Synthesis method of fluazifop-propyl intermediate 6-amino-7-fluoro-2H-benzo[b][1,4]oxazine-3(4H)-one

Abstract

The present invention relates to the technical field of pesticide synthesis, and discloses a method for synthesizing a flumioxazol intermediate 6-amino-7-fluoro-2H-benzo[b][1,4]oxazine-3(4H)-one. The method includes: using m-dichlorobenzene as a raw material, obtaining 6-amino-7-fluoro-2H-benzo[b][1,4]oxazine-3(4H)-one through nitration, fluorination, etherification and hydrogenation reduction ring closure; wherein, in the fluorination step, only one chlorine is fluorinated. The present invention only fluorinates one chlorine when synthesizing the flumioxazol intermediate 6-amino-7-fluoro-2H-benzo[b][1,4]oxazine-3(4H)-one, which can reduce the reaction temperature, reduce the generation of impurities during subsequent etherification, thereby improving product selectivity, and obtaining a higher yield and raw material conversion rate.

Description

Technical Field

[0001] The present invention relates to the technical field of pesticide synthesis, and in particular to a method for synthesizing 6-amino-7-fluoro-2H-benzo[b][1,4]oxazine-3(4H)-one, an intermediate of fluazifop-propyl. Background Art

[0002] Flumioxazin, a pesticide, is a phthalimide herbicide developed by Sumitomo Chemical Co., Ltd. of Japan. Flumioxazin acts on young shoots and leaves. It is effective as a soil treatment for controlling annual broadleaf weeds and some grass weeds. It is easily degradable in the environment and safe for subsequent crops. Soybeans and peanuts have high tolerance to it, while corn, wheat, barley, and rice have moderate resistance. This herbicide is widely used in agricultural production and has great economic value. 6-Amino-7-fluoro-2H-benzo[b][1,4]oxazin-3(4H)-one is an important intermediate of flumioxazin. It can be obtained by alkynylation with 3-chloropropyne and then aminolysis with 3,4,5,6-tetrahydrophthalic anhydride to obtain flumioxazin. Currently, several schemes for the synthesis of the intermediate 6-amino-7-fluoro-2H-benzo[b][1,4]oxazin-3(4H)-one are available:

[0003] Route 1: Using m-difluorobenzene as the starting material, the product is obtained through nitration, hydrolysis, etherification, and subsequent reduction with iron powder and hydrogenation for ring closure. Although the m-difluorobenzene used is relatively inexpensive, the nitration reaction is complex due to the positioning of the nitro group, resulting in numerous byproducts and difficult separation and purification. The numerous reaction steps also result in low yields and the inability to produce a high-purity product. Furthermore, the use of iron powder for reduction results in low yields and difficult handling of iron sludge.

[0004]

[0005] Route 2: Using m-dichlorobenzene as the starting material, the product is obtained through nitration, fluorination, etherification, and hydrogenation reduction ring closure. This route requires the raw material temperature to be raised to 190-200°C to a molten state during the fluorination reaction, which is a relatively harsh condition and not conducive to industrial production.

[0006]

[0007] Therefore, there is an urgent need to develop a method for synthesizing 6-amino-7-fluoro-2H-benzo[b][1,4]oxazine-3(4H)-one with mild synthesis conditions, green environmental protection, high yield, high raw material conversion rate, high product selectivity and high purity. Summary of the Invention

[0008] The purpose of the present invention is to overcome the shortcomings of the existing 6-amino-7-fluoro-2H-benzo[b][1,4]oxazin-3(4H)-one synthesis scheme and provide a method for synthesizing the intermediate 6-amino-7-fluoro-2H-benzo[b][1,4]oxazin-3(4H)-one by using m-dichlorobenzene as a raw material through nitration, fluorination, etherification and hydrogenation reduction ring closure.

[0009] In order to achieve the above-mentioned object, the present invention provides a method for synthesizing 6-amino-7-fluoro-2H-benzo[b][1,4]oxazine-3(4H)-one, an intermediate of fluazifop-propyl. The method comprises: using m-dichlorobenzene as a raw material, and obtaining 6-amino-7-fluoro-2H-benzo[b][1,4]oxazine-3(4H)-one through nitration, fluorination, etherification and hydrogenation reduction ring closure; wherein, in the fluorination step, only one chlorine is fluorinated.

[0010] Through the above technical solution, the beneficial technical effects achieved by the present invention are as follows:

[0011] (1) The present invention is the first in the art to fluorinate only one chlorine when synthesizing the intermediate 6-amino-7-fluoro-2H-benzo[b][1,4]oxazin-3(4H)-one of fluazifop-propyl. This can lower the reaction temperature and reduce the generation of impurities during the subsequent etherification, thereby improving product selectivity and obtaining a higher yield.

[0012] (2) The present invention further studies the specific fluorination temperature and the amount of fluorination reagent to ensure that there is only one fluorination site, and in the subsequent etherification reaction, the chlorine atom is more likely to react with the hydroxyacetic acid ester.

[0013] (3) After the nitration reaction is completed, the concentration of concentrated sulfuric acid is detected. When the concentration of concentrated sulfuric acid is greater than 80%, it can be recycled to reduce the generation of waste acid.

[0014] (4) The present invention selects toluene or the like as a reaction solvent during etherification, and only requires liquid chromatography tracking and detection. After the reaction is qualified, no purification is required, and the product can be simply washed and concentrated before entering the next step of the reaction, thereby reducing the loss of intermediate materials and increasing the yield and content of the intermediate 6-amino-7-fluoro-2H-benzo[b][1,4]oxazine-3(4H)-one.

