C. 24.6 g (0.1 mol) of 7-fluoro-6-bromo-2H-1,4-benzoxazine-3(4H)-one was added in portions until the addition was complete. 1.3 g (0.11 mol) of 3-bromopropyne was added dropwise below 5 °C, completing the addition within 1 hour. The temperature was then raised to 70 °C, and the reaction was maintained at this temperature for 5 hours. After the reaction was complete, the mixture was filtered. The filtrate was first distilled under normal pressure and then under reduced pressure to obtain 24.4 g of the solid product 7-fluoro-6-bromo-4-propyne-2H-1,4-benzoxazine-3-one, with a yield of 86% and a purity of 94%.

[0099] Synthesis of propyzamide

[0100] 200 mL of ethylene glycol dimethyl ether solvent and 0.003 mol of palladium acetate catalyst were added to a reaction flask containing 28.4 g (0.1 mol) of 7-fluoro-6-bromo-4-propyne-2H-1,4-benzoxazine-3-one. The mixture was stirred to dissolve the precipitate, and then 16.6 g (0.11 mol) of 3,4,5,6-tetrahydrophthalimide was added. The mixture was heated to 120 °C and reacted for 12 hours. After filtration and vacuum distillation, 26.6 g of propyzamide was obtained, with a yield of 75% and a purity of 97%.

[0101] Reaction conditions investigation

[0102] Example 3

[0103] Following the method described in Implementation 1, the effects of various process parameters on the reaction were investigated, and the results are shown in the table below.

[0104] In step 2, the synthesis of 4-bromo-5-fluoro-2-nitrophenol:

[0105] Serial Number Brominating reagent Yield % purity% 1 Pyridine tribromide 73 92 2 NBS 75 95 3 bromine 55 Many impurities 4 hydrobromic acid 47 Many impurities

[0106] By optimizing the process route, a safe bromination reaction is used instead of a nitration reaction, which is mild, safe and environmentally friendly; the bromination reagent is a solid reagent, avoiding the use of dangerous reagents such as bromine and hydrobromic acid.

[0107] In step 4, the synthesis of 7-fluoro-6-bromo-2H-1,4-benzoxazine-3(4H)-one:

[0108] Serial Number Ring-closing reaction reagents Yield % purity% 1 <![CDATA[H2 / Raney nickel]]> 92 95 2 Fe / acetic acid 71 92

[0109] The reduction-ring-closure reaction uses H2 / Raney nickel, which has higher selectivity and reaction efficiency, and is also more environmentally friendly.

[0110] In step 6, the synthesis of propyzamide is performed:

[0111] Serial Number Alkylating reagents Yield % purity% 1 3,4,5,6-Tetrahydrophthalimide 97 97 2 3,4,5,6-Tetrahydrophthalic anhydride 75 92

[0112] Using 3,4,5,6-tetrahydrophthalimide as the acylation reagent, propyzamide was obtained in a high yield of 97%.

[0113] The method of this invention has been described through preferred embodiments. Those skilled in the art will readily be able to modify or appropriately alter and combine the methods and applications described herein within the scope, spirit, and context of this invention to implement and apply the technology of this invention. Those skilled in the art can refer to the content herein to appropriately improve process parameters. It should be particularly noted that all similar substitutions and modifications are obvious to those skilled in the art and are considered to be included within the scope of this invention.

Claims

1. A method for preparing propyzamide, characterized in that, Includes the following steps: Step 1: 2,4-Difluoronitrobenzene is hydrolyzed in an inorganic alkaline aqueous solution to obtain 5-fluoro-2-nitrophenol; Step 2: 5-Fluoro-2-nitrophenol reacts with a brominizing agent in a solvent to yield 4-bromo-5-fluoro-2-nitrophenol; In step 2, the brominating agent is one of N-bromosuccinimide and pyridine tribromide, and the selected solvent is one of acetonitrile and chloroform. Step 3: After removing the alcohol from an alcoholic solution of inorganic base, 4-bromo-5-fluoro-2-nitrophenol reacts with ethyl 2-bromoacetate in the presence of a solvent under an inert atmosphere to give ethyl 4-bromo-5-fluoro-2-nitrophenoxyacetate. Step 4: Ethyl 4-bromo-5-fluoro-2-nitrophenoxyethyl reacts with hydrogen in a solvent, with a catalyst, under an inert atmosphere and at a certain pressure to obtain... ; In step 4, the selected catalyst is Raney nickel; Step 5: In the presence of inorganic base and solvent, Reaction with 3-bromopropyne yields 7-fluoro-6-bromo-4-propyne-2H-1,4-benzoxazin-3-one; Step 6: 7-Fluoro-6-bromo-4-propyne-2H-1,4-benzoxazine-3-one reacts with 3,4,5,6-tetrahydrophthalimide in a solvent in the presence of a catalyst to give propyne fluroxypyr. The catalyst used in step 6 is selected from palladium acetate; In step 1, step 3, and step 5, the inorganic base is independently selected from one of sodium hydroxide, potassium hydroxide, sodium carbonate, and potassium carbonate. The inert atmospheres mentioned in steps 3 and 4 are each independently selected from either a nitrogen atmosphere or an argon atmosphere.

2. The method for synthesizing propyzinamide according to claim 1, characterized in that, In step 2, the reaction is stirred and heated to 75-95 ℃, and the reaction is maintained at this temperature for 8-12 hours.

3. The method for synthesizing propyne fluroxypyr according to claim 1, characterized in that, In step 4, the selected solvent is N,N-dimethylformamide, dimethyl sulfoxide, N,N-dimethylacetamide, or N-methylpyrrolidone.

4. The method for synthesizing propyzinamide according to claim 1, characterized in that, In step 4, the selected pressure is 0.6 MPa - 1.2 MPa, and the selected reaction temperature is 70℃ - 150℃.

5. The method for synthesizing propyne fluroxypyr according to claim 1, characterized in that, In step 6, the molar ratio of the catalyst to 7-fluoro-6-bromo-4-propynyl-2H-1,4-benzoxazin-3-one is 0.01:1 to 0.03:

1.

6. The method for synthesizing propyne fluroxypyr according to claim 1, characterized in that, In step 6, the temperature is raised to 100-120°C and the reaction is carried out for 8-12 hours.

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