[0015] (5) The present invention uses hydrogen to replace iron powder, thus avoiding the generation of iron mud, and through a single hydrogenation reduction ring closure, amination and cyclization reactions are carried out simultaneously, with high yield and good purity. DETAILED DESCRIPTION

[0016] The endpoints of the ranges and any values ​​disclosed herein are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoints of each range, the endpoints of each range and individual point values, and the individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered to be specifically disclosed herein.

[0017] A first aspect of the present invention provides a method for synthesizing a fluazifop-propyl intermediate 6-amino-7-fluoro-2H-benzo[b][1,4]oxazin-3(4H)-one, the method comprising: using m-dichlorobenzene as a raw material, and subjecting the raw material to nitration, fluorination, etherification, and hydrogenation reduction ring closure to obtain 6-amino-7-fluoro-2H-benzo[b][1,4]oxazin-3(4H)-one;

[0018] Wherein, in the fluorination step, only one chlorine is fluorinated.

[0019] Existing methods for synthesizing 6-amino-7-fluoro-2H-benzo[b][1,4]oxazin-3(4H)-one, an intermediate of fluazifop-propyl, using m-dichlorobenzene as a raw material, employ a fluorination reaction that converts dichloro to difluoro, resulting in two fluorination sites (e.g., Route 2 in the background art). This fluorination method requires high temperatures (e.g., 190°C-200°C), and the subsequent etherification produces impurities in which both fluorines are etherified, resulting in poor selectivity.

[0020] The inventors of the present invention conducted extensive research to address the above-mentioned issues and surprisingly discovered that if only one chlorine is fluorinated during fluorination (m-dichlorobenzene has two halogen groups -Cl, and only one -Cl is replaced by -F in the fluorination reaction after nitration), that is, if there is only one fluorination site, the reaction temperature can be greatly reduced, the generation of impurities can be greatly reduced, and product selectivity can be improved without adding complex purification steps. At the same time, the yield and purity can be improved.

[0021] In some embodiments of the invention, the method comprises the following steps:

[0022] (1) Nitration: m-dichlorobenzene is nitrated to obtain 1,5-dichloro-2,4-dinitrobenzene;

[0023] (2) Fluorination: reacting the 1,5-dichloro-2,4-dinitrobenzene obtained in step (1) with a fluorination agent in the presence of a first organic solvent to obtain 1-chloro-5-fluoro-2,4-dinitrobenzene;

[0024] (3) etherification: reacting the 1-chloro-5-fluoro-2,4-dinitrobenzene obtained in step (2) with hydroxyacetic acid ester in the presence of a second organic solvent, a first catalyst, and an acid binding agent to obtain a concentrated solution of 2-(5-fluoro-2,4-dinitrophenoxy)butyl acetate;

[0025] (4) Hydrogenation reduction ring closure: In the presence of a second catalyst, hydrogen is introduced into the concentrated solution of 2-(5-fluoro-2,4-dinitrophenoxy)acetic acid butyl ester obtained in step (3) to carry out hydrogenation reduction ring closure to obtain 6-amino-7-fluoro-2H-benzo[b][1,4]oxazin-3(4H)-one.

[0026] In the present invention, the concentrated solution of step (3) is directly used for the next step of hydrogenation reduction ring closure, which can improve the raw material conversion rate. The present invention further improves the yield through the hydrogenation reduction ring closure one-step reaction.

[0027] In some embodiments of the present invention, in the nitration step, a mixed acid of nitric acid and sulfuric acid is used for nitration.

[0028] In some embodiments of the present invention, the mass ratio of nitric acid to sulfuric acid in the mixed acid is 1:3-1:5, preferably 1:4; the mass fraction of nitric acid is 88-98%, preferably 98%; the mass fraction of sulfuric acid is 80%-98%, preferably 90%.

[0029] In some embodiments of the present invention, the molar ratio of m-dichlorobenzene to nitric acid in the mixed acid is 1:2-1:3, preferably 1:2.1-1:2.3, and more preferably 1:2.15-1:2.2.

[0030] In some embodiments of the present invention, the mixed acid is added dropwise to m-dichlorobenzene for nitration, and the adding time is 0.5-1.5 h, preferably 0.5-1 h.

[0031] In some embodiments of the present invention, the reaction temperature in the nitration step is 0-10°C, preferably 0-5°C, and more preferably 0°C.

[0032] In some embodiments of the present invention, the reaction time in the nitration step is 1-3 h, preferably 2-3 h, and more preferably 2.5 h.

[0033] In some embodiments of the present invention, in the fluorination step, the mass ratio of the 1,5-dichloro-2,4-dinitrobenzene to the first organic solvent is 1:3-1:10, preferably 1:3-1:5, and more preferably 1:4.

[0034] In some embodiments of the present invention, the first organic solvent is selected from at least one of N,N-dimethylformamide, N-methylpyrrolidone (NMP) and dimethyl sulfoxide (DMSO).

[0035] In some embodiments of the present invention, the fluorination agent is selected from at least one of potassium fluoride, lithium fluoride and sodium fluoride.

[0036] In some embodiments of the present invention, the molar ratio of 1,5-dichloro-2,4-dinitrobenzene to the fluorination agent is 1:1.1-1:1.5, preferably 1:1.1-1:1.3, and more preferably 1:1.2-1:1.25. In the present invention, too little fluorination agent will not react completely, while too much will increase impurities.

[0037] In some embodiments of the present invention, the reaction temperature in the fluorination step is 50-70° C., preferably 60-65° C., and more preferably 60° C. In the present invention, too high a fluorination temperature will lead to the generation of impurities, while too low a temperature will not allow the reaction to occur.

[0038] In some embodiments of the present invention, the reaction time in the fluorination step is 1-3 hours, preferably 1.5-2 hours.

[0039] In the present invention, by reasonably controlling the amount of the fluorination reagent and the low reaction temperature, and under the strong electron-withdrawing effect of the nitro group (which is conducive to nucleophilic reaction), there is only one fluorination site.

[0040] In some embodiments of the present invention, in the etherification step, the mass ratio of the 1-chloro-5-fluoro-2,4-dinitrobenzene to the second organic solvent is 1:3-1:10, preferably 1:3-1:5, and more preferably 1:4.

[0041] In some embodiments of the present invention, the second organic solvent is selected from at least one of toluene, ethylene dichloride and xylene, preferably toluene.

[0042] In some embodiments of the present invention, the first catalyst is a positional catalyst, preferably at least one of potassium iodide and sodium iodide. In the present invention, the first catalyst functions to replace only one -Cl group with -F during the fluorination reaction, and the catalyst is used to cause the remaining -Cl group to react with glycolate during the etherification reaction (positional etherification).

[0043] In some embodiments of the present invention, the acid binding agent is selected from at least one of trimethylamine, pyridine and triethylamine, preferably triethylamine.

[0044] In some embodiments of the present invention, the glycolate is selected from at least one of butyl glycolate, ethyl glycolate and isopropyl glycolate, preferably butyl glycolate.

[0045] In some embodiments of the present invention, the amount of the first catalyst used is 0.1-0.6% of the mass of 1-chloro-5-fluoro-2,4-dinitrobenzene, preferably 0.2-0.5%, and more preferably 0.3%.

[0046] In some embodiments of the present invention, the molar ratio of 1-chloro-5-fluoro-2,4-dinitrobenzene to the acid-binding agent is 1:1.1-1:1.3, preferably 1:1.1-1:1.2, and more preferably 1:1.15.

[0047] In some embodiments of the present invention, the molar ratio of 1-chloro-5-fluoro-2,4-dinitrobenzene to hydroxyacetic acid ester is 1:1.1-1:1.5, preferably 1:1.1-1:1.3, and more preferably 1:1.2.

[0048] In some embodiments of the present invention, the reaction temperature in the etherification step is 10-30°C, preferably 10-20°C.

[0049] In some embodiments of the present invention, the reaction time in the etherification step is 0.5-2 h, preferably 1-2 h, and more preferably 1.5 h.

[0050] In some embodiments of the present invention, the hydrogenation reduction ring closure step is performed under nitrogen protection.

[0051] In some embodiments of the present invention, the concentrated solution of 2-(5-fluoro-2,4-dinitrophenoxy)acetate is mixed with a solution of a third organic solvent for dilution, and then subjected to hydrogenation reduction ring closure.

[0052] In some embodiments of the present invention, the third organic solvent is selected from at least one of toluene, N,N-dimethylformamide (DMF) and N,N-dimethylethanolamine (DMA).

[0053] In some embodiments of the present invention, the mass ratio of the concentrate to the third organic solvent is 1:3-1:10, preferably 1:5-1:10, and more preferably 1:6.

[0054] In some embodiments of the present invention, the second catalyst is selected from at least one of Pt / C, Pd / C and Raney nickel.

[0055] In some embodiments of the present invention, the amount of the second catalyst used is 1-5% of the mass of the concentrated liquid, preferably 1-3%, and more preferably 2%.

[0056] In some embodiments of the present invention, the pressure of the introduced hydrogen is 1.5-3 MPa, preferably 1.5-2.5 MPa, and more preferably 2 MPa.

[0057] In some embodiments of the present invention, the reaction temperature in the hydrogenation reduction ring closure step is 60-80°C, preferably 65-75°C.

[0058] In some embodiments of the present invention, the reaction time in the hydrogenation reduction ring closure step is 2-4 h, preferably 2-3 h, and more preferably 2.5 h.

[0059] In the present invention, the reaction scheme can be shown as follows:

[0060]

[0061] According to a particularly preferred embodiment of the present invention, a method for synthesizing 6-amino-7-fluoro-2H-benzo[b][1,4]oxazin-3(4H)-one, an intermediate of fluazifop-propyl, comprises the following steps:

[0062] (1) Nitration reaction: First, sulfuric acid and nitric acid are prepared into a mixed acid, and the mixed acid is added dropwise to m-dichlorobenzene. After the reaction is completed, the mixture is cooled and filtered. The concentration of the obtained acid solution is tested. When the concentration is greater than 80%, it is recycled. The obtained filter cake is then washed with water and filtered. The filter cake is then washed with alkaline water until neutral, and then recrystallized with ethanol and filtered to obtain 1,5-dichloro-2,4-dinitrobenzene. The cooling is performed in an ice-water bath; the mass ratio of m-dichlorobenzene to ethanol is 1:2-1:4; the alkaline water used is a saturated sodium bicarbonate solution, a saturated potassium carbonate solution, or a 5% sodium hydroxide solution.

[0063] (2) Fluorination reaction: 1,5-dichloro-2,4-dinitrobenzene is dissolved in DMF solution under nitrogen protection, and potassium fluoride is added to the mixed solution. After the reaction is completed, the mixture is cooled and toluene is added. The filtrate is filtered to obtain a filtrate. Water is added to the filtrate, and the mixture is allowed to stand for separation and stratification. An equal amount of water is added to the upper layer of toluene, and the mixture is subjected to azeotropic desolvation under reduced pressure. The material crystallizes and is filtered to obtain 1-chloro-5-fluoro-2,4-dinitrobenzene. The mass ratio of the added toluene solution to 2,4-dichloro-1,5-dinitrobenzene is 1:1-2:1; the mass ratio of the toluene solution to water is 1:1-1:2; and the pressure for desolvation is a negative pressure of 0.085-0.09 MPa.

[0064] (3) Etherification reaction: First, 1-chloro-5-fluoro-2,4-dinitrobenzene, catalyst and butyl glycolate are dissolved in toluene, and then triethylamine is dissolved in toluene. The mixed solution of triethylamine and toluene is added dropwise to the mixed solution of 1-chloro-5-fluoro-2,4-dinitrobenzene and toluene. After the reaction is completed, the mixture is washed with water, extracted and separated, and the upper organic phase is taken out to obtain a toluene solution of 2-(5-fluoro-2,4-dinitrophenoxy) butyl acetate. Then, the solvent is removed under reduced pressure and most of the toluene is evaporated to obtain a toluene concentrate of 2-(5-fluoro-2,4-dinitrophenoxy) butyl acetate. The mass ratio of toluene to triethylamine in the mixed solution of toluene and triethylamine is 1:1; the addition time of the mixed solution of triethylamine and toluene is controlled between 0.5-1h; the reaction solution needs to be left to stand for 10-30min for extraction and separation; the pressure controlled by the reduced pressure solvent removal is a negative pressure of 0.085-0.09MPa.

[0065] (4) Hydrogenation reduction ring-closure reaction: The toluene concentrate obtained in step (3) is diluted and added to a reactor, a catalyst is added, and hydrogen is introduced to react. After the reaction is completed, the reaction liquid is poured out and filtered, and the filtrate is added with water. The toluene is then distilled off under reduced pressure to precipitate the material, and the intermediate 6-amino-7-fluoro-2H-benzo[b][1,4]oxazin-3(4H)-one is obtained by filtration. The addition of water is to allow the toluene and water to azeotropy; the pressure of the reduced pressure distillation is a negative pressure of 0.085-0.09 MPa.

[0066] The present invention will be described in detail below through examples.

[0067] In the following examples and comparative examples, if no specific conditions are specified, the experiments were carried out under conventional conditions or those recommended by the manufacturer. All reagents and instruments used, if no manufacturer is specified, are commercially available conventional products.

[0068] Example 1

[0069] A method for synthesizing 6-amino-7-fluoro-2H-benzo[b][1,4]oxazin-3(4H)-one, an intermediate of fluazifop-propyl, comprises the following steps:

[0070] (1) 98% nitric acid and 80% sulfuric acid are mixed to obtain a mixed acid, wherein the mass ratio of nitric acid to sulfuric acid is 1:3. According to the molar ratio of m-dichlorobenzene to nitric acid of 1:2.1, m-dichlorobenzene is put into a flask, and the mixed acid is slowly added dropwise for 0.5 hours. The reaction temperature is controlled to 0°C. After stirring for 2 hours, the mixture is cooled in an ice-water bath to precipitate the solid material. The filter cake obtained by filtration is washed with water, and the filter cake after filtration is washed with a saturated sodium bicarbonate aqueous solution until neutral. An ethanol solution (the mass ratio of m-dichlorobenzene to ethanol is 1:2) is added for recrystallization, and the product 1,5-dichloro-2,4-dinitrobenzene is obtained by filtration. The yield is 96.7%, the purity is 98.5%, the raw material conversion rate is 99.1%, and the product selectivity is 97.5%.

[0071] (2) The 1,5-dichloro-2,4-dinitrobenzene obtained in step (1) was dissolved in a DMF solution under nitrogen protection, wherein the mass ratio of 1,5-dichloro-2,4-dinitrobenzene to DMF was 1:3, and potassium fluoride was slowly added, wherein the molar ratio of 1,5-dichloro-2,4-dinitrobenzene to potassium fluoride was 1:1.1, the reaction temperature was controlled at 60°C, and the reaction was carried out for 1.5 hours. After the reaction, the temperature was lowered, toluene was added, and the mixture was filtered. Water was added to the filtrate, wherein the mass ratio of toluene to water was 1:1, and the mass ratio of 1,5-dichloro-2,4-dinitrobenzene to toluene was 1:1. Extraction and stratification were carried out. After the upper organic phase was extracted, an equal amount of water was added, and most of the toluene was removed by azeotropic distillation under a pressure of -0.085 MPa. Water was then added to precipitate the material, and the product 1-chloro-5-fluoro-2,4-dinitrobenzene was obtained by filtration and drying. The yield was 95.9%, the purity was 98.2%, the raw material conversion rate was 98.8%, and the product selectivity was 97.1%.

[0072] (3) The 1-chloro-5-fluoro-2,4-dinitrobenzene obtained in step (2) is dissolved in a toluene solution, wherein the mass ratio of 1-chloro-5-fluoro-2,4-dinitrobenzene to toluene is 1:1.3, and butyl glycolate and a catalyst potassium iodide with a mass ratio of 0.2% of the mass of 1-chloro-5-fluoro-2,4-dinitrobenzene are added, wherein the molar ratio of 1-chloro-5-fluoro-2,4-dinitrobenzene to butyl glycolate is 1:1.1. Then, a mixed solution of triethylamine and toluene is added dropwise for 0.5h, wherein the molar ratio of 1-chloro-5-fluoro-2,4-dinitrobenzene to triethylamine is 1:1.1, and the mass ratio of toluene to triethylamine is 1:1. After the addition is completed, the reaction is stirred at 10°C for 2 hours. After the reaction is completed, the reaction solution is washed with water and allowed to stand for 30 minutes to separate into layers. Most of the toluene is removed from the upper organic phase at a pressure of -0.09 MPa to prepare a toluene concentrate of butyl 2-(5-fluoro-2,4-dinitrophenoxy)acetate.

[0073] (4) The toluene concentrate of 2-(5-fluoro-2,4-dinitrophenoxy)acetic acid butyl ester in step (3) was diluted into the toluene solution, and the mass ratio of the concentrate to the toluene in the toluene solution was 1:5. A catalyst Pd / C was added at a mass ratio of 1% of the mass of the toluene concentrate. After nitrogen replacement, hydrogen was introduced, and the hydrogen pressure was controlled to 2.0 MPa. The reaction was carried out at 65°C for 2 hours. After the reaction was completed, the solution was filtered, and water was added to the filtrate to cause azeotropic distillation with toluene under a negative pressure of 0.09 MPa. The solid was precipitated and filtered to obtain the intermediate 6-amino-7-fluoro-2H-benzo[b][1,4]oxazin-3(4H)-one. The combined yield of steps (3) and (4) was 92.7%, the product purity was 98.7%, the product selectivity was 95.3%, and the raw material conversion rate was 97.3%.

[0074] Example 2

[0075] A method for synthesizing 6-amino-7-fluoro-2H-benzo[b][1,4]oxazin-3(4H)-one, an intermediate of fluazifop-propyl, comprises the following steps:

[0076] (1) 98% nitric acid and 90% sulfuric acid are mixed to obtain a mixed acid, wherein the mass ratio of nitric acid to sulfuric acid is 1:4. According to the molar ratio of m-dichlorobenzene to nitric acid of 1:2.15, m-dichlorobenzene is put into a flask, and the mixed acid is slowly added dropwise for 0.5 hours. The reaction temperature is controlled to 10°C. After stirring for 2.5 hours, the mixture is cooled in an ice-water bath to precipitate the solid material. The filter cake obtained by filtration is washed with water, and the filter cake after filtration is washed with a saturated potassium carbonate aqueous solution until neutral. An ethanol solution (the mass ratio of m-dichlorobenzene to ethanol is 1:2.5) is added for recrystallization, and the product 1,5-dichloro-2,4-dinitrobenzene is obtained by filtration. The yield is 97.1%, the purity is 97.9%, and the raw material conversion rate is 98.9%. The product selectivity is 98.1%.

[0077] (2) The 1,5-dichloro-2,4-dinitrobenzene obtained in step (1) was dissolved in a DMSO solution under nitrogen protection, wherein the mass ratio of 1,5-dichloro-2,4-dinitrobenzene to DMSO was 1:4, and then lithium fluoride was slowly added, wherein the molar ratio of 1,5-dichloro-2,4-dinitrobenzene to lithium fluoride was 1:1.2, and the reaction temperature was controlled to 65°C and the reaction was carried out for 1.5 hours. After the reaction, the temperature was lowered, toluene was added, and the mixture was filtered. Water was added to the filtrate, wherein the mass ratio of toluene to water was 1:2, and the mass ratio of 1,5-dichloro-2,4-dinitrobenzene to toluene was 1:1. Extraction and stratification were carried out. After the upper organic phase was extracted, an equal amount of water was added, and most of the toluene was removed by azeotropic distillation under a pressure of -0.09 MPa. Water was then added to precipitate the material, and the product 1-chloro-5-fluoro-2,4-dinitrobenzene was obtained by filtration and drying. The yield was 96.2%, the purity was 98.7%, the raw material conversion rate was 98.1%, and the product selectivity was 97.9%.

[0078] (3) The 1-chloro-5-fluoro-2,4-dinitrobenzene obtained in step (2) is dissolved in a dichloroethane solution, wherein the mass ratio of 1-chloro-5-fluoro-2,4-dinitrobenzene to dichloroethane is 1:1.4, and ethyl hydroxyacetate and a catalyst sodium iodide containing 0.3% of the mass of 1-chloro-5-fluoro-2,4-dinitrobenzene are added, wherein the molar ratio of 1-chloro-5-fluoro-2,4-dinitrobenzene to ethyl hydroxyacetate is 1:1.2. A mixed solution of pyridine and dichloroethane is then added dropwise for 1 hour, wherein the molar ratio of 1-chloro-5-fluoro-2,4-dinitrobenzene to pyridine is 1:1.15, and the mass ratio of dichloroethane to pyridine is 1:1. After the addition is completed, the reaction is stirred at 10°C for 1.5 hours. After the reaction is completed, the reaction solution is washed with water and allowed to stand for 20 minutes. Most of the toluene is removed from the upper organic phase at a pressure of -0.085 MPa to prepare a dichloroethane concentrate of ethyl 2-(5-fluoro-2,4-dinitrophenoxy)acetate.

[0079] (4) The dichloroethane concentrate of ethyl 2-(5-fluoro-2,4-dinitrophenoxy)acetate in step (3) was diluted into the dichloroethane solution, with the mass ratio of the concentrate to the dichloroethane in the dichloroethane solution being 1:6, and a catalyst Pt / C at a mass ratio of 3% of the mass of the dichloroethane concentrate was added. After nitrogen replacement, hydrogen was introduced, and the hydrogen pressure was controlled to be 2.5 MPa. The reaction was carried out at 65°C for 2.5 hours. After the reaction was completed, the solution was filtered, and water was added to the filtrate to cause azeotropic distillation with DMF under a negative pressure of 0.09 MPa. The solid was precipitated and filtered to obtain the intermediate 6-amino-7-fluoro-2H-benzo[b][1,4]oxazin-3(4H)-one. The combined yield of steps (3) and (4) was 92.5%, the product purity was 98.9%, the product selectivity was 95.5%, and the raw material conversion rate was 96.8%.

[0080] Example 3

[0081] A method for synthesizing 6-amino-7-fluoro-2H-benzo[b][1,4]oxazin-3(4H)-one, an intermediate of fluazifop-propyl, comprises the following steps:

[0082] (1) 88% nitric acid and 98% sulfuric acid are mixed to obtain a mixed acid, wherein the mass ratio of nitric acid to sulfuric acid is 1:5. According to the molar ratio of m-dichlorobenzene to nitric acid of 1:2.2, m-dichlorobenzene is added to a flask, and the mixed acid is slowly added dropwise for 1 hour. The reaction temperature is controlled to 5°C. After stirring for 3 hours, the mixture is cooled in an ice-water bath to precipitate the solid material. The filter cake obtained by filtration is washed with water, and the filter cake after filtration is washed with a 5% sodium hydroxide solution to neutrality. An ethanol solution (the mass ratio of m-dichlorobenzene to ethanol is 1:4) is added for recrystallization, and the product 1,5-dichloro-2,4-dinitrobenzene is obtained by filtration. The yield is 97.2%, the purity is 98.8%, the conversion rate is 97.8%, and the product selectivity is 99.3%.

[0083] (2) The 1,5-dichloro-2,4-dinitrobenzene obtained in step (1) was dissolved in NMP solution under nitrogen protection, wherein the mass ratio of 1,5-dichloro-2,4-dinitrobenzene to DMF was 1:5, and then sodium fluoride was slowly added, wherein the molar ratio of 1,5-dichloro-2,4-dinitrobenzene to sodium fluoride was 1:1.25, and the reaction temperature was controlled at 60°C and the reaction was carried out for 2 hours. After the reaction, the temperature was lowered, toluene was added, and the mixture was filtered. Water was added to the filtrate, wherein the mass ratio of toluene to water was 1:2, and the mass ratio of 1,5-dichloro-2,4-dinitrobenzene to toluene was 1:2. Extraction and stratification were carried out. After the upper organic phase was extracted, an equal amount of water was added, and most of the toluene was removed by azeotropic distillation under a pressure of -0.09 MPa. Water was then added to precipitate the material, and the product 1-chloro-5-fluoro-2,4-dinitrobenzene was obtained by filtration and drying. The yield was 96.7%, the purity was 99.2%, the conversion was 98.1%, and the product selectivity was 98.5%.

[0084] (3) The 1-chloro-5-fluoro-2,4-dinitrobenzene obtained in step (2) is dissolved in a xylene solution, wherein the mass ratio of 1-chloro-5-fluoro-2,4-dinitrobenzene to xylene is 1:1.5, and isopropyl glycolate and a catalyst potassium iodide with a molar ratio of 0.5% of the mass of 1-chloro-5-fluoro-2,4-dinitrobenzene to isopropyl glycolate is 1:1.3. A mixed solution of trimethylamine and xylene is then added dropwise for 1 hour, wherein the molar ratio of 1-chloro-5-fluoro-2,4-dinitrobenzene to trimethylamine is 1:1.2, and the mass ratio of xylene to trimethylamine is 1:1. After the addition is completed, the reaction is stirred at 20°C for 2 hours. After the reaction is completed, the reaction solution is washed with water and allowed to stand for 30 minutes. Most of the xylene is removed from the upper organic phase at a pressure of -0.09 MPa to prepare a xylene concentrate of 2-(5-fluoro-2,4-dinitrophenoxy)acetic acid isopropyl ester.

[0085] (4) The xylene concentrate of 2-(5-fluoro-2,4-dinitrophenoxy)acetic acid isopropyl ester in step (3) was diluted into the DMA solution, with the mass ratio of the concentrate to the DMA in the DMA solution being 1:10, and a catalyst Raney nickel was added at a mass ratio of 2% of the mass of the xylene concentrate. After nitrogen replacement, hydrogen was introduced, and the hydrogen pressure was controlled to be 1.5 MPa. The reaction was carried out at 75°C for 3 hours. After the reaction was completed, the solution was filtered, and water was added to the filtrate to cause azeotropic distillation with DMA under a negative pressure of 0.09 MPa. The solid was precipitated and filtered to obtain the intermediate 6-amino-7-fluoro-2H-benzo[b][1,4]oxazin-3(4H)-one. The combined yield of steps (3) and (4) was 92.9%, the product purity was 98.1%, the product selectivity was 94.9%, and the raw material conversion rate was 97.8%.

[0086] Comparative Example 1

[0087] The intermediate 6-amino-7-fluoro-2H-benzo[b][1,4]oxazin-3(4H)-one was prepared according to the method of Example 1, except that the amount of potassium fluoride was reduced. The molar ratio of 1,5-dichloro-2,4-dinitrobenzene to potassium fluoride was 1:1. The final fluorination reaction conversion rate was 84.3%, the yield was 82.3%, the purity was 86.5%, and the product selectivity was 97.6%.

[0088] Due to the insufficient amount of potassium fluoride used, the raw material conversion rate was low, resulting in a lower product yield. The final yield of the prepared 6-amino-7-fluoro-2H-benzo[b][1,4]oxazin-3(4H)-one was subsequently reduced, significantly affecting its purity and conversion rate, resulting in a conversion rate of 74.2% and a yield of 41.8%. A relatively pure product could not be obtained, with a purity of only 84.5% and a product selectivity of 56.3%.

[0089] Comparative Example 2

[0090] The intermediate 6-amino-7-fluoro-2H-benzo[b][1,4]oxazin-3(4H)-one was prepared according to the method of Example 1, except that the amount of potassium fluoride was increased. The molar ratio of 1,5-dichloro-2,4-dinitrobenzene to potassium fluoride was 1:2. The final fluorination reaction conversion rate was 98.2%, the yield was 86.4%, the purity was 83.5%, and the product selectivity was 87.9%.

[0091] Excessive potassium fluoride usage resulted in the formation of difluorinated impurities (both chlorine groups were fluorinated), reducing purity, selectivity, and yield. The low purity of the fluorinated product made the etherification reaction difficult and the conversion rate low, preventing the production of a high-purity etherified product. This ultimately reduced the conversion rate, purity, yield, and product selectivity of subsequent reactions, resulting in a final yield of 44.2%, a conversion rate of 81.5%, a purity of 82.3%, and a product selectivity of 54.2%.

[0092] Comparative Example 3

[0093] The intermediate 6-amino-7-fluoro-2H-benzo[b][1,4]oxazin-3(4H)-one was prepared according to the method of Example 2, except that the fluorination temperature was 85°C and the time was 3.5 hours. The final fluorination yield was 54.6%, the purity was 89.2%, the raw material conversion was 97.9%, and the product selectivity was 55.7%.

[0094] The high fluorination temperature resulted in an increase in the production of difluoride and hydrolysis impurities, leading to a decrease in purity. Furthermore, the low purity of the resulting fluorinated product prevented a high-purity product from being obtained during the etherification reaction, which affected the subsequent hydrogenation reduction ring-closure reaction. This resulted in a final yield of 41.8%, resulting in a final product purity of 85.7%, a feedstock conversion of 84.2%, and a product selectivity of 49.6%.

[0095] Comparative Example 4

[0096] The intermediate 6-amino-7-fluoro-2H-benzo[b][1,4]oxazin-3(4H)-one was prepared according to the method of Example 3, except that the fluorination temperature was 40°C, and it was found that the reaction did not occur.

[0097] Since the fluorination temperature is too low, the reaction cannot proceed, so the temperature needs to be strictly controlled within the range of 50-70°C.

[0098] Comparative Examples 1-4 show that when too little fluorination reagent is added, the reaction cannot be completed, resulting in a low conversion rate. When too much is added, impurities are generated, resulting in a decrease in yield and selectivity. Excessively high temperatures and excessively long reaction times lead to an increase in impurities, while too low a temperature prevents the fluorination reaction from occurring.

[0099] The preferred embodiments of the present invention have been described in detail above, but the present invention is not limited thereto. Within the technical concept of the present invention, various simple variations of the technical solution of the present invention may be made, including combining the various technical features in any other appropriate manner. These simple variations and combinations should also be regarded as disclosed in the present invention and fall within the scope of protection of the present invention.

Claims

1. A method for synthesizing 6-amino-7-fluoro-2H-benzo[b][1,4]oxazin-3(4H)-one, an intermediate of fluazifop-propyl, characterized in that: The method comprises the following steps: (1) Nitration: m-dichlorobenzene is nitrated to obtain 1,5-dichloro-2,4-dinitrobenzene; (2) Fluorination: in the presence of a first organic solvent, reacting the 1,5-dichloro-2,4-dinitrobenzene obtained in step (1) with a fluorinating agent to obtain 1-chloro-5-fluoro-2,4-dinitrobenzene; wherein the molar ratio of the 1,5-dichloro-2,4-dinitrobenzene to the fluorinating agent is 1:1.1-1:1.5; the reaction temperature is 50-70°C, and the reaction time is 1-3 hours; wherein the first organic solvent is selected from at least one of N,N-dimethylformamide, N-methylpyrrolidone and dimethyl sulfoxide; and the fluorinating agent is selected from at least one of potassium fluoride, lithium fluoride and sodium fluoride; (3) Etherification: reacting the 1-chloro-5-fluoro-2,4-dinitrobenzene obtained in step (2) with hydroxyacetic acid ester in the presence of a second organic solvent, a first catalyst, and an acid-binding agent to obtain a concentrated solution of 2-(5-fluoro-2,4-dinitrophenoxy)acetic acid ester; wherein the second organic solvent is selected from at least one of toluene, dichloroethane, and xylene; and wherein the first catalyst is at least one of potassium iodide and sodium iodide; (4) Hydrogenation reduction ring closure: In the presence of a second catalyst, hydrogen is introduced into the concentrated solution of 2-(5-fluoro-2,4-dinitrophenoxy)acetate obtained in step (3) to carry out hydrogenation reduction ring closure to obtain 6-amino-7-fluoro-2H-benzo[b][1,4]oxazin-3(4H)-one.

2. The method according to claim 1, wherein In the nitration step, a mixed acid of nitric acid and sulfuric acid is used for nitration.

3. The method according to claim 2, wherein: The mass ratio of nitric acid to sulfuric acid in the mixed acid is 1:3-1:5; the mass fraction of nitric acid is 88-98%; the mass fraction of sulfuric acid is 80%-98%; and / or, the molar ratio of the meta-dichlorobenzene to the nitric acid in the mixed acid is 1:2-1:3; and / or, the mixed acid is added dropwise to m-dichlorobenzene for nitration, with the adding time being 0.5-1.5 h.

4. The method according to claim 3, wherein: The mass ratio of nitric acid to sulfuric acid in the mixed acid is 1:4; the mass fraction of nitric acid is 98%; the mass fraction of sulfuric acid is 90%; and / or, the molar ratio of the meta-dichlorobenzene to the nitric acid in the mixed acid is 1:2.1-1:2.3; And / or, the dropping time is 0.5-1h.

5. The method according to claim 4, wherein The molar ratio of the meta-dichlorobenzene to the nitric acid in the mixed acid is 1:2.15-1:2.

2.

6. The method according to any one of claims 1 to 3, wherein The reaction temperature in the nitration step is 0-10°C; And / or, the reaction time in the nitration step is 1-3 hours.

7. The method according to claim 6, wherein: The reaction temperature in the nitration step is 0-5°C; And / or, the reaction time in the nitration step is 2-3 hours.

8. The method according to claim 7, wherein: The reaction temperature in the nitration step is 0°C; And / or, the reaction time in the nitration step is 2.5 hours.

9. The method according to claim 1, wherein In the fluorination step, the mass ratio of the 1,5-dichloro-2,4-dinitrobenzene to the first organic solvent is 1:3-1:10; And / or, the molar ratio of the 1,5-dichloro-2,4-dinitrobenzene to the fluorination agent is 1:1.1-1:1.

3.

10. The method according to claim 9, wherein: In the fluorination step, the mass ratio of the 1,5-dichloro-2,4-dinitrobenzene to the first organic solvent is 1:3-1:5; And / or, the molar ratio of the 1,5-dichloro-2,4-dinitrobenzene to the fluorination agent is 1:1.2-1:1.

25.

11. The method according to claim 10, wherein: In the fluorination step, the mass ratio of the 1,5-dichloro-2,4-dinitrobenzene to the first organic solvent is 1:

4.

12. The method according to claim 1, wherein The reaction temperature in the fluorination step is 60-65°C; And / or, the reaction time in the fluorination step is 1.5-2 hours.

13. The method according to claim 12, wherein: The reaction temperature in the fluorination step was 60°C.

14. The method according to claim 1, wherein In the etherification step, the mass ratio of the 1-chloro-5-fluoro-2,4-dinitrobenzene to the second organic solvent is 1:3-1:10; And / or, the second organic solvent is toluene; And / or, the acid binding agent is selected from at least one of trimethylamine, pyridine and triethylamine; And / or, the glycolate is selected from at least one of butyl glycolate, ethyl glycolate and isopropyl glycolate; and / or, the amount of the first catalyst is 0.1-0.6% of the mass of 1-chloro-5-fluoro-2,4-dinitrobenzene; and / or, the molar ratio of the 1-chloro-5-fluoro-2,4-dinitrobenzene to the acid binding agent is 1:1.1-1:1.3; And / or, the molar ratio of 1-chloro-5-fluoro-2,4-dinitrobenzene to hydroxyacetic acid ester is 1:1.1-1:1.

5.

15. The method according to claim 14, wherein In the etherification step, the mass ratio of the 1-chloro-5-fluoro-2,4-dinitrobenzene to the second organic solvent is 1:3-1:5; And / or, the acid binding agent is triethylamine; and / or, the glycolate is butyl glycolate; and / or, the amount of the first catalyst is 0.2-0.5% of the mass of 1-chloro-5-fluoro-2,4-dinitrobenzene; and / or, the molar ratio of the 1-chloro-5-fluoro-2,4-dinitrobenzene to the acid binding agent is 1:1.1-1:1.2; And / or, the molar ratio of 1-chloro-5-fluoro-2,4-dinitrobenzene to hydroxyacetic acid ester is 1:1.1-1:1.

3.

16. The method according to claim 15, wherein In the etherification step, the mass ratio of the 1-chloro-5-fluoro-2,4-dinitrobenzene to the second organic solvent is 1:4; and / or, the amount of the first catalyst used is 0.3% by mass of 1-chloro-5-fluoro-2,4-dinitrobenzene; and / or, the molar ratio of the 1-chloro-5-fluoro-2,4-dinitrobenzene to the acid binding agent is 1:1.15; And / or, the molar ratio of 1-chloro-5-fluoro-2,4-dinitrobenzene to hydroxyacetic acid ester is 1:1.

2.

17. The method according to claim 1, wherein The reaction temperature in the etherification step is 10-30°C; And / or, the reaction time in the etherification step is 0.5-2h.

18. The method according to claim 17, wherein The reaction temperature in the etherification step is 10-20°C; And / or, the reaction time in the etherification step is 1-2 hours.

19. The method according to claim 18, wherein The reaction time in the etherification step is 1.5 h.

20. The method according to claim 1, wherein The hydrogenation reduction ring closing step is carried out under nitrogen protection; and / or, mixing the concentrated solution of 2-(5-fluoro-2,4-dinitrophenoxy)acetate with a solution of a third organic solvent to dilute it, and then performing hydrogenation reduction ring closure; And / or, the second catalyst is selected from at least one of Pt / C, Pd / C and Raney nickel; and / or, the amount of the second catalyst is 1-5% of the mass of the concentrated liquid; And / or, the pressure of the hydrogen introduced is 1.5-3 MPa.

21. The method according to claim 20, wherein The third organic solvent is selected from at least one of toluene, N,N-dimethylformamide and N,N-dimethylethanolamine; and / or, the mass ratio of the concentrate to the third organic solvent is 1:3-1:10; and / or, the amount of the second catalyst is 1-3% of the mass of the concentrated liquid; And / or, the pressure of the hydrogen introduced is 1.5-2.5 MPa.

22. The method according to claim 21, wherein The mass ratio of the concentrate to the third organic solvent is 1:5-1:10; and / or, the amount of the second catalyst is 2% of the mass of the concentrated liquid; And / or, the pressure of the hydrogen gas introduced is 2 MPa.

23. The method according to claim 22, wherein The mass ratio of the concentrated liquid to the third organic solvent is 1:

6.

24. The method according to claim 1, wherein The reaction temperature in the hydrogenation reduction ring closing step is 60-80°C; And / or, the reaction time in the hydrogenation reduction ring closure step is 2-4 hours.

25. The method according to claim 24, wherein The reaction temperature in the hydrogenation reduction ring closing step is 65-75°C; And / or, the reaction time in the hydrogenation reduction ring closure step is 2-3 h.

26. The method according to claim 25, wherein The reaction time in the hydrogenation reduction ring closure step is 2.5 h.

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